WHO Drug and Therapeutics Committees
Publication date: 2003
Irrational use of medicines is a widespread problem at all levels of health care, but especially in hospitals. This is particularly worrying as resources are generally scarce and prescribers in communities often copy hospital prescribing practices. Use of medicines can be greatly improved and wastage reduced if some simple principles of drug management are followed. But it is difficult to implement these principles because staff from many different disciplines are involved, often with no forum for bringing them together to develop and implement appropriate medicines policies. A drug and therapeutics committee (DTC) provides such a forum, allowing all the relevant people to work together to improve health care delivery, whether in hospitals or other health facilities. In many developed countries a well functioning DTC has been shown to be very effective in addressing drug use problems. However, in many developing countries DTCs do not exist and in others they do not function optimally, often due to lack of local expertise or a lack of incentives. Drug and Therapeutics Committees: A Practical Guide provides guidance to doctors, pharmacists, hospital managers and other professionals who may be serving on DTCs and/or who are concerned with how to improve the quality and cost efficiency of therapeutic care. It is relevant for all kinds of DTCs - whether in public or private hospitals and whether at district or tertiary referral level. This comprehensive manual covers a committee’s functions and structure, the medicines formulary process, and how to assess new medicines. The chapters on tools to investigate drug use and strategies to promote rational use are followed by a discussion of antimicrobial resistance and infection control. The publication concludes by explaining in detail how to start a committee or improve the effectiveness of an existing one. The manual has been developed by the WHO Department of Essential Drugs and Medicines Policy, in collaboration with the Rational Pharmaceutical Management Plus Program of Management Sciences for Health. D R U G A N D T H E R A P E U T IC S C O M M IT T E E S : A P R A T IC A L G U ID E Drug and therapeutics committees A practical guide World Health Organization Department of Essential Drugs and Medicines Policy Geneva, Switzerland In collaboration with Management Sciences for Health Center for Pharmaceutical Management Rational Pharmaceutical Management Program Arlington, Virginia, USA WHO/EDM/PAR/2004.1 Authors Kathleen Holloway1 (Editor) Terry Green2 with contributions from: Edelisa Carandang,1 Hans Hogerzeil,1 Richard Laing,3 David Lee,2 The text was reviewed by: John Chalker,2 Mary Couper,1 Andrew Creese,1 Marthe Everard,1 Anna Paula di Felici,4 Chris Forshaw,5 David Henry,6 Yvan Hutin,7 Sabine Kopp,1 Souly Phanouvong,8 Clive Ondari,1 Lembit Rago,1 Marcus Reidenberg,9 Budiono Santoso,10 Anthony Savelli2 and Rosamund Williams.4 1 Department of Essential Drugs and Medicines Policy (EDM), World Health Organization, Geneva, Switzerland 2 Management Sciences for Health (MSH), Washington DC, USA* 3 Department of International Health, Boston University, Boston, Massachusetts, USA 4 Department of Communicable Disease Surveillance and Response, World Health Organization, Geneva, Switzerland 5 Uganda Health Sector Programme Support, Danida, Kampala, Uganda 6 Department of Clinical Pharmacology, University of Newcastle, New South Wales, Australia 7 Safe Injection Global Network, Department of Blood Safety and Clinical Technology, World Health Organization, Geneva, Switzerland 8 Global Assistance Initiatives, United States Pharmacopeia, Maryland, USA 9 Division of Clinical Pharmacology, Weill Medical College of Cornell University, New York, USA 10Regional Office for the Western Pacific, World Health Organization, Manila, the Philippines * The MSH Rational Pharmaceutical Management Plus Program is supported by the U.S. Agency for International Development, under the terms of cooperative agreement number HRN-A-00-00-00016-00. © World Health Organization 2003 All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. The World Health Organization does not warrant that the information contained in this publication is complete and correct and shall not be liable for any damages incurred as a result of its use. Designed by minimum graphics Printed in France Contents iii 9. GETTING STARTED Acronyms and abbreviations v Preface vii 1 Introduction 1 1.1 Why are drug and therapeutics committees (DTCs) needed? 1 1.2 Goals and objectives of the DTC 2 1.3 Functions of the DTC 2 1.4 Role of the DTC in the drug management cycle 5 2 Structure and organization of a DTC 6 2.1 Principles in setting up a DTC 6 2.2 Steps in setting up and managing the DTC 7 Annex 2.1 Example of a declaration of interest form 12 Annex 2.2 Model terms of reference for a DTC in Zimbabwe 13 Annex 2.3 Example of a mandate for a DTC: excerpts from the Zimbabwe National Drug Policy 1998 14 3 Managing the formulary process 15 3.1 The formulary process 15 3.2 The formulary list (essential medicines list) 16 3.3 The formulary manual 22 3.4 Standard treatment guidelines (STGs) 23 Annex 3.1 Application forms to be filled in by applicants when applying for a new drug to be added to the hospital formulary list 28 Annex 3.2 Drug information included in a comprehensive formulary 34 4 Assessing new medicines 35 4.1 The need for critical assessment of new medicines 35 4.2 Sources of information to assess new medicines 36 4.3 Assessing the efficacy and safety of new medicines from the literature 36 4.4 Measuring and comparing clinical treatment outcomes 38 4.5 Measuring and comparing drug costs 39 Annex 4.1 Sources of information 46 Annex 4.2 Checklist to detect common problems encountered in articles 48 5 Ensuring medicine safety and quality 51 5.1 The need for ensuring medicine safety and quality 51 5.2 Monitoring and addressing medication errors 51 5.3 Monitoring and ensuring medicine quality 54 5.4 Safety of medicines 58 Annex 5.1 Basic analytical medicine tests 65 Annex 5.2 Examples of adverse drug reaction reporting (ADR) reporting forms 66 Annex 5.3 Naranjo algorithm for assessing the causality of an ADR 70 6 Tools to investigate the use of medicines 71 6.1 Stepwise approach to investigating the use of medicines 71 6.2 Analysis of aggregate medicine use data 72 6.3 WHO/INRUD drug use indicators for health facilities 81 6.4 Qualitative methods to investigate causes of problems of medicine use 81 6.5 Drug use evaluation (DUE) (drug utilization review) 85 Annex 6.1 Defined daily doses (DDD) of some common medicines 91 Annex 6.2 DUE criteria on data collection form for amikacin 94 7 Promoting the rational use of medicines 95 7.1 Changing a medicine use problem 95 7.2 Educational strategies 96 7.3 Managerial strategies 99 7.4 Regulatory strategies 102 7.5 Choosing an intervention 103 7.6 Evaluating interventions 103 Annex 7.1 Examples of structured order forms from a hospital in Nepal 106 8 Antimicrobials and injections 108 8.1 Antimicrobials, resistance and infection control 108 8.2 Safe and appropriate use of injections 115 9 Getting started 122 9.1 Addressing the problem 122 9.2 Stepwise approach to starting a DTC where none exists 123 9.3 Revitalizing non-functioning DTCs 126 9.4 Using this manual to solve problems 126 Glossary 130 References 136 Further reading 139 Useful addresses and websites 140 DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE iv Acronyms and abbreviations 9. GETTING STARTED v ABC ABC analysis ADR adverse drug reaction AGREE Appraisal of Guidelines for Research and Evaluation in Europe AHFS American Hospital Formulary Service AMR antimicrobial resistance ARR absolute risk reduction ASHP American Society of Health-System Pharmacists DALYs disability-adjusted life years DDD defined daily dose DTC drug and therapeutics committee DUE drug use evaluation DUR drug utilization review EDL essential drugs list EML essential medicines list EDLIZ Essential Drug List of Zimbabwe GMP good manufacturing practices IM intramuscular INN International Nonproprietary Name INRUD International Network for Rational Use of Drugs IV intravenous MCAZ Medicines Control Authority of Zimbabwe MI myocardial infarction MoH Ministry of Health MSH Management Sciences for Health MUE medication use evaluation NDTPAC National Drug and Therapeutics Policy Advisory Committee NNT numbers needed to treat QALYs quality-adjusted life years RCT randomized controlled trial RPM Rational Pharmaceutical Management Project RR relative risk DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE vi RRR relative risk reduction SC subcutaneous SIGN Scottish Intercollegiate Guidelines Network SK streptokinase STG standard treatment guideline TB tuberculosis TPA tissue plasminogen activator UNFPA United Nations Population Fund UNICEF United Nations Children’s Fund VEN analysis vital, essential and non-essential analysis WHO World Health Organization Preface vii 9. GETTING STARTED Inefficient and irrational use of medicines is a widespread problem at all levels of health care (Hogerzeil 1995). Per capita wastage from inefficiencies and irrational use tends to be greatest in hospitals; this is particularly worrisome since resources are scarce and prescribers in communities often copy hospital prescribers. Many of these sources of wastage could be reduced if some simple principles of drug management and use were followed. However, it is difficult to implement these principles because staff from many different disciplines are involved in different aspects of drug management and use. Often there is no forum for these different disciplines to work together in developing and implementing appropriate drug policies. In hospital settings, a drug and therapeutics committee (DTC) provides a forum to bring together all the relevant people to work jointly to improve health-care delivery. As such, a DTC may be regarded as a tool for promoting more efficient and rational use of medicines. In many developed countries, a well-functioning DTC has been shown to be one of the most effective structures in hospitals able to address drug use problems (Weekes and Brookes 1996). However, in many developing countries DTCs do not exist and in others they do not function effectively. A DTC involves its members in a great deal of work. It may be easy to identify members, roles and functions for a DTC, but it is much more difficult to develop and implement strategies to change medicine use practices. DTCs will not, therefore, work unless the staff involved are motivated and prepared to make the effort. A DTC can only work in health systems where there are: • sufficient staff who understand and are able to undertake the necessary work • incentives (for example recognition, allocated work time for DTC activities) for the professional staff involved • accountability of the hospital and its staff for the money they spend on medicines and the quality of care that they provide. This manual aims to provide practical guidance to doctors, pharmacists, hospital managers and other professionals who may be serving on DTCs, or who are concerned with how to improve the quality and cost efficiency of care. The manual covers: • general principles, strategies and activities that can be adopted to improve the quality and cost efficiency of care • what the roles and responsibilities of a DTC should be and how these may be achieved. The guidance provided in this manual is aimed at all kinds of DTC – whether in public or private hospitals and at all levels, from district level to tertiary referral level. Since health systems in different countries vary widely, not all the information included in this manual will be relevant for all DTCs. Where certain information is only relevant to higher levels of health care, this has been indicated in the text. This manual has been developed by the Department of Essential Drugs and Medicines Policy, WHO, Geneva, in collaboration with the USAID-funded Rational Pharmaceutical Management Plus Programme of Management Sciences for Health, Boston, USA. The draft was developed in a participatory way, building on the course materials used in international training courses on DTCs and on experiences gained from pilot projects conducted in Zimbabwe and Indonesia. The words ‘drugs’ and ‘medicines’ are used interchangeably in the text. We would be very happy to receive comments, which may be sent to: Department of Essential Drugs and Medicines Policy World Health Organization 20 Avenue Appia 1211 Geneva 27 Switzerland Fax: +41 22 791 4167 Email: email@example.com DRUGS AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE viii 1 1. Introduction Summary Inappropriate use of medicines wastes resources and seriously undermines the quality of patient care. A drug and therapeutics committee (DTC) can significantly improve drug use and reduce costs in hospitals and other health care facilities in the following ways: • providing advice on all aspects of drug management • developing drug policies • evaluating and selecting drugs for the formulary list • developing (or adapting) and implementing standard treatment guidelines • assessing drug use to identify problems • conducting interventions to improve drug use • managing adverse drug reactions and medication errors • informing all staff members about drug use issues, policies and decisions. 1.1 Why are drug and therapeutics committees needed? Essential medicines are one of the most cost-effective ways of saving lives and improving health, and constitute 20–40% of health budgets in many developing countries. Increasing costs and lack of resources often result in public health systems being unable to procure sufficient medicines to meet patient demand. Despite this, medicines are often managed and used inefficiently and irrationally. This may be due to many factors, for example inadequate training of health staff, lack of continuing education and supervision, or lack of updated, reliable, unbiased drug information. Particular areas of inefficiency and drug use problems include: • poor selection of medicines, without consideration for relative efficacy, cost-effectiveness or local availability • inefficient procurement practices, resulting in non-availability, inadequate quality, wastage, or use of unecessarily expensive medicines • prescribing not in accordance with standard treatment protocols • poor dispensing practices resulting in medication errors, and patients’ lack of knowledge about dosing schedules • patients not adhering to dosing schedules and treatment advice. Inefficient use of medicines affects the safety and quality of therapeutic care and wastes resources. According to WHO (1985): Rational drug use requires that the patients receive drugs appropriate to their clinical needs in doses that meet their individual requirements (right dose, right intervals and right duration). These drugs must be of acceptable quality, and available and affordable, at the lowest cost to patients and the community. 1. INTRODUCTION DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 2 When the use of medicines is not in accordance with this definition, there are often undesirable health and/or economic outcomes. Such outcomes include insufficient therapeutic effect, adverse drug reactions, preventable side-effects and interactions from medicines, and increasing resistance of bacterial pathogens to antimicrobial medicines; these may all result in increased or prolonged hospital admissions, which are expensive. Some inefficiencies result from lack of an effective forum that brings together pharmacists, clinicians and administrators to balance the demand for quality care with financial constraints. There may be tension between prescribers and financial managers about which medicines should be available for what problems. DTCs are a forum to bring together all stakeholders involved in decisions about drug use; they may exist at any level within the health-care system – at district level (overseeing primary health-care facilities), in hospitals, or at the national level. In developed countries hospital DTCs have been shown to be very effective in safeguarding and promoting efficient and rational use of medicines (Crawford and Santell 1994, Weekes and Brookes 1996) by, for example: • establishing documented rules and policies for all aspects of drug management including the selection of formulary list medicines and agreement of treatment protocols • conducting continuing education, audit and feedback, drug utilization review and monitoring of adverse drug reactions and medication errors. 1.2 Goals and objectives of the DTC The goal of a DTC is to ensure that patients are provided with the best possible cost- effective and quality of care through determining what medicines will be available, at what cost, and how they will be used. In order to achieve this goal a DTC will have the following objectives: • to develop and implement an efficient and cost-effective formulary system which includes consistent standard treatment protocols, a formulary list and formulary manual • to ensure that only efficacious, safe, cost-effective and good quality medicines are used • to ensure the best possible drug safety through monitoring, evaluating and thereby preventing, as far as possible, adverse drug reactions (ADRs) and medication errors • to develop and implement interventions to improve medicine use by prescribers, dispensers and patients; this will require the investigation and monitoring of medicine use. 1.3 Functions of the DTC There are many possible functions of a DTC, and the committee must decide which to undertake as a priority; this decision may depend on local capacities and structure. Furthermore, certain functions will require liaison with other committees or teams, for example the infection control committee or the procurement team. The most important DTC functions are summarized below. 1.3.1 Advisory committee to medical staff, administration and pharmacy The DTC is a valuable resource that can provide advice to medical staff, nurses, administration, pharmacy and other departments and groups within the hospital. The DTC can advise on all issues, policies and guidelines concerning the selection, distribution and 3 use of medicines. Usually a DTC will provide advice and an executive body, usually the pharmacy or hospital management, will implement it. 1.3.2 Development of drug policies The DTC is the most appropriate body to develop drug policies within a hospital or group of health facilities, since the committee members will have the most experience and training in drug therapy and supply. Policies and procedures are the primary activity within a DTC, since they provide the foundation for other recommendations that may later arise from the DTC. Drug policies may vary in different hospitals and countries, but all hospitals should have specific policies concerning: • criteria for inclusion of medicines on the formulary list (essential medicines list (EML)) • standard treatment guidelines and treatment algorithms, which should be the basis of formulary selection • periodic use of medicines not on the formulary list, for example restricting their use to specified prescribers on a named patient basis only, or only allowing 10% of the hospital medicines budget to be spent on them • expensive or dangerous medicines, such as third-generation antibiotics or oncological drugs, which are restricted to certain practitioners, departments or patients (structured order forms may be used to implement this policy) • drugs that are under investigation for safety or efficacy • generic substitution and therapeutic interchange • drug representatives and promotional literature. 1.3.3 Evaluating and selecting medicines for the formulary list Perhaps the most important function of a DTC is the evaluation and selection of medicines for the essential medicines list or formulary list. Drugs should be selected on the basis of the standard treatment guidelines or protocols that have been developed or adapted for use in the hospital or health facilities. The evaluation of medicines requires significant expertise and time commitment and a rigorous, transparent approach. Documented evidence for the efficacy, safety, quality and cost of all drugs under consideration for inclusion in the formulary list must be examined. Periodic review is necessary because of changing costs and indications, new information on safety, and the emergence of new medicines. The documents reviewed will depend upon the expertise of the committee and may include reputable textbooks, published treatment guidelines and formularies, newsletters and primary drug literature. See section 3.2 and chapter 4 for more information on selection and evaluation of medicines. 1.3.4 Developing standard treatment guidelines Standard treatment guidelines (STGs) or protocols are a proven way to promote rational use of medicines provided they are: • developed in a participatory way involving end-users • easy to read and up to date • introduced with an official launch, training, supervision and wide dissemination (Grimshaw and Russell 1993, Woolf et al. 1999). 1. INTRODUCTION DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 4 Furthermore, STGs provide a benchmark of optimum treatment in the monitoring and audit of drug use. A DTC should either develop STGs from scratch or adapt them from elsewhere for use in their own hospital. Development of STGs from scratch will result in greater local ownership and acceptance, but is difficult and will consume time and resources. Adaptation or adoption of STGs from elsewhere is much easier and quicker, but will result in less local ownership and acceptance. See section 3.4 for more information on treatment guidelines. 1.3.5 Assessing medicine use to identify problems Appropriate changes within the formulary list or other interventions may correct a number of problems in how medicines are used. It is important for the DTC to identify the priority problems and make appropriate recommendations. Appropriate methods to identify drug use problems include: • aggregate drug consumption data review including ABC and VEN analysis and use of defined daily dose (DDD) methodology (see section 6.1) • monitoring indicators of medicine use, including adherence to standard treatment guidelines (see section 6.2) • drug use evaluation (DUE), also known as drug utilization review (see section 6.4) • monitoring adverse drug reactions and medication errors (see chapter 5) • antimicrobial resistance surveillance (see section 8.1). 1.3.6 Conducting effective interventions to improve medicine use There is no point in a DTC collecting information on drug use problems if nothing is done to correct the problems identified. The DTC is the main body within a hospital, or group of health facilities, responsible for ensuring that drug information is provided to health staff and also for conducting interventions to promote more rational drug use. Monitoring and supervision, audit and feedback, educational programmes, in-service training, use of standard treatment guidelines, provision of unbiased drug information, prescribing restrictions and automatic stop orders are some important interventions. See chapter 7 on strategies to promote the rational use of medicines. 1.3.7 Managing adverse drug reactions Adverse drug reactions (ADRs) are serious in terms of patient harm (morbidity and mortality) and avoidable economic costs. One large meta-analysis estimated that ADRs cause 3–4% of all hospital admissions in the USA and that in 1994 the incidence of ADRs was 6.7% (2.2 million events) with 106 000 fatalities (Lazarou et al. 1998). These estimates should be viewed with caution because of the heterogeneity among studies and small biases in the sample, but the data nevertheless suggest that ADRs are a large and serious problem. Adverse drug reactions may be due to the unknown effects of new (or older) drugs, unknown drug combinations and interactions, or poor drug quality. DTCs are responsible for ensuring that patients are treated as safely as possible. Monitoring and minimizing adverse drug reactions is an essential part of this function (see section 5.3). 1.3.8 Managing medication errors Medication errors occur in all health-care settings, no matter how good the health-care staff are at prescribing, dispensing and administering medicines. Even if there is no error on the part of health-care staff, patients may take drugs incorrectly. Causes are numerous and include lack of knowledge, tiredness of staff, careless work attitudes, poor procedures, 5 lack of policies, unfamiliar dosage forms and human error. DTCs can reduce such errors by monitoring, analysing, reporting errors and implementing corrective action (see section 5.1). 1.3.9 Information dissemination and transparency The DTC must disseminate information about its activities, decisions and recommendations to the staff who must implement the DTC’s decisions. This may seem obvious, but it is often forgotten. Inadequate dissemination of information leads to a loss of credibility. It is also very important that the DTC operates in such a way as to ensure transparency of all its decisions and to avoid conflict of interest. In particular, members should either have no relationship with pharmaceutical companies or declare it openly so that conflicts of interest can be avoided. The only acceptable contact with pharmaceutical companies is to ensure the flow of information about their drug products in a way that is as unbiased as possible (see sections 2.1 and 7.4.2). 1.4 Role of the DTC in the drug management cycle The drug management cycle (Figure 1.1) illustrates the necessity for coordination of managerial and technical support with appropriate drug policies and guidelines, in order for any drug system to run smoothly (MSH 1997, part IV, section A on ‘Organization and Management’). The figure highlights the coordination between the DTC and the drug purchasing and inventory control body. 1. INTRODUCTION The DTC will often have to coordinate with those responsible for procurement and distribution of medicines. The DTC would not normally do the procurement itself: its role would normally be to ensure that the formulary system and other drug policies developed by the DTC are implemented by the procurement department. Every effort should be made to avoid the DTC degenerating into a forum only for making procurement decisions and complaining to the pharmacist about stock-outs. Furthermore, it is unwise to concentrate too much power over the pharmaceutical system in any one body, as this may lead to corrupt practices. The functions of selecting medicines, procurement, payments and inventory control are best kept separate (WHO/UNICEF/UNFPA/WB 1999). Figure 1.1 The drug management cycle DISTRIBUTION PROCUREMENTUSE SELECTION Procurement DTC 2. Structure and organization of a drug and therapeutics committee Summary In order for a DTC to function it should have a multidisciplinary, transparent approach, technical competence and an official mandate. It is essential to define and document: • the membership of the DTC, including the chairperson and secretary, and criteria for membership • the goals, objectives and functions of the DTC • how the DTC will operate and its terms of reference • the funding sources identified • the mandate – DTCs will not work without senior administrative support • the relationship of the DTC with other subcommittees for specific areas of work • a process for self-assessment and evaluation. 2.1 Principles in setting up a DTC It may be easy to establish a DTC, with a list of core and additional members, all with different expertise, objectives and functions, but it may be very difficult to ensure that it functions effectively. Success will depend on having strong and visible support from the senior hospital management and abiding by the principles listed below. 2.1.1 A multidisciplinary approach sensitive to local politics DTC activities will involve different cadres of health professional, who will have different experiences, beliefs, skills, practices, motivations and status. Often a DTC must manage conflict arising between clinicians and the pharmacy or administration concerning prescribing restrictions that result from the implementation of agreed guidelines. Such conflicts can be reduced if staff are convinced of the need for, and benefits of, change and there is strong institutional commitment with the support of people in authority. Wide representation on the DTC and documenting and disseminating decisions taken to correct problems in the use of medicines helps to convince health-care workers. Everyone who contributes should be acknowledged. 2.1.2 Transparency and commitment to good service The success of a DTC will depend upon its being active, working regularly in a consistent direction and making sound decisions in a transparent way. This is especially important in medicine selection and procurement policies. The people involved should not be influenced by inappropriate drug advertisements, promotional activities or personal financial interests. All committee members should be required to sign a ‘declaration of interest’ (see annex 2.1). Such a declaration can bind members to the working principles and ethics of the DTC, and to their roles and responsibilities to other health-care staff, the hospital management and the community. DRUGS AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 6 2.1.3 Technical competency A DTC must have the appropriate technical competence. Members will have different competencies and the DTC process of discussion and appraisal of drug use issues is a good way to educate members in areas outside their expertise. Good science and evidence (if possible) must be the basis of all DTC decisions. 2.1.4 Administrative support Administrative support is very important, as otherwise a DTC may not be able to implement its decisions. Administrative support can provide the executive authority needed to gain the cooperation of senior medical staff. The administration can also provided the funds needed to undertake many of the DTC’s activities. 2.2 Steps in setting up and managing the DTC The most effective way of gaining support is through a dynamic DTC that can formulate policy and guidelines with consensus of all parties and that is seen to be sensitive to comments. ■ STEP 1 Organizing the committee and selecting members Opinions vary regarding the optimal size and composition of the committee. Smaller committees may be appropriate for smaller hospitals; larger ones may be useful in big hospitals with wider work perspectives. Fewer members may allow consensus agreements to be reached more easily. More members can provide greater expertise, reduce the workload for individual members, and increase the ease of implementation of decisions. All committees should have sufficient members to represent all stakeholders, including the major clinical departments, the administration and the pharmacy. Members should be selected with reference to their positions and responsibilities and they should have defined terms of reference. In most hospitals, the membership includes: • a representative clinician from each major specialty, including surgery, obstetrics and gynaecology, internal medicine, paediatrics, infectious diseases, and general practice (to represent the community) • a clinical pharmacologist, if available • a nurse, usually the senior infection control nurse, or sometimes the matron • a pharmacist (usually the chief or deputy chief pharmacist), or a pharmacy technician where there is no pharmacist • an administrator, representing the hospital administration and finance department • a clinical microbiologist, or a laboratory technician where there is no microbiologist • a member of the hospital records department. Other members may also be included for their particular expertise, for example a drug information specialist, quality assurance specialist or consumer group representative. In Australia consumer representatives have included a retired judge, a psychiatric patient, a member of a pensioners’ association and a volunteer hospital worker. However, with regard to consumer representatives, “beware the politician with a hidden agenda”. A dedicated and committed chairperson and secretary are critical to the success and efficiency of a DTC. In most hospitals, a senior medical doctor, ideally well-known and respected, is appointed as the chair and the chief pharmacist as the secretary. The chair and secretary should be allotted sufficient time for their DTC functions, and this should be 2. STRUCTURE AND ORGANIZATION OF A DTC 7 DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 8 included in their job descriptions and terms of reference. The allotted time should be sufficient to cover all DTC meetings and other work in relation to the meetings. Non- member specialists can be invited during discussions of important issues. In large hospitals, various subcommittees can be established to address particular issues, for example antibiotic use, adverse drug reactions, medication errors and drug use evaluation/audit. All hospitals should have an infection control committee; if such a committee does not exist, the DTC should establish it. Where other committees exist, the DTC should liaise and coordinate with them in order to avoid duplication of activities. ■ STEP 2 Determine the objectives and functions of the committee It is not possible for a DTC to do everything. The first thing a DTC should do is to agree its terms of reference, which specify the DTC’s place in the organizational structure of the hospital, its goals, objectives, scope of authority, functions and responsibilities. The most important objectives and roles have already been described in chapter 1. Once basic functions, such as a formulary system, are implemented, the DTC can move on to other activities. Annex 2.2 shows the terms of reference of the DTC in a Zimbabwean hospital. Sometimes the initial functions of the DTC, during the time of organization, depend on the prevailing clinical and pharmaceutical management problems that must be immediately addressed. This is a good way of getting the support of the management and the agreement of medical personnel. Figure 2.1 shows how the different possible functions of a DTC interrelate. The DTC is responsible for maintaining standards. In order to do this, the DTC must define standards, Figure 2.1 The DTC’s cycle of activities and function INTERVENTION / STRATEGY Targeted interventions to improve practice • Education of prescribers and dispensers • Education of consumers and drug sellers • In-service and pre-service training • Create drug information unit • Develop & implement STGs and EML • Managerial & regulatory interventions STANDARDS Criteria for appropriate performance • Standard treatment guidelines • Essential Medicines List • Ethical criteria for pharmaceutical promotion • Drug policies and procdeures ASSESSMENT Quantitative assessment of performance • Drug utilization studies of adherence to STG • Availability of essential medicines: % EML • Indicators for monitoring RDU • AMR surveillance • ADR monitoring • Pharmaceutical promotion monitoring • Estimate drug requirement & consumption • Cost-effectiveness/benefit analysis DIAGNOSIS Qualitative assessment to identify reasons underlying poor performance • Logistics and resources • Patient/consumer factors • Health provider factors • Pharmaceutical industry influence • Access to information DU E 9 assess performance, diagnose why performance is poor and introduce measures to improve it. ■ STEP 3 Determining how the committee will operate • Regular meetings of the DTC, at least quarterly and preferably monthly, are important. The schedule may vary depending on needs. Special meetings can be convened when necessary. The length of meetings should be limited, as clinician members of the committee are unlikely to attend or to stay throughout if the meetings are too long. • Regular attendance of members at committee meetings is often a problem. As a solution, some institutions make it a part of the requirements for reappointment. Other institutions provide some monetary incentives, or serve food or refreshment at meetings. • The agenda, supplementary materials and minutes of the previous meeting should be prepared by the secretary and distributed to the members for review in sufficient time before the meeting. These documents should be kept as permanent records of the hospital and should be circulated to chairpersons/directors of all clinical departments. • All DTC recommendations should be disseminated to the medical staff and other concerned parties and authorities in the hospital. Regular hospital activities such as grand ward rounds and clinical discussions can be used as venues to discuss recommen- dations and to educate the health staff on the proposed policies for implementation. • All DTC operating guidelines, policies and decisions should be documented. This documentation should include the decisions on actions to be taken if the decisions, guidelines or policies are not followed. Relevant documentation must be made available to interested parties such as staff members and drug companies. Members of the committee should be responsible for disseminating the resolutions of the DTC. • Liaison of the DTC with other hospital committees and regional or national committees is important, for two reasons: — to harmonize related activities (for example, surveillance of antimicrobial resistance (AMR) and antimicrobial use) — to share information concerning common activities (for example, monitoring of adverse drug reactions and educational strategies such as continuing medical education). ■ STEP 4 Seeking a mandate Only with a mandate from the most senior authority in the hospital is a DTC credible and sustainable. The mandate of a DTC should specify: • its roles and functions • its place in the organizational structure • its membership • its scope and lines of authority. The strongest mandate a DTC can have is that issued by the government, as in Zimbabwe (see annex 2.3). In some industrialized countries, hospitals are required to have DTCs in order to be accredited by professional societies and universities as training institutions. In other countries patients can only get reimbursement for treatment from hospitals that are accredited by the insurance companies and such accreditation may require functioning DTCs. 2. STRUCTURE AND ORGANIZATION OF A DTC DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 10 ■ STEP 5 Identifying budgetary sources The DTC must be able to identify budget resources to support its own activities (such as meetings or incentives for its members) and those activities it recommends for implementation (for example, educational programmes, development of standard treatment protocols, drug utilization review and supervision). Budgeted staff time should also be reflected in their job descriptions. Usually the budget requirement is not substantial and can be justified to the hospital administration on the basis of drug cost savings that can be realized through the DTC activities. The DTC should be able to demonstrate its own cost-effectiveness when requesting a regular budget allocation from the hospital management. To this end, the DTC should prepare an annual action plan with corresponding budget requirements. It is more convincing to present budgetary requirements together with past or potential future cost savings. ■ STEP 6 Forming subcommittees to address specific issues Often there are specific areas which need a great deal of extra work and expertise that the DTC cannot provide or give time to, for example, the use of antimicrobials. Many DTCs have dealt with this issue by forming a subcommittee to work in the specified field on behalf of the DTC and report back. See chapter 8 on antimicrobials and injections. BOX 2.1 INDICATORS TO ASSESS DTC PERFORMANCE AND IMPACT • Is there a DTC document that indicates its terms of reference, including its goals, objectives, functions and membership? • Is the DTC in the organizational chart of the hospital? • Is a budget allotted to DTC functions? • Does the DTC have established criteria and authority concerning drug selection? — How many medicines are there in the hospital formulary? — Are there documented criteria for addition to and deletion from the list and requests for the use of non-formulary medicines? — What percentage of prescribed medicines belong to the hospital formulary? • Has the DTC been active in the development and implementation of STGs? — Has the hospital developed/adopted its own STGs? — Have drug utilization studies been performed to assess adherence to STGs? • Has the DTC organized educational activities about medicines? — Have there been any organized training and lectures for health-care staff? — Is there an established library accessible to staff? — Is there continuing medical education? — Is there a drug information service available to staff? • Have any intervention studies to improve medicine use been undertaken? • Has the DTC been involved in drug budget allocation? — Was the DTC consulted during drug budget allocation? — Was DTC clearance needed prior to drug budget approval? • Has the DTC developed a policy for controlling the access of drug representatives and promotional literature to hospital staff? 11 2. STRUCTURE AND ORGANIZATION OF A DTC ■ STEP 7 Assessment of the DTC’s performance Self-assessment and evaluation of the DTC are very important if performance and impact are to be improved. The organizational development and performance of the DTC should be monitored continuously and documented, especially if the DTC expects the hospital management to provide continuing funds. Some indicators that can be used in DTC self- assessment are shown in box 2.1. These indicators are considered to be core parameters that should be used. However, the DTC can develop other indicators and measures that will suit its purpose. Most important is for the indicators to be used in evaluating the impact of the DTC. In this way, the DTC may see if it is achieving its goals and objectives and justify the continued support of the hospital management. DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 12 ANNEX 2.1 Example of a declaration of interest form DECLARATION OF INTEREST FORM Name ……………………………. Position ……………………………. Have you, or anyone in your family, any financial or other interest in any pharmaceutical manufacturer or supplier, and which may constitute a real, potential or apparent conflict of interest? Please tick: ■■ Yes ■■ No Have you had, during the past 4 years, any employment or other professional relationship with any organization that is a pharmaceutical manufacturer or supplier or represents such organizations? Please tick: ■■ Yes ■■ No If you answered ‘yes’ to either question, please give details in the box below. Type of interest, for example Name of Belongs to you, Current interest? patents, shares, employment, commercial your family or or year that association, payment* entity work unit? interest ceased * Amounts do not have to be declared Is there anything else that could affect, or be perceived to affect, your objectivity or independence in carrying out your duties in the DTC? I hereby declare that the disclosed information is correct and that no other situation of real, potential, or apparent conflict of interest is known to me. I undertake to inform you of any change in these circumstances. Signature ……………………………. Date ……………………………. Types of financial or other interests • Any payment for performance of work or research or educational grants during the past four years by any commercial entity that has an interest in the DTC’s work. • Current proprietary interest in a substance, technology or process (for example ownership of a patent), being considered by the DTC or otherwise related to the DTC’s work. • Current financial interest (for example shares, bonds) in a commercial entity with an interest in the DTC’s meetings or work. Share holdings through general mutual funds etc., where the person has no control over the selection of shares, are exempt. • Any employment, consultancy, directorship, or other position during the past 4 years or presently under negotiation, whether paid or not, in any commercial entity (for example a pharmaceutical company) that has an interest in the DTC’s work. 13 ANNEX 2.2 Model terms of reference for a DTC in Zimbabwe Name: Hospital Drug and Therapeutics Committee of ………………….…. Hospital. Status: The DTC is a standing hospital committee responsible, through its chairman, to the hospital executive. Chairman: The hospital executive shall appoint the Medical Superintendent or a senior doctor to chair the committee. Secretary: The committee secretary will usually be the pharmacist. In hospitals without a pharmacist, the hospital executive can appoint the pharmacy technician or any other member of the committee to be secretary. Members: The hospital executive appoints the other committee members on a representational basis and also to take advantage of the available human resources in the hospital and community. Goals: • Improved health and economic outcomes of hospital care, particularly those related to drug use. • Rational and cost-effective drug use through collaborative drug management involving all health workers. Objectives: The committee will be responsible for defining its own specific objectives on an annual basis. Each committee can do that by reviewing the following objectives and choosing what they want to work on. 1. To formulate and implement policies for selection and use of drugs: — to develop and manage a hospital essential drugs list — to develop and implement standard treatment guidelines — to carry out drug utilization reviews in the hospital — to provide prescribers with objective drug information — to monitor and analyse expenditure on drugs. 2. To carry out educational and other activities aimed at improving prescribing and dispensing practices in the hospital. 3. To monitor and report adverse drug reactions to the Medicines Control Authority of Zimbabwe (MCAZ). 4. To monitor medication errors and act to prevent their recurrence. 5. To regulate operations of the pharmaceutical industry in the hospital. 2. STRUCTURE AND ORGANIZATION OF A DTC DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 14 ANNEX 2.3 Example of a mandate for a DTC: excerpts from the Zimbabwe National Drug Policy 1998 • The Ministry of Health (MoH) will formally establish the National Drug and Therapeutics Policy Advisory Committee (NDTPAC) by providing appropriate terms of reference and a working budget. The NDTPAC will be composed of experts in all the medical and pharmaceutical fields, representing different levels of the health- care system. • The MoH recognizes the need for Drug and Therapeutic Committees (DTCs) in order to promote the rational use of drugs in the health-care institutions. • The MoH will ensure that DTCs are established in district, provincial and central hospitals, local authorities and private institutions. The committees will be composed of senior staff, pharmacy personnel, doctors, nurses, laboratory staff and co-opted members when indicated. • The MoH will issue guidelines for the formation and functioning of these committees and the NDTPAC will coordinate and advise on the work of the committees. • The committees will, among other duties, be responsible for determining the range, number and quantity of the Essential Drug List of Zimbabwe (EDLIZ) drugs to be available in the health facility, guiding all health workers in the rational use of drugs and use of the EDLIZ standard treatment guidelines (STGs). • The committees will make hospital formularies and monitor drug use. The MoH through the Directorate of Pharmacy Services will monitor and evaluate their activities. 15 3. MANAGING THE FORMULARY PROCESS 3. Managing the formulary process Summary The formulary process is critical to good health care and consists of developing and implementing: • a formulary list (essential medicines list) consisting of the most cost-effective, safe, locally available drugs of assured quality that will satisfy the health care needs of the majority of the patients • a formulary manual containing summary information on medicines • standard treatment guidelines containing essential information on how to manage common diseases. A formulary list and formulary manual should be developed and maintained based on recommended treatments from standard treatment guidelines, using explicit drug selection criteria, that have been agreed previously by all departments. Standard treatment guidelines can be adopted or adapted from elsewhere, which is less work, or developed from scratch, which involves a great deal of work but may result in more acceptability and use due to a sense of ownership. Critical to future use by health workers is their involvement in the development and updating process, the quality of the content, a user-friendly format, adequate distribution and follow-up supervision. 3.1 The formulary process The formulary process is the cornerstone of good pharmaceutical management and rational drug use. It consists of preparing, using and updating a formulary list (essential medicines list, EML, or essential drugs list, EDL), a formulary manual (providing information on drugs in the formulary list) and standard treatment guidelines (STGs). Choosing the most appropriate therapies and selecting the most cost-effective good-quality drugs leads to better quality of care and more efficient, equitable use of resources. Strict adherence to a formulary list alone will not improve treatment practice if drug selection is not based on STGs (i.e. if there is no consistency between the formulary list and the STGs). Furthermore, essential medicines can also be used inappropriately if there are no guidelines for disease management. Ideally, a formulary list should be developed after the appropriate treatment guidelines for common diseases have been identified or developed. In many countries, there are already national STGs and other texts on standard treatment protocols that can be followed and used as a starting point when developing a hospital formulary list or local STGs. Once a formulary list is established, a formulary manual, containing information on all the medicines in the formulary list, can be developed. Figure 3.1 shows the relationship between STGs and EMLs and how these affect respectively the use and the availability of medicines. DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 16 3.2 The formulary list (essential medicines list) Essential medicines are those that satisfy the priority health care needs of the population. They are selected with due regard to disease prevalence, evidence of efficacy, safety and comparative cost-effectiveness. Essential medicines are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford. The implementation of the concept of essential medicines is intended to be flexible and adaptable to many different situations; exactly which medicines are regarded as essential remains a national responsibility (WHO 2002a). It is difficult to achieve efficiency in the hospital pharmaceutical system if there are too many medicines. All aspects of drug management, including procurement, storage, distribution and use, are easier if fewer items must be dealt with. Appropriate selection of drugs can achieve the following results: • Cost containment and enhanced equity in access to essential medicines: Procuring fewer items in larger quantities results in more price competition and economies of scale with regard to quality assurance, procurement, storage and distribution. Such economies can lead to improved drug availability at lower costs, so benefiting those who are in most need. • Improved quality of care: Patients will be treated with fewer but more cost-effective medicines for which information can be better provided and prescribers better trained. Prescribers gain more experience with fewer drugs and recognize drug interactions and adverse reactions better. Quality of care will be further improved if medicine selection is based on evidence-based treatment guidelines. Figure 3.1 How STGs and EMLs lead to better prevention and care List of common diseases and complaints Treatments of choice Treatment guidelines Essential Medicines List and Formulary Manual Training and supervision Financing and supply of drugs Improved availability and use of medicines 17 3.2.1 Criteria in medicine selection Which drugs are selected depends on many factors, such as the pattern of prevalent diseases, the treatment facilities, the training and experience of available personnel, the financial resources, and genetic, demographic and environmental factors. WHO (1999) has developed the following selection criteria: • Only those medicines should be selected for which sound and adequate data on efficacy and safety are available from clinical studies, and for which evidence of performance in general use in a variety of medical settings has been obtained. • Each selected medicine must be available in a form in which adequate quality, including bioavailability, can be assured; its stability under the anticipated conditions of storage and use must be established. • When two or more medicines appear to be similar in the above respects, the choice between them should be made on the basis of a careful evaluation of their relative efficacy, safety, quality, price and availability. • In cost comparison between medicines, the cost of the total treatment, and not only the unit cost of the medicine, must be considered. Where drugs are not entirely similar, selection should be made on the basis of a cost-effectiveness analysis. • In some cases, the choice may also be influenced by other factors, such as pharmaco- kinetic properties, or by local considerations such as the availability of facilities for storage or manufacturers. • Most essential medicines should be formulated as single compounds. Fixed-ratio combination products are acceptable only when the dosage of each ingredient meets the requirements of a defined population and when the combination has a proven advantage over single compounds administered separately in therapeutic effect, safety or compliance. • Drugs are specified by the international nonproprietary name (INN) or generic name without reference to brand names or specific manufacturers. All DTCs should agree an explicit set of criteria, based upon the WHO criteria, for selecting medicines, so that the selection process can be objective and evidence-based. Without an evidence-based approach, decisions may be taken according to the doctors who ‘shout loudest’, and it may be difficult to persuade other prescribers to abide by the list. The criteria for drug selection and the procedure for proposing a drug to be added to the formulary list should be published (see section 3.2.3). Not all evidence is equally strong. For example, randomized controlled trials are less subject to bias than expert opinion and are therefore thought to constitute a higher level of evidence. The level of evidence should be acknowledged when publishing selection criteria and decisions. One classification scheme for levels of evidence is that used by the Scottish Intercollegiate Guideline Network (SIGN), as shown in Table 3.1. 3.2.2 Developing and implementing a formulary list The hospital formulary list should be consistent with the national essential medicines list (EML), if the latter is available. It is very important that an explicit and previously agreed process and selection criteria be followed at each step in order to increase prescriber confidence in the validity and usefulness of the list. 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 18 ■ STEP 1 Prioritize a list of common problems/diseases being treated in the hospital and determine the first choice of treatment for each problem The diseases may be ranked to identify the most common diseases being treated in the hospital by consulting all medical departments and reviewing the previous hospital mortality and morbidity records. For each disease, an appropriate first-choice of treatment should be identified using STGs – either nationally or locally developed. If there are no published STGs endorsed by the health ministry, publications by WHO, unbiased professional organizations and academia can be used. Alternatively, an expert committee can be brought together to identify the appropriate treatment for each of the common health problems. A commonly used alternative method of developing a formulary list – easier, but not recommended – consists of reviewing the existing formulary list of the hospital concerned or any other hospitals in the country. In such circumstances, the WHO model list of essential medicines (WHO 2002a) may also be used as a starting point. The capability of the hospital and its staff to handle specific drugs should not be forgotten during the selection process. For example, warfarin is not suitable for use unless the hospital has a facility to monitor prothrombin time (blood clotting time). ■ STEP 2 Draft, circulate for comment, and finalize the formulary list A draft of the list must be prepared. It is useful to identify: • the most important medicines (which are absolutely essential) and those that are less essential • the most expensive medicines • whether all the medicines that are prescribed in large volumes, or are expensive, are essential (see ABC analysis and VEN analysis in chapter 6). Each department, whether clinical or involved in non-clinical drug management, must be given the chance to comment on the list. The DTC must deliberate on their comments and provide feedback. All information to be discussed and deliberated upon, such as disease profile and STGs, must be available during the discussions, together with evidence-based reviews where possible. Finally, the DTC must agree and disseminate the formulary list and the reasons for its choices. Table 3.1 SIGN levels of evidence 1++ High-quality meta analyses; systematic reviews of randomized controlled trials (RCTs); or RCTs with a very low risk of bias 1+ Well conducted meta analyses; systematic reviews of RCTs; or RCTs with a low risk of bias 1– Meta analyses; systematic reviews of RCTs; or RCTs with a high risk of bias 2++ High quality systematic reviews of case-control or cohort studies; or high quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal. 2+ Well conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2– Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Non-analytic studies, e.g. case reports 4 Expert opinion. 19 3. MANAGING THE FORMULARY PROCESS ■ STEP 3 Develop policies and guidelines for implementation The formulary list will never be useful unless there are documented policies and guidelines on how it should be used. These should include: • who should use the list (prescribers and the procurement department should both abide by the list) • how the list should be reviewed and updated • a clear mechanism for adding and deleting medicines from the list (section 3.2.3) • how medical staff can request medicines that are not included on the list in exceptional or emergency situations (for example, certain non-formulary drugs may be prescribed by authorized senior doctors for specified less common conditions on a named patient basis). ■ STEP 4 Educate staff about the formulary list and monitor implementation All the staff in the hospital must be educated about the list. A common problem is that prescribers continue to request and use medicines not on the list. This results in patients having to buy their medicines from pharmacies outside the hospital, or the procurement group buying non-formulary medicines, without the approval of the DTC. There should be a clear system of implementation, accountability and enforcement including reprimands and sanctions. End users and opinion leaders can be involved in evaluating and enforcing the implementation. 3.2.3 Managing a formulary list (EML): adding and deleting drugs All applications to add medicines to the list must be made on an official application form (see annex 3.1). Individual doctors making an application must get the endorsement of their head of department. The application should include the following information: • the pharmacological actions of the medicine and its proposed indication • why the medicine is superior to those already on the formulary list • evidence from the literature to support inclusion on the formulary list • declaration of interest as to whether the applicant has received any financial support from the supplier, i.e. the manufacturing company or wholesaler. The request should be sent to the DTC secretary who will arrange for the request to be formally evaluated by the responsible person – either him/herself, or a drug information pharmacist, or drug information centre staff. Evaluations of applications to add new medicines to the list These should be conducted using explicit documented criteria, preferably evidence-based, as previously agreed by the DTC and covering the following areas: • Criteria for consideration of new treatments for conditions not amenable to existing drug therapy, or treatments representing major improvements in survival and quality of life: — the efficacy, effectiveness and safety of the medicine, as assessed by locally available literature (see section 4.1) — the quality of the drug (which may be considered adequate if registered by the national regulatory body) and a supply chain of acceptable quality (with regard to manufacture, storage and transport) DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 20 — whether the hospital has the necessary clinical expertise and laboratory services to use the medicine, and what role specialists should play to regulate therapy — an estimation of the cost (and potential savings) to the hospital should the drug be introduced – this should include costs of the medicine itself, hospitalization and investigation (see section 4.5) — availability of the drug on the market. • Criteria for treatments representing minor improvements in therapy compared to existing listed medicines. The committee should consider all of the above and in addition: — whether the new drug is really superior to existing ones in terms of efficacy, safety, or convenience of dosing/administration; claimed minor improvements are often proved to be unimportant — how the total cost for a course of treatment with the new drug compares with already listed drugs (see section 4.5). • Criteria for treatments that are therapeutically equivalent to existing listed medicines. The committee should consider all of the above and in addition: — whether the new drug is really therapeutically equivalent, and not inferior, to existing drugs in terms of efficacy, safety, or convenience of dosing/administration — whether the total cost for a course of treatment with new medicine is less than with the already listed medicines (see section 4.5.3). • Criteria for use of non-formulary medicines. If the use of non-listed drugs is allowed in certain circumstances, then these drugs need not be included in the list. Such circumstances may include: — non-response or contraindications to available medicines — whether to continue therapy for a patient who had been stabilized on a non-listed medicine before admission to hospital and where changing to another drug is considered detrimental. • Criteria for restricting the use of certain drugs to specified specialist prescribers only. Such circumstances may include: — the danger of unnecessarily increasing antimicrobial resistance with inappropriate use of third- or fourth-generation antimicrobials; thus they should be limited to prescription by infectious disease or clinical microbiology specialists — the danger of serious side-effects that could occur unnecessarily with inappropriate use, for example chemotherapeutic or cytotoxic agents; thus they should be limited to prescription by specialized physicians with knowledge of these medicines. Written report of the drug evaluation A written report should be compiled by the person who conducted the evaluation, and discussed at a scheduled DTC meeting. This report should contain the following information: • the drug monograph, including pharmacology, pharmacokinetics, efficacy as compared to placebo and other medicines, clinical trial analysis (from the literature – see chapter 4), adverse drug reactions, drug interactions, cost comparison • recommendations based on the evidence-based information 21 • expert opinions and recommendations from knowledgeable and respected physicians and pharmacists • how much the new medicine would cost the hospital • whether the new drug belongs to the national EML and whether it is reimbursable by health insurance schemes. Discussion and voting procedures The report should be discussed by the DTC members and a vote taken on the recommendations presented by the person who compiled the drug evaluation report. The final decision should then be disseminated to all health-care staff in the form of minutes, in newsletters and at departmental meetings. Non-listed requests A register of all non-listed medicine requests should be kept by the pharmacy and the name of the requesting doctor, the name and quantity of the medicine and the indication for which the medicine was requested should be recorded. When compiled at the end of the year, this information can tell the DTC about prescriber adherence to the formulary list and can also help in deciding whether or not to add drugs onto the list. Pruning the list If a new medicine is added to the list for reasons of improved efficacy, safety or lower price, serious consideration should be given to deleting the medicine which was previously on the formulary list for the same indication, for two reasons: • if the ‘new’ medicine is better, why continue to have a less good ‘old’ medicine on the list? • if no effort is made to consider deleting medicines, none will be deleted and the list will grow in size. 3.2.4 Maintaining a formulary Routine review of different therapeutic categories is an important part of formulary management. An efficient formulary management process will not passively wait for applications to add new medicines to the formulary. New drugs and treatments are emerging all the time, and without evaluation the formulary may become a collection of older, less effective drugs. Therefore, the entire formulary should be reviewed every 2–3 years. This can be done by evaluating all the formulary medicines within each therapeutic class in a systematic way on a regular basis and comparing them to other new non-formulary medicines within that class. Thus, in order to efficiently maintain a formulary, a DTC should meet regularly to discuss and decide upon: • requests for the addition of new medicines and deletion of old medicines • systematic review of a therapeutic class of medicines • review of programmes to identify and resolve medicine use problems. All decisions of the DTC should be documented (minuted). 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 22 BOX 3.1 PRINCIPLES OF FORMULARY LIST MANAGEMENT • Select drugs according to the needs of patients • Select drugs of choice for the conditions identified • Avoid duplications, both therapeutic and pharmaceutical (dosage forms) • Use explicit selection criteria, based on proven efficacy, safety, quality and cost • Use evidence-based information whenever possible • Be consistent with national EMLs and STGs • Consider requests for the addition of new drugs only when made by health-care staff, not by the pharmaceutical industry • Require that requests for the addition of new drugs are justified using documented evidence on efficacy, relative efficacy, safety and comparative cost-effectiveness and that the person requesting any new drug declare any conflict of interest • Carry out annual systematic reviews of all therapeutic classes to avoid duplication. 3.2.5 Improving adherence to a formulary The existence of a well-maintained formulary does not mean that prescribers will adhere to it. Methods to promote formulary adherence include the following (see also chapter 7 and MSH 1997, chapter 10 ‘Managing Drug Selection’, chapter 11, ‘Treatment Guidelines and Formulary Manuals’ and chapter 38 ‘Hospital Drug Services’): • reviewing and taking action on all non-formulary medicine use; action may include adding the medicine to the formulary, educating the prescriber about the non-formulary status of the medicines or banning use of the medicine within the hospital • prohibiting the use of non-formulary drug samples in the hospital • establishing procedures and approved drug product lists for therapeutic interchange or substitution (see section 7.3.3) • providing easy access to the formulary list, with copies at each drug ordering location and in pocket manuals for staff • involving medical staff in all formulary decisions • advertising and promoting all formulary changes • establishing agreed procedures for clinical trials with non-formulary medicines. 3.3 Formulary manual The formulary manual is the publication that brings all the important summary information on medicines in the formulary list together in a manual. There is no set standard on how this document is arranged or what is in the manual. Normally it would contain an alphabetically and therapeutically arranged listing of all the formulary drugs, and a section on drug usage including doses, contraindications, side-effects, drug interactions and price. Ideally the manual should include a section on the medicines of choice and alternates for treating the medical conditions of the region. Annex 3.2 shows a list of the information that should be available in a comprehensive formulary. The DTC may be selective in what information is presented for each item, depending on what has been approved for use locally; for example, including only some but not all dosage forms, strength, indications 23 for use, etc. A good comprehensive formulary can provide excellent drug information for health-care staff, but developing one is a very time-consuming process. If it is to be used, it will need to be pocket-sized, distributed widely (ideally to every prescriber), regularly updated, and developed in a transparent, participatory way (see section 3.4.2 on STG development). The WHO model formulary (WHO 2002b), which is available in electronic format, may be a good starting point for developing a formulary manual. 3.4 Standard treatment guidelines Even with an ideal formulary list, inappropriate use of formulary drugs may occur. STGs or treatment protocols are a proven, effective strategy to promote appropriate prescribing, when used in conjunction with educational strategies to promote their use (Grimshaw and Russell 1993). STGs may be defined as ‘systematically developed statements to help practitioners or prescribers make decisions about appropriate treatments for specific clinical conditions’ (MSH 1997). As a minimum, they should contain information on clinical features, diagnostic criteria, non-drug and drug treatments (first-, second-, third-line), and referral criteria (see step 5, section 3.4.2). Contrary to what is often alleged, STGs do not constrain but advise prescribers, who still retain their responsibility to decide upon appropriate treatments. STGs merely define the boundaries between the accepted norms in treating a disease based on good clinical evidence, and the practice of relying purely on clinical experience. The latter provides a very limited scientific basis and is often subject unknowingly to bias and misinterpretation which may result in expensive, inefficient disease management. STGs are very useful in: • providing guidance to health professionals on the diagnosis and treatment of specific clinical conditions • orienting new staff about accepted norms in treatment • providing prescribers with justification for prescribing decisions made in accordance with STGs • providing a reference point by which to judge the quality of prescribing • aiding efficient estimation of drug needs and setting priorities for procuring and stocking drugs. The problems associated with STGs include: • a development process which is difficult, time-consuming, and requires human and financial resources • the need to update regularly to avoid STGs becoming obsolete • the danger of inaccurate or incomplete guidelines which provide wrong information to prescribers, so doing more harm than good. Common pitfalls that need to be avoided include, for example, • including treatment choices that reflect common existing practices rather than best practice according to the evidence • recommending treatment choices that do not take into account existing expertise or infrastructure. In Europe there has been a great deal of concern about the quality of STGs and as a result there is now a move to evaluate all STGs according to defined criteria, such as those of the Scottish Intercollegiate Guideline Network (SIGN 1999) or the Appraisal of Guidelines for 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 24 Research and Evaluation in Europe, AGREE (Biomed 2000). Since STGs are so important with regard to monitoring and promoting more rational use of medicines, a DTC should be very concerned with developing STGs and promoting their use. Since good-quality STGs are so difficult to develop and implement, the DTC should focus on the most common, clinically important or costliest conditions treated in the hospital. Conditions where treatment is frequently suboptimal or wasteful may also be the focus of STG development. 3.4.1 Developing, adapting or adopting standard treatment guidelines STGs can range from protocols covering diseases commonly seen in primary health care to those seen only in major medical centres and tertiary hospitals. An STG manual may contain a few or many clinical conditions. The DTC can develop new STGs from scratch – a very difficult and time-consuming activity, which may be appropriate for large hospitals. Alternatively, the DTC may adapt existing national or institutional STGs to form their own local version, or simply advocate the use of existing STGs published by other groups. Adaptation or adoption of existing STGs is much easier and may be especially appropriate for small hospitals with inexperienced DTCs. Some guidelines are freely available on the web such as those from South Africa (Essential Drugs Programme South Africa 1998) and Australia (Therapeutic Guidelines Ltd 2000). Development and publication of a hospital’s own STGs, with its own book cover, may create a sense of ownership and acceptance of the guidelines. However, the DTC will need to decide whether this sense of ownership will promote the use of the STGs sufficiently to justify the extra work involved. Whatever option is chosen, the DTC should: • document and disseminate its choice, and the rationale for that choice, to all health workers • ensure that any STGs developed, adapted or adopted are consistent with national STGs and the guidelines of any national disease programmes (sexually transmitted infections, HIV/AIDS, malaria, diarrhoeal disease, tuberculosis (TB) and acute respiratory infections) • ensure that all prescribers have a copy of the chosen STG; this may mean paying for the publication of an STG manual and giving one copy to each prescriber for personal use rather than relying on prescribers buying a copy • make provision for review and updating of any guidelines that are developed • educate all prescribers in the use of STGs • do follow-up and give feedback on whether prescribers are adhering to the STGs (see sections 6.3, 6.5 and 7.3.2). 3.4.2 Steps in developing and implementing STGs Credibility, ownership, and hence use, will be increased if the development process uses evidence-based medicine, is participatory, is documented, and all contributors are acknowledged. It is important to document the affiliations of the contributors so that prescribers can see that authors had no conflict of interest, for example business interests with a local manufacturer or wholesaler. The procedure may follow the steps listed below. ■ STEP 1 Identify the working group to adapt/develop the hospital STGs The DTC may give responsibility for drafting the guideline, searching the literature and reporting back to the DTC on progress, to one or two DTC members or to a working group or subcommittee. Whoever is chosen, it is important that staff from all departments, including general practice, clinical pharmacy and pharmacology, be encouraged to comment 25 on the draft. They should be provided access to the information upon which the DTC will base its decisions. Hospitals without sufficient clinical experts should get an external consultant group to assist in developing, adapting and updating the STGs. ■ STEP 2 Develop an overall plan for developing and implementing the STGs It is not enough merely to identify a working group and experts. The DTC should agree and document who will be responsible for drafting the STGs, who will review them and who will edit them. Other things that need to be agreed include a format, a budget, and what kind of information will be used. It is useless to put a vast amount of effort into developing STGs that will not be used by prescribers or supported by hospital management (in terms of distribution or inclusion in pre- or in-service training), so a plan and budget should also be made at this stage for publication, dissemination and implementation (see step 7). ■ STEP 3 Identify the diseases for which STGs are needed Each department should be asked to identify the most common diseases in their specialty area, for both outpatients and inpatients. The list of diseases as identified by the different departments should be consolidated and ranked based on prevalence, severity, impact on general health of the population and the cost to the hospital of treating the condition. Some diseases, such as skin diseases, contribute substantially to the number of patients treated and the cost of drugs provided, but cause little significant morbidity or mortality. In some situations the DTC may decide not to select all the common diseases or problems but select a small number of problems or diseases: • where there is variation in practice and inappropriate use is known to occur • which are not covered in other published STGs • which are expensive to treat or which are treated with drugs that are dangerous to use, for example cancers treated with cytotoxic drugs or diabetes treated with insulin. ■ STEP 4 Determine the appropriate treatment This step is critical to the development of any new STGs. Experts and clinical specialists should consider the evidence concerning appropriate treatment for each disease or clinical problem and reach a consensus based as far as possible on evidence-based information sources. Consistency with national STGs is important and recommended treatments should: • consider non-drug treatments • use the fewest medicines necessary • choose the most cost-effective treatments • use approved formulary list drugs only (although the formulary list may need to be changed according to a review of the evidence) • identify first-, second- and if necessary third-line drugs • determine dose and duration, contraindications and side-effects for all medicines recommended • take into account — the existing level of prescribers (and their diagnostic skills) — the hospital facilities and monitoring capacity — the affordability and availability of the drug of choice in the market. 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 26 ■ STEP 5 Determine what information should be included in the STGs The decision on how much information to include must be weighed carefully. A small book that fits into the prescriber’s pocket will be used more readily than a large comprehensive textbook that is kept in the library. It is always important to state clinical signs and symptoms, diagnostic criteria, drugs and dosage, clearly and concisely, but other information may be omitted. Instead, the users may be referred to more comprehensive guidelines and references that should be made available in the hospital library or drug information unit/ centre. Information that may be included in hospital STGs includes the following: • clinical condition, its natural history and diagnostic criteria, including signs and symptoms and laboratory tests • treatment objective, for example elimination of Plasmodium parasites from a blood smear, sputum negativity in a previously sputum-positive TB patient • non-drug treatment • the drug of choice for the specific disease/condition • alternative second- and third-line drugs, together with their indications • relevant prescribing information – dose, duration, contraindications, side-effects, warnings, toxicity and drug interactions • referral criteria • what to tell the patient • cost of treatments, especially if alternatives are proposed. ■ STEP 6 Draft the STGs for comments and pilot test STGs generate widely varying opinions especially among prescribers, who are unlikely to use them unless they have been involved in the development process and a consensus is reached during drafting. Thus, the draft should be circulated widely and relevant comments incorporated. In order to ensure that comments are constructive, it may be helpful to ask for responses to be given in a structured way. For example, one may ask: • what should be changed and how • why it should be changed, providing evidence and justification. Once the content of an STG is agreed, a draft should be pilot tested in order to ensure that the document is clear and easily understood and the information is accurate. The size, presentation of information and layout can affect how easy a document is to read and use. Piloting STGs may be done by circulating the draft to a number of prescribers and finding out if they are able to use the draft STG. ■ STEP 7 Implement – publish, launch, disseminate, train and supervise Once the final draft is approved by the DTC, it can be published and distributed to staff. Distribution should be accompanied by an official launch, some initial training for staff on the STG, its importance and how to use it. Thereafter, follow-up (in-service) training, monitoring of adherence to STGs and supervision should be carried out (see chapters 6 and 7). As with formulary manuals, use will be enhanced if the STGs come in a pocket-size format and are distributed as widely as possible, ideally to every prescriber. Use of the STGs will also be encouraged if there is consistency of medicine selection between the STGs and the formulary list. 27 ■ STEP 8 Update Treatments can change rapidly, for example with the emergence of new drugs or new patterns of antimicrobial resistance. Thus, STGs must be updated regularly by reviewing the local antimicrobial susceptibility pattern, and other sources of information from evidence-based sources (for example reputable textbooks, drug and therapeutics bulletins or respected medical journals). The various experts and clinicians within the hospital should keep abreast of the current developments in drugs and therapeutics within their own disciplines, and inform the DTC appropriately. Once the DTC has received and accepted a sufficient number of requests for treatment revisions, the STGs can be updated. Between editions of the STGs, new information can be disseminated through circulars or drug bulletins. Unless the STGs are updated regularly (every 2–3 years) using data sources that all staff agree are acceptable, the STGs will quickly lose their credibility. 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 28 ANNEX 3.1 Application forms to be filled in by applicants when applying for a new drug to be added to the hospital formulary list In a Zimbabwean hospital Applicant’s name: Signature: Date: Generic name: Therapeutic class: Trade name and supplier: Unit cost: Is this drug on the national formulary list? Proposed indications for use: Principal mode(s) of action: Major adverse effects and drug interactions: Precautions and contraindications: State prescribing restrictions, for example ‘specialist only’: Are there prescribing guidelines? Please attach Average dose and frequency: Average duration of therapy: List drugs already approved for same indication: List drug(s) to be replaced by requested drug: Estimated number of patients per year: Estimated annual expenditure on drug: Advantages over listed alternative(s). Please attach references. Source: Zimbabwe DTC manual (1999). 29 3. MANAGING THE FORMULARY PROCESS In a Nepali hospital DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 30 In a South African hospital 31 In a South African hospital (continued) 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 32 In a South African hospital (continued) 33 In a South African hospital (continued) 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 34 ANNEX 3.2 Drug information included in a comprehensive formulary 1 Formulary list or essential medicines list Alphabetical and therapeutic category lists 2 Brief information about each medicine Generic name Dosage and strengths Indications, contraindications and precautions Side-effects Dosage schedule Instructions and warnings Drug, food, laboratory interactions 3 Supplementary information for medicines Price Regulatory category Storage guidelines Patient counselling information Labelling information Brand names and synonyms 4 Prescribing and dispensing guidelines Rational prescribing techniques Principles of prescription writing Guidelines for quantities to be dispensed Controlled drug requirements Adverse drug reaction reporting requirements Dispensing guidelines List of precautionary labels Common drug interaction tables 5 Treatment protocols IV drug administration guidelines Drugs used in pregnancy and lactation Drugs used in renal failure Poisoning (intoxication) guidelines Prescribing in the elderly 6 Other components Metric tables Adverse drug reaction form Formulary request form Indexes Abbreviations 35 4. Assessing new medicines Summary The assessment of new medicines is critical to managing a formulary list, which involves adding new medicines and deleting old ones. Drugs should be evaluated and compared on the basis of: • efficacy, comparative efficacy • effectiveness, comparative effectiveness • safety, comparative safety • cost of use • quality. Efficacy, effectiveness and safety can be evaluated from a critical assessment of the literature. Much of the information may be biased and it is very important that those evaluating new medicines have the necessary skills and time to assess the literature critically. Once efficacy and safety are established, medicines should be compared according to cost of use and, if possible, cost-effectiveness. Drug costs and quality will vary with locality. 4.1 The need for critical assessment of new medicines There has been an incredible increase in the number of drugs marketed over the past 20 years and today there are over 100 000 pharmaceutical preparations on the world market. Pharmaceutical manufacturers not only research and develop drugs for the ultimate goal of treating and preventing disease, but also for high profits. In order to make available a reasonable number of medicines that are effective, safe, of desirable quality and of reasonable cost, the DTC must take meaningful steps to review medicines and select the most appropriate ones available. New medicines should be evaluated on the basis of efficacy, safety, quality and cost. Assessment of efficacy can only be done by critical assessment of the drug literature. Assessment of safety must also be done through critical review of the literature as well as monitoring adverse drug reactions (section 5.4). Quality (section 5.3) and cost (section 4.5) will vary with local circumstances, but even here international publications may play a role in providing information about specific relevant issues. For example, bioavailability of combination TB drugs is known to be problematic and many manufacturers in developing countries do not have the capacity to test for adequate bioavailability. The International price indicator guide, published by Management Sciences for Health (website http:// www.msh.org), provides international cost comparisons for most drugs on the WHO model essential medicines list (EML) (WHO 2002a); this helps to decide whether certain drugs merit the price. Finally, assessment of whether the benefits of a medicine are worth the cost, i.e. cost-effectiveness, can often only be done by critical review of pharmacoeconomic evidence. Since much of the literature is difficult to interpret and often biased, cost- 3. MANAGING THE FORMULARY PROCESS DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 36 effectiveness and benefit analyses can usually only be done by experts at the national level. 4.2 Sources of information to assess new medicines Adequate resources to obtain information and to evaluate drugs are essential. Medical information sources include three categories: primary, secondary, and tertiary. Addresses and websites are provided in annex 4.1. • The primary literature includes journal articles and unpublished studies. These may be obtained from journals and services (electronic or otherwise) that provide the entire articles. An original article contains the most complete information about a subject because readers have access to all the data and study methods and therefore can draw their own conclusions. The disadvantages are that readers must have sufficient time to read and evaluate the article, the skills to evaluate it and compare its information with that in other articles. • The secondary literature includes indexing and abstracting services that provide abbreviated reviews of articles. Such literature is usually published in newsletters, CD- ROM databases and online services, for example the Cochrane Library. The main advantage of such information sources is that the information is accessible and easy to read. A disadvantage may be the length of time between publication of the original data and its republication in a newsletter or abstracting service. • The tertiary literature consists of published textbooks. These are usually very good sources of information if reputable and current sources are used. The advantage of textbooks is that one can read and assimilate the information in a relatively short time, since all the information is in one volume. The disadvantages are the lack of access to the original information sources, bias introduced by the writers of the text, and information becoming outdated because of long delays in publishing a text. • Information from pharmaceutical companies should be used with caution, since such information is biased in favour of positive results in order to promote sales. These materials are usually tailored to the various health professions. They may take the form of scientific articles in professional journals, symposia proceedings, news reports or pamphlets distributed by drug representatives. See also section 7.4.2 • The Internet is a rapidly expanding source of drug information. Although pharmacists or physicians in many parts of the world may not have Internet access, it is a resource that should be used if at all possible. However, it is best to use only those sources that have been recommended by reputable sources and to verify the source of information available on the Internet (WHO 1999b), as the quality of drug information from other sources may be either good or poor. 4.3 Assessing the efficacy and safety of new medicines from the literature Ideally, the hospital will have a drug information centre to handle requests concerning adding drugs to the formulary or requesting changes to the STG. If not, a pharmacist or a physician can provide the necessary drug evaluations, given the time and at least some of the resources listed above. However, very few pharmacists or physicians take the time or have the skills to accurately evaluate a journal article describing a drug study. Health professionals frequently read the abstract and conclusions with little or no attention to the structure and validity of the written article. They may therefore fail to recognize articles based on poorly designed studies with inaccurate or invalid conclusions. National DTCs and tertiary hospitals must review the primary literature, i.e. the actual drug studies. 37 However, for most hospital or sub-national DTCs, review of good-quality secondary or tertiary literature should be sufficient. It is not necessary for different centres to all review the same literature, nor do most of them have the time and capacity to do so. Discussion of critical review of the primary literature is beyond the scope of this manual. However, it is important that DTC members have some skills in this type of critical review in order to better assess and use commonly available secondary and tertiary literary sources and literature from the pharmaceutical industry. For literature concerning a new medicine to be sufficient for a DTC to decide whether to add or delete a medicine from the formulary, it should: • Compare the drug of interest to another standard drug in its class and not just to a placebo or another drug of poor performance. Unfortunately in many studies a new drug is compared only to a placebo or to a drug of poor performance. • Test the drug of interest in patients that are representative of those who would take the drug in the DTC’s institution and not just in healthier ‘study patients’. Whether the sample of patients is representative and relevant can only be judged by a description of the inclusion and exclusion criteria for patients in the study. • Measure clinically important outcomes, for example blood pressure or blood sugar, using established methods, for example relative or absolute risk reduction (see section 4.4); the amount by which a clinical outcome is improved (for example mmHg for blood pressure) is just as important as whether the difference between one medicine and another is statistically significant. • Use adequate study design, preferably a randomized controlled trial (see section 7.6), and test the medicines in a sufficient number of patients; this is necessary in order to ensure that any observed effects are not due to factors (confounders) other than the medicine being tested and are also not due to chance. Trials comparing a drug against a placebo will require at least 40 patients to demonstrate symptom relief and usually several thousand patients to demonstrate a reduction in mortality. Several hundred to several thousand patients are required to show superiority of one drug over another. • Take adequate precautions to ensure that the results are not biased. If possible, patients, prescribers and any researchers judging clinical outcomes, should be blinded to which medicine a patient is taking; this will ensure that their opinions do not influence the results (measurement bias). Patients should be randomly selected to receive the new drug, comparator drug or placebo and the random selection process concealed from patients and professionals alike; this will ensure that there are no differences that could influence the results between patients receiving the new drug and those receiving the comparative drug or placebo (selection bias). • Apply appropriate statistical analysis to the results. — p values of less than 0.05 are taken by convention to mean that the results of a study are not due to chance. A p value of 0.05 indicates that there is a 1 in 20 probability that any study result is due to chance, meaning that there is a 5% chance of observing a result which does not exist in the population. This means that there is a 95% chance that any difference observed, for example, between the drug of interest and the comparator drug, is a true difference in the population. — The power of a study indicates the likelihood of a hypothesized result being observed and is dependent on sample size. A value of 80% is taken by convention to be the minimum and indicates that there is an 80% chance of observing a real difference, for example, between the drug of interest and the comparator drug, meaning that there is a 20% chance of not observing a difference that really exists in the population. 4. ASSESSING NEW MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 38 — The confidence interval indicates the range within which the true study results lie. By convention 95% confidence intervals are used and indicate that there is a 95% chance that the true result lies within the estimated or observed range. The larger the sample size the narrower the confidence interval of an observed value (for example, mean reduction in blood pressure or percentage of patients with pain relief). • State its funding sources and whether it has been peer reviewed; this is necessary because studies funded by the pharmaceutical industry are often only published if they are positive and in journals that are peer reviewed less strictly or not at all. More detail about common problems seen in many drug studies is summarized in annex 4.2, with a checklist to use when critically reviewing articles. 4.4 Measuring and comparing clinical treatment outcomes In order to interpret the results of studies, the treatment outcomes need to be presented in a way such that the relative benefits of one medicine over another or over placebo can be easily seen. A number of particular measures are described below, and a practical example of using such measures is given in box 4.1. • The event rate is the rate of a particular event (for example treatment outcome) in both treatment and control groups. event rate = events in group/number of subjects in group • The relative risk (RR) is the ratio of the incidence of an event occurring in the treatment group to the incidence of an event occurring in the control group. If the RR < 1, then the event is less likely to happen in the treatment group than the control group and if the RR > 1, then the event is more likely to happen in the treatment group. RR = event rate in treatment group/event rate in control group • The relative risk reduction (RRR) is the difference between the event rates in the treatment (experimental) and control groups as a proportion of the event rate in the control group. This is a measure of relative treatment efficacy within the study population. RRR = (event rate in control group – event rate in treatment group)/event rate in control group • The absolute risk reduction (ARR) is the difference between the event rates in the treatment (experimental) and control groups. This is an absolute measure of efficacy and may often be much lower than the relative efficacy (see box 4.1). ARR = event rate in control group – event rate in treatment group • The number needed to treat (NNT) is the number of patients who need to be treated to achieve one additional favourable outcome. It is the reciprocal of the ARR (the number 1 divided by the ARR). This calculation provides the reader with an easier interpretation of the results, one that can be compared to other treatment groups and treatment modalities. NNT = 1/ARR 4.5 Measuring and comparing drug costs Evaluating a new medicine for the formulary involves not only efficacy, safety and quality, but also cost and cost-effectiveness. A simple determination of price is inadequate for determining the actual cost of a medicine for the health-care system. This section provides 39 basic summary information on how to evaluate the cost of a drug, and compare different drugs, not only in terms of procurement costs, but also in terms of cost impact on the health-care system and patient outcome. Detailed description of pharmacoeconomic methods is beyond the scope of this manual and unnecessary for the average hospital DTC member to know. Nevertheless, it is important for DTC members to understand the basic principles of various pharmacoeconomic methods in order to better understand the literature on drug cost-effectiveness and cost benefit. 4.5.1 Price of a drug The unit acquisition price (for example the cost of a tablet or vial) from a supplier is the easiest and most obvious measure of drug cost that is available to the DTC. Comparison of prices is useful when comparing drugs which are exactly the same chemical entity and dosage form but produced by different manufacturers. Price and other supplier considerations (such as reliability and quality) are compared when choosing which drug product to procure. Usually it is the procurement department that will make such comparisons, but the DTC may have a role to play in deciding whether the different brands are bioequivalent. When comparing medicines of a different chemical entity, even if they have equal therapeutic effect, unit price alone is inadequate for comparison. This is because the unit dosage or 4. ASSESSING NEW MEDICINES BOX 4.1 THE HELSINKI HEART STUDY 4081 asymptomatic men, aged 40–55 years, with dyslipaemia (total cholesterol minus HDL >5.2 mmole/l), were enrolled in a 5-year double-blind randomized study to compare gemfibrozil 600 mg twice daily with matched placebo. The number of events (fatal and non-fatal myocardial infarction and other cardiac death) was measured. Gemfibrozil Control Number of events 56 84 Number of subjects 2051 2030 Event rates 56/2051 = 2.73% 84/2030 = 4.13% relative risk (RR) = 2.73/4.13 = 0.66 i.e. gemfibrozil was associated with less risk of an adverse event relative risk reduction (RRR) = (4.13 – 2.73)/4.13 = 33.9% i.e. there was a large relative reduction (33.9%) in risk absolute risk reduction (ARR) = 4.13 – 2.73 = 1.41% i.e. only a small number of cases will benefit from the decreased risk number needed to treat for 5 years to prevent one event (NNT) = (1/1.41%) = 100/1.41 = 70.9 i.e. 71 patients need to be treated with gemfibrozil for 5 years to see an effect in one patient The researchers concluded that although gemfibrozil was associated with a relatively large reduction in risk (33.9%) of adverse event, the actual numbers of patients normally suffering such events is in fact very small, so the resulting reduction in absolute risk is small (1.41%). Thus, a large number of patients (70.9) must be treated over 5 years in order for one patient to avoid an adverse event. In addition, 2.4% of cases taking gemfibrozil suffered from moderate to severe upper gastrointestinal symptoms, as opposed to 1.2% of cases taking placebo. Taking side-effects and cost into account, many countries and hospitals may decide that the efficacy is not sufficient to justify the cost and increased risk of side-effects. (Frick et al. 1987) DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 40 treatment duration or mode of administration to achieve the same clinical result will not be the same for the different medicines. 4.5.2 Cost of a drug The acquisition price from a supplier may be the most basic cost of a drug, but is not the complete cost of using the drug. When choosing between different medicines of the same therapeutic class for inclusion in the formulary, the DTC will want to know the cost of using the medicine, not merely the price of an individual tablet or vial. There are three types of cost associated with drug use in a health-care system: direct, indirect and intangible. • direct costs — acquisition cost of the drug or drug price — supplies to administer the medicine equipment for administration, syringes, gauze, IV sets, filters, pumps, etc. — supply management costs salaries of supply staff, transport costs and storage facilities (including warehouse, refrigerator, freezer) — professional services costs pharmacist salary, preparation and dispensing of medications clinical pharmacy activities nursing salaries, physician fees — other direct costs treating adverse drug reactions inpatient and outpatient treatment of poor response to drug therapy emergency room use hospital overhead costs, for example electricity laboratory services • indirect costs — cost of illness to the patient — lost time from work • intangible costs — quality of life. Although these three costs, taken together, give the most comprehensive assessment of actual drug cost, they will usually only be analysed at national level or for comparative cost-effectiveness studies. Such a comprehensive cost analysis is necessary when deciding what medicines should be on a national EML, but there is no need for every hospital DTC to re-do all such analyses. However, the DTC may wish to evaluate all the direct costs of using a new drug in order to assess whether there is sufficient budget to add it to the formulary list. 4.5.3 Cost minimization analysis Cost minimization (cost identification) analysis is a method of comparing two or more medicines of equal therapeutic effectiveness and safety to find out which one is the cheapest. This method of cost evaluation is the one used most often by pharmacy departments; it can be used to compare • different brands of the same drug, or 41 • therapeutically equivalent drugs, which are not the same chemical entity but belong to the same therapeutic category and can be used interchangeably. Such comparison can be difficult for many medicines, as there may not be a reliable measure of equivalence between the two products. If therapeutic equivalence cannot be demonstrated then this particular type of cost comparison should not be used. When therapeutic equivalence between a new and an old drug is studied, the sponsor of the new drug should provide proof of superiority and non-inferiority. Cost minimization should also reflect the cost to prepare and administer a dose: • pharmacist and nursing time for preparation • laboratory costs • cost of any ancillary equipment, for example syringes, needles, IV sets, sterile diluents. Table 4.1 shows a cost minimization analysis of three oral antimicrobial drugs to treat uncomplicated urinary tract infection. The analysis shows that trimethoprim was the cheapest medicine. Although norfloxacin was more expensive than amoxycillin with regard to loose tablets/capsules this was not so with regard to prepackaged courses of treatment. The assumption that there is therapeutic equivalence may not be true in areas with high rates of antimicrobial resistance. Furthermore, the different rates and cost of side-effects have not been taken into account. Table 4.1 A cost minimization analysis of three antimicrobial drugs to treat uncomplicated urinary tract infection Cost categories Trimethoprim Amoxycillin Norfloxacin 200 mg tab. 500 mg cap. 400 mg tab. Recommended treatment regimen for 200 mg twice 3 g twice 400 mg twice uncomplicated urinary tract infection daily x 5 days daily x 1 day daily x 3 days No. tabs/caps per course of treatment 10 12 6 Acquisition price for 1 loose tab./cap. £0.048 £0.088 £0.365 Price for course of treatment £0.48 £1.06 a £2.19 b Cost to treat 10,000 patients per year £4,800 £10,600 £21,900 Treatment regiments and prices were taken from the British National Formulary 2002. a Amoxycillin sachets: price for prepackaged course of treatment was £4.16. b Norfloxacin tablets: price for prepackaged course of treatment was £2.19. £1 = US$ 1.5 approximately. Table 4.2 shows a cost minimization analysis of three injectable narcotic analgesics, one of which (diamorphine) is given by two routes. The analysis shows that pethidine intramuscular (IM) or subcutaneous (SC) injection is the cheapest option. Diamorphine given by slow intravenous (IV) injection is the most expensive option. 4. ASSESSING NEW MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 42 Table 4.2 Hypothetical example of a cost minimization analysis of three injectable narcotic analgesics Cost categories Diamorphine Pethidine Pentazocine 5 mg vial 50 mg vial 30 mg vial Recommended treatment regimen 5 mg 4 hourly 5 mg 4 hourly 50 mg 4 hourly 30 mg 4 hourly for severe pain requiring injectable IV IM or SC IM or SC IM or SC analgesia Acquisition price for one vial (US$) 1.84 1.84 0.83 2.61 No. doses needed per day 6 doses/day 6 doses/day 6 doses/day 6 doses/day Price for one day’s treatment (US$) 11.04 11.04 4.98 15.66 Nursing salary @ US$2.00 per IM – 12.00 12.00 12.00 or SC injection Specialist nursing salary @ US$4.00 24.00 – – – per slow IV injection Equipment: syringe + needle 12.00 12.00 12.00 12.00 US$2.00 per set Total drug costs per day (US$) 47.04 35.04 28.98 39.66 Anticipated no. days treatment 3000 days 3000 days 3000 days 3000 days per year Total drug costs for 3000 days 141,120 105,120 86,940 118,980 treatment (US$) Treatment regimens and prices were taken from the British National Formulary 2002 and converted into US$; equipment prices were from the Drug Tariff November 2002, UK Department of Health, and salary estimated for 3 minutes per IM or SC injection and 6 minutes per slow IV injection. Sensitivity analyses are very important in any kind of economic analysis. Such an analysis tests how sensitive the conclusions are to the different assumptions made. For example, in table 4.2, if we change the assumption that IV injections take twice as much nursing time as SC or IM injections, and assume instead that IV, IM and SC injections take equal nursing time, then IV diamorphine would cost less than IM or SC pentazocine. 4.5.4 Cost-effectiveness analysis Cost-effectiveness analysis is used to compare two or more medicines which are not exactly equivalent in terms of dose or therapeutic effect, but which are used to treat the same clinical condition. This form of analysis is difficult and is often only done at the national level. It requires measuring the cost per defined measurable clinical outcome (effect) for each of the drugs. The cost of the drug should include indirect as well as direct costs and some examples of measures for clinical outcomes include: • hypertension – blood pressure measurements • diabetes – glycosylated hemoglobin, blood glucose results • coronary heart disease –frequency of angina attacks • urinary tract infections – incidence of infections • obesity – weight measurement • seizures disorders – frequency of seizures • HIV/AIDS – CD4 counts • heart failure (and any other disease) – years of life saved or quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs). 43 Cost-effectiveness measurement can be presented in many different ways. Some examples include: • for acute illness: cost per course of treatment or cost per cure • for chronic illness: cost per month of satisfactory control • for disease prevention: cost per case prevented • for health promotion: cost per month of desired outcome. Table 4.3 shows an example of a cost-effectiveness analysis to compare two types of antibiotic ear drop. Ear drop A costs US$6.50 and has been found to be 80% effective; ear drop B costs US$7.90 and has been found to be 90% effective. Table 4.3 Hypothetical example of a cost-effectiveness analysis for two antibiotic ear drops Ear drop A Ear drop B Cost (US$) 6.50 7.90 Effectiveness 80% 90% Cost-effectiveness US$6.50 to treat 0.8 of one US$7.90 to treat 0.9 of one case successfully case successfully Amount (US$) needed to 6.50/0.8 = 8.125 7.90/0.9 = 8.778 treat one case successfully Thus, although ear drop A was less effective than ear drop B, it was found to be more cost- effective in terms of the amount needed to treat one case successfully. The additional cost of B was not worth the small extra benefit. The additional cost for extra benefit, known as incremental cost-effectiveness, can be calculated as follows for this example: (7.90 – 6.50)/(0.9 – 0.8) = 1.4/0.1 = US$14.00 Is it reasonable to pay an extra US$14 per additional case successfully treated? This judgement will need to be made by the DTC. Steps for conducting a cost-effectiveness analysis 1 Define the objective of the analysis, for example which drug regimen should be the treatment of choice? 2 Identify the different ways to achieve the objective, for example should we use a cheaper slightly less efficacious medicine or a more expensive and slightly more efficacious one? 3 Identify and measure the drug costs of each option. 4 Identify and measure the benefits (clinical outcomes) of each option. 5 Calculate and interpret the benefits of each option. The cost-effectiveness ratio is the total drug cost divided by the number of units of outcome. 6 Perform sensitivity analysis on the conclusions. This is where some of the assumptions in the analysis, for example costs of staff salaries and hospital overheads, are varied to see if changing these assumptions also changes which medicine is found to be most cost-effective. If the conclusion about which medicine is most cost-effective does not change with varying the assumptions, then the conclusion is likely to be valid. If however, the conclusion is very sensitive to changing the assumptions, then the study result is likely to be subject to error and no firm conclusion can be drawn. 4. ASSESSING NEW MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 44 Box 4.2 shows a real example of how two different kinds of thrombolytic agent for the treatment of myocardial infarction were compared from the point of view of efficacy and cost-effectiveness in Australia. The treatment of myocardial infarction in the usual way was compared with usual treatment plus the use of either streptokinase or plasminogen activator. Comparison was done in terms of (1) total treatment costs, (2) death rates, and (3) cost per life saved (or death averted). The treatment costs included all the direct and indirect costs mentioned in section 4.5.2. 4.5.5 Cost utility analysis Cost utility analysis is a cost-effectiveness analysis, where a composite measure of effectiveness is used to reflect both the quantity and the quality of health outcome. Examples of utility measures are quality adjusted life years (QALYs) or disability life years (DALYs). As well as measuring outcome of cases cured, deaths averted, or lives saved, these measures take account of the fact that impairment, discomfort and handicap mean that a ‘life-year’ is sometimes too crude a measure of effectiveness to capture all that is clinically important. A quality adjustment factor is normally obtained through surveys where people are asked to indicate their preferences between different states of health. Because of the difficulty of assessing quality of life, this method is controversial for comparing medicines and is likely to be beyond the scope of a DTC. 4.5.6 Cost benefit analysis In cost benefit analysis, there is calculation of (1) the cost of the medicine, and (2) the monetary value of the benefits or change in outcome. Such benefits should measure the total gain in economic welfare associated with the intervention. This is sometimes broken down into the value of healthy time gained, savings in treatment costs, and other savings or benefits. The selection and valuation of benefits is often controversial and incomplete. Cost benefit analysis is very controversial because of placing a monetary value on clinical outcomes such as life years saved. The cost benefit ratio is the total drug cost divided by the monetary benefit (in terms of money saved by using the drug, for example less future illness, less hospitalization, etc.). Unlike cost-effectiveness analysis, where comparable medicines are analysed for the same outcome, cost benefit analysis can be used to compare different treatments with different outcomes. However, cost benefit analysis is very difficult to do, requires major assumptions that may be incorrect, and is unlikely to be useful for most DTCs. 45 4. ASSESSING NEW MEDICINES BOX 4.2 ECONOMIC ANALYSIS OF TWO THROMBOLYTICS IN ACUTE MYOCARDIAL INFARCTION A review of the literature concerning the cost-effectiveness of different thrombolytics in the treatment of myocardial infarction was conducted in Australia. The cost of the various treatments and the mortality rate following myocardial infarction were evaluated and the results are shown below. Prices are given in Australian dollars (AUD). Cost of treatment and mortality rates Usual care of myocardial infarction (MI): AUD 3.5 million/1000 cases, 120 die Usual care of MI + streptokinase (SK): AUD 3.7 million/1000 cases, 90 die Usual care of MI + plasminogen activator (TPA): AUD 5.5 million/1000 cases, 80 die Comparison of the different treatments Difference between SK and usual care of MI: Cost of treatment = AUD3.7–3.5 million/1000 cases = $0.2 million/1000 cases = AUD200/case No. of deaths that will be prevented = 120–90 = 30 deaths/1000 cases treated Cost-effectiveness of SK = AUD0.2 million/30 lives = $6700 per life saved Difference between TPA and usual care of MI: Cost of treatment = AUD5.5–3.5 million/1000 cases = 2.0 million/1000 cases = AUD2000/case No. of deaths that will be prevented = 120–80 = 40 deaths/1000 cases treated Cost-effectiveness of TPA = AUD2.0 million/40 lives = $50 000 per life saved Difference between TPA and SK treatments for MI: Cost of treatment = AUD2.0–0.2 million/1000 cases = 1.8 million/1000 cases = AUD1800/case No. of deaths that will be prevented = 90–80 = 10 deaths/1000 cases treated Marginal cost of TPA over SK = AUD1.8 million/10 lives = $180 000 per life saved If one has a budget of only AUD 500 000, which drug should one use? For SK: No. cases that can be treated = 500 000/200 = 2500 No. lives that can be saved = (30/1000) x 2500 = 75 For TPA: No. cases that can be treated = 500 000/2000 = 250 No. lives that can be saved = (40/1000) x 250 = 10 Conclusion Although TPA is slightly more efficacious and saved marginally more lives, when cost was taken into account, more patients could be treated and more lives saved using SK. In other words, the extra cost of TPA over SK was so high ($180 000 per life saved) that with the limited budget available fewer people could be treated and lives saved, using TPA as compared to SK. Sources: Fibrinolytic Therapy Trialists’ Collaborative Group (1994); Aylward (1996) DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 46 ANNEX 4.1 Sources of information Examples of primary literature sources Websites that provide entire articles online, for example: • The Iowa Drug Information System (http://www.silverplatter.com/catalog/idis.htm) • Medline (http://www.nlm.nih.gov/databases/freemedl.html) Peer-reviewed journals that publish original articles, for example: • American journal of health-systems pharmacy (formerly the American journal of hospital pharmacy) • Annals of internal medicine • British medical journal (http://www.bmj.com) • Journal of the American Medical Association • The Lancet (http://www.thelancet.com) • New England journal of medicine Examples of secondary literature sources Medical letters, newsletters or bulletins produced by national bodies responsible for monitoring drug efficacy, safety, and cost, for example: • Drug and therapeutics bulletin of the UK, 2 Marylebone Road Street, London NW1 4DF, UK, email: firstname.lastname@example.org (http://www.which.net) • Medical letter of the USA, 1000 Main Street, New Rochelle, New York 10801, USA, (http:// www.medletter.com) • Prescrire international (English summaries of La Revue Prescrire) (http://www.prescrire.org) • Australian prescriber (http://www.Australianprescriber.com) Peer review journals that publish review articles of the published literature, for example: • Journal watch (http://www.massmed.org/) Electronic databases that can be used to search for primary literature and provide abstracts, for example: • Index Medicus • Medline • EMBASE • Micromedex CD ROM • International Pharmaceutical Abstracts (IPA) Electronic databases that provide evidence-based evaluations, for example Cochrane Library abstracts (which are free) and evaluations. 47 Examples of tertiary literature sources Textbooks and reference manuals on drug efficacy and safety, e.g: • AHSF drug information, 1999, American Society of Health System Pharmacists, 7272 Wisconsin Ave, Bethesda, MD 20814. • British national formulary, biannual, British Medical Association and Royal Pharmaceutical Society of Great Britain, BMJ Books, P.O. Box 295, London WC1H 9TE, UK, ISSN0260- 535X, email: email@example.com • Martindale: the complete drug reference, 1999, Pharmaceutical Press, 1 Lambeth High St, London SE1 7JN, UK, ISBN: 0-85369-429X. • USP DI Drug information for health care providers, Volumes 1, 2, and 3, 1996, USPC Board of Trustees, 12601 Twinbrook Parkway, Rockville, MD 20852, USA, ISBN: 0-913595- 91-8. • WHO, 2002, WHO model formulary, Department of Essential Drugs and Medicines Policy, WHO Geneva, ISBN: 92-4-154559-3, email: firstname.lastname@example.org (http://www.who.int/ medicines/organization/par/formulary.shtml). International drug price lists, for example: • IDA price indicator, International Dispensary Association, PO. Box 37098, 1030 AB Amsterdam, The Netherlands, email: email@example.com (http://www.ida.nl); tel: +31 20 40 33 051; fax: +31 20 40 31 854. • International drug price indicator guide, annual publication by MSH in collaboration with WHO, 165 Allandale Road, Boston, MA 02130-3400, USA. Tel. +1 617 524 7799 Fax: +1 617 524 2825; email: firstname.lastname@example.org, (http://www.msh.org/publications, http://erc.msh.org and http://www.who.int/medicines/organization/par/ipc/ drugpriceinfo.shtml) Internet resources, for example: • Australian prescriber (http://www.Australianprescriber.com) • British national formulary (http://www.bnf.vhn.net) • British medical journal (http://www.bmj.com) • Biomail (http://biomail.sourceforge.net/biomail/) is a new search tool which periodically does a user-customized Medline search and sends the articles to the user’s email address • Centres for Disease Control and Prevention (CDC) Atlanta, USA, online information system (http://www.cdc.gov) • Cochrane Collaboration (http://www.cochrane.org) • Facts and comparisons – an Italian database website (http://www.burioni.it/script/ rec.htm) • Federal Drug Authority (FDA), USA, online information system (http://www.fda.gov/) • Health InterNetwork Access to Research Initiative, which provides free online access to some journals for institutions in the poorest countries (http:// www.healthinternetwork.org) • Hirewire Press (http://Pstanford.edu) • Internet browser searches, for example http://www.google.com or http:// www.altavista.com • International Society of Drug Bulletins (http://prn.usm.my/isdb.html) 4. ASSESSING NEW MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 48 • Liverpool School of Hygiene and Tropical Medicine website (http://www.liv.ac.uk) provides links to an number of journals, websites and databases • Micromedex drug monographs, information from the United States Pharmacopeia (USP) (http://www.usp.org and www.micromedex.com/products) • Medline (http://www.nlm.nih.gov) • National Institute of Health (NIH) online information system: http://www.nih.gov • PubMed Central (http://pubmedcentral.nih.gov) • Satellife free information services to health professionals (http://www.healthnet.org) • The free medical journal site (http://www.freemedicaljournals.com) • The Lancet (http://thelancet.com) • The Lancet’s experimental research archive in international health (http:// www.thelancet.com/era) • World Health Organization (http://www.who.int/medicines) • WHO library site (http://www.who.int/hlt/virtuallibrary/English/subject.htm) • WHO drug price information site (http://www.who.int/medicines/organization/par/ipc/ drugpriceinfo.shtml) 49 ANNEX 4.2 Checklist to detect common problems encountered in articles Adapted from Fowkes and Fulton (1991) and Bero and Cho (1994). Checklist Potential problems Objectives Are the objectives stated in the abstract, A drug may be tested only against a placebo, or introduction or methods? against a drug with poor past performance and not against the standard or most effective drug in its class. Is sufficient information given about the disease Clinically unimportant outcomes may be used. outcomes and the effects of the drug studied, so that you may judge how clinically important they are? Methods Was a randomized controlled trial (RCT) done? The study design may be insufficient to be able to — best design for efficacy ascribe observed differences to the new drug Was a case control study done? being tested. — commonest design for safety Was the study blinded? If not, is this explicitly Study participants or investigators are not discussed? and are the confounders accounted for? blinded, leading to possible bias in interpreting the results. Is sufficient information given on the drugs used Study patients may not be representative of the and the disease states treated in order to judge population that will take the drug. Often the whether the study is relevant to your patient patients in studies are fitter and have a more population? certain diagnosis and fewer concurrent diseases than the population who would take the drug. Was the sample size of patients sufficient to The number of patients may be too small to detect significant differences in outcomes between ensure any differences are not due to chance. intervention and control groups? Were the inclusion and exclusion criteria of Patients may not have been randomized to study patients specified? and treatment groups so that patients treated Was the assignment of patients randomized? with the new drug may not be similar to those Were the control subjects appropriate? treated with the comparator drug. Is the drop-out rate of patients in the intervention Patients randomized to take the new drug may not and control groups reported? have completed the study so that side-effects or Were the rates the same? If not, is any explanation less effect of the drug may not be reported. given for the different rates? Patients with more side-effects or less effect may be more likely to drop out. How many dose regimes were compared for each Different drugs may be compared using fixed non- drug? Were they equivalent? equivalent doses; the comparator drug may be under-dosed. Review articles and meta-analysis (analysis across Review articles and meta-analysis may be biased different RCT studies) by which studies are included and which not, and — What criteria were used to find the articles? how each study was appraised. Studies with — How was the search done? negative results may have been excluded. — Which databases were used and were unpublished articles included? — Is there a description of how individual studies were appraised, and, if relevant, meta-analysis done? 4. ASSESSING NEW MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 50 Checklist Potential problems Economic articles Are all the costs associated with drug treatment, Economic articles may be biased due to including good and bad outcomes, described? incomplete reporting of all the costs associated (not just prices) with a drug treatment i.e. non-drug costs (for example equipment) and outcomes, including negative ones (for example side-effects). Has discounting been used to reflect the costs of Different discounting rates for drug costs and any future benefits or consequences in present future benefits may be used to emphasize a drug’s day values? cost-effectiveness ratio. Results What measures of outcome were used? The presentation and analysis of data may be Were any differences shown due to real differences misleading. between intervention and control groups or just Differing efficacy can only be assessed by using due to chance from small sample size or by established measures, for example relative or selecting a small subset of patients? absolute risk reduction or number of patients needed to treat (see section 4.4). For economic studies: Economic evaluation requires using standard What type of analysis was done? cost analyses (see section 4.5). minimization? cost-effectiveness analysis? Has a sensitivity analysis been done? Were the differences in clinical outcome between The statistical significance of a trial may be valid groups large, important and relevant as well as but the clinical significance may be weak. statistically significant? Were all recruited patients taken into account in Confounding variables may not have been the analysis? If patients who died or dropped out adequately controlled so that any differences seen of the study are excluded from the analysis, there are due to the confounders not the new drug. may be a bias towards greater efficacy. Conclusions Were the populations for which conclusions were The conclusions may not agree with the results or drawn represented by the subjects in the study? may be extrapolated too widely. Was there any discussion of whether the potential There may be little discussion of safety in relation benefits were worth the potential harm? If not, to efficacy. maybe the likely benefits are not worth the risk. Funding Is there a description of how the study was The study may have been funded by a drug funded? company for their own product; often drug What is the reputation of the authors, and are companies do not publish negative studies. their affiliations described? Is the study published in a peer-reviewed journal Study may not be peer reviewed but published that is listed in Index Medicus, which covers all either in a ‘throw-away’ journal or in symposia major reputable journals? proceedings; alternatively it may be published in Are references cited, and are they reputable? a journal with less rigorous peer review. 51 5. Ensuring medicine safety and quality 5. ENSURING MEDICINE SAFETY AND QUALITY Summary A significant amount of harm to patients and wastage of resources is caused through the use of unsafe, poor-quality medicines. The DTC has a role to ensure that all medicines prescribed and dispensed to patients are safe and of good quality. This involves: • monitoring and addressing medication errors • ensuring medicine quality through ensuring good practices concerning procurement, storage and distribution and monitoring and addressing drug quality problems • monitoring and addressing adverse drug reactions, which may be caused by the chemical entity itself or may be due to medication errors or poor drug quality. These activities necessarily involve looking at the health system as a whole to identify practices and environmental problems that may be contributing to poor drug safety and quality. 5.1 The need for ensuring medicine safety and quality Medicine safety problems are commonly caused by medication errors, poor quality, and certain drugs that are inherently unsafe (cytotoxic drugs, for example). Such safety problems are manifested through adverse drug reactions (ADRs), which may result in serious patient harm, extended hospital stay and large consumption of resources. A drug and therapeutics committee (DTC) has a role in ensuring that all medicines are prescribed, dispensed and administered to patients in as safe a way as possible, and that all medicines so given are, in themselves, safe and of adequate quality. Some assessment of safety can be made from the literature, as described in chapter 4 on assessing new medicines. However, there are three very important areas where the active involvement of a DTC can help to ensure the safe use of safe medicines that are of adequate quality: • monitoring and addressing medication errors • monitoring and ensuring drug quality • monitoring and managing ADRs. 5.2 Monitoring and addressing medication errors A medication error is any preventable event where a dose of medication that is received by a patient differs from what the prescriber has prescribed, or from hospital policy and procedures (AHSP 1999). These errors may result in therapeutic failure and adverse drug reactions as well as wasting resources. It has been estimated that medication errors cause 7000 deaths per year in the USA (Philips and Christenfeld 1998). In another study, 2% of inpatients in two teaching hospitals experienced preventable ADRs increasing the cost of their hospitalization by US$4700 per admission and the length of their stay by 4.6 days DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 52 (Bates et al. 1997). One of the functions of the DTC is to monitor and report on the occurrence of medication errors in order to ensure that they occur as rarely as as possible. The following are some of the possible errors that can occur either in the prescribing, dispensing or administration processes, and which should be monitored: • prescribed medication not given • administration of a drug that was not prescribed • medicine given to the wrong patient • wrong medicine or IV fluid administered • wrong dose or strength given • wrong dosage form given, for example eye drops instead of ointment • wrong route of administration • wrong rate of administration, for example IV infusion • wrong time or frequency of administration • medicine given for the wrong duration • wrong preparation of a dose, for example incorrect dilution of a dose, not shaking a suspension • incorrect administration technique, for example unsterile injection technique (see section 8.2) or incorrect installation of eye ointment • medicine given to a patient with a known allergy. Having a pharmacist or nurse, or another doctor or prescriber, review the prescriptions before the drugs are administered can prevent some of these errors. Whenever an error is identified, it must be documented and the prescriber or nurse administering the medication informed. All errors should be compiled and a report presented monthly. It is important to do this in a non-confrontational manner without mentioning names of the doctor, nurse or pharmacist responsible for the errors. The report should contain information about the number and type of errors, the type of staff reporting each error and the ward or department. The DTC should review all medication errors in order to (1) address individual incidents, and (2) look for patterns and trends in order to address health system, managerial and environmental problems that may be encouraging such errors. Table 5.1 shows a sample report of medication errors from a Zimbabwean hospital. Common underlying problems that are associated with medication errors, and which the DTC could address, include: • high staff workload and fatigue • inexperienced and inadequately trained staff • poor communication among health-care workers, including poor handwriting and verbal orders • environmental factors, for example poor lighting, much noise, frequent interruptions • increased number or quantity of drugs per patient • frequency and complexity of calculations needed to prescribe, dispense or administer the drug • large number of formulary medicines and dosage forms (such as injections) that are associated with more errors 53 5. ENSURING MEDICINE SAFETY AND QUALITY Table 5.1 Medication errors report for September 1999 in a Zimbabwean hospital Type Ward Brief description Reporter Total A C6 heparin 15000 u/100 ml given instead of 10000 u/100 ml Nurse A B4 ofloxacin 200 mg tablet given instead of 400 mg tablet Doctor A A4 theophylline 5 mg/kg loading dose given instead of 6 mg/kg Pharmacist All errors of dose or strength 3 (42.9%) B A2 amoxicillin given 4 times instead of 3 times daily Nurse B C1 furosemide prescribed every 4 hours but given every 6 hours Nurse B B3 potassium chloride prescribed every 8 hours but charted Pharmacist 1000hrs, 1600hrs and 2100hrs All errors of time or frequency 3 (42.9%) C A4 chlorpromazine given instead of chlorpropamide Pharmacist All errors of actual drug 1 (14.2%) Source: Zimbabwe DTC manual (1999). Key: A, wrong dose or strength; B, wrong time or frequency; C, wrong drug. • confusing drug nomenclature, packaging or labelling • lack of effective drug policies and procedures. Some ways of preventing medication errors, particularly in hospitals, include: • establishing a consensus group of physicians, nurses and pharmacists to select best practices • introducing a punishment-free system to collect and record information about medication errors • developing written procedures with guidelines and checklists for the administration of intravenous fluids and high-risk drugs such as insulin, heparin and narcotics • developing standardized times to administer medicines and a policy to do so only when patients are on the wards • requiring that a patient’s identity be confirmed before administering a drug • allowing verbal or telephone orders only in an emergency • requiring legible handwriting and complete spelling of a drug name • requiring the use of standardized notation • dose units written in one way only, for example ‘mcg’ not ‘µg’ or ‘g’ not ‘gm’ • use of leading zeros for values less than 1 (0.2 instead of.2) and avoidance of trailing zeros for values more than 1 (2 instead of 2.0) • requiring that the route of administration and the complete directions (for example ‘daily’ not ‘OD’) be written on all drug orders (prescriptions) • requiring that prescribers write generic and brand names for medicines with ‘look-alike’ or ‘sound-alike’ names. DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 54 5.3 Monitoring and ensuring medicine quality Poor quality of medicines undermines health care and is unfortunately quite common in many countries. Accepted quality standards for testing drugs are published in various pharmacopoeias, for example the US, British, European or International Pharmacopoeias. Quality criteria are purity, potency, uniformity of dosage form, bioavailability and stability. All these aspects of quality may be affected by the manufacturing process, packaging, storage and other factors. Poor quality may result in lack of therapeutic effect, and cause adverse or toxic reactions; these in turn may result in harm to patients (through prolonged or drug-induced illness), as well as waste of limited resources. Product quality is ensured through adherence to a quality assurance system. Brief definitions are given below (MSH 1997, chapter 18 on ‘Quality Assurance for Drug Procurement’ and chapter 24 on ‘Drug Management for Health Facilities’; WHO 1999a). • Quality assurance is the sum of the activities and responsibilities intended to ensure that medicines reaching patients are safe, effective and acceptable to the patient. • Good manufacturing practices (GMP) are part of quality assurance and should ensure that products are consistently produced and controlled to the quality standards appropriate to their intended use and required by drug regulatory authorities. • Quality control is the part of GMP where drug samples are tested against specific quality standards. Laboratory testing of drug samples is done by the manufacturer during the process of manufacture (resulting in a certificate of analysis for each batch). Testing may be carried out during the licensing process by the national drug regulatory authority. Testing may also be done by the purchaser (or DTC) after receipt of medicines. Non- compliant, poor-quality samples found at this stage may result from a variety of causes such as poor manufacture, storage or handling. Inadequate quality of medicines not only undermines health care in general, through lack of therapeutic effect and increased adverse reactions, but also other aspects of medicines policy. For example, a DTC may be unable to implement a generic substitution policy because it cannot distinguish between good-quality and poor-quality generic products and therefore prescribers believe all these products to be of poor quality. Many bodies are involved in drug quality assurance – drug licensing authorities, regulatory bodies, enforcement authorities and inspectorates, drug procurement offices, pharmacies and prescribers (by reporting on non-effectiveness). DTCs can help to ensure drug quality through coordination of all the various actors within health facilities and liaison with manufacturers and drug regulatory bodies. Efficient management of the hospital medicine system will help to ensure the availability of medicines of adequate quality as well as containing costs. The DTC should work closely with the hospital pharmacy to provide guidance and promote recommended principles in procurement, storage and distribution. Where there are no existing policies and guidelines on supply management, the DTC should initiate action and give advice to the pharmacy. Pharmacists are vital in ensuring good drug quality and supply management; they are also the partners of prescribers in ensuring that patients receive safe and effective drug therapy. However, in many developing countries, pharmacists often have rather low status. It is therefore important that the image and status of the pharmacy and the pharmacist be raised when human resource development is considered. 5.3.1 Role of the DTC in procurement Procurement practices can have a significant bearing on drug quality. The DTC should ensure that the practices followed by the responsible department will ensure adequate 55 drug quality. The DTC should not spend committee time and meetings in deciding order lists, nor should DTC members generally be on tender committees assessing bids to supply drugs. However, a DTC should monitor and ensure implementation of good procurement procedures. In some hospitals this may mean the DTC has to reassess and identify the limits of its role. The DTC must be represented in the preparation of the annual hospital budget, including review and allocation of the drug budget. Criteria for good procurement practices have been agreed by WHO, UNICEF, UNFPA and the World Bank (WHO/UNICEF/ UNFPA/WB 1999) and are summarized in box 5.1 in the context of hospital practices. 5.3.2 Role of the DTC in medicine distribution and storage The quality of medicines can be adversely affected by poor storage and distribution. The DTC has a role in ensuring that the practices followed by the responsible department are consistent with those that ensure the highest possible drug quality. In some situations this may mean that the DTC must be able to assist the pharmacy in initiating and monitoring an adequate system for drug storage and distribution. Good storage and distribution practices are summarized in box 5.2. 5. ENSURING MEDICINE SAFETY AND QUALITY BOX 5.1 GOOD PROCUREMENT PRACTICES Efficient transparent management • Divide procurement functions and responsibilities (selection, quantification, product specification, pre- selection from suppliers and adjudication of tenders), among different offices, committees and individuals to ensure that no one individual is dealing with all activities and thus susceptible to undue external influences. The DTC should be responsible for selection and product specification, and the procurement department for the other functions. • Follow explicit documented procedures for adjudicating tenders and awarding procurement contracts. The procurement department should do this and should regularly report to the DTC and senior management, and undergo external audit annually. Drug selection and quantification • Base procurement on the formulary list, using generic or International Nonproprietary Names (INN). The DTC should decide the formulary list and approve purchase of non-formulary drugs. • Select formulary drugs carefully to ensure safety and efficacy. This includes choosing appropriate dosage forms, preparations and packaging and defining the specifications of the products to be purchased; for example, theophylline elixirs for children should not contain alcohol. • Use the method of quantification best suited to the available data – morbidity method if morbidity data are available and standard treatment guidelines (STGs) are followed, or consumption method if there are no morbidity data and STGs are not followed. Adjustments may have to be made cautiously if there is not enough budget to procure all the medicines needed (see point below). • Use VEN analysis (see section 6.2.3) to identify the most essential medicines, especially if there is insufficient budget to finance all medicine needs. The DTC should assist the procurement group to do this once each department has submitted the yearly quantification of medicine needs. Financing and competition • Buy in bulk if possible. DTCs of small hospitals can collaborate with other hospitals and recommend that bulk procurement be done jointly to get good value for money. Continued DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 56 BOX 5.1 CONTINUED • Agree a regular procurement schedule and decide criteria for emergency purchase in circumstances where it is absolutely indispensable to prevent immediate danger to life. • Purchase only from the supplier who holds the current contract as decided through the competitive tender adjudication process to ensure the lowest possible purchase price. Supplier selection and quality assurance • Procure only registered products from reliable, licensed suppliers and manufacturers that comply with GMP and have good records of performance, to ensure that medicines procured meet the required standard of quality. The qualification of suppliers can be checked through networking with the national drug regulatory body and other agencies, obtaining all appropriate certification and, if necessary, laboratory testing of received products. Some purchasers have negotiated with manufacturers to pay for quality testing at a laboratory of the purchaser’s choice. Suppliers who do not have permanent addresses or who are not prepared for visits to their premises without prior notice are unlikely to be reliable. • Only accept medicines with the appropriate documentation, including: — a certificate of analysis issued by the manufacturer (batch certificate) — for imported medicines, a WHO-type certificates issued by the drug regulatory authorities of the exporting country — detailed product specifications. • Ensure quality through the inclusion of certain pre-tendering criteria, for example specifying a minimum shelf-life, or insisting manufacturers have a minimum turnover or proof of GMP compliance. • Find out from various sources (such as regulatory bodies) whether a generic product is bioequivalent to the brand product. If it is not, efficacy can only be established by a clinical trial. If possible, ask the manufacturers to produce evidence of bioequivalence. Adapted from WHO/UNICEF/UNFPA/WB (1999) 5.3.3 Monitoring and analysing medicine quality problems A very important role of the DTC is to monitor and analyse all reports of inadequate medicine quality. The problem may present in the following ways: • visual deterioration of the product as reported by health staff, for example discolouration, fragmentation, leakage, smell • lack of therapeutic effect • ADRs. Once a problem has been reported, it should be investigated (see section 5.4.3) to see if the problem is one of manufacture (including counterfeit), storage, distribution, administration or use. This may involve the following steps: • Confirming the exact nature of the problem. • Visually inspecting the product, including the expiry date, the packaging and the labelling. • Eliciting information concerning the product’s procurement, storage and distribution. • Observing how the product is administered, for example injection technique, dispensing process, interviewing the patient if necessary to check on compliance. 57 5. ENSURING MEDICINE SAFETY AND QUALITY BOX 5.2 GOOD STORAGE AND DISTRIBUTION PRACTICES • Documented drug distribution and control procedures are in place, for example — procedures for inventory control and management — minimum and maximum safety stock levels — visual inspection of all medicines, their packaging and labelling, on arrival at the facility. • Facilities/departments use pre-defined re-ordering quantities (or methods for calculating drug quantities) for drug orders from the store to avoid shortage and stock-outs. • Storage conditions should be adequate to maintain the quality of the medicines and free from factors that can cause the deterioration of drug products: — Appropriate medicines only are stocked in hospital patient care areas (VEN analysis important). — Manufacturers’ storage instructions are followed; if no special instructions are given, use ‘normal storage conditions’ (temperature 15–25 °C). — Storage areas are clean and dry. — Medicines are arranged either alphabetically or by therapeutic category. — Repackaging is avoided wherever possible and done only by staff trained to do it; likewise, pre-packaged drugs for individual patients are prepared only by trained staff. • The expiry date is one important assurance of drug quality. Drugs should be stored according to a first- expiry, first-out policy and there must be a mechanism to dispose of expired medicines. For medicines with the same expiry date, a first-in first-out policy should be followed. • Narcotics and other controlled drugs should be stored in a separate area locked by two keys, each key controlled by a different person. • Transport is speedy and conditions are sufficient to maintain medicine quality. In particular, cold-chain procedures should be documented and strictly enforced. • Appropriate dispensing procedures are in place, for example containers, labelling, patient information and counselling. • Observing how the patient is managed. For example, when dealing with a complaint that a hypoglycaemic drug is not effective, one might do a patient chart audit to check (1) how the drug was being prescribed, and (2) what was the evidence about poor blood sugar control. A prescriber could not claim that a drug was ineffective if blood or urinary sugar was not monitored. • Analysis of the product. A product may be analysed first using basic (less expensive) tests, which can screen out counterfeit medicines or those of very poor quality. If the product passes such a screen, but has been the subject of complaints about quality, it should be subjected to further full pharmacopoeial (more expensive) tests in a properly equipped laboratory. See annex 5.1 for basic tests. • Reporting to the national regulatory authority drug products found to be of poor quality on receipt from the manufacturer or supplier. Quality problems are likely to be more serious in medicines that are inherently unstable or have a narrow therapeutic index (narrow range for effective serum levels). These medicines are listed in table 5.2. The same drug product produced by different manufacturers may have differences in bioavailability and therefore be non-bioequivalent. It is much harder DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 58 to ensure bioequivalence between products where the drug has a narrow therapeutic index. An additional quality factor to consider in drug selection and management is the varying stability of different forms of oral medicines. Generally speaking, solid forms are more stable than liquid forms, especially in tropical or humid conditions. Syrups and injections that are in powder form are more stable than those in liquid form. Decreasing stability of oral drugs: tablets capsules suspensions syrups and solutions Table 5.2 Drugs with known potential bioavailability or stability problems Bioavailability problems Stability problems aminophylline furosemide nitrofurantoin acetylsalicylic acid tablets ampicillin glibenclamide oestrogens amoxycillin tablets carbamezepine glyceryl trinitrate phenytoin ampicillin tablets chloramphenicol griseofulvin prednisolone penicillin V tablets chloroquine hydrochlorthiazide quinidine retinol tablets chlorpromazine iron sulfate rifampicin paracetamol liquid digitoxin isosorbide dinitrate spironolactone penicillin V suspension dihydroergotamine levodopa theophylline ergometrine injection ergotamine methotrexate L-thyroxine methylergometrine injection erythromycin methyldopa warfarin Source: Managing Drug Supply (MSH 1997), p.273. 5.4 Safety of medicines The safety of medicines is critically important to health care. A DTC may have a significant impact on preventing and managing drug safety problems through: • assessing the literature on safety issues of new medicines proposed for the formulary (see chapter 4) • preventing the occurrence of ADRs by ensuring that patients are carefully evaluated before medicines are prescribed and ensuring staff are trained accordingly (see section 7.2) • implementing systems to monitor the occurrence of ADRs, which includes the regular review of ADR reports • evaluating suspected ADRs • reporting ADRs to regulatory authorities and manufacturers • monitoring and investigating medication errors (see section 5.1) • monitoring and investigating problems of medicine quality (see section 5.2). 5.4.1 Definitions The following definitions were adopted by national centres participating in the WHO International Drug Monitoring Programme in September 1991. Further information can be obtained from the WHO Collaborating Centre at Uppsala (http://www.who-umc.org). ▲ 59 Side-effect Any unintended effect of a pharmaceutical product occurring at doses normally used in humans which is related to the pharmacological properties of the drug. Such effects may be either positive or negative. Adverse event or experience Any untoward medical occurrence that may present during treatment with a pharmaceutical product but which does not necessarily have a causal relationship with this treatment. Adverse drug reaction (ADR) A response to a drug which is noxious and unintended, and which occurs at doses normally used in humans for the prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function. An unexpected adverse reaction refers to a reaction, the nature or severity of which is not consistent with domestic labelling or market authorization, or expected from characteristics of the drug. A serious adverse reaction is any medical occurrence that at any dose normally used in humans: • results in death • requires inpatient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability or incapacity • is life-threatening. Causality assessment of suspected adverse reactions This refers to the likelihood that a medicine has caused an adverse event, and is described further in box 5.3. • Certain causality is where a clinical event (including a laboratory test abnormality) occurs in a plausible time relationship to drug administration, and cannot be explained by concurrent disease or other drugs or chemicals. A plausible (expected) clinical response to withdrawal of the medicine must be demonstrated and, if possible, the clinical response to restarting the medicine should also be demonstrated. • Probable or likely causality is where a clinical event occurs with a reasonable time sequence to drug administration, and is unlikely to be due to any concurrent disease or other drugs or chemicals. A plausible clinical response to withdrawal of the medicine, but not to restarting the medicine, must be demonstrated. • Possible causality is where a clinical event occurs with a reasonable time sequence to drug administration, but which could be explained by concurrent disease or other drugs or chemicals. Information on drug withdrawal may be lacking or unclear. 5.4.2 Adverse drug reactions (ADRs) ADRs are a serious problem with increasing incidence, as more drugs become available and more people become exposed to them. In the USA, a review of prospective studies showed that in 1994 hospitalized patients had 2.2 million adverse drug reactions (6.7% incidence) and this resulted in 106 000 fatalities. (Lazarou et al. 1998). Box 5.3 shows the different types of ADRs. 5. ENSURING MEDICINE SAFETY AND QUALITY DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 60 BOX 5.3 CLASSIFICATION OF ADRS Type A reactions These are an exaggerated but otherwise normal pharmacological response to the effects of the medicine given in therapeutic dose. These reactions cause significant morbidity but are rarely severe. Examples include: • pharmacodynamic, for example bronchospasm with beta-blocker administration • toxic, for example absolute or relative overdosing of aminoglycosides causing deafness • withdrawal syndrome or rebound effect, for example spontaneous rise in blood pressure with clonidine discontinuation. Type B reactions These are bizarre and unpredictable with no relation to dose and are often allergic in nature. They are often severe and cause high mortality. Examples include: • idiosyncratic reactions, for example irreversible aplastic anaemia caused by chloramphenicol • anaphylactic reactions, for example anaphylactic shock with penicillin • drug-induced diseases, for example antibiotic-associated colitis. Adverse events as a result of drug interactions These may be of all degrees of severity and type, for example • reduced absorption of tetracycline if administered with ferrous salts • reduced anticonvulsant effects of phenytoin if administered with some antimalarials such as pyrimethamine • serious and severe rise in blood pressure following concurrent administration of monoamine oxidase inhibitor antidepressants with tricyclic antidepressants or some antipsychotics. All new medicines undergo a significant amount of testing and evaluation before marketing to ensure the product is not only effective, but also safe. There are no drugs that are free of side-effects or adverse reactions. Though many products have an extremely low incidence, some have a relatively high incidence of adverse reactions that may result in death. Even the most effective medicines, prescribed by the most careful practitioners, have a certain amount of risk attached. For example, oral polio vaccine has nearly eliminated the disease worldwide but can, very rarely, cause cases of polio. Thus, every drug has risks and benefits, which must be balanced, and which may depend on many factors such as the condition(s) being treated, other problems, age, gender, etc. Although all medicines undergo mandatory clinical trials before marketing in order to establish efficacy, safety, and quality, such trials will only uncover the commonest ADRs (>1% incidence). Less common ADRs (<1% incidence) will only be discovered through post-market surveillance of much larger numbers of patients taking the drug. Such post- market surveillance relies mostly on spontaneous reporting by physicians, pharmacists and patients. Often the national regulatory body is responsible for monitoring ADRs at the national level. If this authority identifies a serious drug safety issue, it may organize recall of the drug, or revision of the package insert, or distribution of letters to doctors explaining the safety issues. What is done will depend on the nature and seriousness of the problem. However, many ADRs are due not to inherently unsafe drugs but to problems of use or quality, which can be corrected locally. The DTC should implement a system to monitor, track, investigate and report adverse reactions to drugs and vaccines within their hospital and/or health facility. Any serious 61 findings should be reported to the national monitoring centre, which is often the drug regulatory body. ADRs are monitored not just for the sake of reporting and statistics, but more importantly, to encourage safer use of medicines by minimizing unsafe use of all drugs and avoiding the use of unsafe medicines. The DTC should therefore investigate all serious ADRs in depth and collate and report on all ADRs in order to see how they can be avoided and risk factors for their occurrence reduced. Any ADR monitoring system should include, as a minimum: • reporting of an ADR to the DTC on standard forms (see annex 5.2) • investigation and analysis of reports by a selected DTC member • discussion and evaluation of reports by the DTC on a regular schedule (quarterly) and report to medical staff • reporting to manufacturers and national regulatory authorities of all events thought to be ADRs (and not known side-effects). 5.4.3 Assessing and managing spontaneous ADR reports An important part of monitoring ADRs is to process and analyse spontaneous ADR case reports arising from patients and medical providers. These spontaneous reports may be difficult to interpret and to assign causality. Common problems include the following: • A generic drug is alleged to cause an ADR whereas the brand named product does not. • A brand named product is alleged to cause more side-effects than another branded product. • An antibiotic suspension causes a reaction and it is unclear whether the antibiotic is responsible or one of the components of the suspension, i.e. a dye or other excipient in the suspension. • An injectable product causes a reaction and it is unclear if the causative agent is the active ingredient, or the preservative or some other agent in the solvent, or the injection technique. • A patient is on several medicines when a new adverse event is reported and assigning causality is difficult because any of the medicines could be the cause. • The patient has co-morbidity that may have a bearing on the medicine and suspected ADR. ADRs should be assessed and managed in three steps, as described below; an example is shown in box 5.4. ■ STEP 1 Evaluate the nature of the ADR • Obtain a detailed history of the patient including current health status, current drug therapy, past medical history. Use an ADR reporting form to organize reporting (annex 5.2). • Establish and document the clinical syndrome described by checking the description with health workers and looking up the clinical description and suspected medicine(s) in the literature. • Classify severity of the reaction: — severe: fatal or life threatening 5. ENSURING MEDICINE SAFETY AND QUALITY DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 62 BOX 5.4 INVESTIGATION OF AN OUTBREAK OF ADRS IN PANAMA A DTC in Panama served 11 clinics and a hospital. Recently a different brand of procaine penicillin injection had been purchased and distributed. Shortly after introduction of the new brand of procaine penicillin, one clinic reported to the DTC that within a short period of time there had been an unusually high number of ADRs following intramuscular injection of penicillin. The nurses were alarmed, refused to use the new product and demanded to change back to the old brand of penicillin. The adverse event was described as an adult patient suddenly (within seconds of the injection) experiencing feelings of doom, anxiety and faintness, necessitating lying down. Patients were reported to be pale, but with normal or slightly high blood pressure. The nurses immediately gave diphenhydramine (intravenous or intramuscular) for a suspected anaphylactic reaction to penicillin. After 10–15 minutes the patients would completely recover and leave the clinic unassisted. A DTC member was assigned to investigate the ADR outbreak and the issue was dealt with as follows: • The clinical syndrome described was looked up in the literature and found to be consistent with Hoigné syndrome or pseudo-allergy to penicillin caused by the procaine component of the injection when accidentally injected intravenously. Diphenhydramine was thought to be inappropriate treatment for either this reaction to procaine or any potential anaphylactic allergic reaction (where adrenaline was the recommended treatment). • Using the number of penicillin-related ADR events reported in the clinic injection rooms and the number of procaine penicillin doses used, an event rate was calculated for each health facility for a fixed time period. This revealed that the rate of procaine penicillin-related ADRs in two clinics was double the rate occurring in the other clinics, and that the two affected clinics had a relatively high workload. Although one clinic had noticed and complained about the increased rate of ADRs, the other clinic had not noticed the problem before the investigation. • The DTC staff member visited the two clinics with higher event rates, interviewed the nurses and observed the giving of injections. The nursing assistants were observed to use less water than required to reconstitute the injections. The DTC concluded that the accidental intravenous injection of more concentrated procaine was accounting for the ADRs. • DTC staff discussed the findings and conclusions of the investigation with the nursing staff concerned, who reviewed how to prepare and give procaine penicillin injections. The nurses agreed to continue using the new brand of procaine penicillin injection. The DTC also discouraged the use of diphenhydramine for treatment of this clinical syndrome as it was not an allergic reaction. After this intervention, the DTC again measured the recorded event rates and found that the ADR rate had decreased in the two affected clinics and was similar across all clinics. Source: David Lee, Management Sciences for Health. Personal communication — moderate: requires antidote, medical procedure, or hospitalization — mild: symptoms requiring only the discontinuation of drug therapy — incidental: very mild symptoms where the patient can choose whether to continue drug therapy or not • Assess the likelihood of the suspected medicine being the cause of the ADR. This may be done using the definitions of causality (section 5.4.1). An alternative method is to use the Naranjo algorithm (see annex 5.3). This algorithm asks specific questions (based on the same definitions of causality) and scores the answers. Individual scores are then added up and the total score used to give some indication of the likelihood that an ADR was caused by the suspected medicine. ■ STEP 2 Establish the cause of the ADRs • Confirm the clinical syndrome constituting the ADR to be investigated. 63 5. ENSURING MEDICINE SAFETY AND QUALITY • Inspect the suspect medicine visually and check its procurement, storage and expiry date. • Calculate the rate of ADRs occurring in different departments or clinics. • Check whether there are any other differences between the departments or clinics showing high and low rates of ADRs to a particular medicine. • Visit the departments or clinics with the highest rates of adverse drug reaction to observe how the suspect drug is being prescribed, dispensed and administered; this may require carrying out a drug utilization review (section 6.5) or observing the dispensing or administration processes. • Contact other agencies, hospitals or the regulatory authorities to see if others have experienced similar ADRs, and if necessary or possible send the drug for quality testing. ■ STEP 3 Possible DTC action after ADR evaluation Possible actions will depend on what the cause of the ADR is and may involve any or all of: • reporting to the national drug authority and/or manufacturer • implementing new prescribing procedures including restrictions • educating prescribers if needed • changing the formulary, if necessary, to obtain a drug of improved safety; this may mean substituting a drug that is absolutely safer or one that is easier to use by staff • adapting the STG or formulary manual if necessary; either in terms of which medicines are recommended for the formulary, or what recommendations are made concerning how and when a formulary medicine should be used • educating patients if necessary • following up the rate of ADRs after action has been taken to reduce the ADRs to ascertain whether the DTC action has been successful. 5.4.4 Preventing ADRs Prevention of ADRs is possible, and indeed necessary! Studies have shown that over 50% of adverse drug reactions may be preventable. Most ADRs are related to the prescribing of an incorrect dose or the administration of a drug to a patient with a known allergy. Many ADRs could be avoided if the relevant health worker asked specific questions before prescribing and/or dispensing a drug, as shown in box 5.5. The DTC can do the following things to help promote safety and limit the occurrence of ADRs: • Encourage ADR reporting (and introduce it if it is not already in place). • Educate staff about ADRs through in-service education, drug information bulletins and reports of collected adverse events. • Identify drugs on the formulary that are ‘high risk’ and monitor their use closely (examples include aminoglycosides such as gentamicin, antineoplastics, digoxin, heparin, warfarin). • Identify ‘high risk’ patient populations and monitor their treatment closely. Such patients include pregnant women, breast-feeding women, elderly people, children and patients with renal or liver dysfunction. • Review ADR reports regularly and inform professional staff of the incidence and impact of ADRs in the region. DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 64 • Review medication error reports to take steps to control and limit these events. • Undertake prescription audits and drug utilization evaluations (see section 6.5) in order to identify prescribing errors and take corrective action. • Review product quality complaints and take necessary action to manage quality problems with the procurement department. • Change the formulary or standard treatment guidelines where necessary for significant or recurring problems with adverse drug reactions. Known side-effects Unavoidable Avoidable Medication and device error Product defects Preventable adverse events Injury or death Remaining uncertainties • Unexpected side-effects • Unstudied uses • Unstudied populations Figure 5.1 Preventing ADRs BOX 5.5 QUESTIONS TO ASK BEFORE PRESCRIBING AND/OR DISPENSING A MEDICINE • Is this the correct medicine for the patient’s clinical condition? • Is this the correct dose, route and interval? • Has the patient had the appropriate laboratory test ordered and evaluated? • Does the patient have any medical or physical conditions that would affect the pharmacokinetic aspects of the medicine? • Does the patient have an allergy to this medication or a similar one? • Is the patient on another drug (or herbal product) that would cause a significant drug interaction? • Is the drug being prescribed a ‘high risk’ drug for producing ADRs (aminoglycosides, digoxin, warfarin, heparin, antineoplastics)? Such drugs require special precautions such as increased monitoring of the patient by the prescriber or increased laboratory monitoring (for example blood counts, drug levels, urea and electrolytes). • Is the medicine date-expired? • Does the drug show any visual deterioration, for example discolouration? • Is the injection equipment sterile? 65 5. ENSURING MEDICINE SAFETY AND QUALITY ANNEX 5.1 Basic analytical medicine tests The objective of basic tests is to provide a simple analytical method that is readily applicable, in the absence of a fully equipped laboratory, for verifying the identity of a medicine and whether there has been any gross degradation. Basic tests can never, under any circumstances, replace the requirements of the pharmaceutical monographs which give better assurance of quality. Basic analytical tests may be done by trained pharmacy assistants in inexpensive, relatively low-tech laboratories, which could be run by the pharmacy departments in big hospitals. The minimum equipment needed for such a laboratory includes: • An analytical balance that can measure weights of 50–200 g to within 1 decimal place of a milligram, and weights under 50 g to within 2 decimal places of a milligram). • At least 50 chemical reagents (solid, liquid, gas), reference substances, chemical indicators, and solvents (to dissolve the reagents). • Glassware, for example burettes, beakers and pipettes with a standardized scale. • A recent copy of one of the major pharmacopoeias – British, US, European or International (WHO 1979, 1981, 1988b, 1994c, 2003) – which contain the quality specifications for medicines. Even if a hospital does not have access to a laboratory, it is important that the DTC understands what tests are available in order to investigate drug quality issues and to understand pharmaceutical manufacturer documentation. The basic screening tests should be done on at least 10 samples (tablets, capsules, etc.) of the drug and the result of each test compared against pharmacopoeial or national regulatory body standards. Tests consist of: • Identification of the active ingredient through reactions of chemicals to produce colour or other changes or through thin layer chromatography. • Assay to test for quantity, which is done by burette titration and requires a precise balance. • Disintegration tests of the tablets or capsules in water or 0.1 normal solution of hydrochloric acid at 37°C (simulating gastric acid). The time taken for a tablet (or capsule) to disintegrate is measured and compared against pharmacopoeial standards; for most compounds disintegration should occur within 30 minutes. • Homogeneity or consistency tests where the weights of different tablets (or capsules) of the same drug are compared and the range of weights compared with pharmacopoeial or other national standards. Basic screening tests are described in WHO documents (WHO 1986, 1991, 1998). Bio- availability and bioequivalence can only be ascertained through very much more complex analytical tests. DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 66 ANNEX 5.2 Examples of ADR reporting forms A standard ADR report form for hospital and primary care clinic use only Patient and reaction information Comments Date: Chart number: Name: Date of birth: Physician: Ward/OPD: Drug: Dose: Date drug started: Date of reaction: Diagnosis for use (Indications): Relevant medical history and concurrent drug therapy: Description of ADR: 1. (use reverse side if necessary) 2. 3. 4. Outcomes attributed to ADR: 1. 2. 3. 4. Probability of reaction Naranjo Score (see annex 5.3) Severity code Severe Moderate Minor Incidental DTC action Mark patient’s chart Yes No Discuss with prescriber Yes No Add to database Yes No Report to national drug authority Yes No Report to manufacturer Yes No Reported initiated by: Date report initiated: 67 ADR report form for the US Department of Health and Human Services Food and Drug Administration 5. ENSURING MEDICINE SAFETY AND QUALITY DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 68 ADR report form for the US Department of Health and Human Services Food and Drug Administration (continued) 69 ADR report form for the National Centre for Pharmacovigilance in Ghana 5. ENSURING MEDICINE SAFETY AND QUALITY DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 70 ANNEX 5.3 Naranjo algorithm for assessing the causality of an ADR Question Yes No Do not know Are there previous conclusive reports on this reaction? +1 0 0 Did the adverse event appear after the suspected drug was administered? +2 –1 0 Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? +1 0 0 Did the adverse reaction reappear when the drug was re-administered? +2 –1 0 Are there alternative causes (other than the drug) that could solely have caused the reaction? –1 +2 0 Was the drug detected in the blood (or other fluids) in a concentration known to be toxic? +1 0 0 Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? +1 0 0 Did the patient have a similar reaction to the same or similar drugs in any previous exposure? +1 0 0 Was the adverse event confirmed by objective evidence? +1 0 0 Total score Total score categories are defined as follows: ADR is: certain > 9; probable 5–8; possible 1–4; unlikely 0. Source: MSH (1996.) 71 6. Tools to investigate the use of medicines Summary The first step to addressing problems of irrational use of medicines is to measure the problem, analyse it and understand the causes underlying it. There are four main methods, all of which should be regularly used by DTCs. • Aggregate data methods involve data that do not relate to individual patients and can be collected relatively easily. Methods such as ABC analysis, VEN analysis and DDD methodology are used to identify broad problem areas in drug use. • Drug indicators studies involve collecting data at the level of the individual patient but do not usually include sufficient information to make judgements about drug appropriateness for diagnosis. Such data can be collected by non-prescribers and can be used to identify problem areas in medicine use and patient care, and evaluate interventions designed to correct the problems identified. • Qualitative methods such as focus group discussion, in-depth interview, structured observation and structured questionnaires are useful for identifying why drug use problems occur. • Drug use evaluation is a system of ongoing criteria-based evaluation of drug use that will help to ensure appropriate use at the individual patient level. This method involves the detailed analysis of individual patient data. 6.1 Stepwise approach to investigating the use of medicines Medicines have been used irrationally for as long as they have been available; this reduces quality of care, wastes resources and may cause harm to patients. The first step to improving drug use is to investigate what kinds of problems there are and the extent to which they occur. Unless drug use is investigated, measured and documented, it is impossible to evaluate the effectiveness of interventions to promote rational use. This chapter describes a number of methods or tools to investigate drug use. It is up to the reader to choose the combination of methods most suited to the type of problem to be investigated and the type of data available. ■ STEP 1 General investigation to identify problem areas Initial investigation should identify broad areas of inappropriate use of medicines. There are two main ways of doing this: • Aggregate data methods (section 6.2) use data that are not collected at the individual patient level; such data are often routinely available for purposes other than investigating drug use, for example stock records. Aggregate data give an overview of drug use, which is useful in managing the formulary list. 5. ENSURING MEDICINE SAFETY AND QUALITY DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 72 • Indicator study methods (section 6.3) use data which are collected at the individual patient level, for example prescriptions or patient–provider interactions. Indicator study data are collected specifically to investigate medicine use, but do not include sufficient information to make individual judgements concerning the appropriateness of a drug prescription for an individual diagnosis. Such data can therefore be collected by trained personnel who are not doctors, pharmacists or nurses. ■ STEP 2 In-depth investigation of specific problems Once an area of inappropriate medicine use is identified, it should be examined in depth in order to determine the size and nature of the problem and the reasons underlying the problem. Such investigation may include, for example: • Prescription audit to see if the treatment of a specific disease is in accordance with guidelines (see section 6.3 on the complementary indicator – the percentage of prescribing encounters in accordance with standard treatment guidelines). • Qualitative methods to determine the causes of a drug use problem (see section 6.4). There may be many rational reasons why people use medicines inappropriately; unless these reasons are understood it is impossible to devise an effective strategy to change behaviour. • Drug utilization review to see if the use of a specific medicine is in accordance with previously agreed criteria (see section 6.5). ■ STEP 3 Develop, implement and evaluate strategies to correct the problem Strategies to promote more rational use of medicines are described in chapter 7. Box 8.3 in section 8.2 describes how the use of injections was investigated in Indonesia and then a strategy developed and implemented to reduce inappropriate use. 6.2 Analysis of aggregate medicine use data Aggregate data can be used to conduct ABC analysis, therapeutic category analysis, VEN analysis, and to enable the use of defined daily dose in analyses (MSH 1997, chapter 41, pp. 633–642). All these methods are very powerful tools that a DTC can and should use to manage the formulary medicines list and identify medicine use problems. Aggregate data on drug use can be obtained from many sources within the health-care system, including procurement records, warehouse drug records, pharmacy stock and dispensing records, medication error records and adverse drug reaction (ADR) records. Aggregate data sources can be used to obtain a variety of information, for example: • Cost of drugs used – individual drugs and drug categories (see section 6.2.1) — Which are the most expensive drugs? — On which drugs is most money spent? — What are the most expensive therapeutic categories? — What is the percentage of the budget spent on certain drugs or drug classes? • Quantities (in units, for example tablets) of drugs used (see section 6.2.4) — Which are the most frequently and infrequently used drugs? — Does actual drug consumption match expected consumption according to morbidity records? 73 — Per capita use of specific products • Relative use of therapeutically substitutable products (see section7.3 on generic substitution and therapeutic interchange) • Incidence of adverse drug reactions (see section 5.4.2) and medication errors (see section 5.2). All of this data may be broken down (disaggregated) by area of the hospital – surgical wards, medical wards, casualty department, etc. Any identified problems discovered in reviewing this data should be promptly analysed by the DTC, and a strategy to remedy the problem instituted. 6.2.1 ABC analysis Most pharmacists and managers know that only a few drug items account for the greatest drug expenditure. Often 70–80% of the budget is spent on 10–20% of the medicines. ABC analysis is the analysis of annual medicine consumption and cost in order to determine which items account for the greatest proportion of the budget. ABC analysis can: • Reveal high usage items for which there are lower-cost alternatives on the list or available in the market. This information can be used to: — choose more cost-effective alternative medicines — identify opportunities for therapeutic substitution — negotiate lower prices with suppliers. • Measure the degree to which actual drug consumption reflects public health needs and so identify irrational drug use, through comparing drug consumption to morbidity patterns. • Identify purchases for items not on the hospital essential medicines list i.e. the use of non-formulary medicines. ABC analysis can be applied to drug consumption data over a one-year period or shorter. It can also be applied to a particular tender or set of tenders. A summary of the steps is shown in box 6.1. After an ABC analysis has been completed, individual drugs, particularly from category A, should be examined to identify duplication, use of non-formulary drugs and expensive drugs for which there are cheaper therapeutic equivalents. In some cases the ABC analysis may need to take into account varying price levels, brand products and medical devices, such as syringes. ABC analysis can also be used to analyse one therapeutic class, where all the medicines have equal or similar efficacy. In summary, the major advantage of ABC analysis is that it identifies those medicines on which most of the budget is spent; a major disadvantage is that it cannot provide information to compare medicines of differing efficacy. Using a spreadsheet computer programme such as Microsoft Excel or Lotus 1-2-3 makes ABC analysis much easier. The ABC analysis shown in table 6.1 identifies five drug/chemical entities as consuming 62% of the budget: benzyl penicillin 1 MU injection, chloroxylenol 5% solution, fortified procaine benzyl penicillin 4 MU injection, ampicillin 125 mg/5 mL powder for suspension and 100 mL chlorhexidine 5% solution. The next step would be to investigate whether these high-cost items were all needed and were being used effectively. Such investigation might involve a drug utilization review (section 6.5) for the different antibiotics or a comparison of the efficacy and price for the different antiseptics. 6. TOOLS TO INVESTIGATE THE USE OF MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 74 BOX 6.1 SUMMARY OF STEPS OF ABC ANALYSIS • List all the items consumed or purchased. • For each item consumed or purchased, write down — the unit cost of each item (using the prices for a fixed date if prices have varied over time) — the quantity of each item consumed or purchased. • Calculate the monetary value of consumption by multiplying the unit cost by the number of units consumed for each item. The total value of consumption is the sum of all items. • Calculate the percentage of the total consumption value represented by each item by dividing the value of each item by the total consumption value. • Rearrange the list by ranking the items, in descending order, by percentage value of total consumption. • Calculate the cumulative percentage value of the total value for each item; beginning with the first (top) item, add its percentage to that of the item below it in the list. • Categorize your items into: — A, those few items accounting for 75–80% of total value — B, those items which take up the next 15–20% — C, the bulk of items which only account for the remaining 5–10% of value. Typically, class A items constitute 10–20% of all items, with class B items constituting another 10–20% and the remaining 60–80% being in category C. The results may be presented graphically by plotting the percentage of total cumulative value on the vertical or y axis and the number of items (accounting for this cumulative value) on the horizontal or x axis. 6.2.2 Therapeutic category analysis Building on the ABC analysis, therapeutic category analysis can: • identify therapeutic categories that account for the highest consumption and greatest expenditures • indicate potential inappropriate use if taken together with information on the morbidity pattern • identify medicines that are overused or whose consumption is not accounted for by the number of cases of a particular disease, for example chloroquine and malaria • help the DTC choose the most cost-effective drugs within a therapeutic class and to choose alternative medicines for therapeutic substitution. The procedure is similar to ABC analysis, and the steps are shown in box 6.2. As in ABC analysis, a small number of high-cost therapeutic categories account for most of the expenditure. More detailed analysis can be performed within each high-cost category to identify the higher cost drugs and more cost-effective therapeutic alternatives. 6.2.3 Vital, essential and non-essential (VEN) analysis Sometimes there are insufficient funds to buy all the desired medicines. VEN analysis is a well-known method to help set up priorities for purchasing medicines and keeping stock. Drugs are divided, according to their health impact, into vital, essential and non-essential categories. VEN analysis allows medicines of differing efficacy and usefulness to be 75 Table 6.1 ABC Analysis example – Calculations and Ranking PRODUCT Basic Unit Total Value % Total Rank by Cumu- DESCRIPTION unit price US$ units (US$) value value lative Benzylpenicillin 1MU inj amp 0.5276 144,000.00 75,974.40 25.66% 1 25.7% A Chloroxylenol 5% solution ml 0.0034 10,728,000.00 36,475.20 12.32% 2 38.0% A Fort. Procaine Penicillin 4MU inj vial 0.3026 100,000.00 30,260.00 10.22% 3 48.2% A Ampicillin 125mg/5ml powder for susp, 100ml bot 0.5119 43,970.00 22,508.24 7.60% 4 55.8% A Chlorhexidine 5% solution ml 0.0073 2,504,000.00 18,279.20 6.17% 5 62.0% A Chlorhexidine+Cetrimide 1.5%+15% sol ml 0.0064 1,552,000.00 9,932.80 3.36% 6 65.3% B Erythromycin 250mg tab tab 0.0350 262,000.00 9,170.00 3.10% 7 68.4% B Cotrimoxazole 400mg/80mg tab tab 0.0098 860,000.00 8,428.00 2.85% 8 71.3% B Gentamicin Sulfate 80Mg Inj, 2ml amp 0.0628 130,800.00 8,214.24 2.77% 9 74.1% B Chloroquine 50mg base/ml syrup ml 0.0014 5,610,000.00 7,854.00 2.65% 10 76.7% B Multivitamin tab/caps tab 0.0022 3,395,000.00 7,469.00 2.52% 11 79.2% B Hyoscine N-Butylbromide 10mg tab tab 0.0174 380,000.00 6,612.00 2.23% 12 81.5% C Water for injection 10ml amp 0.0287 220,500.00 6,328.35 2.14% 13 83.6% C Dipyrone 500mg/ml inj, 5ml amp 0.0898 65,000.00 5,837.00 1.97% 14 85.6% C Metronidazole 200mg tab tab 0.0052 1,080,000.00 5,616.00 1.90% 15 87.5% C Pseudoephedrine 60mg/Triprolidine 2.5mg tab tab 0.0536 100,000.00 5,360.00 1.81% 16 89.3% C Metronidazole 200mg/5ml suspension ml 0.0055 900,000.00 4,950.00 1.67% 17 91.0% C Nitrofurantoin 100mg tab tab 0.0055 860,000.00 4,730.00 1.60% 18 92.6% C Benzoin, Compound Tincture ml 0.0067 532,000.00 3,564.40 1.20% 19 93.8% C Oxytocin 10 IU Inj, 1ml amp 0.2468 14,500.00 3,578.60 1.21% 20 95.0% C Vitamin B Complex tab tab 0.0025 1,440,000.00 3,600.00 1.22% 21 96.2% C Calcium Gluconate 600mg tab tab 0.0032 995,000.00 3,184.00 1.08% 22 97.3% C Codeine Phosphate 15mg/5ml linctus ml 0.0052 490,000.00 2,548.00 0.86% 23 98.1% C Ferrous Salts, equiv. to 60mg Iron base tab 0.0007 3,280,000.00 2,296.00 0.78% 24 98.9% C Hydrogen Peroxide 6% solution ml 0.0016 632,000.00 1,011.20 0.34% 25 99.2% C Piroxicam 20mg capsules cap 0.0099 97,000.00 960.3 0.32% 26 99.6% C Phenobarbitone 60 mg tab tab 0.0047 135,000.00 634.5 0.21% 27 99.8% C Prednisolone 5mg tab tab 0.0079 65,000.00 513.5 0.17% 28 99.9% C Chlorphenamine maleate 4mg tab tab 0.0009 555,000.00 499.5 0.17% 29 100.1% C Propranolol 40 mg tab tab 0.0067 33,000.00 221.1 0.07% 30 100.2% C Total 296,046.08 Source: Managing Drug Supply, 1997 6. TOOLS TO INVESTIGATE THE USE OF MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 76 BOX 6.2 THERAPEUTIC CATEGORY ANALYSIS • Do the first three steps of ABC analysis to produce a list of all items by volume and value of consumption. • Assign a therapeutic category to each drug using the WHO model list of essential medicines (WhO 2002a) or according to another reference manual such as the Pharmacologic-Therapeutic Classification system used by the American Hospital Formulary Service (AHFS) or the Anatomical Therapeutic Chemical (ATC) classification system adopted by WHO. • Rearrange the list into therapeutic categories and sum the percentage value of items in each category, in order to identify the categories accounting for greatest expenditure. compared, unlike ABC and therapeutic category analyses, where only drugs of similar efficacy or action can be compared. • vital drugs (V): potentially life-saving or crucial to providing basic health services • essential drugs (E): effective against less severe but significant forms of disease, but not absolutely vital to providing basic health care • non-essential drugs (N): used for minor or self-limited illnesses; these may or may not be formulary items and efficacious, but they are the least important items stocked. Many people find it relatively easy to classify medicines as ‘N’ but very difficult to distinguish between the ‘V’ and ‘E’ categories; they prefer to classify medicines as either essential or non-essential. This does not matter, provided that the system clearly defines the different categories used and these categories allow for clear prioritization amongst items. Box 6.3 shows the steps of VEN analysis, together with some sample guidelines for establishing VEN categories. Once a VEN analysis is done, a comparison should be made between the ABC and VEN analyses in order to identify whether there is relatively high expenditure on low-priority drugs. In particular, effort should be made to delete any ‘N’ drugs that are in the high cost/high consumption category A of the ABC analysis. Table 6.2 shows a real example of a VEN analysis from Malawi, where all drugs deemed non-essential were deleted from the National Essential Drugs List. In Malawi some medicines were regarded as non-essential because more effective alternative medicines were listed as vital or essential. For example, ferrous sulfate was regarded as non-essential, whereas ferrous sulfate with folic acid was regarded as vital. Similarly, lignocaine with adrenaline was regarded as non-essential whereas lignocaine local anaesthetic alone was regarded as essential. Some drugs were regarded as non-efficacious, for example multivitamin paediatric drops and thymol mouthwash. 6.2.4 Defined daily dose (DDD) Drug consumption in terms of cost, as used in ABC analysis, can help us check whether the drug budget is spent in the most effective way, and identify problem drugs to investigate further. The analysis of medicine consumption in terms of unit quantities can help to identify over- and under-use of individual medications or therapeutic groups. The defined daily dose (DDD) methodology converts and standardizes readily available product quantity data, such as packages, tablets, injection vials, bottles, into crude estimates of clinical exposure to medicines, such as the number of daily doses. The DDD is the assumed average daily maintenance dose for the medication’s main indication. It is defined globally for each medicine by the WHO Collaborating Centre for Drug Statistics in Oslo, 77 Table 6.2 Example of VEN Analysis in Malawi, 1995 VITAL ESSENTIAL NON-ESSENTIAL (1) Potentially life-saving Effective against less severe but significant (1) Used for minor or self limited illnesses (2) Significant withdrawal side-effects forms of illness (2) Questionable efficacy (3) Major public health importance (3) High cost for marginal therapeutic advantage ALL deleted from EDL Health centre Phenobarbitone tab. 30mg Lignocaine 25ml injection 1% Lignocaine + 1% + Adrenaline inj. 1/ 200,000 Phenoxymethyl penicillin 250mg Praziquantel 600mg Aspirin paediatric tab. 75mg tab. Cotrimoxazole 480mg Gentian violet paint 500ml 0.5% Suramin sodium injection 1gm PFR Nystatin pessaries 100,000 I.U. Benzyl benzoate 100 ml. 25% Nystatin tab. 500,000 I.U. Pyrimethamine + 25mg+ Magnsesium trisilicate tab. Amodiaquine tab. 200mg Base sulfadioxine tab 500mg Ferrous sulfate + 200mg+ Chlorpromazine tab. 25mg Ergotamine tab. folic acid tab 0.5mg Adrenaline 1 ml injection 1:1,000 Aminophylline tab. 100mg Ferrous sulfate tab. 200mg Oral rehydration For 1 litre Vitamin B Complex tab. Propranolol tab. 10mg salts powder Gentamicin 2 ml injection 40 mg/ml Aluminium acetate ear 13% Magenta paint 20ml drops Condoms with spermicide Zinc oxide ointment 15% Anti-snakebite venom 10ml injection Measles vaccine (live) 5 ml Mebendazole tab. 200mg Ergometrine maleate tab. 500mcg 10 dose vial Ergometrine maleate 500mcg/ml Ferrous sulfate 60mg/5ml Multi-Vitamins 1 ml. inj. paediatric mixture paediatric drops Salbutamol sulfate 4mg Chlorpheniramine 4mg. Thymol mouthwash maleate tab. Vitamin A cap. 200,000 I.U. Lidocaine dental cartridge 2% + + Adrenaline 1/ 80,000 District hospital Diazepam 2 ml. Injection 5 mg/ml Diazepam tab. 5mg Atropine sulfate 1ml. 600mcg/ml Paracetamol tab. 500mg Injection Nalidixic acid tab. 500mg Codeine phosphate tab. 15mg Isoniazid and 300mg Amoxycillin elixir 125mg/5ml Thiacetazone tab. 150mg Digoxin tab. 250mcg Erythromycin suspension 125mg/5ml Key : I.U. = International Unit; mcg = µg = microgram ; gm = g = gram Source: Malawi Essential Drugs Programme, 1995. 6. TOOLS TO INVESTIGATE THE USE OF MEDICINES DRUG AND THERAPEUTICS COMMITTEES – A PRACTICAL GUIDE 78 Norway, (http://www.whocc.no; see annex 6.1 for addresses and the DDDs for some medicines). The DDD is based on the average maintenance dose for adults, but it can be adjusted for paediatric medicine use. The units in the recommended dose of a medicine may be milligrams for solid oral formulations like tablets and capsules or millilitres for liquid oral or injection formulations. Converting aggregate quantities available from pharmacy inventory records or sales statistics into DDDs roughly indicates how many potential treatment days of a medicine have been procur
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