Ten-Year Experience for the Center for Drug Evaluation and Research, Part 2: FDA’s Role in Ensuring Patient Safety

Abstract

Background The purpose of this study was to describe the role of the US Food and Drug Administration (FDA) in ensuring the safety of patients receiving investigational drugs under expanded access. Methods To better define FDA’s role in the review of requests for expanded access, multiple queries of FDA’s Center for Drug Evaluation and Research (CDER) document tracking system were performed. The queries identified reasons for, and outcomes of, expanded access requests for investigational drugs that were either not allowed to proceed or denied over a 10-year time period. An in-depth review of a random sample of single-patient, non-emergency investigational new drug (IND) applications that were allowed to proceed was also conducted. Results Overall, 99.3% of the applications for almost 9000 expanded access of an investigational drug were allowed to proceed. There were 62 requests that were either denied (38 emergency INDs) or not allowed to proceed (24 non-emergency INDs). The most common reasons for denying emergency INDs was that the patient was stable on current therapy and that it was not deemed an emergency. The most common reasons for not allowing non-emergency expanded access INDs to proceed were incomplete application, unsafe dosing, demonstrated lack of efficacy for intended use, availability of adequate alternative therapies, and inadequate information provided in the application on which to base a decision. A review of a random sample of 150 single-patient, non-emergency INDs revealed that FDA recommended changes to dosing, safety monitoring, or informed consent in 11%. Conclusions FDA plays a significant role in the protection of patients who receive investigational drugs under expanded access. An extremely small percentage of applications received are not allowed to proceed; however, FDA provides significant input based on information that may not be available to treating physicians in order to ensure patient safety under the applications that do proceed.

Oversight of Right‐to‐Try and Expanded Access Requests for Off‐Trial Access to Investigational Drugs

“…Although the FDA's expanded access pathway has been available to patients for decades, product developers have many reasons to sometimes deny requests for offtrial access to their investigational medical products, 10 and there has been confusion about the steps and sequence of the expanded access process. 13 RTT critics stressed that the FDA sometimes suggests modifications to treatment plans to maximize the chance of benefit and minimize the risk of harm to patients 14 and that removing the agency from the process could harm patients. The treating physician must certify that the patient has exhausted all treatment options and is unable to participate in an ongoing clinical trial testing the drug.…”

“…27 Likewise, data from an early 2018 survey of IRB professionals suggest that IRBs do not approve all expanded access requests they review; a few respondents noted that their IRB had declined to approve requests as a result of concerns about the risk-benefit ratio of the investigational product and/or the existence of other therapeutic or research options. Review by the FDA is not a "rubber stamp" approval, especially given the agency's access to confidential data and knowledge about other drugs in the same class as the investigational product of interest.…”

Impact of Expanded Access on FDA Regulatory Action and Product Labeling

“…In our previous reviews of the Center for Drug Evaluation and Research (CDER) experience with expanded access, we have shown that more than 1000 applications are received each year, more than 99% of the individual access requests are allowed to proceed, the median review time is 4 days for nonemergency requests and less than 24 hours for emergency, and that FDA requests changes in 11% of those allowed to proceed to ensure patient safety. 1,2 Moreover, it is extremely rare for serious adverse events or deaths that occur under expanded access to interrupt the development program for an investigational drug.…”

Where Can Patients Obtain Information on the Preapproval Access Pathway to Investigational Treatment in Japan? A Survey of Patient Advocacy Organizations’ Websites

“…Patients who cannot participate in clinical trials often seek alternative ways to receive investigational treatment. The US Food and Drug Administration has developed an expanded access program that, since 1938, has allowed patients with a terminal illness to request access to investigational treatments . In addition, a federal right‐to‐try act was enacted in May 2018, which has provided terminally ill patients with a new pathway to receive investigational treatments .…”

“…The US Food and Drug Administration has developed an expanded access program that, since 1938, has allowed patients with a terminal illness to request access to investigational treatments. 4 In addition, a federal right-to-try act was enacted in May 2018, which has provided terminally ill patients with a new pathway to receive investigational treatments. 5 In the European Union, the European Medicines Agency provides recommendations for Member States to develop their own legal framework of compassionate use (CU).…”