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For nearly a decade, the Food and Drug Administration (FDA) cited osteopath Michael Harris for egregious errors in clinical trials he was overseeing. Agency inspectors found a litany of problems at Harris's private firm, Aspen Clinical Research in Orem, Utah, which had contracts to evaluate many drugs, including ones aiming to treat postoperative pain, pediatric schizophrenia, and migraines. FDA found there were serious lapses in obtaining informed consent from trial volunteers, unqualified staff made medical assessments, and Harris failed to properly report abnormal lab test results. He also did not disclose that trial participants were taking opioid, antidepressant, or antipsychotic drugs—which could have skewed results or posed safety concerns. The agency said Aspen's records were disorganized, contradictory, and sometimes backdated in a way that "begs the question of the authenticity and veracity of data collected."
Those "serious, ongoing deviations" might constitute "fraud, scientific misconduct," and "significant human subject protection violations," according to FDA documents obtained by Science through the Freedom of Information Act (FOIA). Inspectors told Harris he could be subject to fines, permanent disqualification from clinical research in the United States, and legal prosecution. Repeat problems and a raft of new ones emerged during inspections in 2014, 2015, and 2019. Each time, in responses to FDA, Harris admitted some transgressions, strenuously disputed others, and promised to improve.
Through all that, FDA never formally sanctioned Harris or pursued other penalties. The agency never made public the alleged offenses or told trial participants they might have been put at risk. Nor did it tell companies sponsoring some of the trials that their data might have been compromised. (The documents Science obtained were heavily redacted, making it impossible to know which trials were in doubt and, thus, which volunteers might have been harmed or endangered.) Meanwhile, pharmaceutical and medical device companies continued to contract with Aspen. Since 2011, they have paid the firm millions of dollars for work on at least 65 trials, and Aspen is now recruiting people for nine new trials on Alzheimer's disease, autism, depression, and other serious disorders.
Harris declined to comment on the FDA reports and the agency refused to discuss its dealings with him. Wayne Croft, Harris's business partner at Aspen, also would not reply to questions, but he describes FDA's treatment of Harris as bureaucratic harassment that drove away business. "Anytime he hears about the FDA," Croft says, Harris experiences "post-traumatic stress."
Scrutiny of the agency's clinical trial oversight for the past 11 years suggests its interactions with Harris and Aspen are commonplace. FDA's enforcement of clinical research regulations is often light-handed, slow-moving, and secretive, Science has found in an investigation that included a review of some 1600 agency inspection and enforcement documents for other trials that FDA said violated rules and law. Almost all were acquired via FOIA requests, including many made by FDAzilla, a commercial service that tracks the agency.
The period examined covered former President Barack Obama's administration and the first 3 years of President Donald Trump's term. Clear corrections of inspector-reported dangerous or unlawful clinical trial practices were the exception, even amid signs that trial participants were harmed and that data underpinning evidence-based medicine were corrupted. On the rare occasions when FDA formally warned researchers of findings that they had broken the law, the agency often neglected to ensure that fixes occurred, Science found. Moreover, the agency frequently closed cases on the basis of unverified claims by those accused.
The apparent neglect appears to be worsening. The agency issued 99 "warning letters" for serious clinical trial transgressions during Obama's first 3 years in office, 36 in his last 3 years, and just 12 during the first 3 years under Trump. "It certainly looks like FDA is enforcing clinical trial requirements much less frequently, which is troubling for protecting subjects' welfare and ensuring the validity of data for our medical products," says Patricia Zettler, a lawyer who reviewed Science's findings. She worked for FDA from 2009 to 2013, rising to associate chief counsel.
Jill Fisher, a social scientist at the University of North Carolina, Chapel Hill, who studies clinical trials, is also troubled that when an FDA inspection exposes apparent mistakes, recklessness, or fraud in a trial, neither the agency nor the scientists running it are obliged to notify participants. She calls that failure to inform "a travesty." At the least, Fisher says, volunteers in a trial should be told when the integrity of a research center running the study or its investigator is in question.
Although best known for overseeing food safety and evaluating experimental drugs, vaccines, and medical devices for marketing approval, FDA performs many other tasks with its $5.7 billion annual budget (for fiscal year 2019). Among them is overseeing most clinical research in the United States and some conducted elsewhere for the U.S. market—including many high-stakes vaccine and drug trials for COVID-19. The agency now deploys 102 inspectors to respond to whistleblower complaints of dangerous operations, conduct routine visits to trial sites, and review records of those sites or the institutional review boards (IRBs) that oversee trials locally. Over the period Science examined, FDA conducted roughly 6700 inspections of clinical researchers or IRBs.
FDA inspections can result in a range of responses, from "no action" declarations; to "official action indicated" (OAI) reports, which require a violator to clean up serious transgressions; to warning letters, which threaten further regulatory action unless corrections are made promptly. In extreme cases, the agency can even disqualify a scientist from clinical research.
But Science found that FDA rarely levels sanctions. The agency almost always rules that no action is warranted or requests voluntary corrections, according to documentation on all inspections that drew an OAI designation or more severe enforcement action. Since 2009, FDA has used the OAI designation to direct only 291 of the inspected researchers or institutions—about 4%—to correct serious, illegal, and potentially dangerous clinical trial problems. Furthermore, FDA officials sometimes downgraded a problem originally classified by inspectors as OAI—in which compliance must be confirmed by a follow-up inspection or other actions—to "voluntary action."
Holly Fernandez Lynch, a lawyer and bioethicist at the University of Pennsylvania (UPenn), says the agency prefers voluntary action. "When people fail to comply, it's hard to know what to do about it, short of completely ending a trial or all research at that institution," which might deprive patients of a chance at an effective treatment in trials, Lynch notes.
Under Trump, the number of FDA inspections per year has increased significantly, yet enforcement actions have nosedived (see graphic, above). About 6% of FDA inspections were classified as OAI during the Obama administration, although the proportion began to decline in his second term. During Trump's first 3 years, however, OAI reports fell to less than 1% of the total. Even voluntary action designations declined sharply under Trump, whereas "no action" inspections spiked. The agency disqualified an average of three investigators per year under Obama but just two total during Trump's first 3 years.
FDA did not dispute Science's figures on OAIs and warning letters—but the agency said Trump-era policies were not a factor. "The number of warning letters can ebb and flow," the agency wrote in an email.
For extreme problems in a clinical trial, when patients or data reliability are at immediate and serious risk, FDA can use warning letters to immediately halt the trial or restrict an IRB from approving new trials. The agency did so seven times during Obama's first term and not once since Trump took office.
Among the 291 OAI cases Science identified, only 71 resulted in a clear regulatory endpoint—such as disqualification, a "closeout letter" certifying that corrections were completed, or another formal statement. For the remaining 220, no clear outcomes could be found in public documents or data banks, leaving trial participants and others in the dark. FDA can also deem violations "not correctable," ending its enforcement with neither compliance nor any form of disclosure. From outside the agency, it's impossible to know how often that occurs.
In addition to searching public documents and FDA databases and filing FOIA requests for key documents in nearly all 291 cases, Science filed additional FOIA requests in 28 of those cases for every essential document, including any that described a resolution. After about 10 months, FDA released documents describing how 16 cases were resolved. Most were based on written promises from researchers. In one, the researcher pledged to never again conduct clinical studies and then violated that pledge, according to records posted by drug companies that hired him for clinical trials—with no apparent FDA response.
In an email, FDA defended its approach, noting its "strategy to focus inspectional resources on higher-risk facilities." FDA tries to address clinical trial problems early in the process, it also noted, so "an issue that might warrant a warning letter could be resolved before the problem rises to that level." (Agency officials would not agree to an interview. Spokespeople instead emailed selective responses to written questions.)
Yet FDA sometimes issues closeout letters even when nothing material has changed. In 2016, the agency sent a warning letter to the medical director of a Texas research firm. He had enrolled trial participants who suffered from kidney impairments, an agency inspection reported, and then overdosed them with an experimental drug that could have further damaged their kidneys. The physician responded with a plan to prevent future overdoses, but FDA replied that it was inadequate. Yet on the same day as that reply, the agency sent a letter closing the case.
"The agency should follow through and complete actions—so they don't initiate a process and never resolve it," says Joshua Sharfstein, vice dean at the Johns Hopkins Bloomberg School of Public Health and a top FDA official under Obama. "And it's important for the agency to share information about its processes, so people can understand what happened."
When FDA does follow up on the problems it identifies, the process can be slow. Agency documents and databases covering the 291 OAI cases show dozens of cases that took 10 months to 14 years to be escalated to a warning letter. Some delays can be "egregious," Lynch says.
In 2015, the agency issued an OAI after it inspected a Pennsylvania hospital IRB that oversees more than 100 trials annually. The agency's findings read like a functional collapse: records glitches, including failure to keep a list of IRB members and their qualifications or record attendance at meetings; approval of trials without a quorum; sloppy reviews of trials; a lack of required written policies on how to determine the risk of devices being tested on patients; neglecting to promptly inform FDA or the hospital's own leaders about trial problems; and poor or no training for IRB members. According to FDA documents, the agency waited 4 years to follow up. In a second inspection, in 2019, many of the same problems were found, resulting in a warning letter. Only then did the IRB finally resolve the deficiencies.
A St. Louis IRB received citations about similar problems in a 2012 warning letter, which noted that pervasive lapses at the IRB were also found in 2003 and in 1998. That IRB finally addressed the issues after the warning, according to an FDA closeout letter.
That sparse, slow enforcement puts participants and the research process itself at risk, critics say. Given the extremity of violations that lead to little or no punishment, Fisher asks: "What would it take for the FDA to take serious action to ensure that clinical research is being conducted with the most integrity possible?"
The secrecy of the process also means trial participants are kept unaware of possible harm, violating "a basic human right," says Vinay Prasad, a hematologist-oncologist at the University of California, San Francisco, who studies how drug funding affects research. Steven Joffe, a medical ethicist at UPenn, agrees, citing an obligation to be transparent to the people who have volunteered their bodies for clinical research: "We owe that back to them."
"Systemic problem" ignored
A clinical trial scandal that erupted in Minnesota in 2018 illustrates the potential public health hazards posed by FDA's lax enforcement. That year, the consumer advocacy group Public Citizen and more than 60 clinicians and medical ethicists alleged that a large Minneapolis community hospital operated by Hennepin Healthcare had violated informed consent requirements in trials comparing ketamine, a powerful sedative and anesthetic, with other drugs for people who came to the emergency room with agitation. The critics said the emergency department doctors did not obtain informed consent from trial participants, even though ketamine was much more likely to cause serious breathing problems and movement disorders. Many patients who received ketamine developed such symptoms.
After Public Citizen's allegations, FDA inspectors confirmed the lapses in informed consent. They concluded that Hennepin's IRB had waived the requirement to obtain consent and did not institute additional safeguards "to protect the rights and welfare of those subjects." And inspectors said researchers running the trials neglected to properly report serious adverse events. Nevertheless, the agency did not classify the inspection as OAI or send a warning letter. Hennepin rejected most of the FDA findings, although the health system agreed to some procedural changes and suspended one trial for review.
FDA already knew of alleged problems in Hennepin's ketamine research at the same hospital before the Public Citizen allegations, according to new documents obtained by Science. In 2014, the agency inspected a Hennepin trial led by Brian Driver, a staff physician, and James Miner, then and now chief of emergency medicine at the hospital where the later trials took place. The trial compared ketamine with another drug used to sedate patients who required breathing tubes. As in the later trials, the agency detailed failures to properly obtain informed consent from patients.
A 2016 follow-up review by FDA of the ketamine trial detailed failures by Driver and Miner to properly report 13 patient deaths to Hennepin's IRB—a required practice to verify that the trial itself does not pose safety hazards. In a response to FDA, Driver acknowledged his reporting error in three of the deaths but did not address the other 10 deaths, and FDA documented no further information on them. In an email to Science, Driver wrote that FDA had never discussed those additional deaths with him, but he acknowledged failing to report the deaths of the 13 FDA initially flagged, as well as 10 others in the trial that it did not document. Driver attributed all 23 deaths to acute illnesses or injuries unrelated to the study drugs, including sepsis, stroke, and heart attack.
It certainly looks like FDA is enforcing clinical trial requirements much less frequently, which is troubling.
- Patricia Zettler, former FDA lawyer
Driver became a member of the hospital's IRB in 2016 and was on it when the group approved or reviewed the later ketamine trials flagged by Public Citizen. Science showed the FDA documentation of his earlier ketamine trial to Michael Carome, who directs health research at Public Citizen. "We have a group of physicians, all in the emergency department, over a period of several years … not complying with FDA regulations regarding human subjects protection," says Carome, a physician himself. The clinical trial missteps exposed "a pattern of sloppiness and carelessness" by Hennepin researchers and their IRB, he adds, raising broad doubts about its oversight of human subjects research.
The IRB chair, a hospital spokesperson, Miner, and Driver all declined to comment about the later clinical trial problems FDA identified. In a public statement, Hennepin defended the trials while apologizing for "not involving the community in a proactive way" before the studies. Hennepin said it would increase training for clinical researchers and improve study monitoring and public disclosure. But the health system refused to answer questions such as why—after years of FDA inspections cited serious problems with ketamine trials—the IRB and emergency department launched new trials with no special precautions to protect patients.
Hennepin's ketamine controversy also raises questions about FDA oversight. Despite the problems it identified as early as 2014, FDA never issued a warning letter or otherwise demanded that Hennepin researchers rectify trial procedures. The agency imposed no restrictions on the hospital's clinical research or IRB operations. FDA never mandated that trial participants who suffered adverse effects—or their loved ones—be advised about inspection findings. FDA declined to comment on Hennepin's clinical trials—or on any specific cases described in the Science investigation.
"FDA is just dropping the ball here," says Carome, a former research regulation executive at the Department of Health and Human Services. "I think the institution should have gotten a very strong warning letter for the [latter] ketamine trials, and that letter perhaps should have noted the prior history with Dr. Driver, to signal a systemic problem."
By not coming down hard on IRBs and the scientists running clinical trials, FDA lets those parties avoid possible negligence lawsuits or other legal liability if patients are harmed, Prasad says. He adds that the lack of enforcement also lets the drug companies sponsoring the trials off the hook. "FDA is a regulatory agency charged with protecting the public's best interests. But at times it behaves like an attorney working on behalf of the companies."
For the most extreme violations of rules governing human subjects research, FDA can brandish the threat of a publicly announced disqualification—effectively the death penalty for a clinical research career. But how the agency has used that sanction captures many flaws of FDA's clinical trial oversight.
Since the beginning of Obama's presidency, the agency has disqualified just 24 clinical trial investigators, mostly for deliberate and repeated falsification of data or other information such as patient referrals for a trial. And although disqualification bars a scientist from receiving any experimental drug or device or conducting any trial involving FDA-regulated drugs or other substances, it can sting less than it sounds. Drug companies often continue to lavish money and prestige on disgraced investigators.
Investigators under a cloud also can continue to run lucrative trials while FDA considers whether to disqualify them, a process that takes, on average, more than 3 years. Scientists or IRBs facing FDA accusations, including those that ultimately lead to disqualification, have collectively conducted or overseen thousands of trials during the past decade, Science found in a review of public records. Take Oregon allergist-immunologist James Baker, one of only two disqualifications by Trump's FDA.
Between 2009 and 2017, FDA inspected Baker-led trials on four occasions and each time found violations. Time after time, Baker promised to do better, according to agency documents. Again and again, he broke his promises, FDA documents conclude. The agency, however, waited until 2018 to disqualify him.
Baker's abuses were not mere technicalities. FDA said they "placed unnecessary risks to human subjects and jeopardized the integrity of data." Inspectors found informed consent breakdowns involving children and adults—some of whom were injected with experimental allergy or immunology drugs or biologics despite taking other drugs, such as cough medicine and antibiotics, that could interact with them. He failed to properly document or follow up on a child's emergency department visit for severe abdominal pain. People were enrolled against eligibility rules—with some participating in more than one trial, for example, or having conditions that should have disqualified them. FDA said Baker kept substandard case histories, overdosed patients on experimental medicines, and repeatedly conducted trials without IRB approval. Baker conceded to agency inspectors that one of his employees, who had no relevant medical credentials, prescribed drugs to trial volunteers. She worked on 30 of his trials.
FDA finally disqualified Baker after he was caught backdating many clinical trial reports beginning in 2013. The records indicated he performed patient exams in Oregon when he was actually in Las Vegas, Hawaii, and elsewhere attending medical meetings and, in one instance, a wedding. (FDA inspectors had earlier caught him similarly falsifying records in 2015, when he admitted he had "gone fishing" on days he purportedly saw trial patients.)
FDA documents show Baker conducted at least 115 clinical trials from 2005 until 2017, often testing drugs for which companies later sought agency approval. Yet his disqualification stemmed from FDA's review of just a few of those trials. Not long before his disqualification, the agency asked Baker whether any data or patient records had also been doctored in his other completed trials. Baker said he lacked the capacity to review those studies. As far as Science could ascertain, FDA did not investigate the other trials.
Baker declined to say whether he had informed participants in his many trials that he had been disqualified. Science also contacted multiple companies that sponsored Baker's trials during the period for which FDA found falsified information. Asked whether they told trial volunteers about the government's findings, none responded.
Baker, who declined to answer most questions submitted by Science, contended in an email that his patients suffered no adverse events. But he also added: "I agree with [the] way the FDA controls the research world and regret running afoul with those studies."
Had FDA acted earlier, Baker's clinical trial venture—the Baker Allergy, Asthma and Dermatology Research Center—might have lost a lot of business. The French drug giant Sanofi and other companies paid him at least $1.2 million for trials conducted between the time FDA detected his falsified exams in 2016 through 2019, according to the federal Open Payments system, which tracks pharmaceutical industry payments to doctors.
Yet the work kept flowing from Sanofi to his research business even after he was disqualified. Sanofi assigned responsibility for Baker's trials to another doctor at his center, which Baker operated with his dermatologist wife in the same building as their medical practice.
Likewise, the disqualification leaves Baker free to operate his other company, Xtract Solutions, a suburban Portland, Oregon, purveyor of allergy and immunology technology to hospitals and physicians. In 2014, FDA issued a warning letter to Baker and Xtract for allegedly selling "adulterated devices" and failing to establish and maintain quality-control procedures for its syringe-filling systems—meant to speed up vaccinations during pandemics.
Xtract eventually dropped its injection device. But the company still sells software to guide doctors and hospitals on a subject Baker has ample experience, if not always success, with: FDA regulatory compliance.
With reporting by Meagan Weiland.