Regulatory agencies require sponsors to collect and provide data on the safety and efficacy of drugs that they have obtained from clinical trials. In addition to age, gender, and racial subgroups, these trials should also incorporate data on patient populations that are historically underrepresented in clinical research. Indeed, information from a diverse patient population supports the generalizability of results to wider patient populations for an approved drug. Demographic factors such as race, ethnicity, age, gender, etc can influence disease occurrence, outcome, and even toxicity to a certain level. The latter may occur due to intrinsic and/or extrinsic factors.
Regulatory agencies, like the US FDA, encourage sponsors to obtain safety and efficacy data from diverse and representative patient populations in early drug development. However, they recognize that this kind of information may be limited and should, wherever possible, be balanced within the benefit-risk framework. Obtaining crucial information during early stages of drug development can be beneficial as PK, PD, safety, and efficacy data can facilitate the efficiency in subsequent clinical trials and successful drug development. To support sponsors in the collection of post-market safety data for underrepresented populations in clinical trials, the US FDA issued a guidance that discusses how the relevant and required safety & efficacy data can be collected.
PMR vs PMC: Obtaining post-market safety data
The FDA may require sponsors to conduct post-approval studies or clinical trials as a post-marketing requirement (PMR) or the FDA, with the sponsor, may submit a written agreement that the applicant will collect the data, as a post-marketing commitment (PMC).
If active risk identification and analysis (ARIA) and adverse event reporting is not sufficient, sponsors should conduct post-market studies or clinical trials (as applicable) at the time of or after approval. PMRs may assess a known serious risk, signals associated with serious risk, or identify unexpected serious risks if there is information/data that indicates serious risk potential. This may be a post-market study or clinical trial to further investigate this serious risk associated with failure of pharmacological action.
The FDA and applicant may provide a written agreement that the applicant shall conduct post-market studies and clinical trials under the PMC as applicable, and additionally collected data from other data sources to characterize clinical benefit or safety in sub-populations that are underrepresented.
According to the guidance document, there are certain statistical considerations that the applicant must take into account for different post-marketing approaches:
- Can be designed by way of sample size calculation intended to rule out a historical rate of safety/efficacy to help provide assurance that the medical product is safe and effective in the relevant subpopulation(s).
- Designs may ‘borrow’ patients from pre-approval studies as appropriate for the purpose of a larger sample size of sub-population of interest.
- Should obtain PK and PD data that may support in understanding any differences within and between subpopulations of interest detected in registrational studies.
- Can enroll and evaluate underrepresented subpopulations in the primary analysis population in a separate cohort as ‘parallel’ trial arm.
- Those that are planned at the time of NDA or BLA submissions can be revised in order to support the trial for subpopulation of interest when collecting post-market data.
- Sponsors may stratify if there are potential prognostic implications that are associated with the subpopulation of interest.
- Should collect adequate and sufficient PK and PD information to determine differences within and/or between subpopulations of interest.
Real-World Data Sources
- Sources such as electronic health records (EHRs) and registries can be used when appropriate.
- The US FDA recommends discussing the proposed real-world data source that the sponsor wishes to use in order to obtain feedback as early as possible.
- Meta-analyses for randomized trials can support in obtaining post-market safety data. However, this is based on the fact that the trials must be of similar designs and focus on the drug.
- evaluation with respect to sufficient enrollment of subpopulation and comparable drug exposure across selected studies and therapeutic indications.
- Pooling of data across trials can facilitate a more “meaningful” drug assessment in patients from various clinically relevant sub-populations provided the clinical studies have sufficient number of patients and PK, PD, safety & efficacy data from each subpopulation of interest.
The FDA and sponsor must work together to facilitate the development of recruitment strategies that are tailored towards the population of interest. It is important to note that the FDA may approve marketing applications that are based solely on foreign clinical data provided this is applicable to the population in the USA and in accordance with American medical practice (in addition to other factors).
References and Further Reading
- US FDA. Postmarketing Approaches to Obtain Data on Populations Underrepresented in Clinical Trials for Drugs and Biological Products. United States Food and Drug Administration. 2023