[D66] Fwd: Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial

[Dr. Marc-Alexander Fluks]

-------- Oorspronkelijke bericht --------
Onderwerp: Covid-19: Researcher blows the whistle on data integrity 
issues in Pfizer’s vaccine trial
Datum: 2021/11/05 08:55
Afzender: RO <jugg at ziggo.nl>
Ontvanger: "Dr. Marc-Alexander Fluks" <fluks at combidom.com>

https://www.bmj.com/content/375/bmj.n2635
https://science.thewire.in/the-sciences/company-that-managed-pfizer-vaccine-trial-sites-falsified-data-whistleblower/

  bmj.com
Covid-19: Researcher blows the whistle on data integrity issues in
Pfizer’s vaccine trial
Thacker P D.
13-17 minutes


Feature BMJ Investigation BMJ 2021; 375 doi:
https://doi.org/10.1136/bmj.n2635 (Published 02 November 2021) Cite this
as: BMJ 2021;375:n2635


     Paul D Thacker, investigative journalist

     Madrid, Spain
     thackerpd{at}gmail.com

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, 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.
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.

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RO