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?


  • Joachim Y. Doua,

    Corresponding author
    1. International Health Unit, University of Antwerp, Antwerp, Belgium
    • Corresponding Author Joachim Y. Doua, International Health Unit, Epidemiology and Social Medicine, University of Antwerp, Universiteitsplein 1, 2610 Antwerp (Wilrijk), Belgium. E-mail:

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  • Jean-Pierre Van Geertruyden

    1. International Health Unit, University of Antwerp, Antwerp, Belgium
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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.


Les nouveaux médicaments sont enregistrés suivant processus exigeant. Malheureusement, dans les pays à faibles revenus (PFR), la demande l'emporte sur les ressources. Pour faciliter l'enregistrement dans les PFR, les procédures d’évaluation rigoureuses de l'Agence Européenne des Médicaments (EMA Article 58), de la Food and Drug Administration (FDA PEPFAR-linked Review) et de la Pré-qualification de l’OMS (OMS - PQD) ont été établies. Seule l’évaluation par la PEPFAR-linked Review donne une approbation tandis que les autres font des recommandations pour approbation. Cette étude a évalué la performance et discuté les défis de ces trois procédures rigoureuses d’évaluation. Les données de l’OMS, de la FDA, de l’EMA, de Medline et d'Internet ont été analysées. Plus de 60% des médicaments évalués par des procédures d'examen rigoureux sont fabriqués en Inde. Jusqu'en 2012, l’OMS a pré-qualifié 400 médicaments (211 vaccins, 130 antirétroviraux, 29 antituberculeux, 15 antipaludéens et 15 autres). La PEPFAR-linked Review a approuvé 156 antirétroviraux, alors que l’EMA Article 58 n'a recommandé que l'approbation de 3 antirétroviraux, 1 vaccin et 1 antipaludique. La pré-qualification par l’OMS et l’évaluation par la PEPFAR-linked sont gratuits et en conséquence ont accéléré l'accès aux antirétroviraux. Ils ont tous deux renforcé les compétences en Afrique subsaharienne, mais la pré-qualification par l’OMS s'appuie techniquement sur des autorités réglementaires rigoureuses et financièrement sur des bailleurs de fonds. L'Article 58 assure l’évaluation du plus large éventail de maladies et les plus fortes compétences techniques, est coûteux et implique peu de PFR. Pour répondre à la forte demande pour des médicaments de qualité dans les PFR, ces procédures de contrôle rigoureuses doivent d’élargir leur éventail de maladies. Pour améliorer l'enregistrement, l'Article 58 de l’EMA devrait activement impliquer les PFR. De plus, les activités de réglementation dans les PFR ne doivent pas complètement démissionner face à la procédure d’évaluation rigoureuse.


Los nuevos medicamentos se registran después de un proceso que exige una importante asignación de recursos. Desafortunadamente, en países con bajos ingresos (PBIs), se han establecido procedimientos estrictos de la Agencia Europea del Medicamento (EMEA Artículo-58), la Agencia de Alimentos y Medicamentos (FDA, revisión por PEPFAR) y la precalificación por la OMS (OMS-PCAL). Solo la revisión por PEPFAR otorga una aprobación, mientras que las otras dan recomendaciones para la misma. Este estudio evalúa el desempeño y discute los retos de estos tres procedimientos estrictos de revisión. Se analizaron datos de la OMS, FDA, EMEA, Medline, e Internet. Sobre un 60% de los medicamentos revisados por procedimientos estrictos de revisión han sido producidos en la India. Hasta el 2012, la OMS precalificó 400 medicamentos (211 vacunas, 130 antirretrovirales, 29 tuberculostáticos, 15 antimaláricos y 15 otros). La revisión por PEPFAR aprobó 156 antirretrovirales, mientras que mediante el Artículo-58 de EMEA se recomendó la aprobación de 3 antirretrovirales, 1 vacuna y 1 antimalárico. La OMS-PCAL y la revisión por PEPFAR son procedimientos gratuitos y como resultado ha habido una aceleración del acceso a los antirretrovirales. Ambos han aumentado la capacidad de implementación de África subsahariana, aunque la OMS-PCAL depende técnicamente de autoridades regulatorias estrictas y a nivel financiero, de donantes. El Artículo-58 ofrece la mayor cobertura de enfermedades y las capacidades técnicas más sólidas, es caro e involucra a menos PIBs. Si se quiere satisfacer la alta demanda de medicamentos de alta calidad que tienen los PIBs, estos procedimientos de revisión tan estrictos deben crecer en su cobertura de enfermedades. Para mejorar el registro, el Artículo 58 de EMEA debería involucrar de forma activa los PIBs. Más aún, las actividades reguladoras de los PIBs no deberían resignarse a los procedimientos de evaluación estrictos.


The socio-economic development of sub-Saharan Africa is impeded by poverty-related diseases such as tropical infectious diseases and non-communicable chronic diseases (NCD) (Hotez & Kamath 2009). The control of these diseases is essential for achieving the UN millennium development goals related to poverty reduction, child mortality and maternal health (Sachs & McArthur 2005). Efficacious and safe medicines are key elements in disease control, whereas registration is a crucial phase in drug development as it permits their legal use. Before registration of any novel medicine, preclinical and clinical trials must provide data on its safety and efficacy alongside with the proof of its quality. Failure of regulatory authorities at registration to assess these data may result either in waste of investments for manufacturers or a public health concern.

Registration of novel medicines and vaccines by regulatory authorities requires complex technical resources and finances. In contrast, copackaged, fixed-dose combinations and generics registration are easier because only bioequivalence and quality are assessed in comparison with the original product. With the exception of South Africa, African regulatory authorities do not have the infrastructure to guarantee the quality, efficacy and safety of medicines. Hence, for medicine registration, they have to rely on high-income countries (HICs) regulatory authorities that are considered to be consistently stringent with their abilities (Burki 2010; WHO 2010a). This inability of African regulatory authorities may lead to use of substandard medicines by African populations (Dorlo et al. 2012).

To facilitate the access to quality medicine in low-income countries (LICs), HICs and WHO established stringent review procedures (SRP) exclusively for LICs. However, HICs medicine regulations and guidelines are not always adapted to LICs' contexts (Lang et al. 2010). WHO has therefore raised concerns about the implementation of HIC guidelines for non-HIC countries (WHO 2002).

We reviewed (i) current medicines regulatory practices in sub-Saharan Africa; (ii) assessed the performance of SRPs of the European Medicines Agency (EMA), US Food and Drug Administration (FDA) and WHO Prequalification programme (WHO-PQP) for LICs; (iii) discussed technical or political factors that may challenge their effectiveness and (iv) made suggestions for improvement.

Data were collected through the web portals of EMA, FDA and WHO-PQP. WHO-PQP publishes an overview of prequalified medicines, public assessment reports, and summary of product characteristics. FDA publishes tables of approved antiretrovirals in association with the US President's Emergency Plan For AIDS Relief (PEPFAR) and of orphan medicines. EMA provides lists of medicines applications, public assessment reports, a risk management programme and a summary of product characteristics for Article-58 and orphan medicines procedures. The web portals of WHO-PQP, FDA and EMA also publish medicines guidelines and regulations. We further screened Internet and Medline databases to compile relevant papers, reports and press releases. From the compiled data, we drew conclusions and recommendations.

Current medicines registration practices in sub-Saharan Africa

The majority of novel medicinal products are indicated for NCDs such as cancers, cardiovascular and neuropsychiatric diseases (WHO 2004). NCD medicines are the largest contributor to generics globally and account for 66% of the LICs medicine market (WHO 2004). However, data about NCD medicine approval in sub-Saharan Africa are scarce. Most novel medicines for African countries are first approved by stringent regulatory authorities (SRAs) or WHO-PQP (Moran et al. 2011).

Routinely, applicant companies will first submit a dossier to an SRA or WHO-PQP for approval. Then, they will seek approval from the African authorities where abridged dossier submission is allowed with proof of SRA approval (Moran et al. 2011). By doing so, applicants rely on SRAs' decades of experience and resources. Reversely, some manufacturers seek approval at an African regulatory authority first before submission to SRAs. For instance, Coartem was approved in Gabon in 1998 before its approval in the UK, Switzerland, and by WHO-PQP (Novartis International 2012).

As result of growing research and development in the last decades, novel neglected infectious diseases medicines have been put in trial of regulatory assessment (Moran et al. 2010). FDA, EMA and WHO created SRPs exclusively for LICs to support their registration assessments. In 2010, WHO piloted a joint-assessment strategy in the Eastern African Community through which abacavir antiretroviral and amikacin tuberculostatic were registered (WHO 2011f). Joint assessment may be beneficial to manufacturers because of their fast and broader market access (WHO 2011f).

Harmonisation and regionalisation efforts in sub-Saharan Africa

Efforts are being made towards medicines regulatory harmonisation and regionalisation in sub-Saharan Africa. The African Union's African Medicines Regulatory Harmonisation Initiative has a regional economic community approach. The Eastern African Community launched a harmonisation of medicines registration in its member states in 2012 (AMRH n.d.). A strategic business plan was developed for centralised registration, inspection and testing. A similar initiative was created in the Communauté Économique des États de l'Afrique Centrale. In the Southern African Development Community, a pharmaceutical business plan has been agreed to build capacity for less experienced regulatory authorities and to develop regulatory guidelines (AMRH n.d.). The West African Union Économique et Monétaire Ouest Africaine established in 2006 a regional committee for veterinary medicines which has reviewed 21 regional medicines applications (UEMOA 2006). The Union Économique et Monétaire Ouest Africaine has started harmonising registration of human medicines by directive N°06/2010/CM (UEMOA 2010). However, to date, the harmonisation of medicines regulatory activities is not yet finalised in all sub-Saharan African regions due to the lengthy appraisal and long negotiating processes by stakeholders (AMRH n.d.).

SRPs for low-income countries

The major SRPs used for LICs are WHO-PQP, European Article-58 and FDA's PEPFAR approval or Tentative Approval. WHO-PQP was created in 2001 and endorsed by the International Conference of Drug Regulatory Authorities to facilitate access to quality medicines in LICs (International Conference of Drug Regulatory Authorities (ICDRA) 2004; WHO 2011a; WHO Prequalification of Medicines Programme (WHO-PQP) 2011). WHO-PQP lists prequalified medicines manufactured in sites that meet WHO standards. WHO-PQP applies an abridged procedure to products already registered by a SRA. However, PEPFAR- and Article 58-related products are added to WHO-PQP list without further assessment (WHO 2011d). WHO-PQP also performs post-marketing quality monitoring of the medicines. A WHO survey performed on antimalarials circulating in sub-Saharan Africa in 2008 found that prequalified antimalarials were of the best quality (WHO 2011c).

The FDA applied the approval or tentative approval procedure to the PEPFAR programme in 2004 to enable funded projects of this programme to procure safe, effective and quality antiretrovirals for exclusive use in Africa and Asia. FDA approves new formulation or fixed-dose combination of previously approved antiretrovirals by the New Drug Application. However, generics are approved under the Abbreviated New Drug Application. FDA issues a full approval if the applicant product does not infringe on any patented product.

Conversely, if for patent protection of the reference product a qualifying antiretroviral cannot be marketed in the US, the FDA issues a tentative approval that makes the applicant product eligible for purchase under the PEPFAR programme only. Pro-actively FDA liaises with counterpart regulatory authorities and WHO to help understand FDA approval decisions for their local implementation (Curtin & Schulz 2011; Food and Drug Administration (FDA) 2011a). FDA also possesses a supply chain management system to facilitate procurement of the medicines.

The European Commission initiated Article-58 in 2005 to facilitate access to new medicines in non-EU countries. The scrutiny of data evaluation is in principle at the same standard as with the European applications. Therefore, the European requirements for safety management and safety risk minimisation apply to the Article-58 procedure when they can improve the benefit-risk ratio. After registration, a positive approval opinion can be revised if serious risks emerge (European Medicines Agency (EMA) 2005).

All three SRPs cover HIV. But there is a slight difference in disease coverage between WHO-PQP and EMA Article-58 because of the differences between neglected infectious diseases and novel medicines (Table 1). WHO-PQP is unique in that it collaborates with user countries although it is the least staffed and relies on donations (WHO 2011a). These stringent review procedures have mainly reviewed antiretrovirals (Figure 1). PEPFAR-linked antiretrovirals comprised 97 generics and 59 novel formulations. Few medicines underwent the EMA process; WHO-PQP has been the most used process. Almost all vaccines applications underwent prequalification. EMA, FDA and WHO advertise summary of product characteristics and information leaflets of approved medicines for appropriate use by care providers and patients.

Table 1. comparison of European Article-58, PEPFAR-linked Review and WHO-Prequalification
ProcedureEuropean Article-58WHO-PQPPEPFAR-linked Review
  1. a

    Many additional fees are demanded for the other regulatory actions. Fee waivers are possible if public health imperative.

  2. b

    1 officer for liaison, 1 officer capacity building, 1 officer for sampling, and 1 for monitoring.

  3. c

    LICs and WHO Experts are consultants or observers but they don't have any voting rights on the approval process.

Fee charging


254 100 Euroa

Assessing committees

Committee for Human Medicinal Products (CHMP)

EMA member agencies (30 in total) Involvement of the Paediatric Committee (PDCO) and Pharmacovigilance Risk Assessment Committee (PRAC)

WHO-PQP Staff includes

1 manager

6 inspectors

8 assessors

8 supporting staff

4 othersb

Center for Drug Evaluation and Research

Office of Generic Drugs (>100 staffs) Division of Antimicrobial Products

Disease coverage






 Vaccines of the WHO Expanded Programme on Immunization Vaccines for public health need

Less large


 Malaria Tuberculosis

 Vaccines of WHO Expanded

 Programme on Immunization

 Vaccines for public health need

 Reproductive health

 Zinc-related diarrhoea


 HIV/AIDS (only ARVs)

LICs involvementNOc


 SSA-assessors represent 20–30% of all external assessors

 WHO-PQP staff has a 3-months rotational post for LICs

Capacity buildingNO




 Medicines monitoring


 Good Clinical Practice



 Risk communication

Candidate medicines

All types

 Novel Active Pharmaceutical

 Ingredient Medicines for NIDs

 Single entity


 Fixed dose combination


Almost all types

 Active Pharmaceutical


 Single entity

 Co-packaged medicines

 Fixed dose combinations Vaccines

Selected types

 Single entity

 Co-packaged medicines

 Fixed dose combinations

Complexity of assessmentVery highFairly highHigh
Average assessment duration


 7 months (excludes the time periods given to applicants to address)


 4.3 months for innovators

 31.6 months for generics

Fast track

 0.5–1.5 months

Figure 1.

Number of approved products by Article-58, PEPFAR-link review, and WHO-PQP. (a) Number of products approved by Stringent Review Procedure. (b) Breakdown of approved medicines by disease indication. *Others: Anti-contraceptives and anti-influenza antivirals.

Western orphan pathways: a possible bypass for SRPs?

Orphan medicines are intended for rare diseases. Regulatory authorities have considered that the financial returns for orphan medicines may not balance the investments of their development without incentives. To encourage development of orphan medicines, EMA and FDA waive the registration fees for companies and scientifically assist applicant companies to facilitate development and registration. EMA and FDA also provide 10 years' market protection in the EU and 7 years in the US for orphan medicines; the standard market exclusivity is 8 and 5 years, respectively, for non-orphan medicines (Sharma et al. 2010). In the US orphan medicines applicants may obtain research grants through FDA or the National Institutes of Health and in the EU through the ‘Seventh Framework Programme for Research and Technology’ or ‘the International Rare Diseases Consortium’ (European Medicines Agency (EMA) 2012b; Food & Drug Administration (FDA) 2011b). Furthermore, although the safety and efficacy requirements and approval processes of orphan medicines are identical to non-orphan medicines, regulatory authorities need to apply a different benefit-risk analysis for rare diseases due to the small size of the exposed population and the lack of treatment alternatives (Joppi et al. 2012). Because large controlled trials are not always possible, orphan medicines exceptionally may benefit of fast track review and of double standard assessment (Joppi et al. 2012). These advantages are not given to non-orphan medicines applicants.

Western orphan medicines are, in principle, not approved for LICs. However, one may consider that tropical diseases are rare diseases in HICs. Therefore, for travellers and oversee operations, many medicines targeting tropical diseases (i.e. malaria, leishmaniasis and sleeping sickness) are approved by Western orphan pathways. Medicines targeting tropical diseases approved through the FDA and EMA orphan pathways are shown in Table 2 and 3. Between 1993 and 2013, FDA approved 28 HIV/AIDS-related orphan disease indications, 5 for malaria, 5 for tuberculosis and 7 for neglected infectious diseases. In the EU, only one ‘tropical’ orphan indication was approved. Many of the medicines for these orphan indications were either new formulations or new indications of approved medicines (Villa et al. 2009). Eurartesim (piperaquine–dihydroartemisinin), an antimalarial combination therapy, was approved in August 2007 as orphan medicine by EMA (WHO 2011b). However, the company withdrew the orphan approval in July 2011 and sought and obtained approval in October 2011 for the same medicine through the European centralised procedure tailored to European populations (European Medicines Agency (EMA) 2011). It can be expected that Eurartesim® review following both pathways did not account of LICs specificities for malaria in analogy with other medicines approved through SRPs for LICs. In parallel, Eurartesim® was registered in Cambodia, but no information has been made available on the review by the Cambodian regulatory authorities (Sigma Tau 2012). A WHO-PQP is also submitted, and further registrations are being sought in sub-Saharan Africa.

Table 2. FDA approved orphan indications with tropical diseases target (from 1/1/1983 to 1/1/2013)
Generic NameTrade NameDisease designationMarketing Approval Date
BedaquilineSirturoTreatment of active tuberculosis12-28-2012
Varicella Zoster Immune Globulin (Human)VarizigPassive immunization for the treatment of exposed, susceptible individuals who are at risk of complications from varicella12-20-2012
TenofovirVireadTreatment of pediatric HIV infection.03-24-2010
Artemether/lumefantrineCoartemFor the treatment of infections due to Plasmodium falciparum or mixed infections including P. falciparum.04-07-2009
Hepatitis B immune globulin (human)HepagamPrevention of hepatitis B recurrence following orthotopic liver transplant04-06-2007
Quinine Sulfaten/aTreatment of malaria08-12-2005
Vaccinia Immune Globulin (Human) IntravenousCnj-016Treatment of complications of vaccinia vaccination05-02-2005
Vaccinia Immune Globulin (Human) Intravenousn/aTreatment of severe complications from the smallpox vaccine02-18-2005
TinidazoleTindamaxTreatment of amebiasis05-17-2004
TinidazoleTindamaxTreatment of giardiasis05-17-2004
RibavirinRebetolTreatment of chronic hepatitis C in pediatric patients07-29-2003
NitazoxanideAliniaTreatment of intestinal giardiasis11-22-2002
NitazoxanideAliniaTreatment of cryptosporidiosis.11-22-2002
NitretinoinPanretinTreatment of AIDS-related Kaposi's sarcoma.02-02-1999
AtovaquoneMepronPrevention of Pneumocystis carinii pneumonia (PCP) in high-risk, HIV-infected patients defined by a history of one or more episodes of PCP and/or a peripheral CD4+ (T4 helper/inducer) lymphocyte count less than or equal to 200/mm3.01-05-1999
Cytomegalovirus immune globulin (human)CytogamPrevention or attenuation of primary cytomegalovirus disease in immunosuppressed recipients of organ transplants.12-04-1998
RifapentinePriftinTreatment of pulmonary tuberculosis.06-22-1998
Liposomal amphotericin BAmbisomeTreatment of visceral leishmaniasis.08-11-1997
Liposomal amphotericin BAmbisomeTreatment of cryptococcal meningitis.08-11-1997
PaclitaxelTaxolTreatment of AIDS-related Kaposi's sarcoma.08-04-1997
Amphotericin B lipid complexAbelcetTreatment of invasive fungal infections.10-18-1996
Somatropin for injectionSerostimTreatment of AIDS-associated catabolism/weight loss.08-23-1996
AlbendazoleAlbenzaTreatment of hydatid disease (cystic echinococcosis due to E. granulosus larvae or alveolar echinococcosis due to E. multilocularis larvae).06-11-1996
AlbendazoleAlbenzaTreatment of neurocysticercosis due to Taenia solium as: 1) chemotherapy of parenchymal, subarachnoidal and racemose (cysts in spinal fluid) neurocysticercosis in symptomatic cases and 2) prophylaxis of epilepsy and other sequelae in asymptomatic neurocysticercosis.06-11-1996
Daunorubicin citrate liposome injectionDaunoxomeTreatment of patients with advanced HIV-associated Kaposi's sarcoma.04-08-1996
Ganciclovir intravitreal implantVitrasert ImplantTreatment of cytomegalovirus retinitis.03-04-1996
Sulfadiazinen/aFor use in combination with pyrimethamine for the treatment of Toxoplasma gondii encephalitis in patients with and without AIDS.07-29-1994
Aminosalicylic acidPaser GranulesTreatment of tuberculosis infections06-30-1994
Rifampin, isoniazid, pyrazinamideRifaterFor the short-course treatment of tuberculosis.05-31-1994
Immune globulin intravenous, humanGamimune NInfection prophylaxis in pediatricpatients affected with the human immunodeficiency virus.12-27-1993
Trimetrexate glucuronateNeutrexinTreatment of Pneumocystis carinii pneumonia in AIDS patients.12-17-1993
Megestrol acetateMegaceTreatment of patients with anorexia, cachexia, or significant weight loss (≥10% of baseline body weight) and confirmed diagnosis of AIDS.9-10-1993
RifabutinMycobutinPrevention of disseminated Mycobacterium avium complex disease in patients with advanced HIV infection.12-23-1992
DronabinolMarinolFor the stimulation of appetite and prevention of weight loss in patients with a confirmed diagnosis of AIDS.12-22-1992
AtovaquoneMepronTreatment of AIDS associated Pneumocystis Carinii Pneumonia.11-25-1992
HalofantrineHalfanTreatment of mild to moderate acute malaria caused by susceptible strains of P. falciparum and P. vivax.07-24-1992
ZalcitabineHividTreatment of AIDS.06-19-1992
Epoetin alfaEpogenTreatment of anemia associated with HIV infection or HIV treatment.12-31-1990
Eflornithine HClOrnidylTreatment of Trypanosoma brucei gambiense infection (sleeping sickness).11-28-1990
Ganciclovir sodiumCytoveneTreatment of cytomegalovirus retinitis in immunocompromised patients with AIDS.06-23-1989
Pentamidine isethionateNebupentPrevention of Pneumocystis carinii pneumonia in patients at high risk of developing this disease.06-15-1989
RifampinRifadin I.V.For antituberculosis treatment where use of the oral form of the drug is not feasible.05-25-1989
Mefloquine HClLariamTreatment of acute malaria due to Plasmodium falciparum and Plasmodium vivax.05-02-1989
Mefloquine HClLariamProphylaxis of Plasmodium falciparum malaria which is resistant to other available drugs.05-02-1989
Interferon alfa-2a (recombinant)Roferon-ATreatment of AIDS related Kaposi's sarcoma.11-21-1988
Interferon alfa-2b (recombinant)Intron ATreatment of AIDS-related Kaposi's sarcoma.11-21-1988
ZidovudineRetrovirTreatment of AIDS related complex.03-19-1987
ZidovudineRetrovirTreatment of AIDS.03-19-1987
Pentamidine isethionatePentam 300Treatment of Pneumocystis carinii pneumonia.10-16-1984
Table 3. EMA approved orphan indications with tropical diseases target
Generic NameTrade NameDisease designationMarketing Approval Date
HydroxycarbamideSiklosSymptomatic sickle cell syndrome29-06-2007

To prevent misuse of Western orphan approvals in LICs, legislation might be jointly taken by SRAs and LIC regulatory authorities by requesting, for example, a signed commitment of applicants at registration that a stringent authority's orphan certificate will not be used for LICs applications.

Challenges of SRPs

Although there are successes, some challenges have been identified for SRPs. One is the registration fee charging: a company may invest in a medicine if the expected revenues are covered by the invested costs. The expected revenues of a medicine depend, among other parameters, on the volume of drug sold and the average income of targeted populations (Villa et al. 2009). For tropical diseases, expected revenues cannot justify investment as the target population's average income is low (Villa et al. 2009). Small companies in India have manufactured >60% of the medicines reviewed by Article-58, PEPFAR and WHO-PQP (Table 4). The fees charged by Article-58 may deter from use of this avenue in contrast to WHO-PQP and PEPFAR-linked review. To improve the attractiveness of companies for Article-58, EMA could explore dropping the fees for pre-approval scientific advice, inspections and registration.

Table 4. Post-approval risk management program of Article-58 reviewed products
Reviewed productsActive substanceIndicationSafety concernsaRisk management programme
  1. a

    Issues for which a relationship has not yet been established with the concerned medicinal product.

HexaximDiphtheria, tetanus, pertussisPrimary and booster vaccination-hypotonic hyporesponsive-Post-approval surveillance
(acellular, component), hepatitisOf infants and toddlers from 6episode-Routine adverse events reporting
b rdna), poliomyelitisweeks to 24 months of age-extensive limb swelling-Periodic Safety Update Reports
(inactivated) and haemophilusagainst diphtheria, tetanus,-anaphylaxis-Signal detection process
influenzae type b conjugatepertussis, hepatitis B,-convulsions
vaccine (adsorbed)poliomyelitis and invasive-apnoea-Clinical trial program
 diseases caused by Haemophilus influenzae type b



-sudden Infant

-death syndrome

-sudden unexplained death

-apparent life threatening event

-lack of data in immune-compromised patients

-lack of data in patients with chronic diseases

-planned studies in Europe and Latin America

-local studies

-post approval safety

-studies Study in immuno-compromised population

Lamivudine ViiVLamivudineAntiretroviral therapy (in combination with other ARVs) for the treatment of Human Immunodeficiency Virus infected adults and childrenNoNo
Alluvia200 mg lopinavir/50 mg ritonavirAntiretroviral medicinal products for the treatment of human immunodeficiency virus (HIV-1) infected adults, adolescents and children above the age of 2 yearsNoNo



150 mg lamivudine/300 mg


Antiretroviral combination therapy for the treatment of human immunodeficiency virus (HIV) infected adults and childrenNoNo
Pyramax180 mg pyronaridineAdults and children weighing 20 kg or more to treat uncomplicated malaria, caused by two types of malaria parasites, Plasmodium falciparum and Plasmodium vivax-Increases in liver Transaminases-Post-approval surveillance
Tetraphosphate/60 mg-Routine adverse events reporting

-Exacerbation of anaemia




-Interaction with medication metabolised through CYP2D6 or via P-gp efflux

-Use in pregnant and lactating women

-Proactive cohort event monitoring for liver function and adverse events Set up a pregnancy register

-Clinical study programme

-Repeat dose study in patients

-Repeat dose in healthy volunteers

-Pregnancy register

-Interaction with primaquine

 -Neurotoxicity-Mass balance study
-Prolongation of QT Induction of resistance-Interaction study with metoprolol
-P-gp interactions which are likely to be primarily for the use of digoxin
-Tissue accumulation Skin discolouration
-Drug interactions with TB or HIV agents
-Effect of repeat courses
-Significant anaemia (patients with Hb < 8 g/dl)
-Use in infants, elderly, and HIV/AIDS patients Significant anaemia (Hb <8 g/dl)
-Patient with haemoglobinopathy
-Patients with renal or cardiac impairment

The lack of pharmacovigilance systems in LICs is another challenge. Not all adverse events are captured when new medicines are registered, as adverse events may pass clinical trial phases unobserved. For example, in February 2012, FDA reported an increased risk of rhabdomyolysis, a muscle disease with fatal consequences, subsequent to co-administration of anti-HIV protease inhibitors with certain statins (Food & Drug Administration (FDA) 2012). FDA subsequently recommended cautious co-use of statins with the lowest dose necessary. For ACTs, despite large clinical studies and meta-analyses conducted, the complete safety profile is not yet defined (Efferth & Kaina 2010). Because data on repeated use of ACTs are limited and the elimination half-life of some ACTs is long, a single treatment or restricted number of treatments is recommended. For Pyramax, a novel ACT, only one treatment course per year is recommended (European Medicines Agency (EMA) 2012a). To assure that adverse events are captured in post-approval, companies should put in place pharmacovigilance systems at registration. Among the three SRPs, only Article-58 requires pharmacovigilance programmes at registration (Table 5) (European Medicines Agency (EMA) 2005). However, these pharmacovigilance programmes may not be effective in sub-Saharan Africa (WHO 2011e). One may wonder how effectively Western SRAs can control pharmacovigilance activities outside their boundaries.

Table 5. Geographical overview of site of manufacturing of PEPFAR-linked Review, Article-58 and WHO-PQP reviewed medicines for LICs
Review procedureManufacturing siteNumber (%)
  1. a

    Three affiliates of EU multi-national companies.

  2. b

    Four of the manufacturers are affiliates of Western multi-national companies.

PEPFAR-linked ReviewAfrica2 (0.4)
China2 (0.4)
India150 (26.7)
Western World2 (0.4)
WHO-PQP vaccinesAfricaa3 (0.5)
India67 (12)
Western World101 (18)
Others40 (7.1)
WHO-PQP medicinesAfricab13 (2.3)
China4 (0.7)
India136 (24.2)
Western World36 (6.4)
European Article-58Western World4 (0.7)
South Korea1 (0.2)

The potential reluctance by user countries arises because some LICs countries prefer reviews by FDA or EMA, while others prefer WHO-PQP (WHO 2011d). Four African countries refused to register a PEPFAR-linked antiretroviral in 2005 because the medicine was not prequalified by WHO (Caudron et al. 2008). Fortunately, PEPFAR and Article-58 approved products are now directly listed on WHO-PQP list. However, it is not known how effectively SRP approvals are implemented in user countries. Hypothetically, a suspicion of double standard by LICs may not be excluded, as Western SRAs recommend medicines for use in LICs while banning them for their own markets.

The need of local experience and regulatory collaboration The perception of risk and of benefit differs between societies (Van Roey & Haxaire 2008; Curtin & Schulz 2011). As a result, the benefit risk of a candidate medicine has to account for the local realities. The registration of rifapentine®, a novel tuberculostatic, in 1998 by the FDA highlighted the need of local expertise for LIC medicine registration by SRAs. A multicentre clinical trial was conducted in South Africa, US and Canada to assess the safety and efficacy of rifapentine®. Due to the high prevalence of tuberculosis-HIV co-infection in sub-Saharan Africa, interaction studies with antiretrovirals were warranted. However, the sponsor excluded HIV patients in the study, leading to a restriction of rifapentine to the US market in spite of the immediate and greater need in sub-Saharan Africa (Roehr 1998).

Except for WHO-PQP, the number of assessors with tropical expertise involved in SRPs is not made publicly available, although this is important for medicines for tropical diseases as malaria for example (WHO 2012b). Indeed, malaria morbidity differs accordingly to its endemicity. In hyperendemic areas, about 2% of malaria infections complicate to severe illnesses, whereas in malaria-free areas, any infection may complicate to severe disease (Greenwood et al. 1991). In practice, SRA' assessors may have severe malaria in mind instead of the uncomplicated malaria syndrome, the indication for ACT use. Furthermore, they may ignore overuse and off-label use, both of which are common practices in sub-Saharan Africa (Mwanziva et al. 2008). As a result, a risk-benefit assessment by SRAs for medicines for LICs use without an active role of targeted countries would be challenging (Van Roey & Haxaire 2008; Moran et al. 2010, 2011).

To improve their effectiveness, PEPFAR-linked review and Article-58 should actively involve local countries. Collaboration enables sharing of experience and workload and sustainably facilitates implementation of SRP approval opinions in LICs. Collaboration can also shorten approval durations in local countries (International Conference of Drug Regulatory Authorities (ICDRA) 2004). For each Article-58 application, for example, a rapporteurship or a corapporteurship could be given to a regional LICs Regulatory Authority along with peer review by WHO. HIC–LIC collaboration may also be used to improve the Western guidelines for medicines for exclusive use in LICs, with particular regards for pharmacovigilance and risk management (WHO 2012a). To avoid unnecessary workload to European national regulatory authorities for applications intended for diseases and medicines unfamiliar to them, a specific working group could be established at the EMA for Article-58. With identical stringent standards, there would be no added value involving all EMA member agencies for an Article-58 review.

Political implications of SRPs

Stringent review procedures may spark questions about Western interference with local countries autonomy and sovereignty (WHO Regional Office for Africa 2012). In fact, Article-58, PEPFAR-linked review and WHO-PQP deliver approval recommendations only. The approval decision remains firmly in sovereign user countries. SRPs support but do not replace local regulatory agencies (WHO 2012b). Nevertheless, there is a regulatory ground for stronger involvement of SRAs in LICs medicine registration as access to essential medicines is a global concern that obtained commitment from all nations including HICs (Sachs & McArthur 2005; WHO 2013). Access to medicines is also a human right embedded in the Universal Declaration of Human Rights (WHO 2013).

Key efforts to improve SRPs for LICs

For higher efficiency, SRPs should avoid work duplication and focus on medicines that can attend LIC review before any SRA review. Also, SRPs should cover all LIC diseases with public health impact (WHO 2012a). In sub-Saharan Africa, such diseases can be classified into three categories: NCDs, poverty-related infections and ‘tropical’ inherited NCDs (International Policy Network (IPN) 2004). Merely, second-line or generic applications of NCD medicines may be submitted first at African regulatory authorities as original products are expected to be reviewed by SRAs (International Policy Network (IPN) 2004; WHO 2010b). Conversely, for poverty-related infections and ‘tropical’ inherited NCDs (i.e. sickle cell, thalassaemia and G6PD deficiency), novel and generic applications could be submitted to sub-Saharan Africa regulatory authorities before any SRP. As a result, SRPs would at least cover novel medicines and generics for poverty-related infections, and inherited ‘tropical’ haemoglobinopathies, generics for NCDs and WHO listed vaccines for public health need (WHO Regional Office for Africa 2012).

To build capacity for the long term in Sub-Saharan Africa, regulatory sciences should be integrated into post-graduation academic programmes (WHO 2012a). The strategy of WHO-PQP of appointing African assessors in WHO-PQP staff could be explored for Article-58 and PEPFAR-linked review (WHO 2012c). All aspects of regulatory sciences should be covered: quality, non-clinical toxicity, clinical safety and efficacy, pharmacokinetic, pharmacovigilance and risk management, inspection, regulatory and administrative dossier management (WHO 2010a). However, consistent with the increasing demand for generics in Africa, the priorities should be quality, pharmacokinetics and inspections (International Conference of Drug Regulatory Authorities (ICDRA) 2004). Regulatory capacity building is an urgent need in Africa. SRPs for LICs at the current pace cannot be guaranteed in years ahead as resources for WHO-PQP, and PEPFAR may decline in the near future (WHO 2012a). Local countries will therefore have to assure the responsibilities for the quality of their medicines themselves. This warrants rapid support of the African Medicines Regulatory Harmonisation programme.


Many sub-Saharan African countries rely on medicines reviewed by SRPs. Article-58, PEPFAR-linked review and WHO-PQP have facilitated medicines registration for LICs. By September 2011, PEPFAR had directly enabled more than 3.9 million antiretroviral treatments worldwide and saved approximately $320 million treatment expenditures to LICs (President's Emergency Plan For AIDS Relief (PEPFAR) 2011; Holmes et al. 2010). WHO-PQP and PEPFAR-linked review have accelerated access to antiretrovirals in sub-Saharan Africa (Moran et al. 2011). Article-58 has been the least used although it has the largest disease coverage and applicable products. However, Article-58 could be, without the fee charging, more advantageous due to its multilevel technical review, resource availability and large disease coverage. WHO-PQP is the most used, incorporates the most user countries' expertise but relies on external funding. PEPFAR-linked review, as part of the US development cooperation, has the strongest political commitment but focuses on generic antiretrovirals. Further improvement for the three SRPs consists of increasing the regulatory collaboration, building capacity, developing guidelines for LICs and enlarging disease coverage particularly for PEPFAR-linked review. To ensure effective implementation and avoid any suspicion of double standards, all SRPs should actively involve user countries. As the most promising review procedure, global donors should pursue support of WHO-PQP. Importantly, SRPs should rapidly serve as transition towards development of SRAs in Africa to avoid abdication of African countries from their responsibilities.


We particularly valued the review and comments of Dr Mary Moran of Policy Cures, Sydney, Australia; Ms Raffaella Ravinetto of Institute of Tropical Medicines, Antwerp, Belgium; Dr Gilbert Komlan Akoda of Service de Pharmacie-Toxicologie, Département de Santé Publique-Environnement, École Inter-États des Sciences et Médecine Vétérinaires, Dakar, Senegal; Dr Sayed Tabatabaei F.A., Senior Pharmacovigilance Assessor for the Medicines Evaluation Board of the Netherlands and the European Medicines Agency; and other contributors who preferred not to be listed here. We thank the Division of Drug Information, Center for Drug Evaluation and Research, Food and Drug Administration; the Prequalification of Medicines Programme Staff of the World Health Organization; the Department of Anti-Infectives and Vaccines, Safety and Efficacy of Medicines, European Medicines Agency; the UEMOA Commission for the information and documents provided and or the telephone conferences.