The SARS-CoV-2 pandemic that has infected to date more than 10,000,000 people worldwide continues to present an extraordinary challenge to global health. Some of the commercial vaccine manufacturers engaged in the development of SARS-CoV-2 vaccine candidates have either completed, or are in the process of, conducting early phase clinical trials and approached respective National Regulatory Authorities (NRA) with their proposals for Phase 3 clinical trials to demonstrate the efficacy of their vaccines.
The June 22, 2020 teleconference of global regulators convened jointly by EMA and US FDA under the auspices of ICMRA, discussed preclinical and clinical data requirements to support proceeding to Phase 3 clinical trials with SARS-CoV-2 vaccine candidates. In addition, participants discussed concepts of trial design for these studies including trial population, endpoints and statistical considerations.
- Preclinical and clinical data required to support proceeding to Phase 3 clinical trials
- Considerations for study design for Phase 3 clinical trials
The following represents generally agreed positions among global regulators in attendance.
Preclinical and clinical data required to support proceeding to Phase 3 clinical trials
- Depending on the SARS-CoV-2 vaccine and on existing human data, nonclinical safety studies may be required to support proceeding to Phase 3 clinical trials.
- Nonclinical data characterizing the vaccine-induced immune response derived from studies in animal models vaccinated with clinically relevant doses of the SARS-CoV-2 vaccine candidate are needed. These should include an evaluation of immune markers of potential enhanced respiratory disease (ERD) outcomes, e.g., assessments of functional immune responses (such as neutralizing antibody) versus total antibody responses and Th1/Th2 balance.
- Even though it is desirable, postvaccination challenge data using nonhuman primates to evaluate the potential for ERD may not be available at the time of Phase 3 trial initiation, especially for those SARS-CoV-2 vaccine candidates that are more advanced. Preliminary data derived from studies in animal models conducted to date evaluating the potential for SARS-COV-2 vaccine-induced ERD, do not show evidence for a risk of ERD, although additional data relevant to this issue are expected to be available in the near future.
- In general, participants acknowledged the value of postvaccination challenge data derived from non-human primates to support proceeding to Phase 3 clinical trials. Proceeding into Phase 3 clinical trials will be determined on a case-by-case basis and depends on the specific SARS-CoV-2 vaccine construct, and the totality of preclinical and clinical data available for this construct. Data from other challenge models, e.g. hamsters, ferrets, transgenic mice, could provide valuable supportive evidence.
- Initiation of Phase 3 clinical trials should be preceded by adequate characterization of safety and immunogenicity for each dose level and age group to be included in late stage trials, to support general safety and immunogenicity of the respective vaccine candidate.
- Clinical data characterizing the vaccine-induced immune response should include an evaluation of immune markers of potential enhanced respiratory disease outcomes, i.e., assessments of functional immune responses (neutralizing antibody) versus total antibody responses and Th1/Th2 balance. If older subjects (e.g., subjects older than 55 years) are included in Phase 3 clinical studies, preliminary safety and immunogenicity data derived from these populations are also needed.
Considerations for study design for Phase 3 clinical trials
- Phase 3 clinical trials to demonstrate vaccine efficacy will need to enroll many thousands of participants, including those with medical comorbidities, to generate relevant data for the key target populations.
- It is important to establish vaccine safety and efficacy in SARS-CoV-2 naïve individuals. However, because pre-vaccination screening for prior infection is unlikely to occur in practice with licensed COVID-19 vaccines, safety and efficacy data in individuals with prior SARS-CoV-2 infection should be collected as well. It was agreed that the primary analysis for efficacy would be conducted in SARS-CoV-2 naïve subjects.
- Phase 3 studies should be powered to assess the overall vaccine efficacy across subgroups enrolled. It was acknowledged that trials will not be powered to demonstrate vaccine efficacy by subgroup, e.g., age.
- Efforts should be made to include diverse populations, e.g. race and ethnicity, in Phase 3 clinical trials to enhance confidence that vaccines are safe and effective for everyone in the indicated populations.
- It is important to include older adults (e.g., over 55 years of age) including those with co-morbidities in Phase 3 clinical trials. Inclusion of this population will need to be guided by safety and immunogenicity data obtained from healthy younger adults and healthy older individuals who participated in Phase 1 and 2 clinical trials with the respective SARS-CoV-2 vaccine. Participants acknowledged the relevance of evaluating safety and efficacy of subjects older than 75 years.
- Participants agreed that it is important for vaccine manufacturers to plan for pediatric assessments of safety and effectiveness for SARS-CoV-2 vaccines, given the epidemiology of COVID-19 in this population, and as safety and effectiveness of SARS-CoV-2 vaccines may be different in children compared with adults. It was acknowledged that initial licensure of SARS-CoV-2 vaccines would likely be in adults.
- Sponsors should provide their plans for accruing data in pregnancy and consider the following eligibility criteria for Phase 3 clinical trials a) pregnant women and b) women of childbearing potential who are not actively avoiding pregnancy.
- The decision to include pregnant women in clinical trials is case-by-case and would be based on the totality of data available for the vaccine construct, including available data from developmental and reproductive toxicology studies conducted with the specific vaccine construct or with a different vaccine based on the same platform. Favorable safety and immunogenicity data in women of childbearing potential derived from early Phase clinical trials are also needed.
- Phase 3 clinical trials should be randomized, double-blind and controlled either using placebo or active comparator. Other Phase 3 clinical trials should be discussed with the respective NRA.
- Phase 3 trials using adaptive design elements should include pre-specified criteria, e.g., for adding or removing vaccine candidates or dosing regimen.
- Follow-up of study participants for COVID-19 outcomes should be long enough (i.e., 1 year or longer post-vaccination) to evaluate safety, duration of immune response and risk of disease enhancement as antibody titers wane.
- Endpoints used in Phase 3 clinical trials should preferably be standardized across trials to allow vaccine effectiveness and safety comparison of different SARS-CoV-2 vaccine candidate.
- The primary endpoint should be laboratory-confirmed COVID-19 of any severity. Other important endpoints include SARS-CoV-2 infection monitored for and confirmed either by virologic methods, or by serologic methods evaluating antibodies to SARS-CoV-2 antigens not included in the vaccine, and severity of disease as measured by hospitalization, mechanical ventilation or death.
- Participants agreed that stringent success criteria to ensure that SARS-CoV-2 vaccines have adequate efficacy should be specified in initial clinical efficacy trials. These should include efficacy point estimates that reflect the desired vaccine efficacy and specification of the lower bound of appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate. These should also apply to interim and final efficacy analyses. There was agreement that the studies should be adequately powered to estimate vaccine efficacy as robustly as possible, generally favoring more conservative stances on the success criteria that would rule out licensure of weakly effective vaccines that could do more harm than good. However, a specific numeric value to be used for the lower bound and vaccine efficacy point estimate was not agreed upon at this stage It was also reflected that efficacy estimates crossing a certain pre-specified lower bound for efficacy, due to factors such as epidemiological evolution of the pandemic, would not preclude the possibility of a positive benefit risk conclusion if there also were other data supportive of efficacy.
- Phase 3 clinical trials should also include interim analyses to assess risk of enhanced disease and futility.
- Safety evaluation as part of Phase 3 clinical trials (including solicited local and systemic adverse events, unsolicited adverse events, serious or other medically attended adverse events) as well as the size of the safety data base and follow-up time should be in the same range as for other preventive vaccines. The protocol should include pre-specified criteria for study halt or pause, based on signals of potential vaccine-induced enhanced disease.