Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

A retrospective landscape assessment of the use of real-world data in the FDAs recent (Jan 2019-Jun 2022) regulatory decision making for the pharmaceutical products ***

Ketki Revashankar Purohit (Abschlußjahr: 2023)

Summary
Language: English
The perspective of health authorities on the use of real-world evidence for regulatory purposes has been evolving. This is evidenced by the issuance of RWE guidance documents by the US FDA in recent years. This master's thesis makes an effort to comprehend what the regulatory agencies anticipate from the sponsors when they submit real-world evidence. This is accomplished by conducting a retrospective analysis of the submissions (to the US FDA between Jan -2019 and Jun-2022) where RWE has been utilized by the Sponsor to contribute to the totality of the evidence (either for trial design considerations, as supportive evidence or as primary/substantial evidence for efficacy or safety) and to assess the benefit-risk relationship based on the inclusion criteria mentioned in the section 2 Methods.
Despite numerous guidance documents, a gap still exists between the understanding of the Pharma-Company and the view of the FDA. This is due to the fact that the probability of acceptance of RWE for a marketing authorization is based on the use case as seen in the analysis of the 34 cases. The analysis of the assessment reports of the marketing authorization applications for the identified 34 cases, revealed successful strategies used by the Sponsors which enabled acceptance of RWE to support the benefit-risk assessment and thus expedite the approval for the drug products. It also highlighted common mistakes in the approach of Sponsors whose RWE was not accepted by the Agency. A clear determinant for the success has been early and regular communication with the Agency about the intent to use RWD for evidence generation. This has helped many pharma companies to get an early signal from the FDA whether the use of RWE would be beneficial to support their application or not. Also, an early engagement with the FDA helped the Sponsor to select the right inclusion and exclusion criteria, accurate data curation methods and to carry out relevant comparisons which otherwise could later result in a review issue. The FDA has highlighted time and again that RWD can support the totality of evidence in cases of an unmet medical need or rare diseases, in cases where the preliminary data shows large treatment effect but there are no active comparators and use of placebo is out of question, or in case of off-label use of approved medicinal products to support extension of indication. But RWE is not always accepted by the US FDA in all these use cases.
An analysis of the indications utilizing RWE in the submissions also showed that the US FDA often accepts RWE in case of rare diseases where the sponsor faces difficulty recruiting patients for a randomized clinical study. This is in line with the FDA’s intention to support innovation in areas of unmet medical need to bring treatment options to patients as early as possible. In these cases, the RWD helps fill the gap in the evidence and supplement the totality of evidence which helps reduce the development time and thus ensures early access to the patient population.
In most cases seen in this master thesis, the natural history data has been used by the Sponsor as external control to benchmark the treatment effect of the medicinal product or to show that the improvement in symptoms is not possible without intervention. From the examples it is evident that the natural history data for benchmarking treatment effect is only accepted and useful when the treatment effect is otherwise difficult to establish and when use of placebo control would be deemed unethical. But not when the available data shows a clear, durable treatment effect with the use of the medication. In such cases use of natural history data as external control is unnecessary.
Another key fact highlighted in this thesis is that the US FDA sets a great value on the use of fit-for purpose RWD from reliable sources with clear scientific rationale. The Sponsors must keep in mind that RWE is not mandatory to be used in case of rare indications and cannot always replace evidence generated from the randomized controlled clinical studies. The purpose of RWE should be to supplement the evidence by filling the gaps and needs to be planned well in advance.
Comparing the timelines with use of RWE against the traditional approach of the randomized clinicals studies, it seems that the use of RWE is less time consuming and requires less efforts which is misleading. As use of RWE to supplement the evidence for efficacy or safety also requires a lot of resource planning with specialized expertise. RWE should be used only when it can support the totality of evidence. Finally, this work highlights the need to develop a more streamlined interactive approval strategy when using RWE by involving the right stakeholders with clear scientific objective from the beginning to provide a customized solution which fulfils the purpose of faster approval.
Pages:  62
Annexes: 1, Pages: 37