Understanding the Significance of CRLs Being Released: Beyond the Regulatory Language
The FDA's Complete Response Letter (CRL)-- few documents hold as much weight in the complex and often opaque world of pharmaceutical development, as the CRL. Metis Consulting can help navigate them, learn more at our blog, The Guard Rail.
Written by Michael Bronfman, July 28, 2025
This week in The Guard Rail, we at Metis are looking at a hot topic for our industry. Michael Bronfman tackles a hidden power in the pharmaceutical and medical device manufacturing world: the FDA's Complete Response Letters (CRLs). These are not just dry documents. The contents have traditionally been kept secret, known only to the receiving company. However, that secrecy might now be coming into the open. Why? Because a CRL can instantly derail a company's future, send stock prices plummeting, and, most critically, determine if a life-saving treatment ever sees the light of day. Join us as we uncover why these once-confidential letters are at the heart of a tidal wave push for transparency.
The FDA's Complete Response Letter (CRL)-- few documents hold as much weight in the complex and often opaque world of pharmaceutical development, as the CRL. For many outside the industry, the term might sound dry, bureaucratic, or even cryptic. But for drug developers, investors, patients, and clinicians, CRLs are pivotal turning points; letters that can reshape company strategy, impact stock prices overnight, and, most importantly, influence when or even if a new therapy reaches patients.
Historically, the contents of CRLs have often remained confidential, known only to the company receiving them and occasionally, selectively disclosed to the public. Yet the idea of CRLs being more broadly released, whether voluntarily by sponsors or systematically through policy change has gained traction. Why? Let us explore why these letters matter, what they contain, and why making them public can be a significant step forward for science, business, and patient trust.
What exactly is a CRL?
A Complete Response Letter is issued by the U.S. Food and Drug Administration (FDA) when it completes its review of a New Drug Application (NDA) or Biologics License Application (BLA) but decides not to approve it in its current form. Importantly, a CRL does not mean the drug is permanently rejected. Instead, it outlines the deficiencies that prevent approval and often provides guidance on what the sponsor could do to address them.
Deficiencies can include:
Issues with clinical efficacy or safety data (e.g., not enough evidence that the drug works, or safety concerns in certain patient populations)
Manufacturing or quality control shortcomings
Problems with labeling or risk management strategies
Statistical or methodological issues in trial design
For sponsors, receiving a CRL is both a setback and a roadmap. It’s an official document telling them: “Here is what is missing; come back when you have fixed it.”
The FDA's Complete Response Letter (CRL) few documents hold as much weight, in the complex and often opaque world of pharmaceutical development, as the CRL. For many outside the industry, the term might sound dry, bureaucratic, or even cryptic. But for drug developers, investors, patients, and clinicians, CRLs are pivotal turning points; letters that can reshape company strategy, impact stock prices overnight, and, most importantly, influence when or even if a new therapy reaches patients.
Historically, the contents of CRLs have often remained confidential, known only to the company receiving them and occasionally, selectively disclosed to the public. Yet the idea of CRLs being more broadly released — whether voluntarily by sponsors or systematically through policy change — has gained traction. Why? Let's explore why these letters matter, what they contain, and why making them public can be a significant step forward for science, business, and patient trust.
What exactly is a CRL?
A Complete Response Letter is issued by the U.S. Food and Drug Administration (FDA) when it completes its review of a New Drug Application (NDA) or Biologics License Application (BLA) but decides not to approve it in its current form. Note, a CRL does not mean the drug is permanently rejected. Instead, it outlines the deficiencies that prevent approval. Often, the letter will provide guidance on what the sponsor can do to address the issue.
Deficiencies can include:
Issues with clinical efficacy or safety data (e.g., not enough evidence that the drug works, or safety concerns in certain patient populations)
Manufacturing or quality control shortcomings
Problems with labeling or risk management strategies
Statistical or methodological issues in trial design
For sponsors, receiving a CRL can be a setback, but it is also can be a roadmap. It is an official document that says: "Here is what is missing; come back when you have fixed it."
Why are CRLs so important?
CRLs carry enormous significance because they sit at the intersection of science, business, and public health. Consider:
1. Strategic pivot points for companies
A CRL forces a company to decide: Do we invest more time and money to address the FDA's concerns, or do we walk away? Sometimes the deficiencies are minor and easily fixable; at other times, they are so fundamental that continuing to do so makes little sense.
2. Market-moving disclosures
Because the market places great value on new product approvals, the news of a CRL often leads to sharp drops in a company's stock price — especially if the drug was seen as a major pipeline asset.
3. Impact on patients
For patients waiting for new treatment options, CRLs can feel like an unexpected delay. Understanding the nature of the deficiency can help patients and advocates see whether it is a temporary hurdle or a sign of deeper problems.
4. Scientific learning
Each CRL is a detailed FDA critique of a drug's data and the sponsor's responses. While usually kept confidential, if shared, they can become case studies that improve drug development as a whole.
The current situation: Confidential by default
Under U.S. law, CRLs are part of a company's regulatory correspondence and thus are treated as confidential commercial information. Sponsors may choose to disclose the fact that they received a CRL — and often do, given that it's material information for investors — but the actual content is rarely released in full.
Instead, companies often issue press releases summarizing the FDA's concerns. Unfortunately, these summaries can be selective, vague, and overly optimistic:
Selective: emphasizing easily fixable manufacturing issues and omitting more serious efficacy concerns
Vague: using language like "additional analyses requested" without context
Optimistic: framing the CRL as "a minor setback" even if the letter itself is more critical
This practice makes it hard for outside observers — including investors, clinicians, and patient groups — to understand what really happened.
The significance of CRLs being more publicly released
CRLs regularly released in full, could have a profound effect on how new therapies are evaluated, understood, and debated. Here's why:
1. Transparency builds trust
Our industry struggles with perceptions of secrecy. Polished summaries are shared and that is fine but if they are the only data released, it is impossible to know if the sponsor is downplaying serious concerns. Releasing more complete CRLs shows the unfiltered FDA perspective, which can reassure the public that approvals are based on thorough, science-driven review.
2. Better information for stakeholders
Investors could better assess the real risk of resubmission and approval. Clinicians could understand why certain drugs were not approved — whether due to safety concerns in specific populations or inadequate evidence of benefit. Patients and advocacy groups could advocate more effectively if they knew the precise barriers.
3. Industry-wide learning
Drug development is full of repeated mistakes: inadequate trial design, poor endpoint selection, underpowered studies, or manufacturing gaps. Public CRLs can serve as detailed case studies, allowing future sponsors to avoid similar pitfalls.
4. Accountability
Public CRLs help ensure that sponsors fully address the FDA's concerns before resubmitting, rather than trying to sidestep them with minimal new data. They also keep the FDA accountable, making its reasoning transparent and open to scientific debate.
Potential drawbacks and industry concerns
Of course, releasing CRLs is not without controversy. Key concerns include:
1. Proprietary data
CRLs often contain detailed discussion of clinical trial data, manufacturing processes, and commercial plans. Sponsors argue that full disclosure could benefit competitors or harm competitive advantage.
2. Misinterpretation
FDA reviews are technical documents, and taken out of context, statements in a CRL could be misread by the public or sensationalized by the media.
3. Chilling effect on communication
If sponsors know that every word in their submissions could become public, they might be less candid, potentially limiting open dialogue with regulators.
4. Impact on innovation
Some fear that too much transparency could discourage small biotech firms — already operating under tight timelines and budgets — from pursuing high-risk programs.
The evolving conversation
The debate is not purely academic. In recent years:
Some sponsors have voluntarily released CRLs, especially when the market reaction to vague summaries was worse than anticipated.
Regulatory advocates and transparency groups have pushed for routine publication, arguing that CRLs, like European Public Assessment Reports (EPARs), could help demystify the approval process.
The FDA itself has signaled interest in improving transparency, though it is constrained by existing confidentiality laws.
The conversation reflects a broader trend in medicine: moving from "trust us" to "show us." Patients, payers, and clinicians want to see the data and the reasoning behind it, not just the headline.
International context
The U.S. FDA is not alone in grappling with this issue. European regulators, through the EMA, publish relatively detailed assessment reports once a drug is approved, but not if it is rejected. Similarly, Health Canada has taken steps to publish "Summary Basis of Rejection" documents for drugs that are not approved.
These models demonstrate that it is possible to balance transparency with the protection of confidential information, although it requires careful policy design.
A path forward
So, what would be the ideal outcome?
Routine publication of redacted CRLs: Share the FDA's reasoning while redacting truly proprietary data, like detailed manufacturing process steps.
Standardized summaries: Even if full letters aren't released, require sponsors to issue standardized, FDA-reviewed summaries that accurately reflect the deficiencies.
Educational context: Provide plain-language explanations alongside CRLs, so clinicians, patients, and journalists can understand the technical details.
Such steps could bring real benefits without undermining innovation.
Why it matters
At its heart, the significance of CRLs being released is about more than a document. It is about shining light on critical moments in the life of a new therapy: the point where data meets judgment. When companies keep those moments private, the public can only guess at what went wrong. When CRLs are shared, everyone from researchers designing the next trial to patients hoping for a breakthrough can see, learn, and plan accordingly.
Transparency is not a cure-all. It won't eliminate uncertainty, disappointment, or risk. However, in a field where trust is essential and decisions affect both lives and balance sheets, sharing the FDA's reasoning is a powerful way to build confidence, foster learning, and ultimately bring better medicines to the people who need them.
If your organization is grappling with CRLs or needs help avoiding them, please contact us at Metis Consulting Services: Hello@MetisConsultingServices.com.
For more info, see our website www.MetisConsultingServices.com
What We Lose by Cutting Research Funding in the U.S.A.
For decades, the United States has led the world in biomedical innovation, powered by long-term investment in public research infrastructure. Institutions like the NIH, NSF, and CDC have been cornerstones of medical progress and global health preparedness. But that leadership is slipping. Research budgets are flattening or declining in real dollars, while political instability further threatens their continuity.
By Michael Bronfman, June 10, 2025
Author assisted by AI
This week, The Guard Rail is proud to feature a crucial topic impacting the very foundation of innovation in the pharmaceutical and life sciences industries. This comes on the heels of ongoing discussions about the importance of sustained investment in research and development. Our latest post, "What We Lose by Cutting Research Funding in the U.S.A.," delves into the far-reaching consequences of diminishing public funding for scientific endeavors. Please let us know what you think.
Science isn’t self-sustaining. It needs fuel, and that fuel is funding.
For decades, the United States has led the world in biomedical innovation, powered by long-term investment in public research infrastructure. Institutions like the NIH, NSF, and CDC have been cornerstones of medical progress and global health preparedness. But that leadership is slipping. Research budgets are flattening or declining in real dollars, while political instability further threatens their continuity.
In biopharma, where product pipelines rely on early-stage discovery science, this isn’t just a government problem. It’s an industry crisis in the making.
Slower Drug Discovery and Development
Fact: Every one of the 210 new drugs approved by the FDA between 2010 and 2016 was linked to publicly funded research. Biopharma companies rely on foundational science to guide their pipelines, but they rarely fund that science directly. The risk is too high and the payoff too far off. It’s public institutions that decode disease mechanisms, identify new drug targets, and lay the groundwork for innovative therapies.1
Cuts to NIH funding don’t just slow university research—they erode the pipeline feeding the next generation of breakthrough medicines.
Weakened Global Competitiveness
STAT: China now leads the world in total scientific publications and is rapidly closing the gap in high-impact research.(Source: Nature Index, 2023)2 While U.S. funding stagnates, China and the EU are aggressively investing in research. China, in particular, has made biomedical innovation a national priority, pouring billions into AI in drug discovery, gene editing, and translational medicine. As funding dries up at home, U.S. scientists—especially early-career researchers—are lured by more stable prospects abroad. That includes faculty appointments, lab funding, and full-stack innovation ecosystems. Innovation is global. If the U.S. doesn’t lead, someone else will.
Loss of Talent and the “Leaky Pipeline”
STAT: Less than 17% of U.S. biomedical PhDs secure tenure-track positions.(Source: NIH Biomedical Workforce Report, 2021)
“Nowadays, less than 17% of new PhDs in science, engineering and health-related fields find tenure-track positions within 3 years after graduation (National Science Foundation, 2012; Chapter 3). Many PhDs who do not find tenure-track positions turn to positions outside academia. Others who think that they will have better future opportunities accept relatively low-paying academic jobs such as postdoctoral positions and stay in the market for a prolonged period (Ghaffarzadegan et al., 2013). Many engineering PhDs go the entrepreneurial route and become involved in startups or work in national research labs or commercial R&D centres. But our focus is academia.”
Science takes a long time. Researchers spend over a decade training before leading independent labs. But the bottleneck isn’t talent—it’s funding.
When grant paylines fall and budgets shrink, postdocs and junior faculty face fewer opportunities. Many leave academia entirely. Others go overseas. This brain drain disproportionately impacts women and underrepresented minorities, who face systemic disadvantages and less funding security.
Losing these scientists means losing not just skill, but diversity of thought—and long-term industry innovation.
Fewer Breakthroughs in Rare and Neglected Diseases
STAT: 50% of rare disease research projects rely heavily on NIH funding. (Source: NIH Office of Rare Diseases Research)3 Pharma’s ROI models don’t always support research in areas with small patient populations. Rare diseases, neglected tropical illnesses, and pediatric cancers often fall outside commercial viability. Public funding fills this gap—fueling the early science, infrastructure, and data that eventually enable therapies. The first gene therapies, mRNA vaccines, and targeted oncology platforms were born out of public research on “unprofitable” conditions. Cutting funding abandons these patients—and the innovation that often follows from solving hard, overlooked problems.
Delayed Preparedness for Future Pandemics
STAT*: NIH invested over $700M in coronavirus research before COVID-19 emerged.(Source: Congressional Research Service, 2021)4 The rapid development of COVID-19 vaccines didn’t happen overnight. It was built on decades of NIH-funded virology, structural biology, and RNA delivery research. Agencies like BARDA and DARPA took the financial and technological risks long before private companies stepped in. The Moderna and Pfizer-BioNTech vaccines succeeded because the science—and the funding—was ready. Cutting infectious disease research now will leave us vulnerable to the next pandemic. Public health readiness can’t be “turned on” in a crisis—it must be sustained year-round.
A Fragile Clinical Trial Ecosystem
STAT: Over 40% of U.S. clinical trials are led or supported by NIH, VA, or academic medical centers.(Source: ClinicalTrials.gov data analysis, 2023)
“The claim that over 40% of U.S. clinical trials are led or supported by the NIH, VA, or academic medical centers is supported by multiple sources.
NIH's Role in Clinical Trials
The National Institutes of Health (NIH) is the largest funder of biomedical research in the United States. In 2024, more than 80% of its $47 billion budget was allocated to support research, including clinical trials, at over 2,500 scientific institutions. Notably, 60% of this extramural research occurred at academic medical center campuses. (ncbi.nlm.nih.gov, aamc.org)
VA's Contribution to Clinical Trials
The Veterans Health Administration (VHA) also plays a significant role in clinical research. Through its Office of Research and Development, the VA supports numerous clinical trials. As of November 2023, approximately 932,000 veterans were enrolled or expected to be enrolled in studies funded by the VA. (en.wikipedia.org, congress.gov)
Academic Medical Centers and Clinical Trials
Academic medical centers are integral to the U.S. clinical trial landscape. Institutions like Massachusetts General Hospital and Stanford University collaborate with the VA and NIH, contributing to a substantial number of clinical trials. (journals.lww.com)”
Private pharma drives large-scale, late-phase trials. But early-phase, rare disease, and non-commercial trials rely heavily on public funding and academic infrastructure.
From the Cancer Moonshot to the All of Us initiative, federal investment creates platforms and protocols that benefit the entire ecosystem. Without that scaffolding, trials become slower, more expensive, and riskier for sponsors.
When government funding falters, it’s not just public labs that lose—it’s the entire translational pipeline.
Reduced Return on Public Investment
STAT: Every $1 of NIH funding generates over $8.38 in economic activity.(Source: United for Medical Research, 2020)6 Research isn’t charity, it’s investment. From university spinouts to biotech accelerators, public science creates real economic value. This includes IP generation, job creation, tax revenue, and long-term cost savings in healthcare.
Cutting research funding doesn’t save money—it sacrifices return. And once lost, scientific momentum is hard to regain. Labs close. Talent relocates. Innovation stalls.
We’re not just undermining future therapies—we’re eroding the base of an entire innovation economy.
Erosion of Scientific Literacy and Trust
STAT: Public trust in science has dropped by 10+ points since 2020, especially among younger (U.S.) Americans.(Source: Pew Research, 2023)7
Public research supports more than lab benches—it funds data-sharing, transparency, education, and outreach. From open-access journals to science museums and K–12 programs, public science is a social good.
Without investment, we lose more than knowledge. We lose shared understanding. That void gets filled by misinformation, distrust, and anti-scientific sentiment—especially in an era of rapid technological change.
A well-funded, transparent research ecosystem builds trust, and trust saves lives
Final Thoughts: Innovation Requires Stability
Cutting research funding may seem like a short-term budget fix. But the long-term cost is far higher.
We lose:
Therapies that never make it to trials.
Scientists who leave the field.
Competitive edge in a global biotech arms race.
Preparedness for emerging diseases.
Public trust in health science.
The U.S. has always been a leader because it invested in being one. That’s not guaranteed. Leadership in science is a choice—a policy decision. One that affects every sector of pharma, from discovery to market.
If you’re in biopharma, policy, or research, your voice matters.
Support stable, bipartisan investment in:
NIH, NSF, and BARDA budgets
Early-career research funding
Open science infrastructure
Translational and rare disease initiatives
Let’s ensure the U.S. remains a place where great science thrives—and where public funding continues to fuel private innovation for decades to come.
Let’s continue the conversation.
What impact have you seen from federal research funding in your work? What do we risk losing? Drop a comment or share this post to keep science at the center of policy.
1. PNAS study on NIH-funded research and drug approvals(Source: Cleary et al., PNAS, 2018)
2 https://www.nature.com/articles/d41586-023-01867-4
3. https://hr.nih.gov/sites/default/files/public/documents/2022-07/ohr-annual-report-2021.pdf
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC9975718/
6. https://www.nih.gov/about-nih/what-we-do/budget https://unitedformedicalresearch.org/annual-economic-report/