5

Convergence of Regulatory Expectations, Review, and Approval

Participants discussed the need for regulatory convergence and enhanced global regulatory capacity to be able to deploy new products quickly across multiple countries, each with their own regulatory systems and regulations. (Highlights and main points are summarized in the box below.)

COORDINATION, HARMONIZATION, AND CONVERGENCE

Infectious diseases do not adhere to national boundaries, and countries are obligated to work together in a more coordinated and streamlined way in regulating products to treat these diseases, Hamburg said. The Ebola crisis was marked by pressure to ramp up product development and provide access as soon as possible, and by frustration that products were not already available, given that Ebola had long been established as both an infectious disease concern and a potential threat to national security. Heated debates centered around the level of evidence required, the criteria for scientific study, the approach to clinical trial designs, and the nature of ongoing oversight needed for product development in the thick of the crisis.

Hamburg emphasized the need for streamlining processes, including decreasing bureaucratic and logistical complexities, better sharing of data, aligning across jurisdictions regulatory expectations of companies and the scientific community in terms of the burden of proof for product review and approval, moving toward common data and evidence standards, and advancing regulatory science (i.e., identifying gaps and developing the knowledge and regulatory tools necessary for more streamlined oversight). Working together, Hamburg said, global regulatory authorities will be better able to meet expectations in terms of scientific review, more effectively share information about advances in science and emerging technologies, and develop more flexible approaches to assessing complex products and defining acceptable levels of risk in public health emergency situations. Regulatory coordination is vital in a public health emergency to ensure meaningful action, especially given the often limited population to study or time sensitivity. Working together more effectively also helps to ensure quality and safety, Hamburg noted, citing the prevalence of fraudulent products and inappropriate use of products in public health emergencies. During the Ebola outbreak, for example, the U.S. Food and Drug Admin-

istration (FDA) helped to prevent governments from purchasing products that had no proven value. She also suggested that authorities also need to work together to support manufacturing capacity. Hamburg highlighted areas where concrete advances could be made now, ahead of the next crisis:

• pre-positioning clinical trial protocols and templates;
• building clinical trial infrastructure, including training and resources;
• developing prototype or plug-and-play platforms and capabilities that can be quickly built on;
• negotiating agreements for information sharing; and
• creating mechanisms to fast-track development and approval of important new diagnostics.

Hamburg highlighted the International Coalition of Medicines Regulatory Authorities (ICMRA) as an activity geared toward enhancing global regulatory convergence and capacity.¹ This is an executive-level coalition (comprising heads of medicine regulatory authorities) committed to providing umbrella leadership to ensure sustained critical activities and to developing a global framework for increased convergence and more coordinated action and accountability of the global regulatory community (acknowledging that each authority will always be accountable to its sovereign national laws, and there will always be differences in approaches and capabilities). Hamburg added that there are major activities under way to strengthen regulatory capacity in developing economies. Countries with immature regulatory systems are starting to produce important medical products, or components of medical products, that could potentially put all of us at risk if there is not appropriate regulatory oversight and coordination, she said.

Convergence on Regulatory Content and Process

Eichler said that, even though regulators have the same overall goals, there are many different actors and often a divergence of outcomes. There are costs and risk associated with nonconvergence among regulators and other decision makers. Different evidence standards, for example, lead to opportunity costs (e.g., developing a product for a global market might require one study for regulator A and a different study for regulator B, etc., which ties up capital that could be used for other innovations). Multiple assessments of priority or probability of success can lead to uncoordinated competition for clinical trial participants and trial sites, resulting in delays in bringing products to market. Differing regulatory procedures also affect

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¹ For more information on ICMRA see http://apps.who.int/medicinedocs/documents/s21800en/s21800en.pdf (accessed October 30, 2015).

timelines and opportunity costs. Different outcomes (e.g., market authorization in one country or region, but denial in another; product licensed, but not funded or reimbursed) can lead to delayed or unequal patient access to products, as well as political tensions.

Regulators can to help minimize these costs through regulatory convergence on both content and process. Convergence on content includes, for example, alignment on how to balance speed, feasibility of studies, and affordability of product with quality, validity, and robustness of information. In order to have content convergence there is a need for agreement on the kind of evidence needed. Other content areas include agreement on outlines of study protocols; development of bridging authorizations; flexible regulatory tools to give legal certainty to manufacturers to deploy products in countries of need; and building clinical trial infrastructure in country. Convergence on process involves aligning how interactions with product sponsors are handled from beginning to end, and across authorities. Eichler suggested that timelines could be shortened by undertaking some processes in parallel rather than serially (such as product assessment by the European Medicines Agency [EMA], the World Health Organization [WHO] prequalification, and local authorization from the country where the product will be used).

It was discussed whether FDA and EMA could agree on an evidence threshold under which products would be ready for human use under an emergency use authorization (EUA), and whether such guidance could be codified to perhaps give industry more confidence to invest in bringing these medical countermeasures (MCMs) along in development. Hamburg responded that FDA and EMA have regular collaborative meetings, called clusters, across a number of product and disease areas. These clusters look at shared issues in the product review process (e.g., use of biomarkers, clinical trial design), so there is no reason why it could not be discussed. Eichler agreed and added that the legal framework provides for a great deal of flexibility. Revision of the overarching framework is not needed, he said; rather, there is a need for agreement on how to apply it, and how to be more predictable in its application.

A Dynamic Regulatory Environment

Pfleiderer also remarked that convergence of regulatory principles is essential. For nonemergency vaccines and medicines, there is a well-structured pathway from development to testing to licensure to use. In a pandemic situation, however, steps might need to be done in parallel, but the product must still be well tested and well defined. Risk assessment is dynamic, and the benefit–risk ratio of a product is situation dependent. The worse an epidemic situation is, the fewer data are needed in order to con-

clude a positive benefit–risk ratio, he said. For a milder emergency scenario, more data are needed in order to come to the same conclusion. Risk–benefit analysis takes into account whether products are for therapy or prophylaxis, efficacy data, safety data, and the opinion of stakeholders’ representation. The regulatory tools applied in an emergency situation are flexible (e.g., to address situations where there is no time for data generation).

The European Union (EU) pathway for product approval is similar to that of the United States, but the language and legal provisions are different, Pfleiderer noted. EMA tools to approve products that are urgently needed include early approval pathways, and early access options for select populations. A scientific and regulatory framework that would allow licensure of candidate Ebola vaccines, for example, could base approval on animal studies (e.g., the U.S. Animal Rule), immunologic markers predicting efficacy, a combination of data sets (e.g., a comparative analysis of animal challenge data and human data), or efficacy data. A dynamic regulatory environment allows for use of incomplete data sets early in the outbreak, calling for full data sets as the disease burden wanes. From scientific, regulatory, and economic perspectives, Pfleiderer added, it is not possible to start from scratch every time another crisis occurs. Platform approaches, and associated regulatory guidance, need to be further considered and developed for application in other urgent product manufacturing scenarios.

Regulatory Capacity Building in Developing Countries

Mike Ward, Coordinator, Prequalification Team Essential Medicines and Health Products at WHO, emphasized the importance of capacity building for the national regulatory authorities in affected countries, and where epidemics or pandemics would be predicted to take place. These regulatory authorities are confronted with incomplete data sets, rolling submissions, complex clinical trial protocols, and changing strategies in the face of a changing epidemic profile. Many of these regulatory authorities have immature regulatory systems and, in many cases, have little or no experience with clinical trial assessment in a routine situation, much less a crisis situation. Ward relayed that some of the agencies ask for the assistance of WHO because they do not know how to confront scientific issues arising when a plethora of products or compounds are submitted to them (e.g., whether to authorize compassionate use, limited clinical trial, or other options), let alone from a sheer workload perspective. Scientifically and ethically, he said, these countries want to do the right thing.

Leveraging the Capacity of Other Regulatory Authorities

Raymond Chua, Group Director at the Health Sciences Authority, Singapore, explained how Singapore uses a very streamlined process that leverages other countries’ regulatory approvals. The Health Sciences Authority facilitates routine national stockpiling of medicines and vaccines for emergency situations according to usual registration processes, and within usual targeted timelines. Expedited review to facilitate access to critical unregistered medicines and vaccines during emergency situations can be completed within several days, and conversion of a registered prepandemic vaccine to a pandemic vaccine (via a strain change) can be completed in 1 day. Chua explained that the Health Sciences Authority uses a confidence-based approach for evaluation of new drugs and vaccines to be registered in Singapore. If there has been no prior approval of a product by any regulatory authorities, a full dossier review will be done, taking as much as 270 working days. If the product has been approved by any regulatory agency, an abridged dossier containing full quality data and abridged clinical data is reviewed, taking about 180 working days. If the product has been approved by two reference agencies,² evaluation of a verification dossier containing the reference agency assessment report is completed in about 60 working days. A similar approach is used for diagnostic kits that are regulated as medical devices. Chua suggested that this could be a model for a global harmonization framework to bring products to patients quickly in an emergency situation. If a product is approved for use by a leading regulatory authority in collaboration with WHO experts, then other authorities could use that approval to allow early access in their own countries without going through a long regulatory process. Chua emphasized post-market surveillance as an important part of an early access framework, and stressed the importance of collecting safety signals or adverse events at a global level.

Yamada expanded on the possibility of an international organization of the major regulatory agencies agreeing on certain parameters and then, in an emergency, one would review a product and all others would accept that review. He acknowledged that there are some critical issues on clinical trial design for which there is not currently interagency agreement (e.g., use of adjuvant, and trial arms/comparators). Eichler responded that no country wants to give up its sovereignty, and that it took the EU almost 40 years to implement the current system of one centralized review that is accepted by all member states. He was hopeful that it could be done, but said that it will take time. Chua said that Singapore has been working with different regulatory authorities on ways to pool resources and share

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² Reference regulatory agencies include Australia Therapeutic Goods Administration, EMA, FDA, Health Canada, or UK Medicines and Healthcare Products Regulatory Agency.

work. For example, a consortium between Australia, Canada, Singapore, and Switzerland works together on parallel review. One submission goes to the four regulatory authorities, a working group considers the application, and approval is issued by the four authorities simultaneously. Hamburg said that this is something that needs to be first undertaken in day-to-day interactions, working together, learning to share information, and developing trust.

Ward noted that there is interest in regions of Africa on joint reviews of products. There have also been two instances thus far of parallel processes, where the WHO prequalification process was done in parallel with joint reviews by the East Africa community regulators.³ Ward said that AVAREF played a key role during the Ebola crisis in helping to accelerate the scientific assessment of Ebola vaccine trials by facilitating a partnership approach to assessment.

Evolving PPE Standards and Regulations

Since the severe acute respiratory syndrome (SARS) outbreak, many countries have put standards and regulations for PPE in place, especially for respirators, and they are all different, Colton said. In some cases, people who have jurisdiction or influence over selection of PPE do not understand the differences between the standards, which affects their selection and use. For example, during the SARS outbreak, a recommendation was made for a product that met the U.S. standard, which led to the world demanding that particular product, resulting in outstripped supply. It took some education by WHO about the differences between the EU and U.S. standards to establish that other products could be similarly effective. He added that there is an International Standards Organization effort under way to standardize or harmonize the performance of the requirements for respirators.

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³ Though not presented at the workshop, other key initiatives in joint regulatory procedures include Article 58 of Regulation (EC) No. 726/2004 among WHO, EMA, and national regulatory authorities. For more information on Article 58, see http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000157.jsp (accessed November 13, 2015).

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