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A promising start for WHO collaborative registration procedure for medicines in developing countries

This article was originally published in SRA

Executive Summary

Milan Smid and Monika Zweygarth explain how a collaborative registration procedure set up by the World Health Organization is helping regulators in low- and middle-income countries register life-saving generic products faster.

Globalized pharmaceutical manufacturing, the complexity of regulatory requirements and public expectations all put a strain on the resources of regulatory authorities. This is especially true in low- and middle-income countries, where regulators tend to be short of qualified staff and have limited budgets, inadequate infrastructure and suboptimal regulatory processes.

Higher-income countries have for some time now attempted to tackle their own resource problems by establishing schemes that promote co-operation and work-sharing between their regulators. One such scheme, which is fully operational, is the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The EU drug regulatory network is another example of such a solution and there are several bilateral or regional regulatory agreements that have also been in operation for some time. Several initiatives are in the evolution phase and their impact is yet to be confirmed – eg the international collaboration on active pharmaceutical ingredient (API) inspections, the International Generics Drug Regulators Pilot (ICDRP) and the International Coalition of Medicines Regulatory Agencies (ICMRA). In addition, the International Conference on Harmonisation (ICH) and the World Health Organization have been working for many years on harmonizing regulatory standards for medicines at the global level. Other initiatives, on the other hand, were established but have ceased to exist (eg the Pharmaceutical Evaluation Report, or PER scheme) or have been replaced by other co-operation programs (eg the Collaboration Agreement of Drug Regulatory Authorities in European Union Associated Countries, or CADREAC).

With the exception of the WHO agenda, until now, low- and middle-income countries have not have much chance to be involved in or benefit from the above collaboration schemes, although there are several regulatory harmonization initiatives within economic blocs that are promising, for example the Association of Southeast Asian Nations (ASEAN) and the East African Community (EAC).

The WHO established the Prequalification of Medicines Programme in 2001 to assure the quality of essential medicines procured for developing countries by international organizations. Although the WHO is not a regulator, it utilizes the same scientific principles and regulatory approaches to assess quality, safety and efficacy of medicines as do national regulators, including confirmation of compliance with good practices by inspections and organization of the post-approval follow-up. The products being assessed by the WHO are mainly generics.

The WHO Prequalification Programme does not intend to replace national regulatory approvals. On the contrary, it strives to help regulators in resource-limited environments build their capacity to effectively regulate medicines in their jurisdiction.

More recently under the program, a WHO Prequalification of Medicines Team (WHO-PQT) developed and manages a collaborative registration procedure to leverage the work of the WHO-PQT in the national registrations of WHO-prequalified medicines. This procedure is designed to reduce the workload for regulators in countries with limited resources, make quality-assured medicines available more quickly and provide a model for regulatory collaboration and work-sharing.

The collaborative registration mechanism was piloted in the second half of 2012, received final approval from the 66th World Health Assembly in May 2013 and then progressed to the routine operational phase.

Principles

The principles of the procedure are relatively simple. In addition to public assessment and inspection reports, the WHO-PQT shares confidentially with interested national medicines regulatory authorities (NMRAs) the full outcomes of its assessment and inspection process. This information enables participating regulators to fulfil their regulatory responsibility and expedite decision-making.

There are two basic prerequisites: interest of individual NMRAs to collaborate and follow the rules of the procedure, and consent by individual manufacturers to information-sharing for each specific product. The submission of the same product and the same data as prequalified for national registration and commitment to post-registration maintenance are preconditions. There is a defined limited scope of deviations, which does not affect quality and therapeutic properties. Each participating NMRA has the right to decline the use of the procedure for individual submissions and to decide independently from the WHOPQT outcomes. In such cases, the NMRA must give the WHO-PQT an explanation.

The procedure was published in the WHO technical report series1 and is open to NMRAs of all WHO member states. Its principles can serve as a model for other regulatory collaboration initiatives. Not only does the procedure enable NMRAs to speed up processing of registration applications for WHO-prequalified medicines, it also enables them to make use of work already done by the WHO-PQT to strengthen their own regulatory oversight in line with international best practice.

Participation by all stakeholders is voluntary. NMRAs wishing to participate submit an agreement confirming that they will respect the principles of the procedure, treat proprietary information shared by the WHO-PQT as confidential and decide on a registration within 90 days for submissions for which they agree to use the procedure. Each NMRA also designates one or two focal persons to communicate with the WHO-PQT and provides their confidentiality undertakings. In cases where the procedure is initiated for a specific prequalified product, these persons will receive access to the WHO-PQT's evaluation and inspection information via a secured internet server. Because information-sharing under the terms of the procedure does not interfere with national decision-making processes, participation by NMRAs only exceptionally requires modification of regulatory procedures and amendment of legislation. The WHO-PQT lists the participating NMRAs on its website2.

The procedure is currently only applicable to generic medicines that have been prequalified as a result of the WHO-PQT's own evaluation and inspections. It follows three steps. Templates of documents are available to facilitate information exchange at each of the three steps.

Step one

Under step one, a holder of WHO prequalification wishing to register a prequalified product in a participating country submits the application for registration, which is accompanied by an expression of interest (EoI). In the EoI, the company confirms that the product is technically the same as the prequalified medicine, that submitted data correspond to the dossier that was approved during prequalification, and that it authorizes the NMRA to communicate on product-related issues with the WHO-PQT. Within the context of this procedure, the same pharmaceutical product is characterized by the same product dossier, the same manufacturing chain, processes and control of materials, the same API and finished pharmaceutical product specifications and the same essential elements of product information. There may be country-specific differences in administrative data and the language and format of product information and labeling. If required by NMRAs under exceptional circumstances, additional technical data should be provided – eg bioequivalence with a country-specific comparator. In parallel, the company authorizes the WHO-PQT by a pre-defined document to share with the respective NMRA confidentially through a password-protected website the full outcomes of the WHO's assessments and inspections.

Step two

Under step two, the NMRA decides whether or not to apply the procedure for the specific submission, depending on whether it considers its execution to be expedient in the particular case, and informs the WHOPQT accordingly. In the event that the NMRA decides to make use of the procedure, the WHO-PQT grants the focal persons access to product-related assessment and inspection reports and other relevant documents that provide detailed insight into the prequalification decision-making process and its outcomes, including approved product specifications and the applicant's commitments. The WHO-PQT only shares data owned by the prequalification holder. Other data, eg those provided by API manufacturers for the purpose of drug master file procedures, are not shared unless there is a special agreement with the data owner. The WHO-PQT does not share with participating NMRAs the prequalification dossier, because the same technical data are submitted during the national registration process to the NMRA directly. The WHO-PQT is also prepared to provide additional explanations and respond to the NMRA's questions. At their own discretion and depending on their resources, individual NMRAs can recognize the WHOPQT outcome directly, perform some degree of verification, organize a partial evaluation on a risk basis or use the shared data for quality assurance of its own independent assessment. In any case, participating NMRAs should issue their decision on each submission within 90 days of receiving access to the shared information.

Step three

Under the third and final step, in line with the procedure, the WHO and the applicant are informed about the decision within 30 days of the decision having been taken. The NMRA is free to deviate from the WHO-PQT opinion but should provide a brief justification to the WHO-PQT. The WHO-PQT monitors registration times and publishes on its website a list of medicines that were registered in participating countries under the same conditions as prequalified by the WHO-PQT. For such products, the WHO-PQT will collaborate further with the respective NMRAs during product post-registration regulatory maintenance.

Post-registration, stakeholders work together to minimize differences between the nationally registered and the WHO-prequalified product. Companies submit variations to the WHO-PQT and to participating NMRAs, and these two parties inform each other of any major decisions regarding the product. Assurance that the regulatory status of the product remains in line with WHO-PQT conditions helps NMRAs in defining risk-based post-marketing surveillance measures that can be carried out in addition to WHO-PQT's re-assessments and re-inspections. Quality control can be performed according to the same methods and specifications and in co-operation with other countries that have registered the product under the same conditions.

Experience

Ten NMRAs participated in the pilot phase organized in the second half of 20123. Following approval of the procedure by the WHA in 2013, the procedure is open to all WHO member states. As of the end of February 2014, participation had grown to 15 NMRAs, including 12 African authorities that jointly cover 45% of the population of the WHO Africa region. Three NMRAs from Eastern Europe and Central Asia are participating and others countries are considering doing so. The NMRAs participating so far come from: Botswana, Georgia, Ghana, Kenya, Kyrgyzstan, Madagascar, Mozambique, Namibia, Nigeria, Tanzania Mainland and Tanzania Zanzibar, Uganda, Ukraine, Zambia and Zimbabwe.

The WHO-PQT informs pharmaceutical companies about this avenue for accelerated registration at stakeholder meetings and training events, through information on its website and as part of the standard letters sent upon acceptance of each submission in view of prequalification and after prequalification is achieved. Several participating NMRAs have also been referring applicants to this procedure.

So far, 15 companies have been in contact with the WHO-PQT about collaborative registration of their prequalified medicines. By the end of February, eight prequalification holders had submitted a total of 46 EoIs for collaborative registration of a product, supported by data sharing consent, for a total of 26 WHO-prequalified products (14 antiretrovirals, three reproductive health products, three antimalarials and six anti-TB medicines) in a total of ten countries. Participating NMRAs agreed to apply the procedure in 34 cases. The most common reason for non-acceptance (in 12 cases) was the fact that the application for registration in the respective country was already pending and was at an advanced stage of evaluation.

The collaborative procedure led to 16 registrations of a total of 12 prequalified products (nine antiretrovirals, two antimalarials and one reproductive health product) in a total of seven African countries (five in Ghana, three in Zimbabwe, three in Namibia, two in Tanzania, and one each in Kenya, Nigeria and Uganda).

In 14 of the 16 cases, registration was granted within 90 days of accessing WHO-PQT information. The median duration of registration from accessing the information was 61 days. Eight registrations (50%) were achieved within 60 days or less. More than 90 days were taken only in two cases awaiting the constitution of the relevant regulatory body in one participating country (111 and 182 days).

However, there were delays caused by NMRAs in locating pending applications and identify their status, responding to EoIs, arranging access to the confidential website with the shared WHO information, and providing feedback to the WHO-PQT and to applicants. Considering this additional time, the total time taken from the applicant's EoI to approval of 16 already registered products ranged from 19 to 270 days (median: 102 days). In the future, good practices should be promoted to minimize these additional delays as much as possible.

Although the procedure was designed for new registration applications, during the pilot phase it was frequently initiated for applications that were already pending in national registration systems. Considering that 12 submissions, which the NMRAs accepted to review under this procedure, had been in the review queue for a year or more, the collaborative procedure has saved time for all parties. In Zimbabwe, where almost twice as many dossiers were received in 2012 as the registration system is designed to handle, the regulatory focal person has stated:

The PQT Collaborative Procedure is a relief for us in Zimbabwe. … From the pilot phase we established that approval within 90 days is doable. … The procedure allows us to save our meagre resources and focus them on other risky products which have not been subjected to the rigorous PQT 'quality assurance'.

(William Wekwete, Head – Evaluations and Registrations Division, Medicines Control Authority of Zimbabwe)

The procedure recently moved to its fully operational stage. Its use does not yet represent a daily routine for its users and therefore administrative difficulties occur. Effort is being made to develop efficient processes and communication. New participating NMRAs and manufacturers may bring additional experience which can be useful in this regard.

Observations from the pilot phase have generated discussions with representatives of participating countries on further improvement of the procedure in several areas, including the following:

  • Management of product ownership and liability issues among holders of prequalification and their affiliates or representatives in developing countries. It is obvious that representatives of companies in low- and middle-income countries need additional regulatory training to be able to manage this type of "collaborative registrations" effectively.
  • All participating countries accepted to work with dossiers in the common technical document (CTD) format4, as required for WHO prequalification. Use of the procedure contributes in this respect to regulatory harmonization.
  • Abridged dossiers may be acceptable for NMRAs wishing to reduce workload, given that technical advice on specific issues can be sought from the WHO-PQT. Such special arrangements should always be confirmed by individual NMRAs. In any case, the NMRA should make sure that it has sufficient technical information at its disposal to enable effective regulatory control.
  • Proper evidence of versions of regulatory dossiers and handling of variations is necessary to provide consistent information to NMRAs participating in the collaborative procedure. Applicants wishing to use the collaborative procedure should be reminded that they are responsible for keeping regulatory status of the product and documentation updated in line with the WHO-PQT adopted variations when submitting for national registrations.
  • Existing experience with the management of post-prequalification and post-registration variations is still limited. Although the procedure provides general principles for post-approval product maintenance and communication between the WHO-PQT and NMRAs, it does not yet define practical details because there are highly varying practices within NMRAs. Holders of national registrations are expected to keep the regulatory status of the product 'harmonized' with the WHO-PQT status and to reflect WHO-PQT-adopted variations also in national registrations, in line with the regulations of individual countries. Efficient management of variations – saving capacities for all involved parties – is now one of the priorities in the further development of the procedure.
  • Beyond the formal exchanges of pre-defined documents, the collaborative registration procedure requires a flow of ad hoc communication on technical and administrative issues. Such interaction by phone and email between the WHO-PQT and responsible staff at NMRAs is critical for functioning of the procedure. More work needs to be done to bring regulators together for joint discussion and to make the IT system for sharing confidential information more user-friendly.
  • The growing number of NMRAs from different geographical regions participating in the scheme also poses issues relating to translations of pre-defined documents and effective ad hoc communication.
  • The collaborative procedure was designed on the premise that national applications would be submitted after WHO-prequalification is completed. However, a high number of requests for collaboration for pending submissions has been received, reflecting a regulatory backlog in many countries. Applicants were instructed to upgrade the national dossiers in line with prequalified ones or to submit a new dossier. A strategy of parallel submissions by manufacturers to the WHO-PQT and the national authorities is a common practice. The collaborative procedure operates as a verification instrument in that it provides evidence that NMRAs are dealing with technically the same medicines as WHO prequalified.
  • Currently, the collaborative procedure applies only to products that have been fully assessed by the WHO-PQT, not those prequalified in recognition of approval by stringent regulatory authorities. There has been interest by manufacturers to also apply the procedure to the latter category of products and the WHO-PQT has started exploring possible solutions.

Conclusion

Although experience from the WHO-PQT collaborative registration procedure is still limited, it has already demonstrated that sharing of sufficiently detailed regulatory outcomes with regulators in low- and middle-income countries is possible, saves time in registering life-saving generic products and frees up capacity of NMRAs for other priority duties. The WHO-PQT collaborative registration procedure can serve as an example of regulatory co-operation among NMRAs interested to form work-sharing networks, eg at regional level. Co-operation is possible both in the evaluation of submitted data and in compliance verification and monitoring. It provides benefits to all stakeholders and gives assurance that products in registering countries meet international quality standards.

Given shorter registration times already being achieved by the WHO-PQT, such collaborative procedures deserve attention from pharmaceutical companies in the development of their regulatory strategies. Expanding the procedure to collaboration in the registration of innovative medicines based on prior approval by respected regulatory authorities seems possible.

The procedure has benefits for all key stakeholders in the procedure, ie registration applicants, NMRAs, international purchasers and procurers, the WHO and patients. In summary, the most obvious benefits for the various parties are:

Registration applicants

–harmonized data for WHO prequalification and national registrations;

–facilitated interaction with NMRAs in assessments;

–fewer repetitive inspections;

–faster and more predictable registration; and

–easier post-registration maintenance.

NMRAs

–availability of WHO assessment and inspection outcomes to support NMRAs

–decisions and save internal capacities;

–opportunity to learn from WHO-PQT assessors and inspectors;

–demonstration of NMRA efficiency;

–having assurance about "the same" medicine as WHO-prequalified;

–quality control by the same methods and specifications;

–easier post-registration maintenance;

–easier problem management; and

–model of work-sharing.

International purchasers and procurers

–faster start of procurement and wider availability of quality medicines; and

–assurance about "the same" medicine as WHO-prequalified (product list on website).

The WHO

–faster availability of prequalified medicines to patients; and

–feedback on acceptance of WHO prequalification outcomes by national regulators, and reasons for any deviations.

Patients

–timely access to quality-assured products.

References

  1. 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, Annex 4, WHO Technical Report Series, 981, 2013,www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/trs_981/en and http://www.who.int/prequal/info_applicants/collaborative_registration_main.htm
  2. See Reference 1
  3. WHO launches the PQP Collaborative Registration Procedure, WHO Drug Information, Vol 27, No 4, 2013, www.who.int/medicines/publications/druginformation/27-4_collaborative-procedure.pdf
  4. Guidelines on submission of documentation for a multisource (generic) finished product. General format: preparation of product dossiers in common technical document format, Annex 15, WHO Technical Report Series, 961, 2011, http://apps.who.int/prequal/info_general/documents/TRS961/TRS961_Annex15.pdf

Milan Smid is a technical officer for the Prequalification of Medicines Programme at the World Health Organization, based in Geneva, Switzerland. Monika Zweygarth is a consultant associated with the Prequalification of Medicines Programme at the World Health Organization, based in Geneva, Switzerland. Email: smidm@who.int.

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