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Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial | The BMJhttps://www.bmj.com/content/375/bmj.n2635BMJ 2021; 375 doi:
https://doi.org/10.1136/bmj.n2635 (Published 02 November 2021)
Cite this as: BMJ 2021;375:n2635
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Paul D Thacker, investigative journalist
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Revelations of poor practices at a contract research company helping to carry out Pfizer’s pivotal covid-19 vaccine trial raise questions about data integrity and regulatory oversight. Paul D Thacker reports
In autumn 2020 Pfizer’s chairman and chief executive, Albert Bourla, released an open letter to the billions of people around the world who were investing their hopes in a safe and effective covid-19 vaccine to end the pandemic. “As I’ve said before, we are operating at the speed of science,” Bourla wrote, explaining to the public when they could expect a Pfizer vaccine to be authorised in the United States.1
But, for researchers who were testing Pfizer’s vaccine at several sites in Texas during that autumn, speed may have come at the cost of data integrity and patient safety. A regional director who was employed at the research organisation Ventavia Research Group has told The BMJ that the company falsified data, unblinded patients, employed inadequately trained vaccinators, and was slow to follow up on adverse events reported in Pfizer’s pivotal phase III trial. Staff who conducted quality control checks were overwhelmed by the volume of problems they were finding. After repeatedly notifying Ventavia of these problems, the regional director, Brook Jackson (video 1), emailed a complaint to the US Food and Drug Administration (FDA). Ventavia fired her later the same day. Jackson has provided The BMJ with dozens of internal company documents, photos, audio recordings, and emails.
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Video 1
Whistleblower Brook Jackson tells The BMJ about her experience working on the Pfizer covid-19 vaccine trial
Poor laboratory management
On its website Ventavia calls itself the largest privately owned clinical research company in Texas and lists many awards it has won for its contract work.2 But Jackson has told The BMJ that, during the two weeks she was employed at Ventavia in September 2020, she repeatedly informed her superiors of poor laboratory management, patient safety concerns, and data integrity issues. Jackson was a trained clinical trial auditor who previously held a director of operations position and came to Ventavia with more than 15 years’ experience in clinical research coordination and management. Exasperated that Ventavia was not dealing with the problems, Jackson documented several matters late one night, taking photos on her mobile phone. One photo, provided to The BMJ, showed needles discarded in a plastic biohazard bag instead of a sharps container box. Another showed vaccine packaging materials with trial participants’ identification numbers written on them left out in the open, potentially unblinding participants. Ventavia executives later questioned Jackson for taking the photos.
Early and inadvertent unblinding may have occurred on a far wider scale. According to the trial’s design, unblinded staff were responsible for preparing and administering the study drug (Pfizer’s vaccine or a placebo). This was to be done to preserve the blinding of trial participants and all other site staff, including the principal investigator. However, at Ventavia, Jackson told The BMJ that drug assignment confirmation printouts were being left in participants’ charts, accessible to blinded personnel. As a corrective action taken in September, two months into trial recruitment and with around 1000 participants already enrolled, quality assurance checklists were updated with instructions for staff to remove drug assignments from charts.
In a recording of a meeting in late September2020 between Jackson and two directors a Ventavia executive can be heard explaining that the company wasn’t able to quantify the types and number of errors they were finding when examining the trial paperwork for quality control. “In my mind, it’s something new every day,” a Ventavia executive says. “We know that it’s significant.”
Ventavia was not keeping up with data entry queries, shows an email sent by ICON, the contract research organisation with which Pfizer partnered on the trial. ICON reminded Ventavia in a September 2020 email: “The expectation for this study is that all queries are addressed within 24hrs.” ICON then highlighted over 100 outstanding queries older than three days in yellow. Examples included two individuals for which “Subject has reported with Severe symptoms/reactions … Per protocol, subjects experiencing Grade 3 local reactions should be contacted. Please confirm if an UNPLANNED CONTACT was made and update the corresponding form as appropriate.” According to the trial protocol a telephone contact should have occurred “to ascertain further details and determine whether a site visit is clinically indicated.”
Worries over FDA inspection
Documents show that problems had been going on for weeks. In a list of “action items” circulated among Ventavia leaders in early August 2020, shortly after the trial began and before Jackson’s hiring, a Ventavia executive identified three site staff members with whom to “Go over e-diary issue/falsifying data, etc.” One of them was “verbally counseled for changing data and not noting late entry,” a note indicates.
At several points during the late September meeting Jackson and the Ventavia executives discussed the possibility of the FDA showing up for an inspection (box 1). “We’re going to get some kind of letter of information at least, when the FDA gets here . . . know it,” an executive stated.
Box 1
A history of lax oversight
When it comes to the FDA and clinical trials, Elizabeth Woeckner, president of Citizens for Responsible Care and Research Incorporated (CIRCARE),3 says the agency’s oversight capacity is severely under-resourced. If the FDA receives a complaint about a clinical trial, she says the agency rarely has the staff available to show up and inspect. And sometimes oversight occurs too late.
In one example CIRCARE and the US consumer advocacy organisation Public Citizen, along with dozens of public health experts, filed a detailed complaint in July 2018 with the FDA about a clinical trial that failed to comply with regulations for the protection of human participants.4 Nine months later, in April 2019, an FDA investigator inspected the clinical site. In May this year the FDA sent the triallist a warning letter that substantiated many of the claims in the complaints. It said, “[I]t appears that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects.”5
“There’s just a complete lack of oversight of contract research organisations and independent clinical research facilities,” says Jill Fisher, professor of social medicine at the University of North Carolina School of Medicine and author of Medical Research for Hire: The Political Economy of Pharmaceutical Clinical Trials.
Ventavia and the FDA
A former Ventavia employee told The BMJ that the company was nervous and expecting a federal audit of its Pfizer vaccine trial.
“People working in clinical research are terrified of FDA audits,” Jill Fisher told The BMJ, but added that the agency rarely does anything other than inspect paperwork, usually months after a trial has ended. “I don’t know why they’re so afraid of them,” she said. But she said she was surprised that the agency failed to inspect Ventavia after an employee had filed a complaint. “You would think if there’s a specific and credible complaint that they would have to investigate that,” Fisher said.
In 2007 the Department of Health and Human Services’ Office of the Inspector General released a report on FDA’s oversight of clinical trials conducted between 2000 and 2005. The report found that the FDA inspected only 1% of clinical trial sites.6 Inspections carried out by the FDA’s vaccines and biologics branch have been decreasing in recent years, with just 50 conducted in the 2020 fiscal year.7
RETURN TO TEXT
The next morning, 25 September 2020, Jackson called the FDA to warn about unsound practices in Pfizer’s clinical trial at Ventavia. She then reported her concerns in an email to the agency. In the afternoon Ventavia fired Jackson—deemed “not a good fit,” according to her separation letter.
Jackson told The BMJ it was the first time she had been fired in her 20 year career in research.
Concerns raised
In her 25 September email to the FDA Jackson wrote that Ventavia had enrolled more than 1000 participants at three sites. The full trial (registered under NCT04368728) enrolled around 44 000 participants across 153 sites that included numerous commercial companies and academic centres. She then listed a dozen concerns she had witnessed, including:
- Participants placed in a hallway after injection and not being monitored by clinical staff
- Lack of timely follow-up of patients who experienced adverse events
- Protocol deviations not being reported
- Vaccines not being stored at proper temperatures
- Mislabelled laboratory specimens, and
- Targeting of Ventavia staff for reporting these types of problems.
Within hours Jackson received an email from the FDA thanking her for her concerns and notifying her that the FDA could not comment on any investigation that might result. A few days later Jackson received a call from an FDA inspector to discuss her report but was told that no further information could be provided. She heard nothing further in relation to her report.
In Pfizer’s briefing document submitted to an FDA advisory committee meeting held on 10 December 2020 to discuss Pfizer’s application for emergency use authorisation of its covid-19 vaccine, the company made no mention of problems at the Ventavia site. The next day the FDA issued the authorisation of the vaccine.8
In August this year, after the full approval of Pfizer’s vaccine, the FDA published a summary of its inspections of the company’s pivotal trial. Nine of the trial’s 153 sites were inspected. Ventavia’s sites were not listed among the nine, and no inspections of sites where adults were recruited took place in the eight months after the December 2020 emergency authorisation. The FDA’s inspection officer noted: “The data integrity and verification portion of the BIMO [bioresearch monitoring] inspections were limited because the study was ongoing, and the data required for verification and comparison were not yet available to the IND [investigational new drug].”
Other employees’ accounts
In recent months Jackson has reconnected with several former Ventavia employees who all left or were fired from the company. One of them was one of the officials who had taken part in the late September meeting. In a text message sent in June the former official apologised, saying that “everything that you complained about was spot on.”
Two former Ventavia employees spoke to The BMJ anonymously for fear of reprisal and loss of job prospects in the tightly knit research community. Both confirmed broad aspects of Jackson’s complaint. One said that she had worked on over four dozen clinical trials in her career, including many large trials, but had never experienced such a “helter skelter” work environment as with Ventavia on Pfizer’s trial.
“I’ve never had to do what they were asking me to do, ever,” she told The BMJ. “It just seemed like something a little different from normal—the things that were allowed and expected.”
She added that during her time at Ventavia the company expected a federal audit but that this never came.
After Jackson left the company problems persisted at Ventavia, this employee said. In several cases Ventavia lacked enough employees to swab all trial participants who reported covid-like symptoms, to test for infection. Laboratory confirmed symptomatic covid-19 was the trial’s primary endpoint, the employee noted. (An FDA review memorandum released in August this year states that across the full trial swabs were not taken from 477 people with suspected cases of symptomatic covid-19.)
“I don’t think it was good clean data,” the employee said of the data Ventavia generated for the Pfizer trial. “It’s a crazy mess.”
A second employee also described an environment at Ventavia unlike any she had experienced in her 20 years doing research. She told The BMJ that, shortly after Ventavia fired Jackson, Pfizer was notified of problems at Ventavia with the vaccine trial and that an audit took place.
Since Jackson reported problems with Ventavia to the FDA in September 2020, Pfizer has hired Ventavia as a research subcontractor on four other vaccine clinical trials (covid-19 vaccine in children and young adults, pregnant women, and a booster dose, as well an RSV vaccine trial; NCT04816643, NCT04754594, NCT04955626, NCT05035212). The advisory committee for the Centers for Disease Control and Prevention is set to discuss the covid-19 paediatric vaccine trial on 2 November.
Footnotes
Provenance and peer review: commissioned; externally peer reviewed.
Competing interests: PDT has been doubly vaccinated with Pfizer’s vaccine.
This article is made freely available for personal use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
Coronavirus (covid-19) Hub usage termshttps://bmj.com/coronavirus/usageReferences
↵Bourla A. An open letter from Pfizer chairman and CEO Albert Bourla. Pfizer.
https://www.pfizer.com/news/hot-topics/an_open_letter_from_pfizer_chairman_and_ceo_albert_bourla.↵Ventavia. A leading force in clinical research trials.
https://www.ventaviaresearch.com/company.↵Citizens for Responsible Care and Research Incorporated (CIRCARE).
http://www.circare.org/corp.htm.↵Public Citizen. Letter to Scott Gottlieb and Jerry Menikoff. Jul 2018.
https://www.citizen.org/wp-content/uploads/2442.pdf.↵Food and Drug Administration. Letter to John B Cole MD. MARCS-CMS 611902. May 2021.
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/jon-b-cole-md-611902-05052021.↵Department of Health and Human Services Office of Inspector General. The Food and Drug Administration’s oversight of clinical trials. Sep 2007.
https://www.oig.hhs.gov/oei/reports/oei-01-06-00160.pdf.↵Food and Drug Administration. Bioresearch monitoring.
https://www.fda.gov/media/145858/download.↵FDA takes key action in fight against covid-19 by issuing emergency use authorization for first covid-19 vaccine. Dec 2020.
https://www.fda.gov/news-events/press-announcements/fda-takes-key-action-fight-against-covid-19-issuing-emergency-use-authorization-first-covid-19.FDA oversight of clinical trials is “grossly inadequate,” say experts | The BMJhttps://www.bmj.com/content/379/bmj.o2628BMJ 2022; 379 doi:
https://doi.org/10.1136/bmj.o2628 (Published 16 November 2022)
Cite this as: BMJ 2022;379:o2628
Maryanne Demasi, investigative journalist
Author affiliations
maryannedemasi@hotmail.com
Covid-19 vaccines and drugs were developed at “warp speed” and now experts are concerned that the US Food and Drug Administration inspected too few clinical trial sites. Maryanne Demasi reports
On 25 September 2020, the US Food and Drug Administration (FDA) received a complaint by Brook Jackson who had been working for Ventavia Research Group, a Texas based company hired to run clinical trials for Pfizer’s covid-19 mRNA vaccine. Jackson, a regional director, had witnessed problems at three trial sites she was overseeing and complained to an FDA inspector about a range of problems including falsified data, unblinded patients, and inadequately trained vaccinators who were slow to follow up on adverse events. “I thought that the FDA was going to swoop in and take care of everything. What I was reporting was so important,” Jackson told The BMJ. The FDA did not, however, inspect the trial sites in question.This lack of oversight was not an isolated case, The BMJ has learnt. Regulatory documents show that only nine out of 153 Pfizer trial sites1 were subject to FDA inspection before licensing the mRNA vaccine. Similarly, only 10 out of 99 Moderna trial sites2 and five of 73 remdesivir trial sites3 were inspected.Now, facing a backlog of site inspections, experts have criticised the FDA’s oversight of clinical trials, describing it as “grossly inadequate.” They say the problem, which predated covid-19, is not limited to a lack of inspections but also includes failing to notify the public or scientific journals when violations are identified—effectively keeping scientific misconduct from the medical establishment.
The FDA is “endangering public health” by not being candid about violations that are uncovered during clinical trial site inspections, says David Gortler, a pharmacist and pharmacologist who worked as an FDA medical reviewer between 2007 and 2011 and was then appointed as a senior adviser to the FDA commissioner in 2019-21.
“The lack of full transparency and data sharing does not allow physicians and other medical scientists to confirm the data independently and make comprehensive risk-benefit assessments,” continues Gortler, who is now a fellow at the Ethics and Public Policy Center thinktank in Washington DC.
Paused during the pandemic
Between March and July 2020, at the peak of pandemic restrictions, the FDA paused its site inspections and only “mission critical” inspections were carried out. Gortler says, however, that this was the time that the FDA should have ramped up its oversight, not scaled back, especially since covid-19 products were being developed at warp speed and intended for millions of people. “The drug companies took appropriate measures to keep staff safe, which is exactly what the FDA could and should have done,” said Gortler.
A former staffer in the FDA’s Office of Criminal Investigations was also concerned about the agency’s failure to fully tackle Jackson’s complaint about falsified data in Pfizer’s mRNA vaccine trial. In an email dated March 2021, they wrote, “Having worked at the FDA, I see it as surprising, for many reasons, that the agency turned a blind eye . . . They likely feared the criticism they undoubtedly would have received for holding up a vaccine (which they knew they would eventually approve anyway) at the expense of untold lives lost.”
The former FDA employee, who signed a non-disclosure agreement and did not respond to interview requests, went on to write, “My point here is that instead of the regulators protecting the public, they were complicit. At the time, they may have been doing what they believed to be the right thing under extraordinary circumstances. But now, they may soon have some explaining to do.”
The FDA told The BMJ it takes oversight of clinical trials seriously and had adapted to travel restrictions, publishing draft guidance4 for remote regulatory assessments. This guidance describes virtual inspections using live streaming and video conferencing and requests to view records remotely.
Gortler, who is a credentialed FDA inspector, laughed at the proposition. “You can’t do a remote inspection. That’s like saying I’m going to arrest somebody remotely. You have to be there on site and look at every nuance such as cleanliness, organisation, staff coordination—even their body language. During a pandemic, the FDA could’ve put inspectors in hazmat suits if they wanted to, there’s no excuse for not going onsite.”
Historical failure to oversee
The FDA has a long history of failing adequately to oversee clinical trial sites. A report in 2007 by the Department of Health and Human Services’ Office of the Inspector General found the FDA audited less than 1% of the nation’s clinical trial sites between 2000 and 20055 and was highly critical of the agency because it did not have a database of operational clinical trial sites.6 In response to the report, the FDA said it created a dedicated task force and “developed new regulations and guidance further to improve the conduct of clinical trials and enhance the protection of people participating in clinical trials.” The BMJ asked to interview a member of this task force, but the FDA denied our request.
In 2015, Charles Seife, professor of journalism at New York University, conducted an analysis of published clinical trials between 1998 and 2013 in which an FDA inspection found significant evidence of objectionable practices.7 A total of 57 published clinical trials had significant evidence of one or more problems: 39% had falsification or submission of false information, 25% had problems with adverse events reporting, 74% had protocol violations, 61% had inadequate or inaccurate recordkeeping, and 53% failed to protect the safety of patients or had problems with oversight or informed consent. Furthermore, only 4% of the trials that were found to have significant violations were mentioned in the study’s journal publications.
A 2020 Science investigation analysed the FDA’s enforcement of clinical research regulations between 2008 and 2019 and concluded the agency was often light handed, slow moving, and secretive. It said that the FDA rarely levelled sanctions and when it did formally warn researchers about breaking the law, it often neglected to ensure that the problems were remedied.8
It has been 15 years since the Office of Inspector General report and the FDA still has no record of how many clinical trial sites are operating across the US and abroad. The agency told The BMJ it does not compile an annual list of clinical investigational sites submitted for review because it is “resource intensive.”
“It’s unacceptable,” said Gortler. “All it would take is sending a blanket communication to all sponsors or applicants requesting they provide a list of all their international and domestic clinical trial sites. Also, the FDA should publish the names, inspection dates, and unredacted findings at each of these sites clearly on its website, not buried somewhere, nearly impossible to find.” He believes the agency should have implemented a policy decades ago. “The public has a right to learn immediately about any violations before choosing to use an FDA regulated product,” he says.
Some 65% of the FDA’s funding for the evaluation of drugs comes from industry user fees and in return the agency has mandated deadlines for decisions on new product applications. Some experts argue this has been a major contributor to the FDA being rushed and having insufficient resources for other critical activities.9
Insufficient staff and low morale
Historically, the FDA has faced challenges recruiting and retaining sufficient medical staff to meet its needs. According to a Government Accountability Office report published in January 2022, the turnover rate for FDA staff in key scientific areas was twice that of other government agencies in 2007, leaving the agency unable to fulfil its mission.10 Around 70% of the FDA’s career employees working in 2008 were eligible to retire by the end of 2014. Moreover, in 2018, medical product staff in “mission critical” occupations had salaries that were at least 20% lower than the average private sector salary for the same occupations, contributing to low morale. A news report said the pressures of work during the pandemic had led to two FDA reviewers dying by suicide.11
Despite the estimated hundreds of thousands of clinical trial sites in operation across the US and abroad, the FDA told The BMJ that it only has 89 inspectors for its bioresearch monitoring programme, which assure the quality and integrity of data submitted to the agency in support of new product approvals and marketing applications. The FDA told The BMJ it is recruiting more inspectors to reach its yearly average of 100.
“I don’t think that it is a sufficient number of staff to do that kind of level of oversight,” says Jill Fisher, professor of social medicine at the University of North Carolina. “The FDA must have enough of a presence to dissuade investigative sites from committing fraud,” she continues.
Secrecy of inspection findings
Occasionally, the FDA will uncover objectionable practices, such as failure to obtain informed consent, falsification of data, or violations in adverse event reporting.
The FDA publishes its inspection reports12 but the database is not comprehensive, nor are the reports proactively disclosed. When they are disclosed there can be extensive redactions making it difficult to link problems to a particular drug or clinical trial. “FDA redactions can render the document useless—it’s to the point of being comical,” says Gortler, whose current work focuses on FDA oversight and accountability. “Public health information should not be redacted like that,” he says.
The FDA does not typically notify journals when a site participating in a published clinical trial receives a serious warning, or alert the public about the research misconduct it finds.13
Rafael Dal-Ré, physician epidemiologist at the Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain, finds this concerning14 and points to the example of the anticoagulant drug rivaroxaban.
The FDA inspected trial sites of the Record 4 trial and identified serious deficiencies at eight of the study’s 16 trial sites.14 The violations were so numerous and severe that the FDA excluded the trial from its pile of evidence during the drug’s approval. But when the study was published in the Lancet in 200915 there was no mention of the data integrity problems and the paper has been cited more than 1100 times by others.14 When The BMJ sought comment from the authors of the Record 4 study, some said they were not fully aware of the data integrity problems prior to our inquiries. The lead author, Alexander Turpin, said he was seeking more information from the drug company. The Lancet told The BMJ it was looking into the matter.
“If research misconduct is identified, the FDA may reject the affected data from the product’s safety and efficacy evaluations, but then fail to disclose these data in the product labelling,” added Dal-Ré.
Gortler finds it unconscionable that the FDA withholds this information from the public. “Misconduct should be released immediately. It’s malpractice not to; it’s irresponsible,” he says.
In response to the criticism the FDA said that it does not always monitor all publications of data that were submitted to the agency, nor does it have the authority to demand that a journal retract an article.
Road to reform
Fisher says the FDA needs better resourcing. “The clinical trials industry has become a complex global enterprise, and the FDA does not have the resources to oversee all the research that is happening, even within the US. The FDA needs to be better funded and staffed to conduct inspections. At a minimum the agency needs to inspect sites when complaints or concerns have been filed,” she says.
Gortler doesn’t agree, however, that the FDA is under-resourced. With a total budget of $6.1bn in 2021, he suggests the agency needs to be leaner and more efficient, with employees interested in improving public health. “The bottom line is that the FDA has over 18 000 full time employees, more than any other drug regulatory agency by far, so it could have retrained and retooled anybody to tackle the need for increased inspections,” he says. “Half of its budget, about $3bn, is discretionary, which means it could have hired contractors, retirees, or repurpose existing workers. It chose not to. The FDA was just yawning its way through the pandemic. The entire agency is broken.”
“It felt like we were being told to hide things”: FDA’s approval of antibiotic Ketek
In 2004, the FDA approved Sanofi-Aventis’s new antibiotic Ketek (telithromycin) for outpatient treatment of community acquired respiratory tract infections. Since then, it has been implicated in hundreds of reported cases of severe liver injury and dozens of deaths, triggered two Congressional hearings, and led to reforms of the agency’s processes. In 2007, the FDA added a warning to Ketek’s label and removed all indications except for bacterial pneumonia.
David Ross was an FDA medical reviewer who led the initial safety review for Ketek in 2001, as part of a 10 year career at the agency’s Center for Drug Evaluation and Research. In his original review Ross, now an associate clinical professor of medicine at George Washington University School of Medicine and Health Sciences, found that Ketek’s risks included liver injury and other serious adverse events that were concerning given the millions of antibiotic prescriptions written annually for respiratory tract infections.16
In 2001, the FDA recommended to Sanofi-Aventis that the company gather additional safety data. Sanofi-Aventis conducted Study 3014, a 24 000 patient safety study done in only five months. The FDA’s limited resources only allowed one out of 1800 sites to be inspected initially.
The agency decided to inspect the highest enrolling site, reasoning that failure to find any problems there would allow all the other sites to be considered clean. “The FDA inspector found evidence of blatant fraud almost immediately. For example, patients being enrolled at times when the clinic was supposedly closed,” said Ross.
The inspector reported her findings to FDA’s Office of Criminal Investigations, with serious protocol violations subsequently found at several other high enrolling sites. Eventually, the site investigator pleaded guilty to fraud and served a 57 month prison sentence.
At a 2003 public meeting of the FDA’s anti-infective advisory committee, data from Study 3014 were presented to the panel without disclosing the numerous violations and data integrity problems found at the initial trial site, which sparked a criminal investigation. Janice Soreth, Ross’s division supervisor at the time, has previously said that there was no intention to deceive the committee and that the violations were not disclosed so as not to compromise the ongoing criminal investigation.17 But Ross says he was appalled: “I felt like we were being told to hide things from the advisory committee.”
Unaware of the integrity problems, the committee voted 11 to 1 to recommend approval of Ketek. The FDA granted the drug approval on 1 April 2004. In a memorandum from the FDA, the agency said it was “difficult” to rely on Study 3014 for its approval because of the data integrity problems, instead using spontaneous adverse events reports for its understanding of Ketek’s overall risk-benefit profile, which goes against standard drug review practice.18 The first Ketek associated death from liver injury was reported to the FDA seven months later.16
A series of events unfolded during the drug approval process, which would later be revealed at a Congressional hearing in 2007. Ross testified under oath that when he submitted his follow up safety review in 2004, concluding that Ketek carried far too much risk to ever be approved for relatively minor conditions such as bronchitis and sinusitis, Soreth asked him to “soften” the language so that it would give the leadership “more wiggle room.” He told the hearing he sent Soreth a revised version for signing but—without telling her—also put the original in the electronic archive. Soreth did not testify in the hearing and denies this allegation. “No one ordered a change in Dr Ross’s review. He was free to keep his original draft,” she told The BMJ. “His review, moreover, did not include Aventis’s final submission to the agency.”
Ross left the division after Ketek’s approval in 2004 and then left the FDA in 2006, saying “the FDA did nothing for months and they just watched as the adverse event reports piled up. Lives could and would have been saved if the FDA acted sooner than it did to publicise Ketek’s risks and put a boxed warning on the drug.”
Whether it was Ross or Soreth who was right about this, the Ketek controversy led to the FDA Amendments Act of 2007, which stated that a reviewer’s work “shall not be altered by management or the reviewer once final.”
The FDA declined to respond when contacted by The BMJ. A spokesperson for Sanofi said the company complied with all the investigations at the time and that it no longer sells Ketek.
Footnotes
Competing interests: I have read and understood BMJ policy on declaration of interests and have no relevant interests to declare.
This feature has been funded by the BMJ Investigations Unit. For details see bmj.com/investigations
This article is made freely available for personal use in accordance with BMJ's website terms and conditions for the duration of the covid-19 pandemic or until otherwise determined by BMJ. You may download and print the article for any lawful, non-commercial purpose (including text and data mining) provided that all copyright notices and trade marks are retained.
Coronavirus (covid-19) Hub usage termshttps://bmj.com/coronavirus/usageReferences
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↵FDA. Conducting remote regulatory assessments: draft guidance for industry. July 2022. www.fda.gov/media/160173/download.
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Vaccine trial misconduct allegation – could it damage trust in science?https://theconversation.com/vaccine-trial-misconduct-allegation-could-it-damage-trust-in-science-171164This article has been updated and certain passages, which are the subject of disagreement between parties referred to in the article, have been removed.
The success of medical research has been one of the few positives of the COVID pandemic. The effectiveness of vaccines in preventing deaths (see graph below), is particularly impressive given the short time in which they were developed. But if recent allegations from a whistleblower about a Pfizer vaccine trial can be proven, they would indicate that time and financial pressures may have led to serious misconduct.
The whistleblower is Brook Jackson, previously a regional director at a Texas-based contract research organisation called Ventavia, who supplied an account to the BMJ. She alleges that Ventavia falsified data, “unblinded” patients (that is, researchers could see who was receiving the vaccine and who the placebo), employed inadequately trained vaccinators, and was slow to follow up on adverse events during one of the final trials.Given the size of the vaccine trial, and the many centres involved, bad data from a few rogue centres is unlikely to fatally undermine the evidence needed for licensing the Pfizer vaccine. But it is important to examine allegations because research misconduct is a serious issue, especially if linked to a vaccine being given to millions of people. If the alleged activity turns out to be true, there must be severe consequences for Ventavia and those involved.
The international rules for conducting clinical trials are described in the World Medical Association’s Declaration of Helsinki. This document lays out the conditions and considerations needed for researchers and doctors to act with integrity when conducting research.
Research integrity has two aspects, both of which are alleged to have been a problem at Ventavia. Poor record-keeping, glossing over errors and drugs stored inappropriately are breaches of methodological integrity, while reports of participants waiting in corridors (when they were supposed to be under observation) and delays in following up side-effects are breaches of ethical integrity.
While ethics and safety regulators play an important role in the design and conduct of trials, ethics committees and inspectors cannot be aware of everything that goes on. Ethical conduct in particular is based on trust that researchers will carry out their work under the rules agreed with the ethics committee. Similarly, safety regulators are not in the position of policing all aspects of trials. In this case, while the US regulator (the Food and Drug Administration) was reportedly trying to monitor the trial, it only inspected nine out of 153 sites, not including any of the Ventavia sites.
A spokesperson for Ventavia provided the following comment:
Ventavia is aware of recent accusations in an article written by Paul Thacker [investigative reporter and author of the BMJ article]. Mr. Thacker did not contact Ventavia prior to publication. These same accusations were made a year ago, at which time Ventavia notified the appropriate parties. The allegations were investigated and determined to be unsubstantiated. Ventavia takes research compliance, data integrity, and participant safety very seriously, and we stand behind our work supporting the development of life-saving vaccines.
Complicated activity
Medical research is a complicated activity and the careful work needed to produce reliable results often takes a long time. Indeed, recent problems at a UK testing centre – where around 43,000 people may have been wrongly told that their COVID test was negative – show that it is easy to make mistakes, even when conducting the same laboratory process tens of thousands of times. For this reason, universities and other research institutions are required to provide training in research integrity, alongside having processes to detect and investigate serious integrity issues.
In parallel, work by research funders, academic societies and research charities is continuously trying to identify the pressures that lead to integrity issues. Perhaps unsurprisingly, time and money pressures frequently top the list. As the COVID dust starts to settle, more allegations like this will undoubtedly be made.
While misconduct is always regrettable, it is not unexpected. Sometimes the scientific method can be presented in an almost mythical way as if it is somehow entirely objective. This view is incorrect.
In reality, science is a human activity conducted by people with different motivations. But perhaps the difference between science and other activities is that systematic efforts are made to check and confirm results. This does not stop some worrying that science has a “reproducibility crisis” (the problem that not all experiments can be repeated), or that there is a great deal of research waste (research with no societal benefits), or that misconduct requiring retractions does occur, but scientists are aware of these problems and are trying to address them.
Take, for instance, the former physician Andrew Wakefield’s fraudulent research – published in The Lancet, but subsequently retracted – which claimed a link between the MMR vaccine and autism. This was a clear and serious breach of research integrity, and although it caused a lot of harm, it also led to thousands of studies both refuting the fraudulent research, but also arguably advancing vaccine science to the point that it was able to contend with SARS-CoV-2 when it arrived. The Wakefield scandal also caused a great deal of self-reflection and many positive actions trying to prevent such things from ever happening again.
COVID science has produced some amazing results, but it is still too early to fully assess the overall value of the research efforts. Given the vast amount of funding, and thousands if not millions of researchers working on COVID, alongside the successes there will inevitably be more examples of alleged misconduct – leading, inevitably, to sensationalist headlines. But when this happens, it is important to remember how many lives the vaccines and other treatments have saved. Yes, science is a human activity. Yes, integrity can be a problem. Yes, fraud and misconduct will occasionally occur, but science also produces remarkable results.