Real-World Evidence (RWE) offers a potentially transformative new tool for reducing the time and expense in obtaining regulatory approvals for new drugs and medical devices.
Interest in RWE has dramatically increased since the 2016 enactment of the 21st Century Cures Act, which required FDA to develop a program for evaluating RWE. Nearly 95% of pharmaceutical industry respondents expect RWE to play an important role in their organizations by 2022, according to a 2020 survey by Deloitte.
RWE offers an alternative to traditional randomized clinical trials for generating data to support regulatory submissions to FDA. FDA defines RWE as clinical evidence regarding the use and potential benefits or risks of a medical product which is obtained by analyzing “Real-World Data” (RWD). RWD is essentially data regarding patient health or the delivery of health care obtained from sources other than randomized clinical trials. Examples of RWD can include physician electronic health records (EHR’s), records of insurance claims, product or disease registries, and information from patient-wearable devices, among many other sources. As the amount of medical data expands exponentially, FDA and others have looked for ways to incorporate this data into regulatory decision-making.
RWE could complement traditional “randomized clinical trials” (RCTs) as evidence to support FDA approvals for medical drugs and devices. While RCT’s have historically been viewed as the “gold standard” for evaluating new medical products, their limitations have become increasingly obvious. RCT’s are extremely long, expensive and inefficient: new drug approvals can cost hundreds of millions or even billions of dollars, and only about 12% of all drug candidates that enter clinical trials ultimately receive FDA approval. The rigid inclusion and exclusion criteria of RCTs, which commonly exclude patients older than 65 years old and those with comorbidities, often result in a study population that is not representative of the relevant patient population. RCTs often do not measure factors such as patient adherence to a treatment regimen, that affect a drug’s effectiveness under real-world conditions. Consequently, the results of RCTS may not be generalizable beyond the actual parameters and conditions of the specific study. Additionally, while RCT’s may provide evidence as to whether a treatment is effective under controlled conditions, they often provide little insight into “why” the product worked for some patients and not others. The leader of FDA’s Drug Center has on multiple occasions called the current RCT system “broken”.
While FDA is highly unlikely to stop using RCTs in the foreseeable future, incorporating data that is already being generated in the ordinary course of patient treatment into regulatory decisions could reduce the time and expense of obtaining commercial approvals. Even before enactment of the 21st Century Cures Act, FDA had accepted use of RWE in certain situations. RWE was most commonly used in drug approvals for rare diseases, where it was impractical or impossible to obtain a sufficiently large number of patients to conduct a statistically meaningful RCT. In such instances, FDA sometimes permitted drug Sponsors to conduct a “single-arm” study of patients receiving the candidate drug, compared with a “natural history” control generated from historical patients who did not receive the treatment.
Since enactment of the 21st Century Cures Act, FDA has undertaken several steps to encourage and create incentives for broader use of RWE. FDA’s drug and device centers have issued guidance and draft guidances discussing how the Agency would evaluate RWE in regulatory submissions. FDA has also accepted RWE in a handful of approvals for new indications and procedures for already approved products. Additionally, FDA’s Drug Center has published a framework for its RWE program.
To be sure, significant questions remain regarding the use of RWE. Transparency is an issue because unlike RCTs, which are generally registered for Phase 2 and Phase 3 studies on the web site www.clinicaltrials.gov, no mandatory registration or reporting requirement currently exists for RWE studies. There is no common standard on what constitutes “research grade” RWE. Likewise, questions of patient and data privacy exist. The incomplete interoperability of different health care systems also creates challenges in collecting and aggregating RWD. FDA has acknowledged that it is essentially trying to feel its way through RWE and has invited sponsors and others to take the lead in proposing ideas. Quite likely, FDA will rely on sponsors and applicants to fill in gaps in its regulatory policies with real-life examples on a case-by-case basis.
Despite these and other uncertainties, the range of potential applications and uses of RWE in a regulatory context is broad and only beginning to be understood. Among the possible (or actual) regulatory uses of RWE for drugs and medical devices are the following:
- Approval of new indications or labeling expansions for already commercial products;
- Satisfying post-approval study requirements;
- Supporting comparative effectiveness studies (and potentially claims) between Sponsor products and competitor products;
- Identifying patient sub-groups who might respond better to a particular treatment than other patients reporting similar symptoms; and
- Natural history “controls” in single-arm studies (particularly in cases of, but not necessarily limited to, product treatments for rare diseases).
RWE also has great potential in obtaining payer approvals for drugs and devices. Over the longer term, RWE might ultimately support such new approaches as “synthetic control arms” which could dramatically impact how drug candidates are evaluated.
What seems clear already is that RWE could offer major benefits to drug and device companies who are able to effectively utilize it.