FDA Crackdown on Trial Design: What July’s CRLs to Replimune and Capricor Mean for Sponsors

July 25, 2025

Feature

Article

Complete Response Letters recently issued by the FDA signal heightened scrutiny of trial design and reinforce the agency’s shifting regulatory expectations for sponsors and CROs.

© JHVEPhoto - © JHVEPhoto - stock.adobe.com

Image Credit: © JHVEPhoto - stock.adobe.com

Key takeaways

Expect heightened scrutiny of trial design: Recent CRLs underscore that even previously aligned study protocols can be challenged if the FDA determines the design is not sufficiently controlled or robust.
Document all regulatory communications: Clear, written confirmation from FDA meetings—especially around endpoints, control arms, and design flexibility—is now more critical than ever.
Plan for regulatory shifts early in study design: Adaptive protocols, flexible statistical models, and geographic diversity in recruitment are key tools to proactively mitigate shifting regulatory expectations.

Recent Complete Response Letters (CRL) issued to Replimune and Capricor have made the FDA’s new and intensified scrutiny of clinical trial design clear. As the agency demands greater rigor and clarity, sponsors and contract research organizations (CROs) must adapt strategies to avoid regulatory setbacks in a shifting approval landscape.

In July, the FDA issued CRLs to both companies. While CRLs are not an unusual occurrence—with 37% of Biologics License Applications (BLAs) and New Drug Applications (NDAs) being issued one between 2018 and 2022¹—these most recent cases in 2025 have many biotech companies wondering where they stand with the FDA.

Recent CRLs raise industry alarm, trial design under microscope

The common denominator across the Replimune and Capricor cases is that the organizations seemed to be surprised by the CRLs.

The CRL to Replimune concerned its BLA for RP1 (vusolimogene oderparepvec) in combination with nivolumab. The investigational therapy is being evaluated in the Phase I/II IGNYTE clinical trial (NCT03767348) for the treatment of advanced melanoma. In the CRL, the FDA cited concerns with IGNYTE’s trial design, noting that it did not constitute an adequate and well-controlled study.²

“We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data,” Replimune CEO Sushil Patel, PhD, said in a press release.³

Issued earlier in July, the CRL to Capricor was in response to its cell therapy for cardiomyopathy associated with Duchenne muscular dystrophy, Deramiocel. In this letter, the FDA cited the need for additional data, despite the cell therapy being granted Priority Review in March, which was supported by findings from the Phase II HOPE-2 study (NCT03406780).²

Similarly, in a press release from Capricor, CEO Linda Marbán, PhD, said: “We are surprised by this decision by the FDA. We have followed their guidance throughout the process. Prior to the CRL, the review had advanced without major issues, including a successful pre-licensure inspection and completion of the mid-cycle review.”⁴

Biotechs grapple with shifting FDA expectations

Following these actions by the FDA, in the context of a year already filled with changes for the agency, the clinical research industry is wondering where it stands with trial design oversight and regulatory scrutiny.

“With the news of decisions related to Replimune and Capricor, as well as the ongoing challenges related to Sarepta's Elevidys, many drug developers remain challenged by the potential gap between new futures of tomorrow and the existing reviews of today,” said Craig Lipset, co-chair, Decentralized Trials & Research Alliance (DTRA), in an email interview with Applied Clinical Trials (ACT).

“This is particularly challenging for those who have based development strategies and investments on the outcomes of meaningful communications strategies with FDA stakeholders prior to 2025,” he added. “It raises questions for developers today as to whether past understandings still hold true, as well as the potential risks and benefits of re-engaging with FDA on active development programs based on those past agreements.”

Regulatory transparency efforts take shape

This year, the FDA has taken clear actions geared towards tightening up trial design. Amidst the recent CRLs to Replimune and Capricor, the agency published over 200 CRLs issued between 2020 and 2024 with the goal of increasing transparency and enhancing regulatory predictability. In a press release from the time, FDA Commissioner Martin A. Makary, MD, MPH, said: “For far too long, drug developers have been playing a guessing game when navigating the FDA.”⁵

Further, in May, Makary and Head of the FDA’s Center for Biologics Evaluation and Research (CBER), Vinay Prasad, MD, MPH, authored an article published in The New England Journal of Medicine (NEJM) highlighting the agency’s new requirement for any new COVID-19 vaccines to undergo testing in placebo-controlled trials.⁶

New policies may complicate trial design

This new framework around COVID-19 vaccine research calls for randomized, controlled trial data evaluating clinical outcomes before BLAs can be granted, representing a clear shift by the FDA towards increased oversight of trial design.

In anticipation of this shift in the regulatory framework around vaccine trials, ACT previously spoke with Krinx Kong, chief commercial officer, Cognivia, to gain insight.

“Now, if a policy shift were to mandate placebo use in all vaccine trials, even where active comparators might be more appropriate, we'd likely see significant impacts on both design complexity and timelines,” Kong explained in a video interview. “First, ethics boards may push back. If an effective vaccine already exists, withholding it in favor of placebo could be viewed as unethical. This leads to delays, extra review cycles, and potential public concern.”

“Next, placebo-controlled designs often require longer follow ups, which can prolong timelines by months or even years,” he added. “Lastly, these designs are frequently more difficult to recruit for, patients and parents may be reluctant to participate if there's a genuine chance of receiving no active protection. If policy does shift, having tools that can adapt trial design without compromising data integrity or patient trust will be essential.”

Heightened oversight extends beyond vaccines

While the conversation with Kong was related to vaccine trials, his comments are applicable to trial designs at large. Increased scrutiny from the FDA could affect many critical design elements such as patient recruitment, data management, and timelines.

To many, this shift towards increased oversight may not be a surprise. Prasad previously argued against emergency authorization of COVID-19 vaccines for children, raising concerns about how previous studies measured safety risks. He has also questioned the development of CAR-T cell therapies for cancer treatment.⁷

According to BioPharma Dive, over a dozen companies, including Moderna, Allogene, and Sarepta Therapeutics, lost large market value following Prasad’s appointment to head of CBER, as investors worried about slowed regulatory review.

Communication with FDA now more critical than ever

Whether or not these major FDA changes seen in 2025 end up being a positive for the industry remains to be seen. However, CROs and sponsors—those at the front lines of trial design and conduct—are wondering how to remain compliant in this shifting landscape.

While the FDA is clearly focused on more closely scrutinizing trial design, the agency has also been vocal with its efforts in keeping lines of communication open and emphasizing transparency in decision-making with its key stakeholders. It remains imperative that CROs and sponsors keep an open line of communication with the FDA to avoid major delays in conducting trials.

“FDA reviewers provide guidance during the drug development process. However, their perspective may change over time as new information becomes available about the novel product and/or the larger landscape of treatment options,” explained Robin Bliss, vice president, strategic consulting, Veristat, in an email interview with ACT.

“Therefore, having direct and clear communication with the FDA is critical to expedite drug development and reduce risk of misunderstanding of regulatory requirements. In communication with the FDA, direct questions regarding the components of the study design (including, but not limited to, endpoints, control arm selection, durations of treatment, geographic distribution of sample, and sample size) will provide meaningful clarity and direction to help sponsors align their understanding with the FDA expectations.”

Bliss continued by emphasizing that sponsors should not be taking “head shakes or nods” from the FDA as an agreement on a particular topic. When in communication with agency officials, sponsors should be probing for a definitive response if possible, and to request that the agency’s position be clearly reflected in the minutes of the meeting.

“Therefore, questions posed should be written as clearly as possible and discussions during the meeting should be in-depth to make sure the Division’s position is clearly understood, and minuted,” she continued.

Future-proofing trial designs for regulatory success

In terms of planning ahead for challenges such as being issued a CRL, sponsors must utilize strategies that ensure flexibly and meet FDA standards but also leave room for adaptation if endpoints or data cutoffs are challenged.

“When planning an adaptive trial design, sponsors should pre-specify within the study protocol any modifications that may occur, the timing of the interim assessments, and an algorithm for type I error control. For early-phase studies where additional flexibility is needed and in cases where the adaptations cannot be pre-specified, the type I error rate may not be controlled and therefore the study, as designed, may not be appropriate as the primary evidence of efficacy for a marketing application,” Bliss said.

Everything considered, the July CRLs issued to Replimune and Capricor should be interpreted as signals. The messaging from the FDA through its own actions and statements is clear that it wants stakeholders to:

tighten study designs,
over‑deliver on control,
document every regulatory interaction, and
diversify geographic strategy.

The current regulatory environment is too volatile to assume leniency during late-stage approvals.

“Drug developers operate with scientific uncertainty and so thrive on understanding operational and regulatory risk,” Lipset said. “Sponsors must help communicate to FDA leaderships the urgency of regulatory clarity, as new leaders at the agency seem very committed to transparency and communications.”

References

1. Complete Response Letters: Implications for Product Access. Avalere Health. November 30, 2023. Accessed July 24, 2025. https://advisory.avalerehealth.com/insights/what-is-a-complete-response-letter.

2. FDA Issues Complete Response Letter to Replimune for RP1 Combination Therapy in Advanced Melanoma. Applied Clinical Trials. July 22, 2025. Accessed July 24, 2025. https://www.appliedclinicaltrialsonline.com/view/fda-issues-complete-response-letter-replimune-rp1-combination-therapy-advanced-melanoma

3. Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. Replimune. July 22, 2025. Accessed July 24, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics/.

4. Capricor Therapeutics Provides Regulatory Update on Deramiocel BLA for Duchenne Muscular Dystrophy. Capricor. July 11, 2025. Accessed July 25, 2025. https://www.globenewswire.com/news-release/2025/07/11/3113911/0/en/Capricor-Therapeutics-Provides-Regulatory-Update-on-Deramiocel-BLA-for-Duchenne-Muscular-Dystrophy.html.

5. New FDA Initiative Reveals Common Reasons for Drug Application Rejection. Applied Clinical Trials. July 11, 2025. Accessed July 24, 2025. https://www.appliedclinicaltrialsonline.com/view/new-fda-initiative-reveals-common-reasons-drug-application-rejection

6.FDA Outlines Updated Requirement for Placebo-Controlled Trials in Vaccine Research. Applied Clinical Trials. May 21, 2025. Accessed July 24, 2025. https://www.appliedclinicaltrialsonline.com/view/fda-outlines-updated-requirement-placebo-controlled-trials-vaccine-research

7. Biotech is guessing how Vinay Prasad might change the FDA. His research, writing offer clues. BioPharma Dive. May 8, 2025. Accessed July 24, 2025. https://www.biopharmadive.com/news/vinay-prasad-cber-fda-drug-approvals-research/747497/

Stay current in clinical research with Applied Clinical Trials, providing expert insights, regulatory updates, and practical strategies for successful clinical trial design and execution.

Subscribe Now!