Stringent Regulatory Authorities Research Articles

OC 8721 WANECAM II – A CLINICAL TRIAL PROGRAMME TO ASSESS SAFETY, EFFICACY AND TRANSMISSION-BLOCKING PROPERTIES OF A NEW ANTIMALARIAL KAF156 (GANAPLACIDE) IN UNCOMPLICATED MALARIA IN WEST AND CENTRAL AFRICA

BackgroundDespite major progress in the past decade, malaria remains a major public health problem in sub-Saharan Africa. West and Central Africa account for nearly 2/3 of the burden currently attributable to falciparum malaria. Artemisinin-based combination therapies (ACT) are a cornerstone of our strategy for controlling and eventually eliminating malaria. However, reduced responsiveness/resistance to artemisinin derivatives and to ACTs, an increasing problem in South-East Asia is a major concern. It is of utmost importance to develop new antimalarial drugs from novel chemical classes that can replace ACTs. KAF156, an imidazolepiperazine, is a leading candidate in the antimalarial drug development pipeline. Combination of KAF156 with a Solid Dispersion Formulation of lumefantrine (LUM-SDF) is expected to be fast acting, fully curative, improve patient adherence and can potentially reduce malaria transmission.MethodsWANECAM II proposes to advance the clinical development of KAF156 through clinical trials in adults and children, with integrated capacity building and infrastructure development activities. The trial programme will be undertaken in the context of networking, team-building, leadership development and community engagement schemes that will involve intra-European, European-African and intra-African collaborative activities. WANECAM II will accelerate the clinical study of children less than 2 years of age which are the key target for new antimalarial treatments.ResultsBy the end of the project, the results are expected to contribute to the registration of KAF156/LUM-SDF through stringent regulatory health authorities, increase biomedical research capacity in the consortium and effectively promote networking among the respective teams. A new clinical research team in Niger, a grossly underrepresented country in the African research landscape, will be developed and further increase capacity and infrastructure in the consortium.ConclusionProviding a new antimalarial drug combination that does not contain an artemisinin derivative and is effective against resistant P. falciparum strains as well as gametocytes and that is likely to be taken in 3 or fewer single doses will be a major advance in the field. The new combination of KAF156 with LUM-SDF is expected to provide such major advance upon successful conclusion of the WANECAM II project.

Barriers and facilitators to early access of bedaquiline and delamanid for MDR-TB: a mixed-methods study.

Phase II trials for bedaquiline (BDQ) and delamanid (DLM) were completed by 2011 and the drugs were approved by stringent regulatory authorities for the treatment of multidrug-resistant tuberculosis (MDR-TB) between 2012 and 2014. Manufacturers established 'early access' mechanisms to provide drugs before local registration. To inform improvements in early access, we explored experiences of providers and advocates in accessing BDQ and DLM before the end of 2015 using a mixed-methods design. We examined barriers and facilitators to early access through an electronic survey. Barriers and facilitators were classified as occurring at the manufacturer- or country-level. We identified themes using inductive content analysis and illustrated themes through case studies. We analysed 41 survey responses from 36 respondents reporting on 22 countries; early access was attempted in 30 (73%) survey responses. Eligibility restrictions (11/30, 37%) and complicated and slow processes (8/30, 27%) were manufacturer-level barriers; access to companion drugs (10, 33%) and importation difficulties (4, 13%) were country-level barriers. Previous experience with manufacturer (3/30, 10%) and country processes (2/30, 7%) facilitated access. Eight case studies show the human impact of barriers and facilitators. Manufacturers and countries should develop transparent processes to permit early access, particularly for diseases that largely affect the poor, such as MDR-TB. Developers should plan for this need and rapidly register drugs with proven benefit, prioritizing high-burden settings.

A Proposed Framework for a Globally Applicable Pragmatic Approach to Using Facilitated Regulatory Pathways

As regulatory agencies come under increased pressure to review medicines of critical importance through efficient regulatory systems to provide equitable access, the benefits of using expedited review pathways are being explored. These facilitated regulatory pathways (FRPs) provide a variety of review strategies that can also expedite assessments. Stringent regulatory authorities (SRAs) use primary FRPs to accelerate development or to shorten review time. Some emerging national regulatory authorities can implement primary FRPs but are more likely to use secondary FRPs that rely on or recognize an SRA or reference agency decision, the World Health Organization Collaborative Prequalification of Medicines Programme, "altruistic" reviews, or collaborative work sharing. Despite their availability, there are no formal guidelines or consensus for the definition, basic elements, or best practices for FRPs. Herein, we present a 4-step pragmatic approach to a framework designed to help agencies determine how best to use FRPs. Each step is based on characteristics identified through research, surveys, literature assessments, regulatory capacity categorization analyses, and practical experience. Step 1 assesses 4 domains of the environment preparedness, step 2 offers process criteria that should be in place to effectively use an FRP, step 3 tiers agencies through a self-assessment of readiness and capacity, and step 4 provides a pathway for agencies to determine the most relevant FRP for their use. Target timelines are proposed for FRPs. This framework represents the first endeavor to holistically address the multifaceted aspects that should be considered for the effective use of an FRP.

Regulatory requirements for the registration of generic medicines and format of drug dossiers: procedures in Sri Lanka in comparison with selected regulatory authorities

BackgroundThe regulatory requirements for approval of generic medicines and the format of compiling drug dossiers vary among regulatory authorities. The variation is particularly wide between High-income countries (HIC) and lower and middle-income countries (LMIC) with different regulatory frameworks. In this study, document requirements for approval of generic products, approval timelines, and consideration of bioequivalence and/or biowaiver data by Regulatory Authorities (RAs) of 10 selected jurisdictions was studied.MethodsThe guidelines and procedures from 5 purposively chosen RA of HIC and4 regional RAs relevant for Sri Lanka were compared with the Sri Lankan National Medicines Regulatory Authority (NMRA). Information available in the official websites of the selected RAs, published journal articles and via personal communication was collected in2016. Drug approval timelines achieved in Sri Lanka was obtained from data available from another study.ResultsCommon technical dossier (CTD) format of the International Council on Harmonization (ICH) for registration of pharmaceuticals (ICH:CTD) or the Association of South East Asian Nations (ASEAN) CTD format (ACTD) was used by all RAs studied except Sri Lanka which use its own dossier format. Nine out of ten RAs studied request BE data or justification for not submitting BE data for generic medicines. Sri Lanka requested BE studies only for antimicrobials, antiepileptic drugs and narrow therapeutic index drugs. Biowaivers are allowed for Biopharmaceutics Classification System (BCS)-based Class 1drugs in Singapore and India. USA, EMA, Canada and South Korea allowed biowaiver for BCS Class1and Class 3drugs but Sri Lanka does not accept BW at present. Nine NMRAs out of the ten studied reported legislated timelines for approval of generic pharmaceuticals except Sri Lanka.ConclusionsStreamlining the drug regulatory systems in LMIC such as Sri Lanka with that of HIC would facilitate an effective drug regulatory system based on reliance on decisions made by stringent regulatory authorities. Findings of this study encourage Sri Lanka to adopt a CTD format for regulatory submission of drug dossiers. Expanding the BE requirement drug list and accepting BCS-based biowaivers for BSC class 1 and 3 drugs during registration of generic drugs when it is scientifically justified is also recommended for Sri Lanka.

Drugs in Development for Malaria.

The last two decades have seen a surge in antimalarial drug development with product development partnerships taking a leading role. Resistance of Plasmodium falciparum to the artemisinin derivatives, piperaquine and mefloquine in Southeast Asia means new antimalarials are needed with some urgency. There are at least 13 agents in clinical development. Most of these are blood schizonticides for the treatment of uncomplicated falciparum malaria, under evaluation either singly or as part of two-drug combinations. Leading candidates progressing through the pipeline are artefenomel–ferroquine and lumefantrine-KAF156, both in Phase 2b. Treatment of severe malaria continues to rely on two parenteral drugs with ancient forebears: artesunate and quinine, with sevuparin being evaluated as an adjuvant therapy. Tafenoquine is under review by stringent regulatory authorities for approval as a single-dose treatment for Plasmodium vivax relapse prevention. This represents an advance over standard 14-day primaquine regimens; however, the risk of acute haemolytic anaemia in patients with glucose-6-phosphate dehydrogenase deficiency remains. For disease prevention, several of the newer agents show potential but are unlikely to be recommended for use in the main target groups of pregnant women and young children for some years. Latest predictions are that the malaria burden will continue to be high in the coming decades. This fact, coupled with the repeated loss of antimalarials to resistance, indicates that new antimalarials will be needed for years to come. Failure of the artemisinin-based combinations in Southeast Asia has stimulated a reappraisal of current approaches to combination therapy for malaria with incorporation of three or more drugs in a single treatment under consideration.

The Manufacturers' Perspective on World Health Organization Prequalification of In Vitro Diagnostics.

In vitro diagnostic devices (IVDs) help clinicians determine specific conditions, monitor therapeutic efficacy, and prevent drug resistance development. While stringent regulatory authorities (SRAs) regulate IVDs in most high-income countries, regulatory authorities in many low- and middle-income countries (LMICs) are nonexistent or do not enforce rigorous standards. In 2010, the World Health Organization established its Prequalification of In Vitro Diagnostics (PQDx) program to ensure "access to safe, appropriate and affordable" IVDs, especially in LMICs with little or no domestic regulatory frameworks, thereby reaching underserved populations. However, challenges in PQDx policies and procedures include an overloaded pipeline, timelines not publicly available, confusion about which products PQDx focuses on, perceived burden for documenting changes to prequalified products, overlap with SRA approvals, and uncertainty around long-term financing. PQDx can maximize its impact by considering the perspective of IVD manufacturers; similarly, IVD manufacturers should exercise adequate quality control over their submissions and associated processes.

Development of the risk-based, phased-in approach for the international harmonization of the regulation of container closure systems for drugs in Taiwan

The main concern for container closure systems of drugs is to ensure suitability for the intended use which is associated with issues regarding protection, compatibility, safety, and performance. Among various concerns, leachables may pose a safety hazard to patients, while risks might vary depending on the dosage form and the administration route. Stringent regulatory authorities such as the European Medicines Agency and the United States Food and Drug Administration have established risk-based regulatory requirements and published corresponding guidelines to facilitate implementation. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes every effort to harmonize with international regulations and to strengthen protection of public health through regulatory controls. The aim of the present study was to investigate the regulatory framework and policies set by stringent regulatory authorities. The strategy proposed for the development of an eventual guideline was sent to the Taiwan Food and Drug Administration for decision. A risk-based, phased-in approach which was extensively discussed in the expert committee was proposed. The approach proposed herein could also serve as a starting point which is worth considered by other countries in which international harmonization is in process.

Global Progress and Challenges in Implementing New Medications for Treating Multidrug-Resistant Tuberculosis.

Two new drugs—bedaquiline and delamanid—have recently been approved by stringent regulatory authorities to treat multidrug-resistant tuberculosis (TB) and recommended by the World Health Organization for use under defined programmatic conditions. Introducing the medications in TB programs worldwide has not kept pace with the need for these drugs. In response, the DR-TB STAT (Drug-Resistant TB Scale-up Treatment Action Team) task force was formed in April 2015 to monitor progress and help overcome challenges. Information was collected from multiple sources and assessed monthly. Some progress has been made in introducing bedaquiline: as of October 2015, a total of 1,258 persons were on the medication under programmatic conditions. For delamanid, >100 patients, but few under programmatic conditions, have received the medication. Coordinated global action might help assist making these medications accessible for persons who need them most.

The quality of medicines: an ethical issue?

The Hippocratic maxim, "Do no harm," is a long-standing fundamental principle of medical ethics, encompassing both medical practice and medical research. Yet, not enough attention is given to the implications of this principle for sectors related to medical research and practice, such as the pharmaceutical sector. The regulation of the standards of quality in pharmaceutical production and distribution, for instance, is generally considered a purely technical - rather than ethical - subject. Poor enforcement of regulatory supervision of manufacturers and wholesalers of medicine exposes the end-users to low-quality pharmaceutical products, which will result in avoidable "harm", such as therapeutic failure, emergence of resistance and even direct toxicity. A glaring example of this in recent times was the death, in Pakistan, of 120 cardiovascular patients who had received a medicine contaminated with pyrimethamine (1). Due to the globalisation of the pharmaceutical supply chain and the lack of international regulatory oversight, stringent drug regulatory authorities in affluent countries are also exposed to challenges related to quality. In the USA, for instance, at least four patients died after using contaminated heparin from China (2). These and other unnecessary deaths, caused by medical products which harmed rather than benefited the patients, are unacceptable and should be questioned on ethical grounds.

The evolution and challenges for the international harmonization of the regulation of pharmaceutical excipients in Taiwan

Excipients, once considered an inert component, have been shown to greatly influence the characteristics of the drug product, such as quality and safety. Functionality-related characteristics of excipients could affect the performance of the drug product. Moreover, the impact of globalization has complicated the issue and made the supervision of supply chain highly important. Taiwan, a member of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme, makes efforts to harmonize with international regulations and to strengthen the protection of patients through regulatory controls. In order to improve the harmonization and the transparency of regulatory requirements, the aim of the present study was to investigate the regulatory framework and considerations of stringent regulatory authorities and to propose the draft regulatory requirements to the Taiwan Food and Drug Administration for jurisdiction. The proposal which was extensively discussed in the expert committee includes the regulatory considerations to ensure the safety and quality of the excipients and may serve as a platform to facilitate the communication with industries about the current thinking on related issues. Moreover, through the review of the recent guidelines published by the stringent regulatory authorities, the trend of the regulatory considerations was revealed and discussed.

Antivenoms for Snakebite Envenoming: What Is in the Research Pipeline?

Of the 24 neglected tropical diseases (NTDs) and conditions listed by WHO, snakebite is among the top killers [1]. Tens of thousands of people die each year as a result of snakebite envenoming, with close to 50,000 deaths in India alone [2] and up to 32,000 in sub-Saharan Africa [3]. Yet there are few sources of effective, safe, and affordable antivenoms. The regions that bear the highest snakebite burden are especially underserved [4]. The Fav-Afrique antivenom, produced by Sanofi Pasteur (France), is considered safe and effective and is one of the few antivenoms to be approved by a Stringent Regulatory Authority (French National Regulatory Authority), although limited formal evidence has been published [5,6]. It is polyvalent, targeting most of the medically important snake species in sub-Saharan Africa. In particular, it is highly effective in treating envenoming by Echis ocellatus, the West African saw-scaled viper [5–7] that causes great morbidity and mortality throughout the West and Central African savannah. The venom of E. ocellatus may induce systemic haemorrhage, coagulopathy, and shock, as well as extensive local tissue damage. In the absence of treatment, the case fatality rate is 10%–20% [8]. Medecins Sans Frontieres (MSF) uses Fav-Afrique in its projects in sub-Saharan Africa, notably in Paoua in Central African Republic (CAR), where E. ocellatus envenoming is frequent [9]. Worryingly, MSF has been informed that the production of Fav-Afrique by Sanofi Aventis will be permanently discontinued. The last batch was released in January 2014, with an expiry date of June 2016. All the vials produced have already been sold by Sanofi Pasteur. Although several alternative antivenom products target a similar list of species as Fav-Afrique, there is currently no evidence of their safety and effectiveness. We aimed to review the evidence for the efficacy and safety of existing and in-development snake antivenoms, and to list the alternatives to Fav-Afrique in sub-Saharan Africa.

An assessment of the supply, programmatic use, and regulatory issues of single low-dose primaquine as a Plasmodium falciparum gametocytocide for sub-Saharan Africa.

BackgroundGlobal ambitions to eliminate malaria are intensifying, underscoring a critical need for transmission blocking tools. In 2012, the WHO recommended the use of 0.25 mg/kg of single low-dose (SLD) primaquine to stop Plasmodium falciparum transmission. To ensure the availability of SLD primaquine to countries in need of this tool, more information on the supply, programmatic, and regulatory barriers to the rollout of SLD primaquine is required.MethodsChallenges to the rollout of SLD primaquine in sub-Saharan Africa were established through semi-structured qualitative interviews with three primaquine manufacturers, 43 key informants from Ethiopia, Senegal, Swaziland, Zambia, and Tanzania, and 16 malaria research experts.ResultsSanofi and Remedica are the only two sources of SRA-approved primaquine suitable for procurement by international donors. Neither manufacturer produces primaquine tablet strengths suitable for the transmission blocking indication.In-country key informants revealed that the WHO weight-based recommendation to use SLD primaquine is challenging to implement in actual field settings. Malaria programmes expressed safety concerns of SLD primaquine use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency, as well as potential interactions between primaquine and co-morbidities, and drug-drug interactions with HIV and/or tuberculosis treatments. Regulatory processes are a major barrier to the rollout of SLD primaquine, requiring multiple steps at both the country and global level. Despite these barriers, demand for SLD primaquine is growing, and malaria researchers are interested in primaquine deployment through mass screen and treat and/or mass drug administration campaigns.ConclusionDemand for primaquine as a transmission blocking agent is growing rapidly yet multiple barriers to SLD primaquine use exist. Research is needed to define the therapeutic dose range, which will guide dosing regimens in the field, inform the development of new, lower strength primaquine tablets and/or formulation(s), and allay programmatic safety concerns in individuals with G6PD deficiency. Potential interactions between primaquine and co-morbidities and treatments should be explored. To minimize regulatory delays, countries need to prepare for product registration at an early stage, WHO prequalification for suitable primaquine tablet strengths and/or new formulations should be sought, and in the meanwhile only Stringent Regulatory Authority (SRA)-approved primaquine should be used.Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-015-0714-3) contains supplementary material, which is available to authorized users.

Are adaptive randomised trials or non-randomised studies the best way to address the Ebola outbreak in west Africa?

The Ebola outbreak that has devastated parts of west Africa represents an unprecedented challenge for research and ethics. Estimates from the past three decades emphasise that the present effort to contain the epidemic in the three most affected countries (Guinea, Liberia, and Sierra Leone) has been insufficient, with more than 24 900 cases and about 10 300 deaths, as of March 25, 2015. Faced with such an exceptional event and the urgent response it demands, the use of randomised controlled trials (RCT) for Ebola-related research might be both unethical and infeasible and that potential interventions should be assessed in non-randomised studies on the basis of compassionate use. However, non-randomised studies might not yield valid conclusions, leading to large residual uncertainty about how to interpret the results, and can also waste scarce intervention-related resources, making them profoundly unethical. Scientifically sound and rigorous study designs, such as adaptive RCTs, could provide the best way to reduce the time needed to develop new interventions and to obtain valid results on their efficacy and safety while preserving the application of ethical precepts. We present an overview of clinical studies registered at present at the four main international trial registries and provide a simulation on how adaptive RCTs can behave in this context, when mortality varies simultaneously in either the control or the experimental group.

Actions of the National Regulatory Authorities in 10 Low- and Middle-Income Countries Following Stringent Regulatory Authority Safety Alerts on Rosiglitazone.

On September 23, 2010, the US Food and Drug Administration and the European Medicines Agency issued safety alerts for medicines containing rosiglitazone. The authors monitored the actions of national regulatory authorities (NRAs) from 10 low- and middle-income countries to identify the time lag between the issuance of safety alerts by these two stringent regulatory authorities and any actions by these select NRAs. Two NRAs outside Africa took regulatory actions related to safety of rosiglitazone within 2 weeks of stringent regulatory authority safety alerts. For the 7 of the 8 African NRAs where the authors could confirm the date of regulatory action, the median time lag before some regulatory action was 43 days, although there was considerable variability in time to regulatory action. Low- and middle-income countries should create or strengthen systems for timely consideration and management of emerging safety issues for products that they have registered.

Registering medicines for low‐income countries: how suitable are the stringent review procedures of the World Health Organisation, the US Food and Drug Administration and the European Medicines Agency?

New medicines are registered after a resource-demanding process. Unfortunately, in low-income countries (LICs), demand outweighs resources. To facilitate registration in LICs, stringent review procedures of the European Medicines Agency (EMA Article-58), Food and Drug Administration (FDA PEPFAR-linked review) and WHO Prequalification programme have been established. Only the PEPFAR-linked review gives approval, while the others make recommendations for approval. This study assessed the performance and discussed the challenges of these three stringent review procedures. Data from WHO, FDA, EMA, Medline and Internet were analysed. Over 60% of medicines reviewed by stringent review procedures are manufactured in India. Until 2012, WHO prequalified 400 medicines (211 vaccines, 130 antiretrovirals, 29 tuberculostatics, 15 antimalarials and 15 others). PEPFAR-linked review approved 156 antiretrovirals, while EMA Article 58 recommended approval of 3 antiretrovirals, 1 vaccine and 1 antimalarial. WHO Prequalification and PEPFAR-linked review are free of charge and as a result have accelerated access to antiretrovirals. They both built capacity in sub-Saharan Africa, although WHO prequalification relies technically on stringent regulatory authorities and financially on donors. Article-58 offers the largest disease coverage and strongest technical capacities, is costly and involves fewer LICs. To meet the high demand for quality medicines in LICs, these stringent review procedures need to enlarge their disease coverage. To improve registration, EMA Article 58 should actively involve LICs. Furthermore, LIC regulatory activities must not be fully resigned to stringent review procedure.

Selection of the comparator product in the World Health Organisation Prequalification of Medicines Programme

The World Health Organisation’s Prequalification of Medicines Programme (WHO PQP) evaluates generic medicines for the treatment of HIV/AIDS, malaria, tuberculosis, influenza, and neglected tropical diseases, as well as zinc for the treatment of acute diarrhoea, and generic products related to reproductive health. For in vivo (i.e. bioequivalence studies) or in vitro studies (i.e. Biopharmaceutics Classification System-based biowaivers) used to establish the safety and efficacy of a generic product, selection of an appropriate comparator product is of great importance. Generic products prequalified by the WHO PQP are used in treatment programmes on a worldwide basis and therefore, the comparator products acting as a reference for their safety and efficacy should be of globally accepted quality, safety, and efficacy. Thus, to provide guidance to potential applicants and to discourage submission of bioequivalence studies with a comparator product that is not acceptable for the WHO PQP, comparators have been identified which should be employed in bioequivalence or biowaiver studies undertaken for submission to WHO PQP. The comparator of choice is normally the innovator product for which the quality, safety and efficacy have been established. In addition, to ensure that the comparator product has been adequately controlled from production to use, WHO PQP stipulates that comparator products should be procured from markets with a stringent regulatory authority, i.e. from countries participating in ICH or an ICH-associated country. However there can be many challenges associated with identifying appropriate comparators for WHO PQP. These challenges, ranging from the absence of a clear innovator product to the unavailability of a well-established innovator product to availability limited to non-ICH-associated markets, are discussed and the selections of specific comparator products supported. Furthermore, clear guidance on procuring the WHO PQP comparator are given, establishing further confidence that an appropriate comparator has been selected with proven quality, safety and efficacy.

The global pipeline of new medicines for the control and elimination of malaria.

Over the past decade, there has been a transformation in the portfolio of medicines to combat malaria. New fixed-dose artemisinin combination therapy is available, with four different types having received approval from Stringent Regulatory Authorities or the World Health Organization (WHO). However, there is still scope for improvement. The Malaria Eradication Research agenda identified several gaps in the current portfolio. Simpler regimens, such as a single-dose cure are needed, compared with the current three-day treatment. In addition, new medicines that prevent transmission and also relapse are needed, but with better safety profiles than current medicines. There is also a big opportunity for new medicines to prevent reinfection and to provide chemoprotection. This study reviews the global portfolio of new medicines in development against malaria, as of the summer of 2012. Cell-based phenotypic screening, and ‘fast followers’ of clinically validated classes, mean that there are now many new classes of molecules starting in clinical development, especially for the blood stages of malaria. There remain significant gaps for medicines blocking transmission, preventing relapse, and long-duration molecules for chemoprotection. The nascent pipeline of new medicines is significantly stronger than five years ago. However, there are still risks ahead in clinical development and sustainable funding of clinical studies is vital if this early promise is going to be delivered.

Anti-infective medicine quality: analysis of basic product quality by approval status and country of manufacture.

Some medicines for sale in developing countries are approved by a stringent regulatory authority (SRA) or the World Health Organization (WHO) prequalification program; many of these are global brands. This study ascertains whether medicines approved by SRAs or the WHO perform better in simple quality tests than those that have not been approved by either. Over the past 4 years, 2652 essential drugs (products to treat malaria, tuberculosis, and bacterial infections) were procured by covert shoppers from eleven African cities and eight cities in a variety of mid-income nations. All samples were assessed using the Global Pharma Health Fund eV Minilab® protocol to identify whether they were substandard, degraded, or counterfeit. The failure rate among SRA-approved products was 1.01%, among WHO-approved products was 6.80%, and 13.01% among products that were not approved by either. African cities had a greater proportion of SRA- or WHO-approved products (31.50%) than Indian cities (26.57%), but they also experienced a higher failure rate (14.21%) than Indian cities (7.83%). The remainder of cities tested had both the highest proportion of approved products at 34.46% and the lowest failure rate at 2.70%. Products made in Africa had the highest failure rate at 25.77%, followed by Chinese products at 15.74%, Indian products at 3.70%, and European/US products, which failed least often, at 1.70%. Most worrying is that 17.65% of Chinese products approved by the WHO failed. The results strongly indicate that approval by either an SRA or the WHO is correlated with higher medicine quality at a statistically significant level. The comparatively high failure rates among WHO-approved products suggest there may be some weakness in post-marketing surveillance of these products, especially of Chinese-made WHO-approved products. The discrepancy between the failure rate of WHO-approved products from India (2.39%) and China (17.65%) is cause for concern. It is possible that more of the failures originating in China are counterfeit products, but this cannot be ascertained without greater help from the manufacturers themselves.

A study of the capability of manufacturers of generic hormonal contraceptives in lower- and middle-income countries

Purpose Studies were undertaken to assess the capability, competence and capacity of manufacturers of oral and injectable hormonal contraceptives in lower- and middle-income countries. Methods A qualitative study on 41 companies, which comprised in-depth interviews and facility observations, was undertaken. Also an in-depth quantitative study of 14 companies was undertaken, of which 3 have not been included in the first study. Following review of a questionnaire and other documentation, a visit was undertaken to each factory to assess staff competence, manufacturing facilities, manufacturing processes, quality management, worker safety and environmental protection. Results Of the 44 companies from 15 countries, less than 30% would meet the current Good Manufacturing Practice requirements of the World Health Organization (WHO), the Pharmaceutical Inspection Cooperation Scheme or any stringent regulatory authority; a further 20% could comply with investment and improvements in quality management. Few companies are able to develop adequate registration dossiers. Conclusion There is a limited number of companies that are capable of manufacturing high-quality generic products and which can provide a complete registration dossier for use outside their home markets. It is essential that, in the future, procurement agencies only use suppliers that are prequalified by WHO for the procurement of hormonal contraceptives.