Center for Pediatric Clinical Development
PRA Health Sciences
hen on 11 March 2020 the World Health Organization declared the Coronavirus Disease 2019 (COVID-19) a pandemic, regulatory authorities swiftly initiated close cooperation with industry to develop medicines for this virus. A month later, a collaboration through the International Coalition of Medicines Regulatory Authorities (ICMRA) was to expedite and streamline the development, authorization, and availability of COVID-19 medicines. As a result, within only a year of the start of the pandemic, new vaccines were available for adults and adolescents aged 16 and older, and vaccines for younger children will be available imminently. Will our experience gained with speeding up the development of vaccines against the coronavirus accelerate drug development overall?
Authorities Supporting Industry
Shorter Timelines
The FDA created the Coronavirus Treatment Acceleration Program (CTAP) for COVID-19 therapies, which uses numerous methods to progress new medicines to patients as quickly as possible.
An email inbox was created specifically for COVID-19 treatment inquiries. A triage team acknowledged and reviewed submitted inquiries within 24 hours, ensuring that proposals received were sufficient for productive discussion. The team then sent these proposals along with a synopsis to the appropriate FDA unit who provided rapid, interactive input on most proposals. Protocol reviews frequently occurred within 24 hours, and single-patient expanded access requests were reviewed around-the-clock, generally within three hours. Interactions were prioritized; the FDA worked closely with applicants and other agencies to expedite quality assessments.
While the FDA shortened its timelines, its regulatory review and decision-making processes remained unchanged. Developers were given FDA’s best advice, and decisions were based solely on data.
According to the CTAP Dashboard, as of 28 February 2021, more than 590 drug developments were planned, more than 430 trials reviewed, nine COVID-19 Emergency Use Authorizations (EUAs) issued, and one treatment approved.
Similarly, the EMA offered to discuss with developers their strategy as early as possible and created a dedicated email address. Initial discussions addressed suitable mechanisms to fast track development and approval, with priority given to the most relevant or promising proposals. Rapid procedures were implemented for scientific advice, early discussions, and pediatric investigation plans (PIPs).
Table 1. EMA’s Rapid Procedures.
- Free of charge
- No pre-specified submission deadlines
- Review reduced from 40-70 days to max. 20 days
- Flexibility on type and extent of briefing dossier, agreed upon on a case-by-case basis
- No pre-specified submission deadlines
- Review of a PIP reduced from 120 days to min. 20 days
- EMA decision reduced from 10 days to 2 days from review
- Developers able to provide focused scientific documentation on a case-by-case basis
- Compliance checks, if required, could be reduced to 4 days
Table 1. EMA’s Rapid Procedures.
- Free of charge
- No pre-specified submission deadlines
- Review reduced from 40-70 days to max. 20 days
- Flexibility on type and extent of briefing dossier, agreed upon on a case-by-case basis
- No pre-specified submission deadlines
- Review of a PIP reduced from 120 days to min. 20 days
- EMA decision reduced from 10 days to 2 days from review
- Developers able to provide focused scientific documentation on a case-by-case basis
- Compliance checks, if required, could be reduced to 4 days
The EMA’s Committee for Medicinal Products for Human Use (CHMP) urged the research community to prioritize large randomized controlled clinical trials, to generate the evidence needed to enable rapid development and approval of medicines, and emphasized the need to include all EU countries.
While COVID-19 initially appeared to mainly affect adults with cardiovascular or respiratory comorbidities, it was acknowledged that children were also affected. Therefore, the recommendation was made that adolescents be considered for inclusion in adult trials. Coordinated studies of adequate size to provide safety and pharmacokinetic data in children were endorsed. FDA recommended that vaccine developers plan for pediatric assessments of safety and effectiveness in compliance with the Pediatric Research Equity Act.
The EMA recommended concrete actions to be taken to enable the conduct of decision-relevant clinical trials. FDA and EMA provided advice for clinical trial management through new guidelines. FDA recognizes the important role of decentralized clinical trials in COVID-19 drug development, as they provide options for data collection particularly suited to a pandemic.
Pediatric Plans
In June 2020, a joint submission procedure for initial pediatric study plans (iPSP) to the FDA and PIPs to the EMA for COVID-19 medicines was implemented. FDA and EMA used scheduled and ad-hoc Pediatric Cluster calls to discuss COVID-19 medicines issues, aiming to achieve a high degree of consistency between iPSP and PIP with rapid turnaround time. They also provided a Common Commentary to streamline administrative processes and facilitate efficient plan submissions.
As a result, the FDA and EMA agreed on pediatric plans within a few weeks: For remdesivir, iPSP took seven weeks and PIP four weeks. The process included protocol advice with US and EU key opinion leaders as well as a Cluster Meeting.
Medicines Approval
The FDA implemented its guidance on the Emergency Use Authorization (EUA) for Vaccines to Prevent COVID-19. The guidance supports rapid and widespread deployment of vaccines for administration to millions of individuals. Issuance of an EUA would require that the vaccine’s benefits outweigh its risks based on data from at least one Phase 3 trial demonstrating safety and efficacy. Following EUA, a sponsor would continue to collect placebo-controlled data in any ongoing trials and work towards submission of a Biologics License Application (BLA).
The EMA made use of rolling reviews that are permitted during public health emergencies. They consisted of multiple two-week review cycles to enable the assessment of a product as data became available.
When rolling review is not used, the applicant may still apply for accelerated assessment, reducing the maximum review time from 210 to 150 days. Developers can apply to the priority medicines (PRIME) scheme that is predominantly suitable in the earlier stages of development.
ICMRA
Inventing the Future
During this unprecedented period, we have seen Authorities and Industry collaborating globally in novel ways to very rapidly protect adults and children and provide timely access to safe and effective medicines (including vaccines) for COVID-19.
The close cooperation and new rapid procedures implemented have helped reduce review and approval timelines from several months to a few days while protecting regulatory decision-making processes and quality. The efforts and resources invested by all parties involved were huge, but they demonstrated that drug development can indeed be expedited when circumstances demand it. Regulators and industry may well have found new ways to work together productively while maintaining their respective roles in the ecosystem.
These were exceptional circumstances and one cannot expect that all drugs be developed at that speed. However, lessons can be taken and some principles can be implemented for all medicines, such as providing rapid scientific advice, common commentaries for all pediatric development plans, and rolling reviews as well as implementing elements of decentralized clinical trials, quickly creating and issuing guidelines, and providing timely updates that ensure alignment with current science and innovation. These and other innovations would allow patients to access important medicines in a timely manner.
The EU will review its pharmaceutical legislation by the end of 2022. The European Commission will explore options to speed medicines approvals and empower regulators to adapt the terms of marketing authorizations. Hopefully, the experience gained during the pandemic will have a positive influence on these negotiations. The world has seen what is possible in an emergency; practices adopted quickly during an emergency can become best practices after the emergency. In many ways, and for the benefit of patients everywhere, “there is no going back.”