In February 1961, a physician at the Food and Drug Administration named Frances Oldham Kelsey came across a letter in the December issue of the British Medical Journal. It was written by a British physician, A. Leslie Florence, who had been prescribing a new sedative. Some of his patients who had taken it for long periods were reporting a painful tingling in their arms and feet.
The sedative was thalidomide. Kelsey had joined the agency only months earlier and one of her first assignments was the William S. Merrell Company’s application to sell the drug in the United States under the name Kevadon. Merrell expected approval to be a formality. The drug was already on the market in many countries. Kelsey had found the company’s evidence thin, built more on testimonials than on clinical data. The letter turned her unease into something sharper. Nerve damage, she later said, was not the kind of side effect one should expect from a simple sleeping pill. If the drug could reach the nerves of an adult, what might it do to a fetus?
Merrell pressed. Its representatives called and visited, went over her head to her superiors, and at one point described her objections as slightly libelous. Under the law at the time, an application took effect automatically if the FDA did not act on it within 60 days. So Kelsey kept declaring it incomplete, and each time the clock started over.
In late 1961, physicians in Germany and Australia linked thalidomide to a wave of infants born with severely malformed limbs. More than 10,000 children in dozens of countries would be affected. Merrell withdrew its application in 1962. That July, the Washington Post put Kelsey on its front page as the heroine of the FDA. In August, President Kennedy gave her the President’s Award for Distinguished Federal Civilian Service. In October, he signed the Kefauver-Harris Amendments, which required drugs to be proven effective as well as safe and gave the FDA authority over clinical investigations. Nearly everything we now call drug development, the INDs, the phases, the safety reports, grew out of one reviewer’s doubt.
The story is usually told as a triumph. It was also a near miss. While Kelsey was stalling the application, Merrell had been shipping thalidomide to more than 1,200 American physicians as an investigational drug, which the law then allowed with almost no oversight. Roughly 20,000 Americans received it. The FDA later identified 17 American children born with thalidomide-related defects.
More than half a century later, I was leading a team at the FDA rebuilding the process that descends directly from that episode: the review of safety reports from drugs still in clinical trials. At some point we asked a simple question. When had the agency last had a Kelsey moment? When had the FDA, looking at data from an ongoing trial, seen a danger before the company running it? We asked colleagues across the centers, people who had spent entire careers in review. It was not a formal study. But no one could name a single case.
The answer, albeit informal, was zero.
This does not mean FDA reviewers today lack Kelsey’s skill or nerve. It means the system that grew out of her doubt may be structurally incapable of producing another one. And it matters now, because the debate over the agency’s future has fixed on the wrong variable. Over the past 18 months, the FDA has lost roughly 20 percent of the staff in its major medical product centers. One side warns that fewer reviewers will mean weaker oversight. The other points out that review goals are still largely being met. Both assume that the agency’s capacity is a function of how many people it employs.
I spent years at the FDA and don’t think the FDA needs more reviewers. I think it needs to stop asking them to do work that, as designed, cannot succeed.
I. A permission to ship
Surprisingly, many people who work in drug development every day do not fully realize what the FDA’s authority over experimental drugs actually rests on. Six decades of regulations, guidance documents, user fee agreements, advisory committees, workshops, and expedited pathways have been layered on top of it. Strip those layers away and what remains is something almost mundane: the movement of goods across state lines.
The agency’s power derives from the Commerce Clause of the Constitution. Section 505(a) of the Federal Food, Drug, and Cosmetic Act of 1938 prohibits introducing a new drug into interstate commerce unless an application for it has been approved. An investigational drug, by definition, has not been approved. Section 505(i) of the Act creates the exemption that makes clinical research possible, and the Kefauver-Harris Amendments of 1962 turned that exemption into the investigational new drug system now codified at 21 CFR Part 312. Biologics follow a parallel path under Section 351 of the Public Health Service Act.
An IND, then, is narrower than most people assume. It goes into effect 30 days after the FDA receives it unless the agency places it on clinical hold. When the FDA tells a sponsor it is safe to proceed, it is, in legal terms, allowing the sponsor to ship an unapproved drug across state lines to its investigators. It is not an endorsement of the science.
This raises an obvious question: what if everything happened within one state? In theory, the Act reaches only products with a connection to interstate commerce. In practice, there is very little room in that boundary. Since the FDA Modernization Act of 1997 extended it to drugs, Section 709 of the Act (21 U.S.C. 379a) has presumed the interstate connection in any enforcement action, which puts the burden on the company to disprove it. Courts have also held that the requirement is met if any component of a product crossed state lines. In United States v. Regenerative Sciences (2014), the D.C. Circuit upheld FDA jurisdiction over a stem cell procedure performed entirely in Colorado because it used an antibiotic obtained in interstate commerce. A truly intrastate drug, made from in-state materials and tested only on in-state patients, is a legal possibility and a practical rarity. Any sponsor with national commercial ambitions will need the FDA regardless.
Within that framework, the IND stage is where most of the agency’s ongoing oversight takes place, and its focus is safety. Most INDs never become marketing applications; they die somewhere in the valley between first-in-human dosing and pivotal data. Under Section 505(i)(3) of the Act and 21 CFR 312.42, the FDA may place an IND on hold when participants would be exposed to unreasonable and significant risk, when investigators are not qualified, or when the information provided is insufficient to assess risk. For Phase 2 and Phase 3 studies, a hold may also be imposed when a protocol is clearly deficient in design to meet its stated objectives. Doubts about whether a drug will work are not, on their own, grounds for a hold. Efficacy is the sponsor’s bet to make. Safety is the regulator’s responsibility to enforce.
This is the part of the system that descends most directly from Kelsey. To understand why it has not produced a successor, we have to look at how it actually works.
II. The archive
The primary instrument of premarket safety oversight is the expedited IND safety report. Under 21 CFR 312.32, sponsors must notify the FDA within 15 calendar days of a serious and unexpected suspected adverse reaction, and within 7 calendar days when that reaction is unexpected and fatal or life-threatening.
The reports arrive in staggering numbers. From 2006 through 2014, the FDA’s Office of Hematology and Oncology Products alone received an average of 17,686 of them per year. For most of the agency’s history, and throughout my time there, they came on paper, as PDF files, and as MedWatch and CIOMS forms. They were documents, not data. A reviewer could read them one at a time. No one could aggregate them across trials, query them, or look for patterns without first extracting the information by hand.
Most of them were also noise. In 2010, the FDA issued a final rule designed specifically to reduce uninformative reporting. Five years later, we audited randomly selected expedited reports submitted to the oncology office. Only 14% were informative. More than half described adverse events that were already expected and listed in the product labeling or investigator’s brochure. We reported these findings in Clinical Cancer Research in The Majority of Expedited Investigational New Drug Safety Reports Are Uninformative.
What the agency had built, in other words, was not a surveillance system. It was an archive: a vast and growing collection of individual documents, carefully received, dutifully read, and almost impossible to see across.
III. The missing successor
It is tempting to read this as an indictment of FDA reviewers. It is not. The reviewers I worked with were skilled and conscientious and many of them would have done exactly what Kelsey did. My thesis is an indictment of the workflows.
Consider what a reviewer actually faces. Reports arrive one at a time, from one IND at a time. Each describes a single patient. A signal that only becomes visible across trials, across sponsors, or across a class of drugs is, by construction, invisible to someone reading individual documents in sequence. The sponsor holds the underlying data from its own program and will almost always see a pattern first. The FDA learns what the sponsor finds and reports.
Kelsey’s insight, it is worth remembering, did not come from data the agency could analyze either. It came from skepticism and from a letter in a medical journal. Six decades later, the agency has far more information flowing into it, and in some ways it is no better positioned to see. The premarket safety function that grew out of her doubt remains, in practice, almost entirely reactive.
This is where the staffing debate goes wrong. Adding reviewers to a document-based process adds readers. It does not add surveillance. If the current system has, as far as anyone can recall, never found a premarket signal first, then removing reviewers from it may matter less than we fear, and restoring them would matter less than we hope. The more consequential question is what the agency could do if the work itself were redesigned.
IV. What we built
We tried. INFORMED was launched in collaboration with the HHS IDEA Lab and under special federal authorities, which allowed us to bring engineers, data scientists, and entrepreneurs-in-residence into the agency to work alongside FDA physicians, statisticians, and scienstists. Its purpose was to give the FDA the organizational and technical capacity that modern data demands, as we described in Nature Reviews Drug Discovery in From big data to smart data: FDA’s INFORMED initiative and INFORMED: an incubator at the US FDA for driving innovations in data science and agile technology.
The first target was the archive. In 2016, we built a framework for the digital submission of expedited premarket safety reports, replacing paper and PDF with structured data based on the international ICH E2B standard. We published the approach in Nature Reviews Drug Discovery in Evaluating the potential for digital submission of expedited premarket safety reports to the FDA. We piloted it successfully with Merck, AstraZeneca, Novartis, and Genentech. We estimated it would save the agency at least 500 FTE hours per month, before counting the more important benefit: for the first time, the agency would have a premarket safety surrveillence system, being able to look across reports rather than only at them.
INFORMED did other things as well. It conducted the agency’s first real-world evidence studies. It developed the FDA’s first framework for AI. It worked to harmonize the agency’s data assets. It built an automated review pipeline in which submission data in CDISC format could be fed into the system and the label generated instantly. That pipeline was piloted in the Oncology Center of Excellence.
We also began large AI-enabled meta-analyses of the clinical trial data the FDA has accumulated over decades of submissions, internally with entrepreneurs-in-residence and externally through INFORMED fellowships. One example is our collaboration with MIT applying machine learning to FDA clinical trial data, published in JCO Clinical Cancer Informatics as Machine-Learning and Stochastic Tumor Growth Models for Predicting Outcomes in Patients With Advanced Non-Small-Cell Lung Cancer. We established a fellowship in AI and machine learning with Harvard and were developing other ones. The goal was a durable pipeline of technical talent inside the agency.
V. Ten years to a requirement
What happened next is instructive.
In September 2016, we published the digital submission framework in Nature Reviews Drug Discovery. Three years later, in October 2019, the FDA issued draft guidance, Providing Regulatory Submissions in Electronic Format: IND Safety Reports, describing how sponsors would submit IND safety reports as structured E2B data to the agency’s adverse event database (FAERS, since renamed the Adverse Event Monitoring System). The guidance was finalized on April 1, 2024, and the agency began accepting electronic IND safety reports on a voluntary basis that day. The requirement took effect on April 1, 2026.
Three years from a successful pilot to a draft guidance with no impact. Nearly eight to a final guidance. Almost a decade to a mandate. The enabling technology did not change materially in that time. The E2B standards existed in 2016, and our pilot was built on them.
Even now, the requirement is narrow. It covers individual case reports of serious and unexpected suspected adverse reactions, and the FDA itself notes that not all IND safety reports will go to the adverse event database. More importantly, a submission format is not a workflow. Structured data arriving at the agency is a precondition for premarket surveillance, not a substitute for it. To my knowledge, the FDA has not yet implemented aggregate, cross-IND safety analysis as a routine part of premarket review at scale. After a decade, the data is finally trickling in a form that can be seen across. Whether anyone at the agency is positioned to look is a separate question, and it remains unanswered.
VI. Piloted and shelved
Digital safety reporting is not the only example. The automated review pipeline was never implemented. After I left the agency, the INFORMED educational programs were terminated.
The pattern continues. In April 2026, Commissioner Marty Makary and Chief AI Officer Jeremy Walsh announced a real-time clinical trial initiative, with proof-of-concept studies from AstraZeneca and Amgen transmitting trial signals to the agency as they occur. The idea has a long history, including conversations Jeremy, then a contractor at the FDA, and I had years ago about why clinical trials remain so inefficient, why there is a much better way to run them, and why the FDA is well positioned to catalyze it (see “The Ship and the Signal” below). Within weeks of the announcement, Makary resigned and Walsh left the agency. The program is now, in effect, orphaned.
None of these were failures of concept. Each was piloted, and each worked. They were failures of institutionalization. The question worth asking, every time, is why.
VII. Why good ideas die at the FDA
I don’t think the answer is a lack of talent or goodwill. I think it’s structural, and it has four parts.
First, innovation at the agency depends on individuals and special authorities rather than on the institution’s operating model. INFORMED existed because of authorities granted outside the normal structure. Nothing in that structure converted a successful pilot into standard practice. When the people who championed a program leave, the program has no owner, and the default reasserts itself.
Second, the agency is measured on activity and timeliness, not on outcomes. User fee goals track whether reviews are completed on schedule. No metric asks whether the safety review process has ever detected a signal first, or how many of the reports it processes are informative. A process that meets its deadlines is treated as healthy, even if it produces little. That review timelines have reportedly held up after staff reductions of roughly 20% is consistent with this. It tells us the deadlines are being met. It doesn’t tell us what the work is accomplishing.
Third, no one owns the transition from pilot to production. Pilots live in incubators. Production lives in review divisions and IT organizations that have neither the mandate nor the budget to absorb new systems. Changing a workflow also requires coordinated change on the sponsor side, in submission standards and in guidance, and no single office is accountable for all of it. The decade between our digital safety pilot and the electronic reporting mandate is what that looks like in practice.
Fourth, the risks are asymmetric. No one is faulted for continuing a process that has been in place for decades. Adopting a new one carries visible risk for whoever signs off. Kelsey succeeded by refusing to sign. Modernization requires someone willing to sign, and the institution offers that person almost nothing but exposure. In that environment, the rational choice for any individual is to wait.
VIII. What Kelsey would need now
The staffing cuts, whatever one thinks of them, create an opening. An agency that can no longer rely on headcount has every reason to redesign the work itself. A few changes would go a long way.
Measure what the work produces. The agency should track how many premarket safety signals it identifies independently, what share of expedited reports are informative, and how much reviewer time each process consumes. What is not measured will not be defended in a budget discussion.
Use the structured safety data. The electronic reporting requirement is now in place for individual case reports. The next step is to extend it to all expedited safety reporting and to build aggregate, cross-IND analysis into the review workflow, so that a signal visible across trials can be seen by the agency, not only by the sponsor.
Give every successful pilot a decision. When a pilot meets its objectives, a named official should either move it into production by a set date or document why it will not proceed. Pilots should not be allowed to expire quietly when their champions leave.
Make the talent pipeline permanent. Fellowships and entrepreneur-in-residence programs should be part of the agency’s operating model, not experiments that end with a change in personnel.
And we should keep asking specific questions. Why did it take a decade to require structured safety data, and who is now responsible for using it? Why was the automated review pipeline never deployed? Why were the educational programs terminated? Who owns the real-time clinical trial program today?
Frances Kelsey had a single letter, a skeptical mind, and a 60-day clock she could keep resetting. Today the agency receives tens of thousands of safety reports a year, and as of this April, they may soon arrive as structured data. The raw material for her kind of vigilance has never been more abundant. What is missing is a system designed to let someone see across it.
Until we build that system, we will keep arguing about how many people to put in the room, and the next signal, when it comes, will pass through the archive the way the others have: received, filed, and noticed first by someone else.