Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement
Publication date: 2017
Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 2 | P a g e 1 Table of Contents 2 Acknowledgements . 4 3 Abbreviations . 5 4 Glossary . 6 5 Background . 12 6 Scope . 14 7 Intended Audience . 15 8 How to Use this Document . 15 9 Overview of Pregnancy Tests . 18 10 Quality Standards and Regulatory Requirements . 19 Quality Standards . 19 Regulatory Requirements for Marketing Clearance . 20 CE Marking . 21 U.S. FDA 510(k) Clearance . 22 Stringent regulatory assessment by Health Canada, TAG, PMDA and MHLW . 23 National Registrations and ROW Approvals . 23 11 Performance Specifications . 25 Analytical Performance Characteristics of Pregnancy Tests . 25 Target Antigen/Analyte . 25 Analytical Sensitivity (also known as Detection Limit) . 25 Analytical Specificity . 25 Clinical Performance Characteristics of Pregnancy Tests . 26 Clinical Sensitivity and Clinical Specificity. 26 Accuracy . 26 Interfering Agents . 26 12 Operational Specifications . 28 Test Format and Ancillary Items . 28 Components of a Pregnancy Test . 28 The Test Line and Control Line . 30 Test Procedure and Result Interpretation . 30 Claimed Shelf Life . 32 Transportation Stability . 32 Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 3 | P a g e Packaging and Kit Content . 33 Labeling Requirements . 34 Instructions for Use (IFU). 34 Labeling on Primary Packaging . 36 Labeling on Secondary Packaging (Cartons and Boxes) . 36 13 Summary of Current, Recommended and Enhanced Quality and Performance Practices . 38 14 Work instructions for quality evaluation of pregnancy tests . 40 15 References . 41 16 Annexes . 45 Annex 1: Use of Pregnancy Tests and Pregnancy Checklist in Family Planning Programs . 46 Annex 2: Prevailing Quality and Performance Characteristics of Pregnancy Tests in Low Resource Low Resource Settings . 48 Annex 3: IMDRF Management Committee . 49 Annex 4: Checklist for Evaluation of Pregnancy Tests . 50 Annex 5: Recommended Guidance Documents on Procurement Process and Supply Chain Management . 55 Annex 6: The Logistics Cycle . 56 Annex 7: Assay Principle of Pregnancy Test . 57 Annex 8: CE Marking Conformity as specified in Directive 98/79/EC of the European Parliament and of the Council . 58 Annex 9: Screenshot of FDA Premarket Notifications 510(k) Clearance Webpage for Verification Purposes . 59 Annex 10: Desiccants and Their Usage . 60 Annex 11: Definitions of Symbols Recommended for Labeling . 61 Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 4 | P a g e 2 Acknowledgements This work was led by FHI 360 under the Envision FP project, which is funded by the U.S. Agency for International Development (USAID). Work was carried out in collaboration with the Reproductive Health Supplies Coalition’s (RHSC) Market Development Approaches Working Group and the New/Underutilized Reproductive Health Technologies Caucus. The co-authors worked closely with members of an expert review committee that provided extensive review of the document. Committee members: FHI 360: This document was researched and written by Tracey Brett, Ashini Fernando, Kate Rademacher, John Stanback, and David Jenkins. Expert review and input was provided by Aida Cancel, Laneta Dorflinger, Joanne Kochuk, Diane Lou, Kavita Nanda and Markus Steiner. External technical review and input was provided by experts from Abt Associates (Francoise Armand and April Warren), Management Sciences for Health (Kate Cho and Maheen Malik), Marie Stopes International (Jason Bower), PATH (Roger Peck), Population Services International (Munish Mehotra), RHSC (Sophia DeLevie-Orey and Julia White), United Nations International Children’s Emergency Fund (Irene Ayako), USAID’s Center for Accelerating Innovation and Impact (Amy Lin), USAID’s Office of Population & Reproductive Health (Kevin Peine, Jane Mwangi and Hayley Traeger) and World Health Organization (Mozzam Ali). Additional expert review was provided by Anita Sands. Authors would also like to acknowledge suppliers and manufacturers of pregnancy tests who provided input and feedback. Recommended citation: Family Health International 360. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement. USA. 2017. To provide feedback or for more information: FHI 360, 359 Blackwell Street, Suite 200, Durham, North Carolina 27701, USA T: 1.919.544.7040 F: 1.919.544.7261 Email: email@example.com This work was made possible by the generous support of the American people through USAID. The contents do not necessarily reflect the views of USAID or the United States Government. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 5 | P a g e 3 Abbreviations 21 CFR Title 21 of the U.S. Code of Federal Regulations CE European Conformity cGMP Current Good Manufacturing Practice COA Certificate of Analysis DOC Declaration of Conformity EC European Commission EU European Union FIND Foundation for Innovative New Diagnostics FDA Food and Drug Administration (United States) GHTF Global Harmonization Task Force hFSH Human Follicle Stimulating Hormone hCG Human Chorionic Gonadotrophin hLH Human Luteinizing Hormone IFU Instructions for Use IMDRF International Medical Device Regulatory Forum IVD In Vitro Diagnostic ISO International Organization for Standardization MHLW Ministry of Health, Labor and Welfare (Japan) MRDTs Malaria Rapid Diagnostic Tests NGO Nongovernmental Organizations NRA National Regulatory Authority PMDA Pharmaceutical and Medical Device Agency POC Point of Care RDT Rapid Diagnostic Tests SRA Stringent Regulatory Authority hTSH Human Thyroid Stimulating Hormone TGA Therapeutic Goods Administration (Australia) USAID United States Agency for International Development WHO World Health Organization Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 6 | P a g e 4 Glossary Provided below is a compilation of common definitions copied and referenced from normative documents or peer-reviewed journals. Some definitions have been adapted to apply to pregnancy tests, as indicated. 21 CFR 820: Also known as Quality System Regulation (QSR), 21 CRF 820 outlines current good manufacturing practice (cGMP) regulations that govern the methods used in, and the facilities and controls used for the design, manufacture, packaging, labeling, storage, installation and servicing of all finished medical devices intended for human use. These requirements are intended to ensure safety and effectiveness of medical devices for the end user. All medical device manufacturers supplying medical devices to the U.S. are required by the U.S. FDA to maintain a quality management system in compliance with that described in 21 CFR 820 (1). 510(k) clearance: A premarket submission made to U.S. FDA to demonstrate that the device to be marketed is at least as safe and effective (i.e., substantially equivalent) to a legally marketed device that is not subject to ‘premarket approval.’ Submitters must compare their device to one or more similar, legally-marketed devices and make and support their substantial equivalency claims (2). While human data are not required for this assessment, laboratory testing data are almost always required. Accelerated stability evaluation: Study designed to increase the rate of chemical and/or physical degradation or change of an in vitro diagnostic (IVD) reagent by using stress environmental conditions to predict shelf life (3). Note: The design of an accelerated stability evaluation can include extreme conditions of temperature, humidity, light or vibration. Accuracy: Amount of agreement between results from the test under evaluation compared with results obtained with the reference standard on the same subjects. Accuracy can be expressed in a number of ways, including sensitivity-specificity pairs, likelihood ratios, diagnostic odds ratios and area under the curves (adapted from (4)). Analytical sensitivity: Represents the smallest amount of substance in a sample that can accurately be measured by an assay (5). Analytical specificity: Refers to the ability of an assay to measure a particular organism or substance, rather than others, in a sample (5). Ancillary items: Items required to perform the pregnancy test at point-of-use, such as the urine collection cup and dropper (adapted from (6)). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 7 | P a g e Antibody: Immunoglobulin with a particular amino acid sequence and tertiary structure that binds to a complementary structure on the antigen, called the epitope. The combining sites on the antibody and the antigen fit tightly together with a strong attractive force because the matching areas on the surface of each molecule are relatively large (6). Antigen: A substance that can elicit a specific immune response due to specific configurations (epitopes) on the surface of the high molecular mass molecules (e.g. proteins, polysaccharides and nucleic acids) (6). The predominantly used target antigen in pregnancy tests is human chorionic gonadotropin (hCG). Assay principle: Fundamental concepts on the composition and operation of pregnancy tests. Analytical performance: The ability of an IVD medical device to detect or measure a particular analyte (7). Authorized Representative: Any natural or legal person established within a country or jurisdiction who has received a mandate from the manufacturer to act on its behalf for specified tasks with regard to the latter’s obligation under that country or jurisdiction’s legislation (7). Batch: A defined quantity of product manufactured in a single process or series of processes and therefore expected to be homogeneous (6) (sometimes used interchangeably with ‘Lot.’) Expiry date: Date on a container (usually on the label) of a product up to and including which the product is expected to meet specifications, if stored correctly. The shelf life, as established by adequate stability studies, is defined for each batch at the date of manufacture (6). CE mark: On pregnancy test packaging, a mark certifying that the product conforms to the essential requirements of European Medical Device Directive 98/79/EEC (adapted from (8)). current Good Manufacturing Practices (cGMP): That part of quality assurance which ensures that products are consistently produced and controlled to quality standards appropriate to their intended use and as required by the marketing authorization (9). Clinical sensitivity: Also known as diagnostic sensitivity, it is the test’s ability to detect persons with the condition of interest in a population or group and is expressed as a proportion or percentage: the number of persons who have both the condition and a positive test result divided by the number of persons who have the condition (adapted from (5)). Clinical specificity: Also known as diagnostic specificity, it is the ability of an assay to correctly identify a person who does not have the condition in question and is expressed as a proportion or a percentage: the number of persons who do not have the condition and produce negative results divided by the number of persons who do not have the condition (adapted from (5)). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 8 | P a g e Compliance/conformity: Fulfillment of regulatory requirements (7). Directive 98/79/EC: Specific to safety, quality and performance of in vitro diagnostic (IVD) medical devices; manufacturers must meet criteria specified in the directive to qualify for CE marking and legal placement of an IVD on the European Market. Effectiveness: Degree to which activities produce the effects planned (9). Efficiency: Relationship between the results of activities and the corresponding effort expended in terms of money, resources and time (9). EU Declaration of Conformity: The document in which the manufacturer states that the product satisfies the essential requirements of the applicable legislation. By drawing up and signing the European Union (EU) Declaration of Conformity, the manufacturer assumes responsibility for the compliance of the product (10). Human chorionic gonadotropin (hCG): A hormone produced by trophoblastic tissue when fertilization has occurred. In a 28-day cycle with ovulation occurring at Day 14, upon fertilization, hCG can be detected in urine or serum in minute quantities around Day 23, or five days before expected menstruation. Its function includes facilitation of implantation as well as maintenance and development of corpus luteum. In normal subjects, hCG in urine provides an early indication of pregnancy (adapted from (11)). Instructions for use (IFU): Information provided by the manufacturer to inform device user of the medical device’s intended purpose and proper use and of any precautions to be taken (7). Intended use/purpose: The objective intent of the manufacturer regarding the use of a product, process or service, as reflected in the specifications, instructions and information provided by the manufacturer (7). In vitro diagnostic (IVD) medical device: A device, whether used alone or in combination, intended by the manufacturer for the in vitro examination of specimens derived from the human body solely or principally to provide information for diagnostic, monitoring or compatibility purposes (7). Note: IVD medical devices include reagents, calibrators, control materials, specimen receptacles, software, and related instruments/apparatus or other articles and are used, for example, for the following test purposes: diagnosis, aid to diagnosis, screening, monitoring, predisposition, prognosis, prediction, determination of physiological status. In some jurisdictions, certain IVD medical devices may be covered by other regulations. Invalid test: Test wherein the control line does not appear (6). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 9 | P a g e IVD medical device for self-testing: Any in vitro diagnostic medical device intended by the manufacturer for use by lay persons (7). International Medical Device Regulatory Forum (IMDRF): A voluntary group of international medical device regulators whose aim is to accelerate international medical device harmonization and convergence, and builds on foundational work done by the Global Harmonization Task Force on Medical Devices. ISO 15223: Standard that identifies the requirements for symbols used in medical device labeling to convey information on the safe and effective use of devices (12). ISO 13485: A quality management system created by the ISO for medical device manufacturing. The standard prescribes the documentation, procedures and structures that must be followed in all types of organizations to facilitate the production of medical devices of consistent standard (adapted from (13). Labeling: The label, instructions for use, and any other information related to identification, technical description, intended purpose and proper use of the medical device, but excluding shipping documentation (7). Lay person: Individual who does not have formal training in a specific field or discipline (7). Lot: A homogeneous collection of tests made under essentially identical manufacturing conditions using the same lots of raw materials. Manufacturer’s lot identification and recording are required to permit effective product recall in the event of a problem with device quality (adapted from (8)). Lot number or code: A unique identifying alphanumeric code assigned to a Lot (8). Manufacturer: The natural or legal person with responsibility for the design, manufacture, packaging and labeling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party (14). Notified body: A certification organization that the national (competent) authority of a EU Member State designates to carry out one or more conformity assessment procedures described in the annexes of the European Union Directives. The Medicines and Healthcare Products Regulatory Agency is the competent authority in the United Kingdom under the three medical device directives. A notified body must be qualified to perform all the functions set out in any annex for which it is designated. The designation may be restricted to specified types of devices or annexes (6). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 10 | P a g e Packaging: Any material, including printed material, used in the packaging of a medical device but excluding any outer packaging used for transport or shipment. Packaging materials are referred to as ‘primary’ or ‘secondary’ according to whether they are intended to be in direct contact with the product (6). Primary packaging is intended to be in direct contact with the product while secondary packaging is intended to enclose primary packaging. Performance evaluation: The assessment and analysis of data to establish or verify the ability of an in vitro diagnostic medical device to achieve its intended use (13). Point-of-care: A diagnostic test that is performed near the patient or treatment facility, has a fast turnaround time, and may lead to a change in patient management (15) . Procurement process: The process of acquiring supplies from private or public suppliers or through direct purchases from manufacturers, distributors or agencies (6). Quality: The totality of features and characteristics of a product or service that bear on its ability to satisfy stated or implied needs (16). Quality management system: The organizational structure, responsibilities, procedures, processes and resources for implementing quality management. For the purpose of these guidelines, ‘implementing quality management’ includes both the establishment and maintenance of the system (7). Quality assurance: A wide-ranging concept covering all matters that individually or collectively influence product quality. The totality of arrangements made with the objective of ensuring that products are of the quality required for their intended use (9). Real time stability evaluation: A study designed to establish or verify the shelf life of the IVD reagent when exposed to the storage conditions specified by the manufacturer (3). Note: Conditions that can affect stability of an IVD reagent include temperature, transport conditions, vibration, light, and humidity. Regulatory approval: The process by which a party submits information to the regulatory authority in a jurisdiction, regarding the identification and establishment of location(s) of the manufacturer and other parties, responsible for supplying a medical device to the market in that jurisdiction (7). Regulatory authority: A government body or other entity that exercises a legal right to control the use or sale of medical devices within its jurisdiction, and that may take enforcement action to ensure medical products marketed within its jurisdiction comply with legal requirements (7). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 11 | P a g e Regulatory requirements: Any part of a law, ordinance, decree, or other regulation which applies to medical device manufacturers (7). Note: Guidelines, draft documents or the like should not be used as regulatory documents and should not be considered as such, unless formally widely known. For purposes of this guidance, regulatory requirements are restricted to those pertaining to the quality management system. Specimen: Material collected directly from a patient; the term ‘sample’ is reserved for aliquots (portion of a larger whole) of the patient specimen and for processed material (17). Self-testing: Testing performed by lay persons (7). Device is intended by the manufacturer to be able to be used in a clinical setting or home environment. Shelf life: Period of time until the expiry date during which an IVD device/reagent in its original packaging maintains its stability under storage conditions specified by the manufacturer (18). Stability: Ability of an IVD to maintain its performance characteristics within limits specified by the manufacturer (18). Stability testing: Long-term accelerated (and intermediate) studies undertaken on batches according to a prescribed protocol to establish or confirm the re-test period (or shelf life) of a product (6). Specification: A detailed statement of a product’s requirements, as established by the buyer. Usually, a specification is based on an established standard (8). Standard: A detailed statement of the minimum acceptance requirements, as established by a national or international regulatory body (8). Technical documentation/file: The documented evidence, normally an output of the quality management system that demonstrates conformity of a device to the Essential Principles of Safety and Performance of Medical Devices (7). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 12 | P a g e 5 Background Ensuring access to low-cost, high quality, pregnancy tests1 has been shown to increase same- day provision of family planning, and aid in the timely provision of antenatal care (19-22). However, in many settings, pregnancy tests are not routinely available for clients, are marked up to unaffordable prices, are of questionable quality and/or of variable performance. In 2015, FHI 360 partnered with Marie Stopes International to conduct an assessment in Kenya, Malawi and Mali to document the availability, affordability and quality of pregnancy tests. This project was completed with support from the Reproductive Health Supplies Coalition through an Innovation Fund grant. The assessment noted: Concerns about falsified products or falsely CE- marked pregnancy tests entering markets; A lack of knowledge among consumers, providers, importers, distributors, pharmacists and regulatory personnel on internationally recognized quality standards for pregnancy tests, including what existing standards mean and how they can be used to ensure that only pregnancy tests meeting quality and performance standards enter national markets; No publicly available protocol for product qualification or pre-and post-shipment lot verification testing customized for pregnancy tests; Limited visibility for procurers on the supply side (e.g., limited information about suppliers’ prior performance); and A lack of focus and harmonization around quality and performance specifications to be used when selecting pregnancy tests for procurement. 1 Throughout this document, “pregnancy tests” refer to rapid in vitro diagnostic (IVD) pregnancy test used in a point-of-care setting. Ruling out Pregnancy when Providing Family Planning Services In many countries, non-menstruating women are routinely denied same-day family planning services because of a concern among healthcare providers that these women may be pregnant. Several tools can be used by healthcare providers to rule out pregnancy. One is the "Pregnancy Checklist" - a job aid with simple questions that a provider can ask a client to rule out pregnancy. Endorsed by the World Health Organization (WHO) and USAID, the Checklist has been adopted by more than a dozen countries. A simple, low- cost, high quality pregnancy test is another tool. Neither the checklist nor a pregnancy test is clinically effective in all situations. The two tools complement each other. See Annex 1 for more information on when a healthcare provider should use the checklist versus a pregnancy test. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 13 | P a g e Concurrently, FHI 360 carried out an exploratory evaluation of a small number of pregnancy tests, collected from low-resource settings over a two-year period, to develop an understanding of prevailing quality status based on labeling criteria. Preliminary results from this analysis, as summarized in Annex 2, illustrate significant quality, performance and operational gaps in labeling, such as inadequate instructions for use, absence of performance characteristics and standard quality assessment by recognized regulatory authorities. In most developing countries, regulations for IVDs can be inadequate and/or poorly enforced. Global efforts towards harmonization of regulatory approaches have led to internationally accepted standards for a risk-based approach for pre-market assessment of safety, quality and performance of diagnostics. These include a number of regulatory authorities that are founding members of the Global Harmonization Task Force (GHTF): European Union (EU), U.S. Food and Drug Administration (U.S. FDA), Health Canada, Therapeutic Goods Administration (TGA), Australia, and Pharmaceutical and Medical Device Agency (PMDA) and Ministry of Health, Labor and Welfare (MHLW), Japan. The GHTF was later disbanded and its mission was taken over by the International Medical Device Regulatory Forum (IMDRF), which allows for wider participation of some additional regulators – the National Health Surveillance Agency of Brazil; China Food and Drug Administration, Russian Ministry of Health and Singapore’s Health Science Authority (links to main websites provided in Annex 3). In 2016, this guidance document was developed to address some of these gaps in knowledge and practice by outlining requirements for quality standards and performance specifications, derived mainly from the ISO standards, EU and U.S. FDA requirements for marketing clearance, and IMDRF/GHTF and WHO normative documents. This work effect was completed with support from USAID, through its Envision FP award, led by FHI 360 and in consultation with key stakeholder groups. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 14 | P a g e 6 Scope Guidance provided herein is specific to pregnancy tests used in point-of-care (POC)2 settings. It is applicable to the three most common immunochromatographic formats (Figure 1), which are designed to use urine as a specimen, and can be read visually without the aid of an additional device. However, this guidance does not apply to pregnancy tests that use venous or capillary whole blood or serum as a specimen. Specifications cover quality, performance (sensitivity, specificity and accuracy), operational aspects (instructions for use, claimed shelf life, packaging and labeling) and safety criteria, as applicable to pregnancy tests (23). Figure 1: Three formats of pregnancy tests covered in this document 2 POC tests may be performed by non-laboratory personnel, such as physicians, nurses, community healthcare workers, pharmacists and the patient herself (self-test). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 15 | P a g e 7 Intended Audience This document has been designed to provide guidance to personnel involved in product selection in the procurement process. While those who carry out product selection vary depending on country and program context, this group generally includes procurement officers, health officers, quality assurance specialists and/or pharmacists. This group will be collectively referred to as evaluators in this document. This guidance is also relevant to those manufacturers who wish to supply pregnancy tests to global, national and/or local public health programs as well as to policy makers and social marketing and service delivery groups. 8 How to Use this Document Broadly, this document provides recommendations on quality standards (Section 10.1), regulatory requirements (Section 10.2), performance (Section 11) and operational specifications (Section 12) for selection of pregnancy tests. As outlined in Figure 2, areas covered are derived from ISO standards, U.S. FDA and EU regulatory requirements, and GHTF/IMDRF and WHO guidance for IVDs. References for further evaluation by other IMDRF members are provided in Annex 3, while Rest of the World (ROW) regulations are briefly discussed in Section 10.2.4. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 16 | P a g e Figure 2: Areas of guidance covered in this document Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 17 | P a g e When using this document, please note the following: In developing this document, careful consideration was given to the unique challenges in low-resource settings. Recommendations discussed herein were, through a consensus-driven process, considered as adoptable by most countries, regardless of maturity level of regulatory infrastructure. ‘Enhanced quality and performance practices’ have been included in green boxes for consideration by countries with more mature regulatory infrastructure. Recommended documentation for evaluators to request from manufacturers is summarized in orange boxes. For a listing of all documentation that evaluators should request from manufacturers, see checklist in Annex 4. Blue call-out boxes with a magnifying glass highlight further clarifications. This document is not intended to replace existing guidance on product selection processes, but rather to provide additional guidance tailored specifically to selecting pregnancy tests that meet high quality and performance standards. o For guidance on procurement processes and supply chain management, see Annex 5 for a recommended reading list. o For information on the logistics cycle and on continuous quality monitoring and evaluation, see Annex 6. Involvement of technical and quality assurance experts with specific insight into product selection and procurement of health commodities—in particular, IVDs and rapid diagnostic tests (RDTs)—is recommended. Detailed annexes on other pertinent areas also have been provided for those wanting more information. Documentation for evaluators Enhanced quality and performance practices Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 18 | P a g e 9 Overview of Pregnancy Tests Pregnancy tests are also known as ‘urine pregnancy tests,’ ‘home pregnancy tests,’ ‘hCG/HCG tests,’ and ‘over-the-counter pregnancy tests.’ In addition, the term ‘point-of-care pregnancy test’ is often used when the test is administered by a provider. Typical pregnancy tests are designed to provide only a positive or a negative (yes/no) result. The principle behind this type of pregnancy diagnosis is shown schematically in Annex 7. Briefly, a dipstick is assembled by layering a sample pad, a conjugate pad with detection antibodies, a nitrocellulose membrane with test and control lines and an absorbent pad, on to a plastic backing. Test and control lines carry antibodies against human chorionic gonadotrophin (hCG) and mouse immunoglobulin, respectively. For cassette and some midstream pregnancy tests, the dipstick is encased in plastic housing. Adding urine specimen to the dipstick triggers detection antibodies to mobilize through capillary action. Presence of hCG leads to localization of the detection antibody to the test line yielding a positive signal. Localization of the detection antibody to the control line is independent of hCG, and by yielding a signal, it validates that the assay and the reagents are operating as expected. If the test is positive for hCG (and therefore pregnancy), both the test and control lines should develop; if the test is negative, only the control line should develop. A woman begins to produce hCG hormone six to 12 days after egg fertilization. As the pregnancy progresses, hCG levels continue to rise, and plateau around 45 days post-conception (11). Ninety-eight percent of pregnant women have urine concentrations of hCG > 25 mIU/mL by the day of their next expected period (11, 24-26). Due to natural fluctuations in menstrual cycles and variable analytical sensitivity of pregnancy tests, pregnancy diagnosis prior to one or two weeks after the missed period remains challenging (27).3 Other service delivery tools also can be used to rule out pregnancy; this is particularly important when non-menstruating clients present for family planning services. In these cases, providers can often exclude pregnancy with a simple client history, sometimes taken with the help of the “Pregnancy Checklist” job aid (21, 28). The Pregnancy Checklist has been endorsed by the World Health Organization and adopted by many countries. If client history remains inconclusive when using the Pregnancy Checklist, a pregnancy test can help the provider be reasonably certain that the client is not pregnant (and thus eligible for a hormonal contraceptive or an intrauterine device). See Annex 1 for more information about using the Checklist in tandem with pregnancy tests. 3 Highly sensitive tests (analytical sensitivity < 25 mIU/mL) detect pregnancy as early as the first day of missed menses. Lower sensitivity tests (analytical sensitivity >50 mIU/mL) detect about 10 days after missed menses (27). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 19 | P a g e 10 Quality Standards and Regulatory Requirements This document briefly discusses quality standards applicable to IVDs, as detailed in ISO 13485 and market clearance regulatory requirements of U.S. FDA and EU directives. A brief description of regulatory information pertaining to Health Canada, TGA, PMDA, MHLW and ROW is also included. Demonstration of compliance to quality standards and regulatory requirements involves a choice of testing pathways that depends on medical device classification. Such classification is based on perceived risk to the user associated with the device. The U.S. FDA, Health Canada, PMDA, MHLW and TGA have classified the pregnancy test as a Class II device (medium risk), while the EU has classified it as a self-test under Class I device (low risk).4 Quality Standards Quality standards are documented agreements containing technical specifications or other precise criteria used as rules, guidelines or definitions of characteristics, to ensure that materials, products and process fit their purpose (29). A well-established quality management system ensures quality consistency and provides the basis for greater reliability in device safety and performance (29). It is critical for manufacturers to conform with quality standards, and for this conformity to be periodically audited by governmental or third party agencies (29). It is recommended that pregnancy test manufacturing sites comply with quality management system standard ISO 13485,5 a globally recognized system for the design, development and manufacture of medical devices. The U.S. FDA equivalent is 21 CFR part 820 cGMP/QSR. Since pregnancy tests are classified in the low to medium risk category, their compliance with quality- related regulations often depends on the declarations of manufacturers. Manufacturers are expected to prepare technical documentation illustrating how each pregnancy test product has been designed, developed and manufactured. This documentation is typically controlled by quality management systems. 4 Several different international classification systems for IVDs are in use in the world today. Generally, the classification is assigned by the intended use and the risk the device presents to the patient. As the classification level increases from Class I to Class IV, the risk to the patient and regulatory control increases. 5 ISO 13485:2016 was released in 2016 and will coexist with ISO 13485:2003 through March, 2019, after which point only ISO 13485:2016 will be accredited. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 20 | P a g e Documentation for Evaluators on Quality Standards: It is recommended that evaluators request a copy of the manufacturer’s ISO 13485 certification at the time of evaluation. The certificate of conformity should include: Manufacturer’s certified quality management system standard Name and country of assessment body Date of last audit Date of expiration. In addition, the certification should have the same manufacturing site address as that on product labeling, and explicitly include the manufacture of IVDs in its statement of scope. It is recommended that ISO certification be checked and verified on the website of the certification body or by directly contacting the certification body. Verification will have value if the certification body is accredited by the competent body for the country in question. Regulatory Requirements for Marketing Clearance IVDs must satisfy safety, performance, quality system and labeling requirements to meet the varying regulatory requirements of different regulatory bodies (29). The degree of regulatory scrutiny is based on the potential risks of IVDs, and pregnancy tests are classified as low to medium risk. Regulatory authorities acknowledge product clearance for market in various ways. Key mechanisms are summarized below in Section 10.2.1 for the EU and Section 10.2.2 for the The industry standard for quality management, ISO 9001, should not be confused with quality system standard ISO 13485. Proof of compliance with ISO 9001 alone, as commonly seen with pregnancy tests, is not adequate for compliance with ISO 13485. ISO 9001: This standard sets the requirements for an organization-wide quality management system with continual improvement. It helps businesses and organizations be more efficient and improve customer satisfaction (30). ISO 13485: This quality management system standard sets requirements for an organization to demonstrate its ability to provide medical devices and related services that consistently meet customer and regulatory requirements. All ISO 13485 requirements are specific to organizations providing medical devices, regardless of the type or size of the organization (13). This standard is required in many countries as the basis for quality assurance management of IVDs for their registration and regulatory control. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 21 | P a g e U.S. FDA. Approval by other regulatory authorities who were founding members of GHTF also can be considered, subject to evaluators’ understanding and knowledge of these groups (Section 10.2.3). Annex 3 provides a list of regulatory authorities with links to their websites. CE Marking In the European system, IVD directive 98/79/EC addresses safety, quality and performance of IVDs. It aims to ensure that IVDs do not compromise the health and safety of users and third parties, and that performance levels specified by the manufacturer are attained (14). It also provides regulatory requirements for obtaining the CE marking. Since pregnancy tests belong to the “self-test” classification, the conformance process requires involvement of a notified body within the EU. Upon receipt of the EC certificate from a notified body, the manufacturer places the CE mark on or with the device (29). The CE marking should comply with the schematics indicated in Figure 3 and elaborated in Annex 8. It must be accompanied by the identification number of the notified body (usually a 4-digit number). The CE marking and notified body identification number must appear on the device (if practicable), on primary and secondary packaging, and in the product insert. Avoid selecting products that carry nonconforming CE markings, as noted in Figure 3 (31).6 Figure 3. Comparison of CE marking of conformity and nonconformity (32) It is recommended that the manufacturer draw up a Declaration of Conformity (DoC) to declare sole responsibility for conformity to the relevant directive. The DoC should detail 6 Please refer to the WHO fact sheet to find out more about prevalence of substandard, spurious, falsely labeled, falsified and counterfeit medical products: http://www.who.int/mediacentre/factsheets/fs275/en/ Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 22 | P a g e the information highlighted in the orange box below. The DoC should be made available to evaluators at the time of tender submission or supplier selection. Documentations for Evaluators on CE Marking: It is recommended that evaluators request a copy of EU/EC Declaration of Conformity from the manufacturer at the time of assessment. The Declaration of Conformity should indicate: Manufacturer’s name and address Name of device Essential characteristics of device Information of regulatory authority/notified body Marketing clearance with indication of license number Legally binding signature of corporate officer signing on behalf of the organization. U.S. FDA 510(k) Clearance A manufacturer who intends to market a pregnancy test in the U.S. is required to submit a 510(k) application, also known as a Premarket Notification. For this process, the manufacturer must provide evidence demonstrating that the device to be marketed is at least as safe and effective as a legally marketed/predicate device. This is also known as demonstration of ‘substantial equivalence’(2). Once the manufacturer receives written notification of FDA clearance that confirms ‘substantial equivalence’ to a legally marketed product, the test can be marketed in the U.S. Note that FDA clearance is not indicated on the package labeling. 510(k) clearance is required only for pregnancy tests intended for sale in the U.S. market. For international procurers considering pregnancy test products that claim to be U.S. FDA-cleared, it is highly recommended to confirm that the manufacturer holds 510(k) clearance by visiting the 510(k) pre-market notification website: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm Pregnancy test ‘product code’: LCX Refer to Annex 9 for a screenshot of the FDA website. It is likely that a different quality ‘export only’ version of the FDA-approved product is manufactured for use outside of the U.S. It is important for evaluators to check and verify these quality discrepancies for alignment with programmatic needs. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 23 | P a g e Documentation for Evaluators on U.S. FDA Clearance: It is recommended that the evaluator request a 510(k) device clearance letter. In addition, the evaluator should check for 510(k) clearance on the U.S. FDA website (Annex 9) Stringent regulatory assessment by Health Canada, TAG, PMDA and MHLW Authorities acknowledge product clearance for market in various ways. Helpful information to verify pregnancy tests manufactured/approved in Canada, Australia, and Japan is provided below (Table 1). Table 1: Tools to verify pregnancy test regulatory clearance in Canada, Australia, and Japan Regulatory Authority Classification Documentary Evidence Health Canada Class II - Medical device license: https://health-products.canada.ca/mdall-limh/index-eng.jsp - ISO 13485 certificate issued by the Canadian Medical Device Conformity Assessment System TGA, Australia - TGA conformity assessment certificate: https://tga- search.clients.funnelback.com/s/search.html?query=&collectio n=tga-artg - TGA issued ISO 13485 Certificate PMDA and MHLW, Japan - Certification by registered certification body - PMDA General information: https://www.pmda.go.jp/english/ - MHLW General Information: http://www.mhlw.go.jp/english/ Contact PMDA directly for product-specific information National Registrations and ROW Approvals For some markets, ISO 13485 is not sufficient for the regulatory approval of medical devices, and an appropriate regulatory certification issued by the National Regulatory Authority (NRA) also may be required. However, in a number of countries, regulations applicable to diagnostics range from generally weak to non-existent. Given this lack of regulatory oversight, an assessment by another regulatory authority is often used as an alternative or complementary Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 24 | P a g e strategy to gain national approval. It is recommended that the device go through stringent regulatory approval in addition to meeting ISO 13485. While a number of regulatory agencies in developing countries have not yet established regulatory requirements for medical devices (including IVDs such as pregnancy tests), many are in the process of developing such guidelines. The landscape is changing rapidly and different NRAs will have different requirements. Prior to purchasing pregnancy tests for specific markets, evaluators are advised to check the national regulatory requirements of the country in question. The Contraceptive Technology Innovation Exchange provides links to several regulatory agencies and resources. Pregnancy tests may be approved in the country of origin/manufacture either ‘for sale and use in the country of origin’ or ‘for export only’(33). Given differences in regulatory requirements, manufacturers often supply different regulatory versions of the ‘same diagnostic’ for markets with stringent regulatory controls versus those with little or no regulatory control (the latter group is often referred to as ‘Rest of the World’ regulatory versions). While a manufacturer may produce a stringent, regulated version of the product, it may also supply a less regulated or unregulated version of the same product without any assurance that the same quality control components and procedures were used to manufacture it. Regulatory requirements for ‘export only’ products are usually less stringent than those ‘for sale and use.’ Approval for ‘export only’ generally does not provide sufficient evidence of regulatory review of safety, quality and performance (33). It is therefore crucial that evaluators request supportive documentation to verify the exact regulatory status of the product to be procured. Documentation for Evaluators on Other Regulatory Approvals: It is recommended that evaluators: Check the regulatory requirements of the country in question prior to purchasing pregnancy tests Verify regulatory approvals applicable to the pregnancy tests that have been approved by other stringent regulators. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 25 | P a g e 11 Performance Specifications Performance specifications include sensitivity, specificity and accuracy parameters, and are instrumental in identifying performance requirements of pregnancy tests to meet programmatic needs. By knowing the analytical sensitivity of a pregnancy test, service providers can more fully understand how accurately a particular test can diagnose early pregnancy (27).7 This information may be included in the Quality Control (QC) Lot Release Certification, Instructions for Use (IFU) and/or the Technical File. Analytical Performance Characteristics of Pregnancy Tests The specifications and test panels recommended below have been derived from scientific literature and best practices, as outlined in documentation in GHTF, WHO, U.S. FDA and EC directives. Manufacturers’ inclusion of these performance metrics in the IFU and/or QC lot release certification aids the procurement decision-making process. Target Antigen/Analyte As described in Section 9, pregnancy tests are designed to identify hCG protein in urine. In this context, hCG protein is typically considered as the antigen or analyte, which is detected and qualitatively measured by the test. Analytical Sensitivity (also known as Detection Limit) It is recommended that the pregnancy test detect 25 mIU/mL as the criterion for analytical sensitivity; 98% of women who conceive have been shown to have 25 mIU/mL of hCG in urine on the first day after the missed period (24, 26, 34). If clinical evidence exists, the manufacturer may state the number of days after the missed period/menses to yield a positive test result (11). It is further recommended that the manufacturer state the analytical sensitivity in the IFU and have supporting evidence on file that can be made available for review, upon request. Analytical Specificity It is strongly recommended that the manufacturer state the outcomes of any specificity/cross- reactivity testing done with human form of luteinizing hormone (hLH), follicle stimulating hormone (hFSH) and thyroid-stimulating hormone (hTSH). Recommended concentrations for 7 If using highly sensitive pregnancy tests (analytical sensitivity < 25 mIU/mL), pregnancy can be detected as early as the first day of missed menses. If using tests with lower sensitivity (analytical sensitivity > 50 mIU/mL), it is recommended to wait up to 10 days after expected date of menses before testing. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 26 | P a g e testing are: 300 mIU/mL for hLH, 1000 mIU/mL for hFSH, and 1000 µIU/mL for hTSH. It is recommended that the manufacturer state the analytical specificity in the IFU and have supporting evidence on file that can be made available for review, upon request. Clinical Performance Characteristics of Pregnancy Tests Clinical performance characteristics demonstrate that the IVD achieves its intended performance during normal conditions of use in the intended environment (e.g., laboratory, physician’s office, healthcare center, home environment) and in the intended population (35). Clinical performance metrics confirm aspects that cannot be determined by analytical performance metrics. Clinical Sensitivity and Clinical Specificity Regulatory authorities, such as the U.S. FDA, do not require clinical evidence for approval/ clearance of the pregnancy test formats discussed in this document. While manufacturers are encouraged to provide clinical performance metrics, such as clinical/diagnostic sensitivity or clinical/diagnostic specificity, it is not mandatory. Accuracy Diagnostic accuracy can be expressed in a number of ways, leading to exaggerated results that may result from poorly designed studies (4). The U.S. FDA recommends that accuracy claims not exceed 99% (11). Statements such as ‘100% accurate, virtually 100% accurate, nearly 100% accurate’ must always be proven by detailed clinical evidence (performance evaluation). Interfering Agents Interfering agents can be a significant source of error in diagnostic measurements, also leading to falsely increased or decreased results. Potentially interfering agents may originate either endogenously (e.g., hemoglobin, albumin, bilirubin) or exogenously (e.g., a drug or its metabolites, a specimen preservative) (17). Pregnancy test interference screening should take into consideration substances that are likely to be present in urine, the chemistry of the testing procedure and its intended use. Since pregnancy tests are based on immunochemical principles, special attention must be given to cross-reactivity of hCG antibodies and endogenous human antibodies that can yield false positives, as observed with malaria rapid diagnostic tests (MRDTs) (36). Details of any substance that has been tested and shown to cause interference with test performance should be stated. Commonly used medications, such as pain relievers, antibiotics and oral contraceptives, should not interfere with test performance; evidence should be Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 27 | P a g e provided to support claims of noninterference (11). Comprehensive guidelines for interference testing can be found in the CLSI EP7-A2 manual (17). Documentations for Evaluators on Performance Specifications: It is recommended that evaluators ask that manufacturers to provide IFU or a QC Lot Release Certification containing performance specifications that reflect: Analytical sensitivity Analytical specificity Clinical sensitivity and clinical specificity (if available) Accuracy If the IFU or other QC certification does not contain this information, it is recommended that the evaluator ask the manufacturer to provide this information from Technical Files. Enhanced Quality and Performance Practices on Performance Specifications: Include a list of interfering agents Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 28 | P a g e 12 Operational Specifications Operational specifications are equally as important as performance specifications; both must be used in product selection (37). The following sections cover areas of operational specifications, including test formats, ancillary items, test procedure, result interpretation, claimed shelf life, packaging and labeling. Many of the recommended criteria in this section are based on WHO and FIND efforts to standardize and harmonize malaria rapid diagnostic tests (MRDTs), which follow the same assay principle as pregnancy tests (6, 36). Test Format and Ancillary Items Because the three pregnancy test formats operate slightly differently in terms of specimen application, additional components are required to carry out the testing. The sections below discuss these requirements and testing methods, as applicable to each format. Components of a Pregnancy Test Pregnancy tests usually come in three formats: cassette, dipsticks and midstream test strips. Note that certain ancillary items, e.g., sample transfer device/droppers or the urine collection cup as shown in Figure 4, are required but not provided. It is recommended that evaluators determine the need for these items and include them in tender requirements, as appropriate. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 29 | P a g e Figure 4. Examples of the three pregnancy test formats, ancillary items and their usage8 A. Cassette with a well for urine specimen D Cassette The test strip is encased in a plastic cassette. Key features are: control line (C), test line (T) and a sample-well indicating where urine specimen is to be added (S). Ancillary item Sample transfer device/dropper (D), clean cup/tube for urine collection (V) How test is to be used: Collect urine in a clean cup/tube Using the sample transfer device/dropper, transfer a specified volume of urine into the sample-well, placed on a flat surface with result window facing up Read results after the specified period of time (and before the maximum reading time). Based on programmatic point-of-care needs, a space on the cassette to write patient identification information, date and test number is recommended. B. Dipstick Dipstick The test strip is mounted on a laminated strip. Key features are: control line (C), test line (T), and absorbent pad to wick the urine (A). Ancillary item A clean cup/tube for urine collection (V) How test is to be used: Collect urine in a clean cup/tube Dip the dipstick in urine up to the line indicated by arrows (A) for the specified period of time Place the dipstick flat on a surface, with the result window facing up, for the specified period for results to develop. Read results after the specified period (and before the maximum reading time). 8 Diagrams have been adapted from Malaria Rapid Diagnostic Test Performance: Results of WHO product testing of MRDTs; Round 5 (2013). Result window V Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 30 | P a g e C. Midstream test strip Midstream test strip This format is essentially identical to the dipstick format, but has a longer absorbent pad to enable positioning of it directly in the urine stream. Key features are: control line (C), test line (T), and longer absorbent pad to directly hold in the urine stream (A). In an alternate format of midstream test, the dipstick is encased in plastic. Encasing prevents urine from wetting areas other than where intended to capture and absorb it. How test is to be used: Hold the absorbent tip (A) in urine stream for the specified period of time Place the dipstick flat on a surface, with the result window facing up, for a specified period for results to develop. Read results after the specified period (and before the maximum reading time). The Test Line and Control Line Pregnancy tests usually have two lines: one control line and one test line (Figure 4 A, B & C, marked with ‘C’ and ‘T’). It is recommended that IFU include information on exact labeling of these lines per their orientation (i.e., which line is where on the strip). Although not common in low-resource settings, some pregnancy tests may show a ‘plus’ sign (+) or the word ‘positive,’ if positive for pregnancy. Test Procedure and Result Interpretation The test procedure should be documented in sufficient detail to enable an operator to perform a measurement (38). Although RDTs are seemingly robust and simple, they pose significant operational problems due to variations in test procedures and differences in reading and interpreting results (39). Included in the IFU, the test procedure documentation should include step-by-step instructions from collection of urine specimen to reading of results. It should be easy to read and accompanied by illustrations, as highlighted in Figure 5 (39). Timing: When using a pregnancy test, the test and control lines develop, fade and change in intensity over time (6). Because the rate at which this fading takes place depends on the Result window i) ii) Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 31 | P a g e product, ‘stability of results’ must be established by the manufacturer. The time period between when the urine specimen is applied and the results are read is defined as the ‘declared reading time’ (6). As it may not be possible to read a result at an exact moment, especially in point-of-care settings, manufacturers may provide this information as a time range, as in ‘minimum time to results’ and ‘maximum reading time’ or as a ‘recommended reading time’. It is important that the manufacturer display this ‘reading range.’ As outlined in Figure 5, four time points need to be specified by the manufacturer: 1. Time to keep the dipstick immersed in urine or, if using a midstream test strip, time to hold the dipstick in urine stream 2. Time to place the test flat on a surface for the results to develop 3. Time to read the results 4. Time beyond which test results should not be read. Figure 5: Example of test procedure and result interpretation Result interpretation: Figure 5 illustrates four possible result outcomes; all four outcomes should be illustrated in the instructions for use.9 Absence of the control line indicates a problem with the test, and renders the test invalid. 9 The exploratory evaluation of pregnancy tests (Annex 2) illustrates that 66% of pregnancy tests only provide one ‘invalid result’ outcome (the development of test line alone). However, it is important also to include the outcome of a blank result window, which indicates failure in the performance and/or of the procedure of the test. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 32 | P a g e Claimed Shelf Life Claimed shelf life is the period of time during which the test, in its original packaging, maintains its performance characteristics under storage conditions specified by the manufacturer (6, 37). It is the responsibility of the manufacturer to ensure that all claims made regarding shelf life are supported by evidence. It is recommended that manufacturers follow ISO 2364010 when designing shelf life studies. Recommended storage conditions and shelf life should be clearly indicated on the product labeling for all components. It is recommended that pregnancy tests be stable for storage up to 30°C, with stability claims supported by evidence. To assess heat compatibility based on climate conditions of the country/province of supply, an ‘Accelerated Stability Evaluation Report’ with extrapolated data is acceptable for initial shelf life claims, but a ‘Real Time Stability Evaluation Report’ should be provided when it becomes available (3, 37). Documentations for Evaluators on Shelf Life: It is recommended that evaluators request an Accelerated Stability Evaluation Report for initial shelf life claims, but follow up with a Real-time Stability Evaluation Report, when it becomes available. Transportation Stability The basic stability claim for an IVD is claimed shelf life. Two other types of stability claims are ‘in-use claim’ (duration that a product may be used after first opening the primary packaging) and ‘transport stability’ (appropriate shipping and handling conditions for the IVD). Testing for transport stability involves reproducing extreme environmental conditions potentially occurring during transport, such as high and low temperatures, high humidity and light exposure (40). The World Health Organization recommends heat stability testing at 35°C and 40°C for MRDTs as these tests may be subject to extreme temperatures during transport (36). Compromised performance of some MRDT products exposed to high temperatures has been documented (41, 42). Given that the assay principle for MRDTs and pregnancy tests is the same, albeit with different antibodies, it is recommended that evaluators ask manufacturers to provide Transport 10 Current version is ISO 23640:2013 Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 33 | P a g e Validation documentation to demonstrate a heat stability profile within this recommended range, where appropriate. Packaging and Kit Content While packaging covers a range of containers, levels of packaging are usually described as: Primary packaging: individually-sealed pouches containing pregnancy tests (Figure 6A) Secondary packaging: a unit box containing a defined number of pregnancy tests (Figure 6B) (6). Figure 6: Examples of primary and secondary packaging Since pregnancy tests can be sensitive to temperature and humidity, primary and secondary packaging should ensure their protection from high temperatures and humidity throughout the supply chain path (i.e., from manufacturing site, through transport and storage, to point-of-use). Enhanced Quality and Performance Practices for Confirming Transportation Stability: To evaluate the tolerance of IVDs to the anticipated transportation conditions, a Transport Validation Document stating minimum and maximum transport temperatures and durations should be made available. For countries that experience high temperatures and high humidity, evaluators are advised to request supporting data demonstrating IVD stability up to 35-40°C. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 34 | P a g e Based on WHO recommendations for MRDTs for packaging, the addition of desiccants inside primary packaging of pregnancy tests is strongly recommended to preserve the performance of the test (40, 43). Refer to Annex 10 for additional details on desiccants. Packaging specifications should provide sufficient detail on measures taken to ensure integrity of sealing, with no weakness in the sealed areas which could adversely affect performance of the IVD (6). Labeling Requirements Labeling intends to identify the device and its manufacturer, and communicate information on quality, performance, operation and safety to the intended professional or lay user as well as to regulatory authorities (44). In general, labeling should be concise and easy to understand and contain clear illustrations, as applicable. It should cater to the technical knowledge and education of the intended user (44). In regulatory terms, ‘labeling’ includes labels on IVD packaging as well as instructions for use (39). Instructions for Use (IFU) IFU should contain information supplied by the manufacturer to enable safe and proper use of the IVD. Within the context of pregnancy tests, this information should include test procedure and result interpretation, troubleshooting, IVD disposal, warnings, precautions and limitations (38). In low-resource settings, IFUs are typically printed on the primary packaging, which limits the level of detail that can be included. In the developed world, detailed IFU are printed on paper and included as a product insert. Per GHTF (44) and MRDT labeling harmonization recommendations (39), IFU content, tailored to pregnancy tests, should include: a. Name or trade name of pregnancy test b. If not obvious, the device’s intended use/purpose: what is detected (hCG/pregnancy); type of specimen required (urine) c. Intended user: Professional use (may include lay person) d. Indication that test is for IVD use Enhanced Quality and Performance Practices for Packaging and Kit Content: Include humidity-/self-indicator (desiccant that changes color upon exposure to humidity) desiccant in primary packaging, correctly packaged with adequate labeling. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 35 | P a g e e. List of provided materials, along with a list of materials required but not provided (such as urine collection cups and sample transfer devices/droppers, described in Figure 4). f. Performance characteristics (analytical sensitivity, analytical specificity, accuracy, and clinical sensitivity and clinical specificity, if available) g. Indication of special storage and/or handling conditions that apply (e.g., temperature, light, humidity, etc.) h. Warnings, precautions and measures to be taken: For IVD use only Read instructions carefully before performing the test Apply standard biosafety precautions for handling and disposal of potentially infective material and wear gloves while handling specimen and performing test Do not use IVDs beyond the expiration date Do not use if packaging is damaged Do not use if the product has been exposed to excessive heat or humidity Perform the test immediately after opening of primary packaging Do not reuse i. Name and address of the manufacturer in a format that is recognizable and allows the location of the manufacturer to be established, together with a telephone number and/or fax number and/or website address to obtain technical assistance j. Date of issue or latest revision of the instructions for use k. Test procedure including interpretation of results with illustrations: see Section 12.2 and Figure 5. Enhanced quality and performance practices for IFU labeling: Description/summary of the test Principle of the assay procedure Description of the procedural/reagent/specimen volume control in the test Reference intervals Limitations of the procedure: health conditions that can cause a false or irregular result; opportunities for false negative results Circumstances where the user should consult a healthcare professional Instructions for use in national language (e.g., could be glued to the primary packaging as long as labeling is not covered over) Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 36 | P a g e Labeling on Primary Packaging In low-resource settings, labeling on primary packaging also includes IFUs. Use of internationally recognized symbols conveying information on safe and effective use of tests is highly recommended. Annex 11 provides an illustration of recommended labeling for primary and secondary packaging using established symbols per ISO 15223-1 (12). As per GHTF recommendation and MRDT labeling harmonization recommendations, the following information should be included on primary packaging labeling (39, 44): a. Name or trade name of pregnancy test b. If not obvious, the device’s intended use/purpose: diagnosis of pregnancy/POC c. Catalog number/product code d. Name and address of the manufacturer in a format that is recognizable and allows the location of the manufacturer to be established, together with a telephone number and/or fax number and/or website address to obtain technical assistance e. Indication that it is for IVD use f. Batch/lot number g. Expiration date (YYYY-MM-(DD)) h. Indication of quantity of tests per packaging i. Storage conditions (symbols) j. Warnings or precautions in symbols (e.g., do not use if package is damaged, read instructions before use, only for single use) k. For CE-marked IVDs, a conformant CE mark with authorized representative’s identification number l. Contents of packaging (including desiccant) Labeling on Secondary Packaging (Cartons and Boxes) The large carton of smaller boxes, as well as the smaller boxes containing pregnancy tests in primary packaging, should include the label information listed below (39): a. Name or trade name of the test b. Catalog number/product code c. If not obvious, intended use: diagnosis of pregnancy d. Number of tests provided in the box e. Indication that test is for IVD use f. Name and address of the manufacturer in a format that is recognizable and allows the location of the manufacturer to be established, together with a telephone number Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 37 | P a g e and/or fax number and/or website address to obtain technical assistance (or name and address of authorized representative, if applicable) g. Batch/Lot number h. Expiration date (YYYY-MM-(DD)) i. For CE-marked IVDs, a conformant CE mark with authorized representative’s identification number j. Storage conditions (symbol) k. Materials (a list of materials provided and a list of items required but not provided) Important Note to Evaluators Evaluation of manufacture’s documentations and visual assessment of product labeling, in conformance with guidance provided, is a vital first step to selection of pregnancy tests meeting high quality standards. However, document review alone does not guarantee selection of high quality products. The next step should be to ensure that the tests perform to the required performance and operational specifications through Lot testing/laboratory evaluation. This type of testing should be carried out and confirmed by an independent 3rd party ISO 17025 certified testing laboratory or WHO prequalified laboratory. FHI 360 has prepared work instructions for laboratory level evaluation of performance and operational characteristics of pregnancy tests (Section 14). Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 38 | P a g e 13 Summary of Current, Recommended and Enhanced Quality and Performance Practices This guidance document has been prepared taking into consideration potential cost constraints and other challenges commonly present in resource-poor settings. As national-level regulatory mechanisms and overall healthcare landscapes continue to improve, countries may apply increasingly stringent quality review standards for pregnancy tests. Figure 7 illustrates currently prevalent, recommended, and enhanced quality practices. Distinctions between recommendations and enhanced quality practices were determined through stakeholder consensus. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 39 | P a g e Figure 7: Summary of current, recommended and enhanced quality and performance guidance for pregnancy test selection Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 40 | P a g e 14 Work instructions for quality evaluation of pregnancy tests FHI 360's Product Quality and Compliance group has developed detailed work instructions (method manual) that could be used by international or in-country laboratories to evaluate the quality and performance of pregnancy tests. Sampling plans and criteria are provided for three different scenarios (Table 2), based on ISO 2859 standards: 1) product qualification (for potential inclusion within a procurement program) 2) pre-shipment and pre- and post- distribution testing, and 3) temperature stability assessment. The purpose of this document is to provide detailed procedures, in the form of Standard Operating Procedures (SOP), to evaluate performance (inclusive of analytical sensitivity and analytical specificity) under recommended storage and/or heat stressed conditions, and package seal integrity. The SOPs will be designed to suit the requirements of the laboratories in low-resource settings. Additional validation of the procedures may be necessary (i.e., regarding the exact type of standard to use, standard stability and conditions used for package seal integrity). Implementation of the respective procedures for product qualification, pre-shipment, pre- and post-distribution, and/or stability study evaluations should be done while balancing the product source risk and resources, as appropriate, for specific program needs. Table 2: Overall sampling plan and specifications for different testing scenarios Assumed Lot size (35,000- 150,000) Product Qualification (total units) Acceptance/ Rejection Criteria Pre-shipment or pre- and post- distribution (total units) Acceptance/ Rejection Criteria Temperature Stability Assessment Acceptance/ Rejection Criteria Large Scale Evaluation Medium Scale Evaluation Small Scale Evaluation Category 1 - Performance Test for claimed analytical sensitivity 102 Verify claimed analytical sensitivity – positive control testing provides > 95% positive results at claimed sensitivity Accept if number of failing results are < 3 30 Accept if lot provides > 95% of tests results as positive at label claim sensitivity 14 total units/condition Report % compliance at label claim sensitivity Test for analytical specificity 98 50 Accept if number of failing results are < 2 6 total units/condition Accept if number of failing results are < 1 Category 2 - Package Integrity Testing Package Integrity 32 Acceptance/Rejec tion of 2/3 20 Acceptance/Rejec tion of 1/2 5 Acceptance/Re jection of 0/1 Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 41 | P a g e 15 References 1. 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Directive 98/79/EC of the European parliment and of the council. Official Journal of the European Communities; 1998. http://www.gmp- compliance.org/guidemgr/files/IVD_DIRECTIVE.PDF 15. Schito M, Peter TF, Cavanaugh S, Piatek AS, Young GJ, Alexander H, et al. Opportunities and challenges for cost-efficient implementation of new point-of-care diagnostics for HIV and tuberculosis. J Infect Dis. 2012;205 Suppl 2:S169-80. 16. International Organization for Standardization. ISO 8402:1986 Quality Vocabulary. Geneva; 1986. http://www.iso.org/iso/catalogue_detail.htm?csnumber=15570 17. Clinical and Laboratory Standards Institute. Interference tesing in clinical chemistry; approved guidelines - second edition (EP7-A2). USA; 2005. 18. International Organization fo Standardization. ISO/IEC Guide: Standardization and general activities-general vocabulary. Geneva; 2004. http://www.iso.org/iso/catalogue_detail?csnumber=39976 19. Comfort A, Chankova S, Juras R, His N, Peterson L, Hathi P. Proviing free pregnancy test kits to community health workers increases distribution of contraceptives: results from an impact evaulation in Madagascar http://www.contraceptionjournal.org/article/S0010- 7824%2815%2900586-7/abstract 20. Morroni C, Moodley J. The role of urine pregnancy testing in facilitating access to antenatal care and abortion services in South Africa: a cross-sectional study. BMC Pregnancy Childbirth. 2006;6:26. 21. Stanback J, Vance G, Asare G, Kasonde P, Kafulubiti B, Chen B, et al. Does free pregnancy testing reduce service denial in family planning clinics? A cluster-randomized experiment in Zambia and Ghana. Global Health Science Practice. 2013;3. 22. Family Health International 360. How to be reasonably sure a client is not pregnant. 2008. https://www.fhi360.org/sites/default/files/media/documents/checklist-pregnancy-english.pdf 23. World Health Organization. Guidance for procurement of in vitro diagnostics and related laboratory items and equipment. Geneva; 2016. http://www.who.int/diagnostics_laboratory/procurement/170131_guidance_for_procurement_of _ivds_draft.pdf?ua=1 24. Gnoth C, Johnson S. Strips of hope: accuracy of home pregnancy tests and new developments. Geburtshilfe Frauenheilkd. 2014;74(7):661-9. 25. Johnson SR, Miro F, Barrett S, Ellis JE. Levels of urinary human chorionic gonadotrophin (hCG) following conception and variability of menstrual cycle length in a cohort of women attempting to conceive. Curr Med Res Opin. 2009;25(3):741-8. 26. Larsen J, Buchanan P, Johnson S, Godbert S, Zinaman M. Human chorionic gonadotropin as a measure of pregnancy duration. Int J Gynaecol Obstet. 2013;123(3):189-95. 27. Reproductive Health Supplies Coalition. Pregnancy tests for family planning. 2013. http://www.rhsupplies.org/fileadmin/uploads/rhsc/Working_Groups/New_Underused_RH_Techno logies_Caucus/Documents/Technical_Briefs/rhsc-brief-pregnancy_A4.pdf Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 43 | P a g e 28. Stanback J, Diabate F, Dieng T, de Morales TD, Cummings S, Traore M. Ruling out pregnancy among family planning clients: the impact of a checklist in three countries. Stud Fam Plann. 2005;36(4):311-5. 29. World Health Organization. Medical device regulations: global overview and guiding principles. Geneva; 2003. http://www.who.int/medical_devices/publications/en/MD_Regulations.pdf 30. International Organization for Standardization. ISO 9000: 2015 Quality management. Geneva. http://www.iso.org/iso/home/standards/management-standards/iso_9000.htm 31. World Health Organization. Substandard, spurious, falsely labelled, falsified and counterfeit (SSFFC) medical products. 2016. http://www.who.int/mediacentre/factsheets/fs275/en/ 32. What is CE marking? [http://www.ce-marking.org/what-is-ce-marking.html. 33. World Health Organization. Manual for procurement of diagnostics and related laboratory items and equipment. Geneva; 2013. http://www.who.int/diagnostics_laboratory/publications/130627_manual_for_procurement_of_di agnostics-001-june2013.pdf 34. Johnson S, Cushion M, Bond S, Godbert S, Pike J. Comparison of analytical sensitivity and women's interpretation of home pregnancy tests. Clin Chem Lab Med. 2015;53(3):391-402. 35. Global Harmonization Task Force. Clinical evidence for IVD medical devices - key definitions and concepts (Document No. GHTF/SG5/N6:2012). 2012. http://www.imdrf.org/docs/ghtf/final/sg5/technical-docs/ghtf-sg5-n6-2012-clinical-evidence-ivd- medical-devices-121102.pdf 36. World Health Organization, Foundation for Innovative New Diagnostics, Center for Disease Control and Prevention. Malaria rapid diagnostic test performance. Results of WHO product testing of malaria RDTs, Round 5 2014. http://apps.who.int/iris/bitstream/10665/128678/1/9789241507554_eng.pdf 37. World Health Organization. Instructions for compilation of a product dossier: Prequalification of in vitro diagnostic program. Geneva; 2014. http://www.who.int/diagnostics_laboratory/evaluations/141015_pqdx_018_dossier_instructions_ v4.pdf?ua=1 38. International Organization fo Standardization. ISO 18113-2009: In vitro diagnostic medical devices - Information supplied by the manufacturer (labelling) - Part 1-5. 2011. https://www.iso.org/obp/ui/#iso:std:iso:18113:-1:ed-1:v1:en 39. Jacobs J, Barbe B, Gillet P, Aidoo M, Serra-Casas E, Van Erps J, et al. Harmonization of malaria rapid diagnostic tests: best practices in labelling including instructions for use. Malar J. 2014;13:505. 40. World Health Organization. Establishing stability of an in vitro diagnostic for WHO prequalification. Geneva; 2015. http://www.who.int/diagnostics_laboratory/guidance/160613_tgs2_stability.pdf 41. Albertini A, Lee E, Coulibaly SO, Sleshi M, Faye B, Mationg ML, et al. Malaria rapid diagnostic test transport and storage conditions in Burkina Faso, Senegal, Ethiopia and the Philippines. Malar J. 2012;11:406. 42. Jorgensen P, Chanthap L, Rebueno A, Tsuyuoka R, Bell D. Malaria rapid diagnostic tests in tropical climates: the need for a cool chain. Am J Trop Med Hyg. 2006;74(5):750-4. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 44 | P a g e 43. Barbe B, Gillet P, Beelaert G, Fransen K, Jacobs J. Assessment of desiccants and their instructions for use in rapid diagnostic tests. Malar J. 2012;11:326. 44. Global Harmonization Task Force. Label and instructions for use for medical devices (Document No. GHTF/SG1/N70:2011). 2011. Report No.: GHTF/SG1/N70:2011. http://www.imdrf.org/docs/ghtf/final/sg1/technical-docs/ghtf-sg1-n70-2011-label-instruction-use- medical-devices-110916.pdf 45. Johns Hopkins Bloomberg School of Public Health, World Health Organization. Family planning: a global handbook for providers. 2011. http://apps.who.int/iris/bitstream/10665/44028/1/9780978856373_eng.pdf 46. Center for Disease Control and Prevention. Selected practice recommendations for contraceptive use. USA; 2013. https://www.cdc.gov/mmwr/volumes/65/rr/rr6504a1.htm?s_cid=rr6504a1_w 47. World Health Organization. Selected practice recommendations for contraceptive use. Geneva; 2004. http://apps.who.int/iris/bitstream/10665/252267/1/9789241565400-eng.pdf?ua=1 48. Stanback J, Yacobson I, Harber L. Proposed clinical guidance for excluding pregnancy prior to contraceptive initiation. Contraception. 2016. 49. United States Agency for International Development. The logistics handbook: A practical guide for the supply chain management of health commodities. USA; 2011. https://www.k4health.org/sites/default/files/LogiHand_0.pdf 50. The Partnership for Maternal, Newborn and Child Health. PMNCH knowledge Summary 20, Access to FP 2012. http://www.who.int/pmnch/knowledge/publications/summaries/ks20.pdf?ua=1 51. Gillet P, Maltha J, Hermans V, Ravinetto R, Bruggeman C, Jacobs J. Malaria rapid diagnostic kits: quality of packaging, design and labelling of boxes and components and readability and accuracy of information inserts. Malar J. 2011;10:39. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 45 | P a g e 16 Annexes Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 46 | P a g e Annex 1: Use of Pregnancy Tests and Pregnancy Checklist in Family Planning Programs Current clinical guidance indicates that pregnancy should be ruled out prior to initiation of hormonal contraception and intrauterine devices (IUDs) (45-47). The rationale for excluding pregnancy is simple: to avoid providing unnecessary contraception and, in the case of the IUD (including hormonal IUDs), to avoid possible harm to the pregnant woman or her fetus. Because exposure of ongoing pregnancies to contraceptive hormones carries no known risk, it is now widely accepted that hormonal methods can be provided—along with follow-up pregnancy testing—to women for whom pregnancy has not been ruled out conclusively. Pregnancy screening is nonetheless recommended for all family planning clients, and typically constitutes a substantial part of the workload of family planning providers. Family planning providers have three tools at their disposal to help exclude pregnancy in women requesting contraception: medical history (often obtained by using the WHO-endorsed “Pregnancy Checklist”), pregnancy tests, and delay of contraceptive method initiation until the next menses. While each approach has its advantages and limitations, providers sometimes use a combination of these tools. Careful judgment is required because the consequences of denying immediate initiation may be more serious than the risks inherent in contraceptive use while pregnant. The Pregnancy Checklist is shown here in Figure 8 while proposed new guidance for when and how providers should use client history, pregnancy tests, and delayed services in varying circumstances is shown in Figure 9 (48). Figure 8: Pregnancy Checklist Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 47 | P a g e Figure 9: Job aid for ruling out pregnancy prior to contraceptive initiation Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 48 | P a g e Annex 2: Prevailing Quality and Performance Characteristics of Pregnancy Tests in Low Resource Settings To gain a preliminary understanding of quality and performance status of pregnancy tests in low-resource settings, an in-house assessment of 16 individually packed pregnancy tests collected over a 2-year period from pharmacies and clinics in Africa was carried out. These tests were benchmarked against 26 relevant labeling criteria as detailed in this document (Table 3). Table 3: Prevailing quality and performance status of 16 pregnancy tests collected in low-resource settings Indicators used for benchmarking Number of conformant tests (n = 16) Percent of conformant tests International quality standards and regulatory criteria An accepted quality mark (ISO 13485, CE mark or U.S. FDA clearance) 7 44% Of those carrying CE mark, tests that indicate a conformant CE mark 3 43% Of those carrying CE mark, tests that indicate a notified body number 5 71% Packaging/labeling/product insert information Lot number 15 94% Manufacturer 14 88% Contact information of manufacturer 7 44% Date of manufacture 7 44% Date of expiry 15 94% Temperature limitations 15 94% Number of units per package 8 50% Intended use 13 81% Indication that test is for IVD use 12 75% Indication of ‘do not reuse’ 5 31% Inclusion of any form of desiccant Not assessed Not assessed Safety warnings 1 6% Disposal instructions 0 0% Description of test procedure 15 94% Illustrations for test procedure 14 88% ‘Declared reading time’ 12 75% Stability of test results 6 38% Instructions for result interpretation 15 94% Complete instructions for result interpretation 9 56% Test performance characteristics Analytical sensitivity 2 13% Analytical specificity 0 0% Accuracy 1 6% Test limitations 0 0% Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 49 | P a g e Annex 3: IMDRF Management Committee The International Medical Device Regulatory Forum (IMDF) is a voluntary group of medical device regulators from around the world, who have come together to build on the foundational work of the former Global Harmonization Task Force (GHTF). Their aim is to accelerate international medical device regulatory harmonization and convergence. Current IMDRF member countries include Australia, Brazil, Canada, China, Europe, Japan, Russia, Singapore and the United States of America (Table 4). The World Health Organization is an official observer. Table 4: IMDRF Management Committee Country Institution Website Australia Therapeutic Goods Administration https://www.tga.gov.au/ Brazil National Health Surveillance Agency http://portal.anvisa.gov.br/wps/portal/an visa-ingles Canada Health Canada http://www.hc-sc.gc.ca/index-eng.php China China Food and Drug Administration http://eng.sfda.gov.cn/WS03/CL0755/ Europe European Commission Directorate-General for Internal Market, Industry, Entrepreneurship and SMEs http://ec.europa.eu/growth/sectors/medi cal-devices/ Japan Pharmaceutical and Medical Device Agency & Ministry of Health, Labor and Welfare https://www.pmda.go.jp/english/ http://www.mhlw.go.jp/english/ Russia Russian Ministry of Health https://www.rosminzdrav.ru/ Singapore Health Science Authority http://www.hsa.gov.sg/content/hsa/en.ht ml United States of America Food and Drug Administration http://www.fda.gov/ Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 50 | P a g e Annex 4: Checklist for Evaluation of Pregnancy Tests It is recommended that evaluators use this checklist (Table 5) to verify a manufacturer’s compliance with recommended quality, regulatory, performance and operational specifications as part of the product selection process. Line items shaded in green are ‘enhanced quality and performance practices,’ and are recommended for adoption as the country regulatory infrastructure improves or at the evaluators’ discretion, based on organizational risk analysis. Table 5: Checklist for evaluation of pregnancy tests Checklist for Evaluation of Pregnancy Tests for Procurement Name of assessor Date of assessment Name of pregnancy test (brand name) Test format Dipstick Cassette Midstream Manufacturer and address Lot number Catalog number Has a ISO 13485 certification been provided? Yes No Sources of documentation provided as proof of regulatory clearance CE marking U.S. FDA Other RA (specify) Has a QC Lot Release Certificate been provided from a recent Lot/batch for evaluation? Yes No Has an Accelerated Stability Evaluation Report been provided? Yes No Check for consistency of details across labeling, quality and regulatory documentations. For assessment of ISO 13485 certification only: 1. Manufacturer’s certified quality management system standard is specified as ISO 13485 Yes No 2. Name and country of assessment body Name: Country: 3. Last audit date: 4. Expiration date: 5. Has certification been verified by checking the website of the certification body or by directly contacting the certification body? Verified using website Verified by calling Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 51 | P a g e For assessment of CE declaration of conformity only: 6. Manufacturer’s name is correctly indicated Yes No 7. Manufacturer’s address is correctly indicated Yes No 8. Name of pregnancy test is correctly indicated Yes No 9. Essential characteristics of pregnancy test are provided Yes No 10. Name of regulatory authority/notified body 11. License number 12. A legally binding signature on behalf of the organization is present Yes No For assessment of U.S. FDA 510(k) clearance only: 13. A 510(k) clearance letter for the pregnancy test has been provided Yes No 14. U.S. FDA 510(k) clearance website confirms clearance of pregnancy test Yes No 15. Product being evaluated has been manufactured with same quality standard applicable to a U.S. FDA cleared product Yes No For assessment of other regulatory authorities only: 16. Name of regulatory authority 17. License number 18. Other information 19. Have you confirmed clearance/approval in country of manufacture? Yes No 20. Product being evaluated has been manufactured with same quality standard applicable to a country of origin cleared product Yes No IFU/QC Lot release certificate (If listed information is not available, request from the manufacturer) 21. Indicates analytical sensitivity of test Yes No 22. Indicates analytical specificity of test Yes No 23. Indicates accuracy of test Yes No 24. Indicates any clinical sensitivity and clinical specificity metrics, if available Yes No Labeling/Marking on Secondary Packaging (Carton and Boxes) 25. Name or trade name of test included Yes No 26. Batch/Lot number included Yes No 27. Expiry date/shelf life included Yes No 28. Name of manufacturer included Yes No Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 52 | P a g e 29. Address of manufacturer included Yes No 30. If CE-marked, CE marking is accompanied by identification number of notified body Yes No 31. CE-marking is conformant Yes No 32. Catalog number included Yes No 33. Storage/handling conditions included Yes No 34. Intended purpose of test indicated Yes No 35. Listing of materials provided and items required but not provided Yes No 36. Indication that the test is for IVD use Yes No 37. Number of tests included in the box Yes No Packaging and Kit Content 38. Secondary packaging/box containing the tests is in good condition and not torn, wet or with illegible writing Yes No 39. Pregnancy tests are in individually sealed, intact pouches Yes No 40. Desiccant is present in each individually sealed pouch Yes No 41. Desiccant is packaged in material permeable to air Yes No 42. Desiccant packaging has adequate labeling Yes No 43. Desiccant is of humidity-indicator type Yes No Labeling/Marking on Primary Packaging/IFU/Product Insert (individual pouches containing pregnancy tests) 44. Name or trade name of pregnancy test is printed. Yes No 45. Catalog number/product code Yes No 46. Name of manufacturer included Yes No 47. Address of manufacturer included Yes No 48. If test is imported, name of authorized representative within the importing country (if required). Yes No 49. Batch/Lot number Yes No 50. Expiration date/shelf life YYYY-MM-(DD) Yes No 51. Tests are stable up to 30 °C Yes No 52. If product is CE marked, CE marking includes identification number of notified body Yes No 53. CE-marking is conformant Yes No Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 53 | P a g e 54. Where not obvious, intended use of test is indicated Yes No 55. An indication that test is for IVD use Yes No 56. Net quantity of pregnancy tests included in the primary package is indicated Yes No 57. Test is intended for single use as indicated Yes No 58. Materials provided and those required but not provided are listed Yes No 59. Analytical sensitivity included (25 mIU/mL11 is recommended) Yes No 60. Analytical specificity included Yes No 61. Accuracy included Yes No 62. Step-by-step test procedure is provided with illustrations Yes No 63. Timing: minimum to maximum time for reading results provided Yes No 64. Interpretation of results is explained using illustrations that display four possible outcomes Yes No 65. Warnings or precautions included Yes No 66. Contents of packaging (including desiccant) listed Yes No 67. Recommended storage conditions on label. Yes No 68. Interference substances indicated Yes No 69. Summary of test included Yes No 70. Principle of the procedure included Yes No 71. Description of procedural/reagent/sample quality control measures included Yes No 72. Limitations of the procedure included Yes No 73. Transport Validation Document: Tests are stable up to 40 °C (if required by country setting) Yes No 11 If using highly sensitive pregnancy tests (analytical sensitivity < 25 mIU/mL), pregnancy can be detected as early as first day of missed menses. If using tests with lower sensitivity (analytical sensitivity>50 mIU/mL), it is recommended to wait about 10 days after expected date of menses. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 54 | P a g e The flowchart below illustrates how and where the above checklist can be incorporated into the pregnancy test selection process, and takes into consideration relevant customization at the country and programmatic level to support the procurement process (36). Figure 10: A step-by-step guide to selecting pregnancy tests meeting high quality and performance standards Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 55 | P a g e Annex 5: Recommended Guidance Documents on Procurement Process and Supply Chain Management 1. A Model Quality Assurance System for Procurement Agencies. WHO, UNICEF, UNDP, UNFPA & World Bank http://www.who.int/medicines/publications/ModelQualityAssurance.pdf 2. Guidelines for the Storage of Essential Medicines and Health Commodities. WHO http://apps.who.int/medicinedocs/pdf/s4885e/s4885e.pdf 3. Guidelines for Warehousing Health Commodities. USAID http://apps.who.int/medicinedocs/documents/s16875e/s16875e.pdf 4. Managing Access to Medicines and Health Technologies (MDS-3). WHO http://www.msh.org/sites/msh.org/files/mds3-fm-revised-nov2012.pdf 5. Manual for Procurement of Diagnostics and Related Laboratory Items and Equipment. WHO http://www.who.int/diagnostics_laboratory/procurement/130627_manual_for_procurement _of_diagnostics-001-june2013.pdf 6. Procurement Capacity Toolkit: Tools and Resources for Procurement of Reproductive Health Supplies. PATH http://www.path.org/publications/detail.php?i=1652 7. The Logistics Handbook: A Practical Guide for the Supply Chain Management of Health Commodities. USAID https://www.k4health.org/sites/default/files/LogiHand_0.pdf 8. General Technical Provisions for in vitro Diagnostic (IVD) Medical Devices. UNICEF https://www.unicef.org/supply/files/140330_BAZ_Tech_Prov_IVD_Medical_Devices_March_ 2014.pdf 9. The Supply Chain Manager’s Handbook, A Practical Guide to the Management of Health Commodities. John Snow, Inc. http://supplychainhandbook.jsi.com/wp- content/uploads/2017/02/JSI_LogisticHandbook_Final-1.pdf Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 56 | P a g e Annex 6: The Logistics Cycle The goal of every public health logistics system is to ensure that every person is able to obtain and use essential health supplies when needed (49). The logistics cycle determines the success or failure of public health programs. The schematic of the logistic cycle presented in Figure 11 was adapted by those created by the Partnership for Maternal, Newborn and Child Health and USAID (49, 50). As shown in rectangles below, the cycle consists of four elements whose functions depend on each other: 1) serving clients 2) product selection 3) quantification, forecasting and procurement and 4) inventory management. Activities in the center box represent management support functions that inform and impact the other four elements. Quality monitoring, as depicted in the gray arrows, contributes to efficiency and effectiveness of this cycle. Serving clients, the key focus of a logistic cycle, can be fulfilled by ‘six rights’: 1) right product 2) right quantity 3) right quality 4) right place 5) right time and 6) right cost. Figure 11: Logistics cycle Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 57 | P a g e Annex 7: Assay Principle of Pregnancy Test Figure 12: Basic components of the pregnancy test and how it works A. Basic architecture of a pregnancy test strip (Figure 12A): A typical rapid test consists of several components adhered to an inert backing: 1) sample pad designed for specimen application and to enable liquid flow, 2) conjugate pad where dried labeled antibodies are deposited, 3) reaction membrane with a test line carrying pregnancy-specific antibodies12 and a control line carrying antibodies that recognize other antibodies, and 4) wicking pad designed to draw the specimen across the reaction membrane. B. Testing with urine (Figure 12B): Upon application of urine, the liquid moves via capillary action, hydrating labeled antibodies and enabling their migration across the membrane towards the test and control lines. During this process, hCG proteins bind the labeled antibodies as well as those on the test line. C. Development of a positive result (Figure 12C): Recruitment of labeled antibodies to the test line occurs dependent of hCG; accumulation of these labeled antibodies results in the development of a positive test line. Recruitment of labeled antibodies to the control line is independent of hCG, and results in development of a control line indicating that the reagents and the assay have operated as expected. 12 Pregnancy tests typically carry two forms of hCG antibodies: those raised against the alpha subunit of hCG for capture, and those raised against the beta subunit of hCG for detection. Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 58 | P a g e Annex 8: CE Marking Conformity as specified in Directive 98/79/EC of the European Parliament and of the Council The illustration in Figure 13 is an excerpt from EU directive 98/79/EC (14). Please refer to the WHO fact sheet to find out more about prevalence of substandard, spurious, falsely labeled, falsified and counterfeit medical products (31). Figure 13: CE marking of conformity Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 59 | P a g e Annex 9: Screenshot of FDA Premarket Notifications 510(k) Clearance Webpage for Verification Purposes Confirm that the manufacturer holds 510(k) clearance by visiting the 510(k) premarket notification site: (U.S. FDA home page Medical Devices Tab Medical Device Database (under Tools & Resources) select the ‘Premarket Notifications (510(k)’ database type ‘LCX’ under ‘product code’ (Figure 14) Search for the product of interest). Current website URL: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm Figure 14: A screenshot of FDA 510(k) clearance webpage for regulatory status verification of pregnancy tests under evaluation Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 60 | P a g e Annex 10: Desiccants and Their Usage Information below has been summarized in consultation with MRDT guidelines (6, 36, 43). Table 6: Desiccants and their usage Item Purpose of use/criteria to meet Recommendation Desiccant Protects test from exposure to humidity Humidity has been shown to decrease analytical performance of RDTs Recommended Desiccant with humidity indicator Indicates if desiccant, and therefore the test, was exposed to humidity Color indicator desiccant is preferred over non-indicating desiccants Partial indicators are difficult to view for presence of humidity Avoid use of cobalt dichloride as an indicator as it is a carcinogen Enhanced quality and performance practices Material of desiccant package should be permeable to air Enables uptake of humidity by desiccant Avoid use of sachets with plastic packaging as they are impenetrable to air Paper-based sachets are penetrable to air Recommended Sachet with desiccant should be transparent or have a window that allows easy visualization of color change Aids safe and easy visualization of color change in desiccant Enhanced quality and performance practices Warning message indicating not to eat desiccant Desiccant could be harmful if swallowed and should be kept away from children Recommended Sachet with desiccant should carry instructions for: - interpretation of color changes - Steps to follow if test is exposed to humidity - Safe disposal of desiccants Enables appropriate decision making for accurate and safe outcomes Enhanced quality and performance practices Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement 61 | P a g e Annex 11: Definitions of Symbols Recommended for Labeling For the safe and effective use of medical devices, ISO 15223-1:2012 has identified the symbols in Figure 15 for use in labeling standards (12). This information is provided as a source of information for interpreting the meaning of symbols as they appear on various packaging, and to ensure that accurate labeling is used when procuring pregnancy tests. Other normative documents were also referenced in summarizing this information (39, 44, 51). Figure 15: Definitions of symbols recommended for labeling Symbols and Their Definitions In vitro diagnostic medical device Keep away from sunlight/heat Keep dry Contents sufficient for <n> tests Consult instructions for use Do not use if packaging is damaged Lot number Product code/catalog number Conformant CE mark and identification number of notified body Date of manufacture YYYY-MM-(DD) Manufacturer Authorized representative in the European Community Do not reuse Use by YYYY-MM-(DD) Caution, consult accompanying document Temperature limitation Upper limit of temperature Lower limit of temperature P FHI 360 HEADQUARTERS 359 Blackwell Street, Suite 200 Durham, NC 27701 USA T 1.919.544.7040 F 1.919.544.7261 www.fhi360.org For more information about FHI 360’s work in Quality and Performance Guidance on Selection of Pregnancy Tests for Procurement, email us at firstname.lastname@example.org 2 Acknowledgements 3 Abbreviations 4 Glossary 5 Background In many countries, non-menstruating women are routinely denied same-day family planning services because of a concern among healthcare providers that these women may be pregnant. Several tools can be used by healthcare providers to rule out pregnancy. One is the "Pregnancy Checklist" - a job aid with simple questions that a provider can ask a client to rule out pregnancy. Endorsed by the World Health Organization (WHO) and USAID, the Checklist has been adopted by more than a dozen countries. A. See Annex 1 for more information on when a healthcare provider should use the checklist versus a pregnancy test. 6 Scope 7 Intended Audience 8 How to Use this Document 9 Overview of Pregnancy Tests 10 Quality Standards and Regulatory Requirements 10.1 Quality Standards 10.2 Regulatory Requirements for Marketing Clearance 10.2.1 CE Marking 10.2.2 U.S. FDA 510(k) Clearance 10.2.3 Stringent regulatory assessment by Health Canada, TAG, PMDA and MHLW 10.2.4 National Registrations and ROW Approvals 11 Performance Specifications 11.1 Analytical Performance Characteristics of Pregnancy Tests 11.1.1 Target Antigen/Analyte 11.1.2 Analytical Sensitivity (also known as Detection Limit) 11.1.3 Analytical Specificity 11.2 Clinical Performance Characteristics of Pregnancy Tests 11.2.1 Clinical Sensitivity and Clinical Specificity 11.2.2 Accuracy 11.2.3 Interfering Agents 12 Operational Specifications 12.1 Test Format and Ancillary Items 12.1.1 Components of a Pregnancy Test 12.1.2 The Test Line and Control Line 12.2 Test Procedure and Result Interpretation 12.3 Claimed Shelf Life 12.3.1 Transportation Stability 12.4 Packaging and Kit Content 12.5 Labeling Requirements 12.5.1 Instructions for Use (IFU) 12.5.2 Labeling on Primary Packaging 12.5.3 Labeling on Secondary Packaging (Cartons and Boxes) 13 Summary of Current, Recommended and Enhanced Quality and Performance Practices 14 Work instructions for quality evaluation of pregnancy tests 15 References 16 Annexes Annex 1: Use of Pregnancy Tests and Pregnancy Checklist in Family Planning Programs Annex 2: Prevailing Quality and Performance Characteristics of Pregnancy Tests in Low Resource Settings Annex 3: IMDRF Management Committee Annex 4: Checklist for Evaluation of Pregnancy Tests Annex 5: Recommended Guidance Documents on Procurement Process and Supply Chain Management Annex 6: The Logistics Cycle Annex 7: Assay Principle of Pregnancy Test Annex 8: CE Marking Conformity as specified in Directive 98/79/EC of the European Parliament and of the Council Annex 9: Screenshot of FDA Premarket Notifications 510(k) Clearance Webpage for Verification Purposes Annex 10: Desiccants and Their Usage Annex 11: Definitions of Symbols Recommended for Labeling
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