Myth 1
Expedited programs lower the evidence bar and accelerate development
Many companies are thrilled to win a valuable FDA designation, such as Breakthrough Therapy (BTD) or Regenerative Medicine Advanced Therapy (RMAT). They often hope the designation will allow them to progress with a smaller and less persuasive volume of efficacy data, especially for an orphan CGT product. When I worked at the FDA, CGT companies would approach us regularly, asking for a reduction in the number of trials or the quality of evidence because they had an RMAT designation. We would explain that expedited program designations do not reduce the evidentiary requirements for licensure.
The FDA often approves a novel drug or biologic in an orphan drug-designated indication on smaller, single-arm pivotal trials. But additional studies may be required if the product is not associated with a large, transformative clinical benefit. A well-designed natural history study—or other rigorous external control data—may also be required. These requirements may slow development down, not speed it up.
Myth 2
An orphan CGT will automatically get special attention from the FDA
In the current environment of constrained FDA resources, development programs for CGTs may languish due to a lack of intensive interaction with regulators, even if they are first-in-class and address a rare and serious unmet medical need.
In September 2022, the FDA announced that it “elevated” OTAT to a “Super Office” within CBER—and renamed it the Office of Therapeutic Products (OTP), citing the current and anticipated increase in workload. As a former regulator, this suggests to me that the agency lacks the resources to handle the influx of sub-specialized CGT applications. BT or RMAT designation is now a prerequisite for prioritized meetings with OTP, as Director Wilson Bryan recently observed. Without BT or RMAT status—or exceptional preliminary clinical data— orphan designation on its own will not necessarily attract regulatory attention for a CGT.
A benefit of RMAT designation is the RMAT Initial Comprehensive Meeting, a multidisciplinary discussion of the sponsor’s clinical trial and manufacturing development strategy. We’ve received feedback from several clients that the initial meeting is a boon, and every meeting for an RMAT-designated program will be scheduled at a Type B priority. We’ve helped clients prepare for these interactions to maximize the opportunity.
Myth 3
An orphan CGT can get Accelerated Approval on a clinically meaningful endpoint
In the European Union, the European Medicines Agency (EMA) has a licensure option known as conditional marketing authorisation (CMA), under which products that address unmet needs are approved on “less comprehensive data than normally required.” The CMA mechanism allows patients access to drugs despite incomplete benefit-risk data.
The closest comparable pathway to CMA in the United States is the FDA’s Accelerated Approval (AA) pathway. But there is a critical difference between the two. CMA relates to the amount of evidence available for a drug, while the FDA interprets AA to relate to efficacy data collected for a specific type of endpoint. Thus AA for CGTs requires the use of a surrogate efficacy endpoint that is “reasonably likely” to correlate with clinically meaningful outcomes.
Companies often confuse the CMA and AA pathways. I have seen them ask for AA based on a clinically meaningful primary efficacy endpoint and fail because it’s not a surrogate. Regardless of precedent, making assumptions about an expedited regulatory pathway is risky. Sponsors should discuss and agree on endpoints and other aspects of the AA pathway with OTP before they finalize their development plans.
Myth 4
Long-term follow-up CGT studies don’t yield much value for the sponsor
Some sponsors view long-term follow-up (LTFU) trials of approved orphan drugs as a line item on a long checklist of post-approval requirements. They must do the trials because regulators mandate them: for example, the FDA requires 15 years of safety follow-up for lentiviral-based gene therapies. And scientific advances, such as the emergence of gene editing platform technologies, will make longitudinal follow-up data for genomically-targeted treatments even more critical. But well-designed LTFU trials can add value for the sponsor.
LTFU trials can cost almost as much as the pivotal trial—as much as $30 million—because any type of healthcare follow-up is costly. However, sponsors can design and execute LTFU studies to collect data that promote patient safety, support a product’s value proposition, and optimize product lifecycle management. At Parexel, when we design LTFU studies for a client, we always ask whether they want to meet the bare minimum FDA requirement for safety monitoring or whether they also want to generate data that could differentiate their product.
Myth 5
Regulators will make critical development decisions for you
Early meetings with the FDA offer sponsors a chance to de-risk their development strategy and optimize trial designs, endpoints, and the evidence generation plan before submitting an investigational new drug (IND) application. Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT) and pre-IND meetings are two such meetings. (The FDA’s Prescription Drug User Fee Act VII, signed into law on September 30, 2022, expanded the use of INTERACT to CDER products). These are valuable opportunities if sponsors prepare for them.
Many developers hope to receive definitive answers to complex development questions during these exchanges. But regulators have neither the expertise nor the remit to make pivotal development decisions for companies. When I worked at the FDA, companies sometimes asked us to weigh in on two different products—or two routes of administration—and signal which would be more acceptable. We offered a stock reply that products with the most favorable benefit-risk profile should advance.
In the end, developers have to make the critical decisions. The best way for them to arrive at good ones is to listen carefully to regulators and then, with all the data at their disposal, use their best judgment to make thoughtful tradeoffs and take defensible calculated risks.