Concept Foundation - Medicines for Reproductive Health: Ensuring Access to Quality Assured Products

Publication date: 2011

Concept Foundation Medicines for Reproductive Health Ensuring Access to Quality Assured Products Quality of Reproductive Health Medicines © Concept Foundation 2011 This document was funded through the Innovation Fund of the Reproductive Health Supplies Coalition, Subgrant No. GAT.1291-08593-GRT - Accessing Quality Assured Supplies. All rights are reserved by Concept Foundation. This document may be reviewed, abstracted, reproduced and translated, in part or whole, on condition that Concept Foundation is informed and fully acknowledged. Any reproduction must not be sold or used for commercial purposes. Concept Foundation 17 chemin Louis-Dunant 1202 Geneva Switzerland Tel: +41-22-734 2560/1 Medicines for Reproductive Health Ensuring Access to Quality Assured Products Peter E Hall and Lester C Chinery Concept Foundation Bangkok, Thailand and Geneva, Switzerland Quality of Reproductive Health Medicines 1. Introduction 3 2. The role of the public and private sectors in providing medicines for reproductive health 6 3. The role of generic products in achieving MDG5 8 4. How can we ensure the quality, safety and e!cacy of generic medicines? 12 4.1 Quality assurance of reproductive health medicines 12 4.2 Bioequivalence studies 14 5. The United Nations Prequali"cation Programme and its role in assuring quality 16 6. The procurement of quality assured generic medicines 21 7. Conclusion 23 Table of contents 3 Introduction At the turn of the millennium, world leaders gathered to ratify the Millennium Develop- ment Goals (MDGs). Despite the fact that it took a further six years to include the target of universal access to reproductive health, the acceptance of MDG51 to improve maternal health and the world’s population surging past seven billion have galvanized the international community and govern- ments of many lower and middle-income countries into action, grappling to address the reproductive health needs of women in those countries. A recent report by the United Nations Popula- tion Fund (UNFPA) and the Guttmacher Institute2 showed that “maternal deaths in developing countries could be slashed by 70 per cent and newborn deaths cut nearly in half if the world doubled investment in family planning and pregnancy-related care. In addition, investments in family planning boost the overall e#ectiveness of every dollar spent on the provision of pregnancy- related and newborn health care. Simulta- neously investing in both family planning and maternal and newborn services can achieve the same dramatic outcomes for US$1.5 billion less than investing in mater- nal and newborn health services alone.” It is absolutely clear that it will neither be possible to achieve these outcomes nor meet the indicators for MDG5 without universal access to a#ordable reproduc- tive health medicines of assured quality. It is a sad fact that after 50 years of modern contraception, we are still struggling to achieve this goal. This remains one of the greatest challenges to governments, donors and all those involved in improving access to reproductive health. Just looking at family planning alone, in many countries in the developing world, donor agencies have been signi"cant players in the purchase of contraceptives for supply to the public sector, mainly purchasing products from large multinational pharma- ceutical companies. However, this "nancial assistance has become more tenuous over recent years. Furthermore, the population of reproductive-age couples in developing countries is expected to increase by 23% between 2000 and 20153. As such, demand for contraceptives exceeds supplies in many developing countries and is increasing. In response to the growing desire for novel approaches and funding to address these needs, a group of key stakeholders estab- lished the Reproductive Health Supplies Coalition (RHSC) in 2004. The Coalition 1 Millennium Development Goal 5 “Improve maternal health” requires the reduction of the maternal mortality ratio (the number of maternal deaths per 100,000 live births) by three-quarters, between 1990 and 2015; and universal access to reproductive health by 2015. 2 Adding It Up: The Costs and Bene"ts of Investing in Family Planning and Maternal and Newborn Health UNFPA & the Guttmacher Institute, New York. 2009 pp44. 3 United Nations Population Fund.(2002). Reproductive Health Essentials - Securing the Supply: Global Strategy for Reproductive Health Commodity Security. UNFPA, New York. See www.unfpa. org/publications/detail.cfm?ID=27&"lterListType=. M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 4 now comprises some 140 organizations and constituencies that have a signi"cant "nancial and/or programmatic stake in reproductive health supply security, includ- ing donor agencies, procurement agencies, several governments from lower and middle income countries, civil society and product manufacturers. The Coalition is working to resolve problems and ensure the long-term supply of RH supplies using new and exist- ing resources, expertise and approaches4. It is continuing to provide the projections and funding estimates showing the challenge in meeting these needs which lie ahead5. The vision of RHSC is that all people in lower and middle-income countries can access and use a#ordable, high-quality supplies, including a broad choice of contraceptives, to ensure their better reproductive health. Its mission is to ensure that every person is able to obtain and use RH supplies. The Coalition has committed itself to achieving a sustained supply of a#ordable, quality reproductive health supplies in low- and middle-income countries. The World Health Organization (WHO), UNFPA and other agencies developed an Interagency List of Essential Medicines for Reproductive Health6. The document repre- sents “an international consensus” on the rational selection of essential reproductive health medicines. It is intended to support decisions regarding the production, quality assurance and national procurement and reimbursement schemes of these medicines. It was augmented by a guide “Essential Medicines for Reproductive Health: Guiding Principles for Their Inclusion on National Medicines Lists”7. This document addresses the principal reproductive health medicines which are the focus of WHO’s Prequali"ca- tion Programme established in 2006 (see Table 3). One of the fundamental problems in the provision of these essential medicines is cost. Despite the growing private sector, the public sector still remains the principal supplier of reproductive health medicines in many developing countries and purchas- ers, whether they are governments, donors or procurement agencies, are looking for a sustainable supply of the highest quality products at the lowest possible cost to meet the goal of achieving supply security of essential reproductive health medicines. This means that: manufacturers must have the incentives to produce the required essential medicines; procurement and regulatory agencies, together with national and international technical agencies, must ensure they are a#ordable and of assured quality; governments must create budget lines for these essential medicines; and donors must assist in ensuring these activities are supported. 4 Reproductive Health Supplies Coalition: http://www.rhsupplies.org/. 5 Contraceptive Projections and the Donor Gap: Meeting the Challenge, Reproductive Health Supplies Coalition, 2009 pp44. See http://www.rhsupplies.org/"leadmin/user_upload/RMA_WG_meetings/ RHSC-FundingGap-Final.pdf. 6 World Health Organization (2006). The Interagency List of Essential Medicines for Reproduc- tive Health, 2006, WHO, International Planned Parenthood Federation, John Snow Inc, Popula- tion Services International, United Nations Population Fund, World Bank. Geneva: World Health Organization. WHO/PSM/PAR/2006.1, WHO/RHR/2006.1. See http://whqlibdoc.who.int/hq/2006/ WHO_PSM_PAR_2006.1_eng.pdf. 7 World Health Organization, UNFPA and PATH (2006). Essential Medicines for Reproductive Health: Guiding Principles for Their Inclusion on National Medicines Lists. PATH, Seattle pp104. Concept Foundation 5 While contraceptive users in the devel- oped world generally have a broad choice of types and brands, users in developing countries are often limited in what they can buy and a#ord. This gap in product access, as well as the potential of competing in developed markets, has attracted generic pharmaceutical manufacturers to supply their own versions of lower-priced hormo- nal contraceptives as o#-patent copies of popular originator brands. As such, when a woman receives a cycle of contraceptive pills she is unlikely to have any idea of its origin and how the medicine came to be in her clinic. In the USA and other high- income countries it is more than likely to be a generic medicine. Patents have expired on many of the hormo- nal contraceptive and other reproductive health medicines commonly used around the world and on practically all those used in less developed countries. In general health terms the emergence of generic competition is a positive development and provides policymakers with a powerful tool and access to lower drug prices. For less developed countries who depend upon international donor support for the procure- ment of their RH supplies, and indeed for the donor community themselves, lower price medicines means the opportunity of “more for less” a crucial advantage in today’s economic environment. At the same time a woman receiving her contraceptive services in Bangladesh, Burkina Faso, Cambodia, Peru, Zambia or any lower and middle-income country has an absolute right to know that the product she is using is of assured quality and that its safety and e#ectiveness have been evaluated and veri"ed as being identical to the origi- nal drug. For this she relies upon her health professional who in turn relies upon the regulatory authorities of the country. While there is no doubt that generic RH medicines can o#er a signi"cant price advantage over their innovator competitors and have achieved a high degree of penetration in the global market-place, serious questions remain whether, in many lower and middle- income countries, certain products meet internationally accepted safety and e!cacy and quality criteria. This paper analyses the emergence and impact of generic reproductive health medicines and the challenge to interna- tional and national procurers of ensuring the quality, safety and e!cacy of products. It focuses speci"cally on the role of WHO’s Prequali"cation Programme in achieving this objective. 6 The role of the public and private sectors in providing medicines for reproductive health Introduction Since the 1960s donor Governments and international agencies, such as UNFPA, the International Planned Parenthood Federa- tion (IPPF) and many others have mobilized to educate, and provide quality family planning products and services to women around the globe, resulting in signi"cant increases in contraceptive use and improved health and economic circumstances for individuals and their families. Despite the growing private sector, the public sector remains the principal supplier of contra- ception in many countries and purchasers, whether they are governments, donors or non-governmental organizations (NGOs) must be able to provide quality assured products for the public sector or social marketing programmes at the lowest possi- ble prices. Historically, in many countries of the devel- oping world, Western donor agencies have been signi"cant players in the funding and purchase of contraceptives for supply to the public sector, primarily purchasing products from large multinational pharmaceutical companies based in OECD countries. Adopt- ing an innovative and mutually bene"cial strategy, donors and international agencies purchased and delivered specially adapted Blue Lady8 presentations of patented contra- ceptives in support of country programmes, supplied by the innovator pharmaceutical manufacturers at a cost plus price, allowing clients in less developed countries access to high quality products at a fraction of their Western market price. This provided indus- try with an entry point for the introduc- tion of their higher price versions and new preparations, with marketing costs signi"- cantly reduced. Over time as income levels increased in many countries, consumers traded up to the more expensive products. As well as proving an e#ective business model this approach also provided an appropriate vehicle for the companies’ corporate social responsibility (CSR) activities. This model has e#ectively remained in place for over 30 years as the main deliv- ery mechanism, adapted over the years to include social marketing as country markets evolved, segmented and consumer preferences and approaches changed as a result of di#erent educational promotional strategies, economic situations and newer products/formulations coming down the pipeline. In 2011, donor agencies continue to play a critical role in ensuring availability of repro- ductive health medicines, using a wide range of approaches for procuring and channelling products to recipient countries, which include, funding and/or utilizing the services of international procurement 8 The Blue Lady brand was developed as a non-proprietary mark by USAID to di#erentiate public sector products made available to programmes by USAID and IPPF from the commercial versions. Concept Foundation 7 Introduction organizations, supporting social marketing programmes and contracting out procure- ment to other entities in the private and public sectors. Increasingly, within the new aid architecture, donors are opting to provide funding directly to countries who undertake procurement themselves, without interme- diaries. The RHSC publication “Contraceptive Projec- tions and the Donor Gap: Meeting the Challenge”5 shows that almost half the donor support to family planning products goes to hormonal contraception and is evenly split between oral and injectable methods. Despite the mainstreaming of generics in the US and other high-income countries, the current market place for quality assured public sector hormonal contraception can reasonably described as an oligopoly, with three Western research and development (R&D) orientated innovator (or their succes- sors) companies9 still supplying the majority of the market, despite the fact that nearly all of the relevant compositions have been o# patent for many years. From a cost perspective there is a power- ful incentive for establishing a competitive roster of quality assured generic products, both for RH donors and procurers. In 2009, RHCS partners spent an estimated US$127 million on the purchase of hormonal contra- ception10, with UNFPA (US$59 million/46%) the largest procurer in value terms (Table 1). Donor US$ million % share USAID 39.2 31% UNFPA 58.6 46% BMZ/KFW 14.0 11% DFID 4.8 5% PSI 1.5 1% OTHERS 8.1 6% Total 126.2 100% Through the uptake of generics there is an opportunity to make a signi"cant medium- term "nancial impact on the cost of RH medicines, providing these medicines are of assured quality. Based upon the known cost structures and market pricing of generic hormonal contraception this could poten- tially reduce procurement costs for RHSC member organizations by US$60 million, or almost 50% annually. While a woman in the USA is more likely than not to receive a generic medicine of assured quality when she next visits her provider, paradoxically, donor support for RH medicines is still primarily utilized to purchase innovator versions. Morever, in the private sector of lower and middle-income countries there appears to be signi"cant generic penetration of RH medicines, and a number of governments have also made the switch to generic substitutes on an economic basis. The challenge is to ensure over time that these products meet appro- priate quality assurance criteria. In the following sections we will consider some of the constraints. Table 1. Donor funded hormonal contraceptive purchasing by value 9 Research and development innovator companies based in the USA, Europe and other OECD countries. 10 Using published UNFPA value data from 2009, we have extrapolated the value of all donor related purchasing for the same year, cross referenced with the publication; UNFPA - Donor Support for Contraceptives and Condoms for STI/HIV Prevention 2009. 8 The role of generic products in achieving MDG5 Firstly, what is a generic medicine? A generic product is a copy of the original innovator drug which can be produced and marketed in countries where the patent on the origi- nal product has expired; the drug has never been patented; or where a patent is not in force. It must contain the same active ingre- dients at the same strength as the innovator brand; and meet the same pharmacopoeial requirements for the preparation. Manufacturers of generic drugs are not required to duplicate the safety and e!cacy studies that were undertaken on the origi- nal innovator product. However, they must show need to that they are of similar quality, being manufactured under current Good Manufacturing Practice (CGMP) and are pharmacokinetically bioequivalent. Hence, generics are identical in dose, strength, route of administration, safety, e!cacy, and intended use to the original product, although they may have a di#erent colour or shape from the original product and will be marketed under di#erent brand names and presentation styles. For more than "fty years, the Western R&D based pharmaceutical industry has made a truly signi"cant contribution to the "eld of reproductive health by both the develop- ment of a range of products, particularly hormonal contraceptives11 and in conjunc- tion with major aid agencies, made them available at preferential prices for less devel- oped countries. However, it is the R&D based pharmaceutical industry that has, in recent years, faced unprecedented revenue and pro"t declines as a result of generic compe- tition in its "rst tier markets, such as the USA and Europe, and increasingly in middle-in- come and less developed countries. Overall estimates for yearly sales of generic drugs range as high as US$80 billion occurring at a time when the industry is bringing fewer drugs to market. In 2007, Frank12 noted that, by 2010, patents on some 110 drugs will have expired, including some of the indus- try’s most pro"table sellers. In fact, by 2007, generic drugs accounted for 63% of all USA prescriptions for drugs13. In 2008, the hormonal contraceptive market was worth US$6.2 billion across the seven major "rst tier pharmaceutical countries alone, of which 50% is accounted for by oral contraceptives14. If we consider the latter "gures, which relate to women who live in the USA and Europe and, in general, have unrivalled access to health care, they (or 11 Hall PE. (2005). What has been achieved, what have been the constraints and what are the future priorities for pharmaceutical product-related R&D to the reproductive health needs of develop- ing countries? Commission on Intellectual Property Rights, Innovation and Public Health, World Health Organization, Geneva. See http://www.who.int/intellectualproperty/studies/reproduc- tion_health/en/index.html. 12 Frank RG. The Ongoing Regulation of Generic Drugs. N Engl J Med 2007; 357:1993-1996 13 Data from IMS Health, National Prescription Audit Plans, National Sales Perspective, for the 12 months ending June 2007. 14 Commercial Insight: Hormonal Contraceptives - Look Beyond Oral Contraception for a Competi- tive Edge. Datamonitor, Oct 2009, pp243. Concept Foundation 9 their national or private insurance schemes) spend US$3-4 billion on oral contraceptives. The developing world has 85% of the world’s women of reproductive age and estimated sales of US$1.2 billion. Because the oral contraceptive market was the most valuable hormonal contraceptive product in developed countries, for many years major pharmaceutical companies were reluctant to introduce new products, like implants, vaginal rings and patches, in case they cannibalized this market. However, by the mid-2000s, the contraceptive market in these countries, and particularly the USA, changed dramatically, partly because of the growth of generic oral contraceptive manufacturers. In the USA, two generic companies in particular aggressively introduced quality generic oral contraceptives and basically pushed some of the traditional big players out of the oral contraceptive business. Moreover, there was a signi"cant reduction of the number of major pharmaceutical companies in the "eld, primarily because of mergers and acquisitions. Several changed their business strategies, with a number of companies that manufacture RH medicines withdrawing and/or discontinuing the provision of preferential priced medicines to less developed countries and in some cases stopping production of RH medicines altogether. At the same time, more than 60 manufac- turers producing generic hormonal contra- ceptives alone, and a smaller number manufacturing other RH medicines, such as misoprostol, oxytocin and mifepristone have emerged. The vast majority of these compa- nies are located in and are serving lower and middle-income countries. Over the past decade, these companies have been rapidly expanding their reach and gaining market share in almost every country of the world, resulting in signi"cant increase in competi- tion, with the traditional manufacturers of hormonal contraception who are increas- ingly withdrawing their products from developing countries, creating additional space for the new generic entrants. However, while this market transition has resulted in the availability of cheaper products, it has not necessarily created a body of suppliers that can demonstrate to public and social marketing sector procure- ment agencies that their products can meet internationally accepted quality standards. The lack of a competitive and equitable supplier base represents a signi"cant and growing problem for procurement organi- zations, many of which are, by necessity, purchasing to some degree from generic developing country manufacturers. This problem was exempli"ed in a study undertaken by Concept Foundation15 which showed that relatively few manufacturers of generic hormonal contraceptives in lower and middle income countries currently achieve acceptable levels of quality assur- ance. The study assessed 47 manufacturers in 15 lower and middle-income countries in late 2005 and early 2006. It found signi"cant disparities between manufacturers in terms of their facilities and their ability to meet CGMP. Despite the fact that every one of the 47 factories visited had received national GMP certi"cation, it is unlikely that, at the time 15 Hall PE, Oehler J, Woo P, Zardo H, Chinery L, Singh JS, Jooseery SH and, Essah NM. (2007).A study of the capability of manufacturers of generic hormonal contraceptives in lower and middle income countries. Contraception. 75:311-317. M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 10 of the study, any one of them could have met WHO, PIC/S16 or stringent drug regula- tory authority (SRA)17 requirements. It was considered that 30% of the factories could eventually meet these requirements by the end of 2009; it was also possible that 16 The Pharmaceutical Inspection Convention and its related Pharmaceutical Inspection Cooperation Scheme (PIC/S) are two international instruments between countries and pharmaceutical inspection authorities, which provide active cooperation in the "eld of GMP. Membership consists of 28 European states plus Argentina, Australia, Canada, Israel, Malaysia, Singapore, South Africa, Ukraine and the USA. Other countries such as Indonesia and Thailand are now transitioning to PIC/S GMP. 17 Stringent Drug Regulatory Authority (SRA) means a regulatory authority (in case of the European Union both EMEA and national competent authorities are included) which is: (a) a member of the International Conference on Harmonization of Technical Requirements for Regis- tration of Pharmaceuticals for Human Use, ICH (as speci"ed on its web site:); or (b) an ICH Observer, being the European Free Trade Association (EFTA) as represented by SwissMedic, Health Canada and World Health Organization (WHO) (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally binding mutual recogni- tion agreement including Australia, Norway, Iceland and Liechtenstein (as may be updated from time to time). Table 2. Hormonal contraceptives, patents and the availability of generic products Product type Patent coverage Generic products available? Oral contraceptives - combined (COCs) No (except for a few new products) Yes - progestogen-only (POPs) No Yes Injectable contraceptives - progestogen-only, DMPA No (except for subcutaneous delivery) Yes - progestogen-only, NET-EN No Yes - combined injection, Cyclofem No Yes - combined injection, Mesigyna No No Intrauterine devices - copper T No Yes - LNG-releasing No No Vaginal rings - copper T No Yes - LNG-releasing No No Vaginal rings - Monthly combined Yes Limited Implants - Jadelle No Yes - Implanon Yes No Patches - Weekly combined Yes No Emergency contraception - Levonorgestrel No Yes Concept Foundation 11 a further 35% could comply with these requirements some time later if signi"cant investment and improvements in quality management and practice could be made. The remaining 35% gave considerable cause for concern and many of these companies needed to reconsider their role in produc- tion of products for human use and close the facilities visited. Unfortunately, the expectation that some 15 factories could meet internationally accepted quality standards by the end of 2009 proved to be over-optimistic. Even these “better” companies initially did not understand what was required to meet CGMP, and/or undertake appropriate bioequivalence studies and/or complete the required documentation. Hence many did not seek the necessary technical assist- ance. As a result, by April 2011, no generic reproductive health medicine has yet has been prequali"ed by WHO’s Prequali"ca- tion Programme (see Table 4), although one or two are very close. Nevertheless, in the past "ve years there have been signi"cant changes and appropriate technical assist- ance is being made available which will lead to access to several high quality contracep- tive products by the end of 2012. As mentioned previously, patents have expired on most commonly used hormo- nal contraceptive and other reproductive medicines around the world. As a result, with the exception of contraceptive patch- es, vaginal rings and some of the newer oral contraceptive formulations, which are rarely used in less developed countries because they either have not been made available by the innovator or if they are available most women in the country could not a#ord them, hormonal contraceptive methods are available in generic form. Table 2 shows the situation of various types of contraceptives with regard to patents and the availability of generic products. 12 18 Moran M, Guzman J, McDonald A, Wu L and Omune B. Registering New Drugs: The African context. New tools for new times. The George Institute for International Health, Sydney, Australia. 2010 pp38. See http://www.dndi.org/images/stories/advocacy/regulatory-report_george-institute- dndi_jan2010.pdf. 19 See http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/. How can we ensure the quality, safety and e!cacy of generic medicines? It is critical for both the procurers and the recipients of generic reproductive health medicines to know that the product that is being purchased is of assured quality and is safe and e#ective. However, it is the national drug regulators who are responsible for putting into place the criteria and processes, checks and balances to ensure the quality of the products that they approve for distribu- tion in the country. Most developed countries have well-re- sourced, stringent drug regulatory agencies which can evaluate all aspects of the quality, safety and e!cacy of medicines. However, there are many challenges facing National Drug Regulatory Agencies (NDRAs) world- wide, a report by Moran et al in 201018 which focussed on African agencies stated that only a minority have the resources to e#ec- tively evaluate new medicines de novo. The report considered that the major factors behind the regulatory capacity shortfall to be: lack of a clear legislative framework; dispersion of regulatory responsibility; lack of "nancial resources; lack of experienced and quali"ed sta#; lack of political support; and lack of appreciation of the importance of medicine regulation by stakeholders, including researchers, developers, govern- ment departments and the general public. Given the constraints on regulators world- wide; the emergence of major markets for the manufacturers of reproductive health medicines; and the needs of international and national procurers to maximize the use of limited funds, how can we ensure the quality, safety and e!cacy of generic medicines? 4.1 Quality assurance of reproductive health medicines WHO de"nes quality assurance as “a wide ranging concept covering all matters that individually or collectively in$uence the quality of a product. With regard to pharma- ceuticals, quality assurance can be divided into four major areas: quality control, production, distribution, and inspections. It is the totality of the decisions made with the objective of ensuring that pharmaceu- tical products are of the quality required for their intended use.” It goes on to de"ne Good Manufacturing Practice (GMP) as “that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appro- priate to their intended use and as required by the marketing authorization.”19 So what requirements should a manufac- turer be complying with? Obviously, in order to manufacture product in its own Concept Foundation 13 Hence, in theory, a company only has to manufacture under the GMP requirements of 20 years ago! It is important for all players, whether they be manufacturers, regulatory agencies or procurement agencies, to understand that GMP is not static. Practices to maintain and improve quality are being continuously updated to meet the highest quality stand- ards and address any issues that impact on quality that arise. This is why it is essential that manufacturers, regulatory agencies and procurement agencies understand what current GMP (CGMP) means. Manufacturers must make products to CGMP but they may not know what CGMP is because they either do not know or do not want to know how they may need to upgrade their facilities and processes. Furthermore, their national regulatory agencies may not have updated their GMP requirements and therefore are not inspecting manufacturing facilities for CGMP. In order to assist companies to meet these needs as well as providing guidance to meet best current practice, both WHO and PIC/S20 provide key guidelines and recom- mendations for CGMP. References to WHO’s documents can be found below21 and in the document developed by Concept Founda- tion for WHO’s Prequali"cation Programme entitled “Frequently asked questions on the prequali"cation of medicines for reproduc- tive health”. country, a company must meet national regulations enforced by the drug regula- tory authority. But although it is the obliga- tion of a national drug regulatory agency to ensure that national GMP requirements meet CGMP, unfortunately, many have not done this. This not only means that national requirements are less stringent than those that manufacturers should be complying with to ensure that products are of assured quality, it also means that the products do not meet the needs of stringent regulatory authorities when a company tries to export its products to more lucrative high income export markets. It remains of grave concern that many countries’ regulations are, to a greater or lesser extent, found to be lacking. This can be found even in major drug producing countries that are exporting to countries with stringent drug regulatory agencies. For example, the authorities responsible for regulating products from several major exporters in one particular city still issue Certi"cates of Pharmaceutical Product that state “Do the facilities and opera- tions conform to GMP as recommended by the World Health Organization? Yes/ no, see footnote 15”. Footnote 15 states ”The requirements for good practices in the manufacture and quality control of drugs referred to in the certi"cate are those included in the report of the thirty-second Expert Committee on Speci"cations for Pharmaceutical Preparations (WHO Techni- cal Report series, No 823, 1992, Annex 1”). 20 PE 009-9 PIC/S GMP Guide, 2009, see http://www.picscheme.org/publication.php?id=4 21 WHO, 2007 Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 2, 2nd Updated Edition - Good Manufacturing Practices and Inspection. World Health Organization, Geneva, pp 416. WHO Expert Committee on Speci"cations for Pharmaceutical Preparations, 44th report. Technical Report Series 957, 2010. Annex 2. WHO good manufacturing practices for active pharmaceutical ingredients. Annex 3. WHO good manufacturing practices for pharmaceutical products containing hazardous substances. Annex 4. WHO good manufacturing practices for sterile pharmaceutical products. M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 14 Both the WHO and PIC/S GMP documents have common goals and objectives. They are similar in content and cover the basic principles of CGMP that in$uence the quali- ty of a product. These include the following issues: Starting materials (APIs, excipients, primary containers) Premises Heating, ventilation and air conditioning (HVAC) Water for pharmaceutical use Equipment Methods, speci"cations and sampling Quali"cation and validation Documentation Personnel and training Complaints and product recalls Sanitation and hygiene Self inspection Despite the similarities of their GMP texts, WHO and PIC/S have di#erent roles and responsibilities. WHO, is an intergovern- mental organization, and can only make recommendations, and not implement requirements, to its 193 Member States. The WHO texts pertaining to good practices in production and good practices in quality control tend to be more detailed than other GMP texts. PIC/S has, on the other hand, agreed require- ments for its members. Only inspectorates meeting these speci"ed requirements can become members of PIC/S. PIC/S has recently harmonized its GMP rules with the EU Guide to Good Manufacturing Practice for Medicinal Products. It is essential that national drug regula- tory agencies review and amend their GMP regulations at regular intervals to ensure that their national GMP is similar to WHO or PIC/S GMP and meet international expecta- tions, norms and standards with a speci"c focus on quality assurance and related aspects. The response to manufacturers that wish to make products that meet the requirements of WHO’s Prequali"cation Programme should be complying with WHO or PIC/S guidelines and recommendations, regardless of whatever requirements are demanded nationally. 4.2 Bioequivalence studies As stated above, as well as demonstrating that products meet CGMP, a key require- ment for manufacturers of generic drugs is that they demonstrate that the products are bioequivalent to the innovator product. This is the internationally accepted proxy for the in depth safety and e!cacy studies that had to be undertaken by the innovator company before it could get the drug registered by a SRA and is one of the reasons that generic products are cheaper than innovators since the company has not had to bear the drug research and development costs. Concept Foundation’s 2007 study found that “there was a signi"cant di#erence between companies in their understand- ing of bioequivalence and most had not considered the need for such studies. Few companies have undertaken bioequiva- lence testing programmes, most supplying untested biosimilar products. Some compa- nies had undertaken pharmacokinetic/ pharmacodynamic studies in local univer- Concept Foundation 15 sity clinical departments but it was di!cult to ascertain what had been the comparator products used and how the investigators applied Good Clinical Practice (GCP) in the conduct of the studies or Good Labora- tory Practice (GLP) for the analysis of blood specimens collected.” 15 Virtually all companies in the study had met di!culties in addressing the design and conduct of bioequivalence studies. This also become apparent as products have been submitted to WHO’s Prequali"cation Programme and has been one of the key reasons contributing to the rejection or subsequent cancellation of submissions (see section 5). 22 WHO Expert Committee on Speci"cations for Pharmaceutical Preparations, 40th report, Technical Report Series 937, 2006. Annex 7. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. Annex 9. Additional guidance for organi- zations performing in vivo bioequivalence studies. 23 European Medicines Agency, 2010. Guidance on the investigation of bioequivalence. Doc ref: CPMP/EWP/QWP/1401/98Rev1/Corr. Clear guidelines on the design and require- ments for bioequivalence studies are to be found in WHO TRS 93722 and in the Europe- an Medicines Agency’s (EMA) “Guidance on the investigation of bioequivalence”23. This is something on which manufactur- ers need to access advice from a profes- sional statistician and also identify a quali- "ed Clinical Research Organization that meets internationally accepted GCP and GLP. WHO’s Prequali"cation Programme will provide advice to companies submit- ting products for prequali"cation. The key issues are addressed in Concept Founda- tion’s document entitled “Frequently asked questions on the prequali"cation of medicines for reproductive health”. 16 The United Nations Prequali"cation Programme is managed by the World Health Organization (WHO). It was set up in 2001 to facilitate access to medicines that meet uni"ed standards of quality, safety and e!ca- cy for HIV/AIDS, malaria and tuberculosis. It is supporting the improvement in manufac- turing capacity by prequalifying products which have been assessed, inspected and controlled to meet international norms and standards for quality, e!cacy and safety; giving assurance that international norms and standards are applied at all the steps of the prequali"cation and within the process itself; and enabling access to good quality medicines. Prequali"cation (as in prequali"cation to tender) was originally intended to give United Nations procurement agencies, such as UNICEF, the choice of a range of quality medicines. With time, the growing list of products that have been found to meet the set requirements has come to be seen as a useful tool for anyone bulk purchasing medicines, including countries themselves and other organizations. For instance, the Global Fund to Fight AIDS, Tuberculosis and Malaria (GFATM) disburses money for medicines that have been prequali"ed by the WHO process. In April 2011, there were 255 medicines prequali"ed (HIV/AIDS, 192; in$uenza, 7; malaria, 17; reproductive health, 8; tuber- The United Nations Prequali"cation Programme and its role in assuring quality culosis, 31). The list changes regularly as products are added but also companies may withdraw products or as in the "eld of HIV/AIDS treatment where regimens change. The prequali"cation of products in certain treatment areas such as HIV/AIDS has transformed the availability and a#ord- ability of essential medicines and up to 90% of purchases by GFATM in this area are products prequali"ed by WHO. Since 2006, WHO has worked on prequali- fying medicines for reproductive health. In response to requests from an Inter- agency working group and the Reproduc- tive Health Supplies Coalition, it put out an initial Expression of Interest in October 2006 for hormonal contraceptives. Most are listed on WHO’s Model List of Essential Medicines and represent the main product of each type purchased by public sector procurement agencies. Since then it has expanded its scope and following its most recent Expression of Interest (May 2010) will accept requests for prequali"cation of all products listed in Table 3. It was approximately two years after the launch of the scheme in October 2006 before the programme was fully sta#ed and functional and in a position to e#ectively evaluate dossiers. As shown in Table 4, 42 reproductive health product applications have been submitted, of which, 25 (60%) have been rejected outright since they did Concept Foundation 17 Hormonal contraceptives Combined oral contraceptives, progestogen-only pills and emergency contraceptive pills - ethinylestradiol + desogestrel, tablet 30 micrograms +150 micrograms - ethinylestradiol + levonorgestrel, tablet 30 micrograms + 150 micrograms - levonorgestrel, tablet 30 micrograms - levonorgestrel, tablet 750 micrograms (pack of two); 1.5 mg (pack of one) - norethisterone, tablet 350 micrograms - norgestrel, tablet 75 micrograms Progestogen-only and combined injectable contraceptives - medroxyprogesterone acetate, depot injection 150 mg/ml, in 1-ml vial - medroxyprogesterone acetate + estradiol cypionate, injection 25 mg + 5 mg - norethisterone enanthate, injection 200 mg - norethisterone enanthate + estradiol valerate, injection 50 mg + 5 mg Implantable contraceptives - two-rod levonorgestrel-releasing implant, each rod containing 75 mg of levonorgestrel (150 mg in total) - etonogestrel, implant, 68 mg of etonogestrel Other medicines for maternal health Oxytocics and anti-progestogens - oxytocin, injection 10 IU, 1-ml - mifepristone 200 mg tablet (only to be used in combination with misoprostol) - misoprostol 200 microgram tablet Prevention and treatment of eclampsia - magnesium sulphate, injection 500 mg/ml, in 2-ml and 10 ml ampoules or Uniject Table 3. Reproductive health medicines in WHO’s Prequali"cation Programme 24 http://apps.who.int/prequal/query/ProductRegistry.aspx?list=rh. not respond adequately to stated require- ments or cancelled during the process of initial review. The majority of these were for generic products. The major reasons for rejection or cancellation have related to the product not meeting the required quality assurance standards, inadequate documen- tation or the conduct of an inadequate bioequivalence study. A total of eight products24 have been prequali"ed, although all are hormonal contraceptives produced by the innovator European or USA pharmaceutical company. These are shown in Table 5. As yet no gener- ic product has been prequali"ed. Overall, generic submissions (31) represent 74% of those received since October 2006 and as yet none have been approved, although there are 3 or 4 generic products currently under review which could be prequali"ed in the near future. Prequali"cation of a product normally takes 18-24 months and follows a de"ned process: Product dossiers are submitted by the manufacturer. M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 18 Product Submitted Not accepted Cancelled Pending Approved Levonorgestrel/ ethinylestradiol, 150/30 µg tablets 16 5 5 5 1 Desogestrel/ ethinylestradiol, 150/30 µg tablets 1 — — — 1 Levonorgestrel, 750 µg tablets 5 2 2 0 1 Levonorgestrel, 30 µg tablets 4 1 2 0 1 Lynestrenol, 0.5 mg tablets 1 — — — 1 Levonorgestrel, 150 mg 2-rod implant 2 — — 1 1 Etonogestrel, 68 mg implant 1 — — — 1 Medroxyprogesterone acetate, 150 mg injection 5 — 4 — 1 Norethisterone enantate, 200 mg injection 2 1 — 1 — Norethisterone enantate/ estradiol valerate, 50/5 mg injection 2 2 — — — Oxytocin, 10 IU/ml 3 — 1 2 — Total 42 11 14 9 8 Table 4. Status of submissions of reproductive health medicines, April 201125 Dossiers are screened for completeness before being accepted. If accepted, the dossiers are assessed according to quality, safety and e!cacy. There are two assessment tracks, the quality part and the safety and e!cacy part. This is done in-house together with external international experts, mostly from SRAs. Results are communicated to the applicant. If corrective actions are required, the decision on the acceptability of data and information is postponed. If the assessment is successful an inspection visit will be undertaken by WHO sta# and external international inspectors. If the process is completed satisfactorily, the product and its site of manufacture will be listed on WHO’s web site. There are some incorrect perceptions about the Prequali"cation Programme on the part of certain procurers and manufacturers. One is that the prequali"cation process is unnec- essarily rigid, overly complex and there- fore slow. Another is that it has favoured the western R&D based pharmaceutical companies. Certainly, as stated above, the programme started slowly and for some time there was a lack of information such as that shown in Table 4. However, these perceptions have almost always resulted from the fact that existing suppliers did 25 Adapted from Table 1, Progress Report 2010. Reproductive health essential medicines: achieve- ments, lessons learnt and next steps. WHO/RHR/10.23. WHO, Geneva. pp39. Concept Foundation 19 INN Formulation and strength Applicant Manufacturing site Date of PQ Ethinylestradiol+ levonorgestrel Coated tablets 30µg+150µg Bayer Schering Pharma AG Weimar, Germany 26 May 09 Ethinylestradiol+ desogestrel Tablets 30µg+150µg NV Organon Kloosterstraat, Oss, The Nether- lands 29 Sep 10 Etonogestrel Implant 68mg NV Organon Kloosterstraat, Oss, The Nether- lands 02 Jun 10 Levonorgestrel Coated tablets 30µg Bayer Schering Pharma AG Weimar, Germany 26 May 09 Levonorgestrel Tablets 0.75mg Gedeon Richter Budapest, Hungary 20 Aug 10 Levonorgestrel Implants 2 rods x 75mg Bayer Schering Pharma Turku, Finland 23 Sep 09 Lynestrenol Tablets 500µg NV Organon Kloosterstraat, Oss, The Nether- lands 02 Jun 10 Medroxyprogesterone acetate Suspension for injection 150mg/ml P"zer Rijksweg, Puurs, Belgium 20 Aug 10 Table 5. Reproductive health medicines prequali"ed, April 2011 not have products prequali"ed and usually re$ect their attitudes to prequali"cation, which are then relayed to their customers. The Prequali"cation Programme applies internationally accepted criteria, as discussed in section 4, and uses the most quali"ed assessors and technical knowledge to assess the quality of products. It applies standards similar to those used in the European Union and the USA; it is no more or no less stringent. It certainly does not favour innovator companies and is keen to get generic reproductive health medicines prequali"ed. However, as discussed above, most generic companies have been unable to respond adequately to the requirements of the programme. Prequali"cation does provide several bene"ts to manufacturers, for example, it: allows participation in tender procedures organized by international and certain national procurers; gives the company recognition by being listed on WHO’s web site; can facilitate registration in certain countries; can reduce the number of inspections from some national regulatory agencies: provides the opportunity to receive advice and assistance from experts; and M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 20 provides a learning process to improve the company’s chances of succeeding with submissions to SRAs However, WHO has been acutely aware of some of its limitations and commissioned a study of its service among manufactur- ers26. The conclusions of the study stated that “Overall, the "ndings from this survey indicate that pharmaceutical manufactur- ers consider PQP to be a well-designed, well-executed programme. PQP assessors and inspectors are meeting or exceed- ing manufacturer expectations for service delivery in the process. However, pharma- ceutical manufacturer applicants place a premium on feedback, communications and problem resolution during the prequali"ca- tion process – with particular emphasis on the assessment of product dossiers – and these are potential improvement areas in the service design of PQP.” Based on the survey results, WHO has imple- mented improvements to the Programme and, for example, has set speci"c time limits to inform and respond to manufacturers. 26 WHO, WHO Prequali"cation of Medicines Programme: survey of service quality provided to manufacturers. WHO Drug Information. 2010, 24:293-298. 21 The procurement of quality assured generic medicines The issue of validating medicines quality is an increasingly important issue for procure- ment organizations, such as UNFPA, USAID and other procurers of reproductive health products, charged with the supply of donor "nanced or self-subsidized medicines to country programmes or third parties, and for an expanding group of national procur- ers, government departments/agencies and NGOs. Prior to the availability of gener- ics, neither product quality nor ensuring adequate product liability cover was signi"- cant considerations in a procurer’s job speci- "cation. This was because buyers were able to rely upon the traditional big pharmaceu- tical companies providing adequate quality and cover, as such, they could purchase with a degree of con"dence, particularly as most of the products purchased were approved by an SRA. Currently, if a national or international procurement agency wishes to purchase quality assured reproductive health medicines for use in developing countries they face a marked lack of choice. The quali- ty products available are rarely available at the lowest unit prices, those attractive to cost-constrained procurers supplying developing country markets. As discussed above, the eight prequali"ed products are all hormonal contraceptives produced by European or USA R&D based pharma- ceutical companies and were already SRA approved and available for purchase. Hence at present there is little downward pressure on prices. Moreover, the discontinuation of certain products (a phenomenon witnessed in recent years) is possible as the pharma- ceutical industry continues to consolidate globally. More vigorous markets across these product groups is, therefore, likely to depend on the emergence of prequali"ed (or SRA approved) generic products. The consequence, in this acutely resource- constrained environment, has been the proliferation of non-quality assured repro- ductive health medicines in many develop- ing countries. Since, as of today, there is not a range of prequali"ed, and hence quality assured, reproductive health medicine products that can exert downward pressure on prices, procurers (both international and national) are increasingly buying non-quali- ty assured products in order to maximize the use of limited funds. In e#ect, this amounts to greater availability of products with lower quality guarantees compared with a smaller quantity of quality assured products. As a result, many procurers undertake their own risk management approaches to evalu- ate the safety and e!cacy of the non-quality assured reproductive health medicines they procure. With a broad range of prequali"ed products, risk management will remain necessary but the quality component would have been evaluated under a coordi- nated scheme with much lower transaction costs and without the additional duplica- tion of e#orts and costs seen in the current fractured situation. M e d i c i n e s f o r R e p r o d u c t i v e H e a l t h 22 To achieve this, it is critical that appropriate procurement and other policies are in place within the international institutions mandat- ed for product supply. Governments often require external "nancing of drug procure- ment for the public sector, such "nancing might be provided directly by international agencies, bilateral donors or development banks, or the medicines themselves may be procured by the donor or another organi- zation on behalf of the donor. These insti- tutions can have con$icting policies and regulations regarding drug procurement, which in turn may con$ict with existing local laws and regulations. In addition, major international NGOs may supply products for the public sector or for social marketing or other sectoral programmes. There are currently a number of initiatives underway, examining the issue of ensuring medicines quality, including some, relating speci"cally to reproductive health which are being undertaken under the auspices of the Reproductive Health Coalition and its Working Groups. RHSC members are slowly moving towards adopting a common procurement policy, similar to that used by the Global Fund to Fight AIDS, Tuberculosis and Malaria. As a "rst step, UNFPA submit- ted its new procurement policy which was approved by its Executive Board. This policy states that Finished Pharmaceutical Products will only be procured if they have been prequali"ed by the WHO Prequali"ca- tion of Medicines Programme or author- ized for use by a Stringent Drug Regulatory Authority. This is an important step and as generic products start to be prequali"ed in coming months and years will put pressure on other manufacturers to get their products prequali"ed and on other procurements agencies to procure prequali"ed products. In 2006, there was consensus among most procurers that the WHO scheme was “a good thing”, and an expectation that the programme would rapidly approve the emerging vendors they were engaging. Since then, with no discernible progress in relation to generic manufacturers, they have continued to develop supply relationships based primarily on price, opportunity and demand from the "eld, adopting various, and often incomplete approaches to quality assurance validation. It is fair to argue that the prevailing attitudes to prequali"cation are not entirely positive among procurers. Understandably, there is frustration at what is perceived as a lack of progress. More importantly, as time passes and supply relationships mature, the retrospective evaluation of their vendors becomes a more complicated and troublesome proposition, leading to a degree of resistance. At a Procurer’s meeting, convened by UNFPA in Washington DC in May 2010, many of these issues were articulated and presented in detail for the "rst time, resulting in an increased awareness of the importance of quality assurance, the direct impact on the safety and e!cacy of the products and the institutional risks and potential liabilities for the procuring organizations. It is planned to move towards continuing and consist- ent improvement in procurement practices until there is a su!cient number of prequali- "ed products, and at the same time begin to reduce the risks through more informed purchasing decisions. The objective is to build consensus and acceptance of this more harmonized approach and establish common approaches to limit risk exposure until prequali"cation is able to o#er a range of products in each category, after which time prequali"cation products (or SRA approved) will prevail as the norm. 23 Conclusion We believe that to achieve the Millennium Development Goals, reproductive health commodities do matter! We also believe, like WHO, UNFPA and many members of RHSC, that all reproductive health products made available to developing countries, should be of the same demonstrable quali- ty as similar products provided to people in developed countries To provide universal access to reproductive health commodities, they must be a#ord- able and of assured quality, something that can only be addressed by accessing generic medicines. The recent adoption of UNFPA’s procurement policy similar to that of GFATM underpins this view. As discussed, the primary reason for the lack of prequali- "ed generic products is the ability of the manufacturers to meet this criterion. As such, assistance must be provided to those manufacturers which are willing to make the necessary technical and "nancial commit- ments and which we believe, with techni- cal support and strategic investments, can bridge the gap to prequali"cation in the short to medium term. The report of the 2007 study by Concept Foundation stated that “Generic manufac- turers that understand the need to comply with an internationally accepted set of manufacturing practices governed by the most current GMP regulations will help build the new layer of trusted suppliers into international markets, while others will stay con"ned to their territories of origin with non-competitive products. As such, it is necessary that the regulatory agencies implement the most current GMP require- ments to ensure that quality performance is achieved and hence build the trust of end-us- ers that there is no doubt that products are of necessary quality. Health providers and consumers need to understand that proper- ly produced generic products manufactured under these regulations are as safe and e#ective as branded products from major multinationals.” This remains true but now manufactur- ers have the opportunity of getting their products prequali"ed by WHO and maximiz- ing their markets through participation in tender procedures organized by interna- tional procurers. It also means that build- ing con"dence in the WHO Prequali"ca- tion Programme is critical as procurement agencies begin to accept common quality assurance de"nitions and procedures, based upon the prequali"cation of quality products. There is still much to do. It is essential that within the next two to three years there is an adequate range of quality generic products prequali"ed by WHO and that procurement agencies begin to adopt common procure- ment policies that build on the availability of a#ordable products of assured quality. Manufacturers must have the incentives to produce the required essential medicines for reproductive health; governments must create budget lines for essential reproductive health commodities; and donors must assist in ensuring these activities are supported. Concept Foundation 17 chemin Louis-Dunant 1202 Geneva Switzerland Tel: +41-22-734 2560/1

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