Novel Global Regulatory Agilities: Impact on Multiple Stakeholders
Brenda J. Huneycutt
Virginia Acha
MSD
@MSDintheUK
C

OVID-19 pushed regulatory science and practices to new heights and brought stakeholders together in unprecedented ways to deliver safe and effective vaccines and medicines to patients in record time. While we cannot expect work to continue at this breakneck pace forever, some agilities proved themselves to be of significant value. To ensure that these regulatory lessons from the pandemic are not lost, it is critical to understand the impacts to and perspectives of stakeholders beyond regulators and industry. This article presents a brief summary of the discussions and conclusions of a multistakeholder workshop that allowed the understanding of diverse views on select agilities, which can inform if and how pandemic agilities are incorporated into routine agency practice.

Regulatory agilities are actions taken by any regulatory agency which were driven by and taken in the context of the COVID-19 public health emergency. These “agilities” depart from that regulatory agency’s pre-pandemic actions, procedures, and approaches. They include actions with both positive and negative consequences across stakeholders.

The agilities implemented across the globe have been numerous and may be grouped into different categories. We will focus on five types of agilities that are closely associated with outstanding questions and discussion needs in the pharmaceutical field:

  1. Reliance and mutual recognition
  2. Convergence and harmonization
  3. Decentralized trials
  4. Data expectations for market entry
  5. Use of pre-market real-world evidence

Furthering Reliance and Mutual Recognition

The health emergency proved that reliance approaches reduced individual regulator workload and facilitated faster licensing of new products, but this measure alone did not necessarily guarantee access to products. Collaborative initiatives such as EMA’s OPEN initiative, which included early participation and input from WHO and regulators from low- and middle-income countries (LMICs), created a sense of joint ownership in decision-making and increased regulator comfort with using reliance. The use of virtual technology fundamentally changed the dynamic for reliance, especially for LMICs. The hope is that regulators will continue to use these technologies rather than going back to only in-person meetings. Experience also indicated that the use of reliance for product life cycle updates (variations) can be more impactful than reliance for initial product registration. Variations currently require a huge commitment of resources, and approval delays can lead to stockouts. A rethinking of confidentiality provisions and agreements is needed, looking at a coordinated global regulatory system and sharing of useful documents, which is foundational to reliance approaches.

Value of Convergence and Harmonization

The pandemic highlighted the value of convergent regulatory requirements as an important enabler for timely patient access to products. While groups such as Access Consortium, COVAX, and the International Coalition of Medicines Regulatory Authorities (ICMRA) are successful examples of initiatives that drive regulatory alignment and collaboration, convergence and harmonization are not as global as we sometimes think. Regulatory authorities differ in their awareness of opportunities and access to various regional and global regulatory groups, and more awareness building is necessary, especially for regulators in LMICs. Successful convergence and harmonization balance the simplicity and ease of complete harmonization or convergence with the need for sufficient flexibility to allow tailoring appropriate to the situation.

Case for Decentralized Trials

Use of decentralized clinical trials (DCTs) strategies was a necessity imposed by the pandemic. They should be viewed on a spectrum: each trial using DCT elements in a context-specific way based on disease state, type of therapy, population of study participants, and tailored to individual participant needs and desires. Greater decentralization is not a panacea for historical barriers for participation in clinical trials for all individuals and in fact can even introduce new barriers for some populations. We cannot simply assume all DCT elements benefit all trial participants. Trade-offs exist between benefits (e.g., participants do not have to go to study site) and burden (e.g., participants now must do these things themselves). Understanding individual perspectives and ongoing patient engagement will be critical to the long-term success of greater decentralization of trials. Greater trial decentralization will entail a culture shift for the entire enterprise, require some degree of infrastructure change, and necessitate nontraditional ways of thinking about completeness and confidence in data.

Reassessing Data Expectations for Market Entry

Because of COVID-19, regulators implemented flexibilities around timepoints and different types of data required, including the appropriate amount of data required for submission, before market approval. The trade-off for benefit of faster access with tailored data requirements (e.g., focus on data necessary to make an earlier decision, postponing other data generation) is the potential for a decrease in public trust in the product (and approval decisions). To make this agility sustainable long-term, enhanced communication with the public is needed. Topics that must be explained include:

  1. the overall features of uncertainty (e.g., the fact that it is found at some level in every decision) and how the state of science is constantly evolving;
  2. the level of evidence required, and how the benefit-risk calculus differs among patient populations and therefore demands different levels of evidence to enable speedy access; and
  3. the roles of regulators and public health agencies.

Engagement of the patient community is critical and currently missing. Using the patient only to improve communication approaches (versus ongoing meaningful engagement) will only increase the level of noise without improving trust in the process and product.

Advances in Use of Pre-Market Real-World Evidence (RWE)

Greater utilization of RWE in COVID-19 trials aligned key stakeholders’ interests in accelerating the use of RWE to promote public health. However, RWE data collection limitations still exist, and quality standards are still needed. Expanding RWE to new disease classes post-pandemic will require new strategies to incentivize data collection and information sharing. While setting clear, transparent limitations on the uses of real-world data (RWD) may build trust, it also may open RWE to unproductive public scrutiny.

Conclusion

Now is the time to assess and move beneficial regulatory agilities forward, to ensure that lessons learned from the pandemic are not lost. Diverse stakeholder perspectives on how an agility worked and impacted them will be crucial to successfully and sustainably incorporating some agilities into routine regulatory practice. With this work, we aimed to give voice to more diverse perspectives to inform the next question we need to tackle: How can we achieve this conversion?

While there is considerable consistency in stakeholder views, it is clear that nuances exist and context matters for every agility. Their use is rarely, if ever, “one size fits all,” and we must consider the trade-offs for each. These agilities can create both beneficial and costly consequences on different stakeholders. In addition, while the urgency of COVID-19 necessitated an all-encompassing single purpose, the use of agilities in routine practice will be situationally dependent. Agilities will need to be tailored to what is needed (and feasible), which is not necessarily what was needed in the pandemic. Further, making sure all stakeholder voices are included can elucidate the nuanced trade-offs and balance of benefit and burden (and to whom) inherent in all agilities.

Acknowledgements

The authors would like to thank Avalere Health for its organization and facilitation of the workshop and partnership throughout this initiative, the global experts who spoke at the workshop for sharing their expertise and experience, and all workshop participants for contributing their insights and unique views on the global regulatory agilities seen during the COVID-19 pandemic. The authors would also like to thank Cammilla Gomes (Roche), who advised on this article.
Additional Reading

Call to Action: Fight Against COVID-19 Proves We Can Do More for Patients with Highly Prevalent, Serious Illnesses

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