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 Instead, the dosing mishap was presented to the trial participants
in a letter dated June 8 as an opportunity for University of Oxford
researchers to learn how well the vaccine works at different doses.
The letter was signed by the trial's chief investigator, Oxford
professor Andrew J. Pollard, and sent to the trial subjects.
As Reuters reported on Dec. 24, participants were given about a half
dose due to a measuring mistake by Oxford researchers. The Pollard
letter didn't acknowledge any error. Nor did it disclose that
researchers had reported the issue to British medical regulators,
who then told Oxford to add another test group to receive the full
dose, in line with the trial's original plan.
There is no suggestion there was any risk to the health of trial
participants.
Much is riding on the British-developed vaccine, which is being
rolled out across the UK and has been touted as a low-cost weapon
against the pandemic. The jab has come under scrutiny because of the
dosing error in the Oxford trial and a paucity of data about its
efficacy in older people who are most vulnerable to the virus.
Reuters shared the letter – which it obtained from the university
through a Freedom of Information request – with three different
experts in medical ethics. The ethicists all said it indicates the
researchers may not have been transparent with trial participants.
Volunteers in clinical trials are supposed to be kept fully informed
about any changes.
"They are not clear at all about what they need to be clear about –
what's going on, what they knew, the rationale for undertaking
further research," said Arthur L. Caplan, founding head of the
Division of Medical Ethics at New York University Grossman School of
Medicine. "It is lost in a snowstorm of verbiage."
Steve Pritchard, a spokesman for Oxford, told Reuters: "The
half-dose group was unplanned, but we did know in advance that there
was a discrepancy in the dose measurements and discussed this with
the regulators before dosing and when the dosing was revised."
Pritchard also said, "We have not stated that a dosing error
occurred."
Pollard didn't respond to a request for comment.
The spokesman's suggestion that no error was made is contradicted by
documents produced last year by Oxford and its vaccine partner,
drugs giant AstraZeneca PLC. In December, Reuters reported that a
"Global Statistical Analysis Plan" by Oxford/AstraZeneca, dated Nov.
17 and later published in the scientific journal The Lancet, called
the dosing discrepancy "a potency miscalculation."
A spokesman for AstraZeneca declined to comment.
The Health Research Authority, a British government agency
responsible for approving medical research and ensuring it is
ethical, said in a statement that changes to the study design and
the letter sent to participants were approved by one of its ethics
committees.
The Oxford/AstraZeneca vaccine recently has received authorization
for use in a growing number of countries, including the United
Kingdom, the European Union and India. The UK became the first
country to approve it, and began rolling out the vaccine on January
4.
But questions surrounding the clinical trials continue to plague the
vaccine. Last week, Germany's vaccine committee recommended it
should only be given to people aged under 65, while the EU, which
authorized it on Friday for people aged 18 and over, lowered its
reported efficacy rate from 70.4% to 60%. In both cases, authorities
cited a lack of sufficient data from the clinical trials. The EU
also has sharply criticized AstraZeneca for cutting back its planned
vaccine deliveries to the continent over the next few months. The
company has said it is doing its best to boost supplies.
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The mistaken half-dose – which prompted the letter in June to trial
participants – continues to be a factor in the reported efficacy of
the Oxford/AstraZeneca vaccine.
Oxford had reported interim results in November that showed the
efficacy rate for trial subjects who mistakenly received a half-dose
and a subsequent full-dose booster shot was 90%, and that the rate
for those who received two full doses was 62%. Combining data from
the two dosing regimens resulted in an efficacy of 70.4%.
In authorizing the vaccine, UK regulator, the Medicines and
Healthcare products Regulatory Agency (MHRA), accepted the pooled
results, but didn't approve administering the half-dose/full-dose
regimen. "There is not persuasive evidence of a real difference in"
vaccine efficacy between the two different dosing regimens, it said.
"RECENT CHANGES"
The vaccine's late-stage clinical trial began on May 28. Within
days, Oxford researchers realized trial participants had been given
lower doses than planned after they displayed milder than expected
side effects, such as fever and fatigue. They alerted British
medical regulators.
On June 5, the researchers amended the trial protocol at the request
of regulators to add a new group that would receive the correct full
dose of the vaccine. Three days later, they alerted trial subjects
to what they called "recent changes in the study" in a two-page
letter attached to an updated 13-page "Participant Information
Sheet."
The letter, signed by chief investigator Pollard, stated that
researchers "are not sure what dose of vaccine is most likely to be
protective against COVID disease" and explained that doses "are
measured using standard scientific test methods." It said the
late-stage trial participants received a dose measured using one
method and that another group will receive a dose measured using a
different test to match the dose given in another clinical trial of
the vaccine.
It said the lower dose is "still in the normal range of doses that
are used in clinical trials" and "if it can provide protection, it
might be better for use in vaccine programmes."
Caplan said the explanation would be of "no interest whatsoever to
the subject because it's too technical. To me, that qualifies as
gobbledygook. What you want to know is, why are they doing this, we
made an error, it involved dosing, we're not worried about it."
He and other ethicists interviewed by Reuters said researchers are
obligated to be forthcoming with test subjects when things go wrong.
"As a letter purporting to explain a) an error and b) a change of
protocol I find this entirely inadequate," said Simon Woods, a
professor of bioethics at Newcastle University, in an email. "It
reads like a routine update (and a complex one at that)."
Emma Cave, a professor of healthcare law at Durham University's law
school, said: "Presenting the dosing variation as a planned change
in the study is potentially a breach of trust if in fact the dosing
resulted from an error. The letter makes clear the dosing change but
not the reason for the change."
To read the earlier Reuters report on the dosing error, click:
https://www.reuters.com/article/uk-health-coronavirus-britain-vaccine/special-report-how-a-british-covid-19-vaccine-went-from-pole-position-to-troubled-start-idUKKBN28Y0Y5
(Reported by Steve Stecklow and Andrew MacAskill in London. Editing
by Janet McBride)
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