In countries with limited regulatory resources, management of diseases of major public health relevance is frequently jeopardized because of delayed access to needed therapies. Although a finished pharmaceutical product (FPP) may have undergone review by a globally-recognized regulatory body (such as the European Medicines Agency, the US Food and Drug Administration or another stringent regulatory authority (SRA)), local regulatory processes, that consume additional time and resources, must be completed, before it is approved for use and can be made available to patients.
Sharing of outcomes of SRA assessments and inspections, and cooperation among medicines regulatory authorities, could improve this situation. Just such an approach — as defined under the Collaborative Procedure between the World Health Organization Prequalification of Medicines Programme and National Medicines Regulatory Authorities in the Assessment and Accelerated National Registration of WHO-prequalified Pharmaceutical Products — has already been developed for application to FPPs prequalified by WHO. A new and similar procedure for application to SRA-approved FPPs has now been developed by WHO, with input from national medicines regulatory authorities (NMRAs), the International Federation of Pharmaceutical Manufacturers & Associations, and the European Generic and Biosimilar Medicines Association.
This new procedure aims to facilitate and accelerate national regulatory approvals by providing access to data that documents the relevant SRA decisions, and evidence that either the same FPP, as approved by the SRA, or an FPP whose differences from the SRA-approved product are well-defined and understood, is the FPP that is now being submitted for registration. As with the earlier procedure for prequalified products, the new procedure incorporates a mechanism for confidential sharing of the relevant information.
How will it work?
Participation will be open to any interested NMRA or pharmaceutical company, and the procedure is designed to be applicable to any SRA-approved FPP (innovator or generic) that is relevant to public health needs.
The pharmaceutical company (applicant) will submit an FPP for registration that is the “same” (as defined by the procedure) as the SRA-approved product, to participating NMRAs. In the case of deviations from the SRA-approved product, these must be specified by the applicant. The product dossier will be organized in the common technical document format (CTD) that was approved by the SRA and adapted for the purpose of the procedure.
In the case of innovator medicines, applicants will be advised to also provide a “bridging report” that contains additional discussion of data relevant to the countries to which the application is being submitted, if the SRA assessment report does not cover these elements sufficiently.
The applicant ― with the agreement of the relevant SRA ― will share the full assessment and inspection reports for the FPP with the participating NMRAs, as well as additional data documenting potential deviations from the FPP approved by the SRA. In organizing the sharing of the reports, the applicant will help to minimize any administrative burden on participating SRAs. The role of the SRA will be limited to data authentication, and, when specifically agreed with individual SRAs, provision of additional explanation of their decisions, should either or both be requested by the NMRAs.
Participating NMRAs will use the data submitted to support their decision-making regarding registration. They will seek to issue an “accelerated” decision on registration within 90 days of their acceptance of the submission. The procedure will not interfere with their national, regulatory decision-making processes, or with national legislation, or with levying of regulatory fees. Similarly, it will be the NMRAs’ responsibility to reach agreement with applicants regarding specific risk-management plans and pharmacovigilance follow-up.
To ensure that the FPP remains the same as the SRA-approved FPP, or that any deviations from the SRA-approved product are clearly indicated to the NMRAs, management of SRA-approved post-registration variations will follow principles similar to those applied under registration.
WHO’s role will be to facilitate cooperation among applicants, participating NMRAs and SRAs. It will be involved with application of the procedure to a specific FPP only if WHO considers the FPP to be of public health relevance.
Piloting of the procedure started in 2015 and will continue until sufficient experience in testing its principles and mechanisms has been gathered, and final guidance can be drafted. It will be concluded with the mutual agreement of WHO, participating NMRAs and industry partners, and its end date will be announced publicly.
Pilot of the procedure
The pilot was initiated by WHO, in cooperation with the European Medicines Agency and an interested pharmaceutical company. It is being conducted through the combined efforts of volunteering NMRAs in resource-limited countries, SRAs and applicants. It is focusing on FPPs of significant public health need (e.g. antiretrovirals, tuberculosis or malaria medicines, maternal health medicines or contraceptives) that have been approved by participating SRAs, and irrespective of whether these are innovator or generic products. FPPs prequalified by WHO through application of an abbreviated process (based on SRA approval), FPPs invited for WHO prequalification, or FPPs of specific interest to WHO disease programmes or with other special relevance (e.g. paediatric formulation), are prioritized.
Following conclusion of the pilot a guidance document covering the principles of the process, its proposed scope, the format for sharing information, the milestones and recommended deadlines to be applied during the process, suggested means of communication and practical advice based on WHO’s accumulated experience in serving regulatory authorities in developing countries, pharmaceutical manufacturers and SRAs, will be prepared.
The pilot will also result in:
- substantially accelerated registration of two or three priority FPPs in countries of priority need
- enhanced regulatory expertise of between 5 and 10 national regulatory teams following their participation in assessment of innovative and generic medicines to international standards
- increased regulatory harmonization between participating NMRAs through NMRA networking and training of national regulatory teams in assessment of medicines, in line with international standards.
How can pharmaceutical companies, NMRAs in resource-limited countries and SRAs participate in the pilot?
Pharmaceutical companies may participate in the pilot if they:
- hold a marketing authorization issued by an SRA for the FPP intended for submission
- agree with WHO on:
- the selection of the FPP for which the procedure is to be organized, and on the SRA that will be invited to share its full assessment and inspection reports for the FPP
- participating NMRAs to which they intend to apply for registration and proposed date(s) of submission(s) in the relevant countries,
- agree with the relevant SRA that the full updated assessment report and inspection report may be shared with the NMRAs to which they intend to apply for registration,
- agree with the conditions of the procedure and to submit data to NMRAs as defined by the procedure.
NMRAs in resource-limited countries may participate by confirming their interest in participation and committing to the principles of the procedure by signing the agreement defined by the procedure (Annex 1). The countries of NMRAs that are currently participating in the procedure are listed in the Participating Countries table in this section. Additional NMRAs may be invited to participate by WHO if applicants express interest in registering their FPPs in countries the NMRAs of which are not yet participating in the procedure.
Any SRA that wishes to participate must:
- agree that the holder of the SRA marketing authorization can share with the relevant NMRAs the assessment and inspection reports for the FPP that it intends to submit for accelerated registration
- be willing to share additional information with the relevant NMRAs, in line with the principles of the procedure, if requested to do so (for example, information to be included in the list of participating SRAs, see Annex 2).
Pilot steps for applicants, SRAs and NMRAs
The steps to be followed during the piloting of the procedure are as follows for the different participants:
- The interested holder (applicant) of the SRA marketing authorization:
- agrees with WHO that the procedure will be applied to the specific FPP(s) and that WHO will have access to the data shared with NMRAs (Annex 6)
- grants the SRA permission to share information concerning the FPP(s) with the relevant NMRAs and WHO (Annex 3A) and requests SRA permission to share the SRA’s assessment and inspection reports with NMRAs and WHO (Annex 3B),
- submits an application for registration of the FPP(s), with the same set of technical data, electronically and/or in hard copy, to participating NMRAs in a synchronized way, in line with the procedure and respecting specific national requirements (Annexes 4, 5 and 8).
- The time taken by each NMRA for data analysis, review, preparation of questions and comments should not exceed 60 days.
- If needed, WHO will assist the NMRAs by appointing a rapporteur to prepare the draft assessment report, to be based on the original SRA reports, and including any questions to be forwarded to the applicant. Reaching of a common regulatory position by participating NMRAs on the assessment and the list of questions to be forwarded to the applicant can also be facilitated by a meeting of assessors from participating NMRAs (either staff or collaborating external experts), supported by WHO. SRA assessors can be invited to such a meeting, to explain their SRA’s position with respect to the FPP under review, and comment on its relevance for participating countries. The outcome of the meeting should be a mutually-agreed and consolidated position for the participating NMRAs, elaborated on the basis of the SRA assessment outcomes. The applicant should be prepared to respond quickly to any questions raised and provide any additional information requested.
- Within the next 30 days, the NMRAs should adopt its regulatory decision, inform the applicant of the outcome and notify WHO by completing Annex 7.
Contact for further information: email@example.com
- Draft text of the procedure
- Annex 1 NMRA participation agreement
- Annex 2 Conditions of SRA involvement
- Annex 3A Stringent regulatory authority sharing of non-public information concerning product with the national regulatory authority and the World Health Organization
- Annex 3B Marketing authorization holder’s request to SRA for permission to share information with the NMRA
- Annex 4 Proposed documentation to be submitted by applicants to NMRAs
- Annex 5 Company declaration to NMRA
- Annex 6 WHO confidential disclosure agreement
- Annex 7 Notification of outcomes of national registration procedure
- Annex 8 Concept note on bridging report