Pablo Morales, MD
Recent discussions surrounding the FDA’s interpretation of “substantial evidence” for drug and biologic approvals have sparked media attention resulting from an interview last week by FDA Chairman Marty Makary, MD. [Editor's note: The preceding link to the interview requires a StatNews subscription to view the full text.]
For firms contemplating clinical trials, it is important to clarify the regulatory context and implications, as well as understand the differences in the evidence required between drugs and devices.
Quick Takeaways:
- The recent FDA interpretation primarily affects drugs and biologics, reaffirming flexibility in meeting the substantial evidence standard.
- For medical devices, the regulatory bar remains “reasonable assurance of safety and effectiveness,” and the single-trial approach has been standard practice for years.
- The FDA stated it would publish a press release on the guidance soon.
Since 1962, Congress has required that drugs demonstrate both safety and effectiveness, with effectiveness established through “substantial evidence.” This standard is defined as evidence from adequate and well-controlled investigations, typically interpreted by FDA as requiring two independent clinical trials, each convincing on its own. However, under certain circumstances, FDA has long accepted alternative approaches, such as:
- One large multicenter trial with robust design and characteristics.
- Reliance on prior findings of effectiveness for an approved drug when scientifically justified.
- One adequate and well-controlled trial plus confirmatory evidence, as explicitly recognized in the Food and Drug Administration Modernization Act (FDAMA).
These flexibilities are not new; they have been part of the regulatory framework for decades. The current policy interpretation simply emphasizes these existing provisions, allowing FDA to consider a single trial with supporting evidence as sufficient in appropriate cases.
Biologics fall under similar standards, requiring products to be “safe, pure, and potent” under the Public Health Service Act, with potency historically interpreted to include effectiveness. FDA generally applies the same “substantial evidence” standard for biologics as for drugs.
Medical Devices, however, operate under a different regulatory paradigm. For devices, the statutory standard is “reasonable assurance of safety and effectiveness,” not “substantial evidence.” FDA relies on valid scientific evidence, which may include well-controlled investigations, partially controlled studies, case histories, and significant human experience. The evidence requirements vary based on device characteristics and intended use. Importantly, the concept of a single trial has long been embedded in device regulation, and this recent policy interpretation for drugs and biologics does not signal a major shift for devices.
As such, while headlines may suggest sweeping changes, the reality is that these principles have been part of FDA’s framework for decades. For devices, little is expected to change.
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Dr. Pablo Morales leads the clinical and medical vision for Veranex’s iCRO business, shaping how we deliver innovative, patient-centered, and compliant solutions for our clients across all phases of development. He brings over 15 years of clinical, regulatory, and scientific leadership experience to his role as Chief Medical Officer at Veranex.
Before joining Veranex, Dr. Morales served in senior leadership roles at the U.S. Food and Drug Administration (FDA), including Chief Medical Officer in the Office of Clinical Evidence and Analysis and Senior Medical Advisor in the Office of Clinical Policy. He provided clinical and regulatory oversight on more than 1,000 medical device submissions and played a key role in implementing the FDA’s Early Feasibility Studies (EFS) program.
A trained vascular and endovascular surgeon, he earned his medical degree from Universidad Pontificia Bolivariana in Colombia, with advanced training at Guy’s and St. Thomas’ Hospital in London and a research fellowship at the Cleveland Clinic.