Healthy Skepticism Library item: 5037

Warning: This library includes all items relevant to health product marketing that we are aware of regardless of quality. Often we do not agree with all or part of the contents.

Publication type: Journal Article

Wood AJ, Darbyshire J.
Injury to research volunteers--the clinical-research nightmare.
N Engl J Med 2006 May 4; 354:(18):1869-71
http://content.nejm.org/cgi/content/extract/354/18/1869

Keywords:
Antibodies, Monoclonal/administration & dosage Antibodies, Monoclonal/adverse effects* Clinical Trials, Phase I* Cytokines/metabolism Drug Evaluation/adverse effects Drug Industry Human Experimentation Humans Male Research Subjects*

Notes:

Ralph Faggotter’s Comments:

“ Until now, such trials have had a remarkably good safety record, reflecting both the extent of
the preclinical and animal testing that precedes them and the safeguards
built into their own designs. “

This article, although very good, misses a critical point —that biotech drugs- especially monoclonal antibodies, are fundamentally different from classical drugs.

Your standard pre-1990 classical drug is a small molecule with 2-30 carbon
atoms, broadly targeted at an ancient psysiological system which is
therefore usually widespread in mammals. This means that findings in rodents
and primates can be cautiously extrapolated to humans.

On the other hand, your modern biotech drug is a complex protein which
targets a very specific pathway, and therefore its effects might vary
significantly between species unless you are exactly reproducing a protein
which is normally present in the human, in ways which, to some extent, we
understand .— eg erythropoetin or insulin. or Growth Hormone.

As any geneticist will tell you, to deviate- even by one amino acid in a long sequence- is to court disaster.

Biotech, in its present form, for all its seeming wonderful potential, and
with a handful of noteworthy but expensive exceptions, has serious problems.

Unless there is a remarkable unforseen breakthrough, biotechnology, in spite of being pumped full of speculative money, is unlikey to fulfil its widely prophesized potential.

Full text:

Injury to Research Volunteers – The Clinical-Research Nightmare

http://content.nejm.org/cgi/content/full/354/18/1869?query=TOC

Alastair J.J. Wood, M.D., and Janet Darbyshire, M.B., Ch.B.

At 8 a.m. on Monday, March 13, 2006, eight healthy young men entered a
trial of a drug under development by the small German immunotherapeutics
company TeGenero. Six of the volunteers were assigned to receive active
drug, and two were to receive placebo. The trial was being conducted for
TeGenero by Parexel, a large contract research organization, at its
facility at Northwick Park Hospital outside London. The six volunteers
were to be the first humans to receive TGN1412, a humanized monoclonal
antibody designed as an agonist of the CD28 receptor on T lymphocytes,
which stimulates the production and activation of T lymphocytes. It was
hoped that this product would benefit patients with B-cell chronic
lymphocytic leukemia or autoimmune diseases such as multiple sclerosis
or rheumatoid arthritis. Preclinical testing, including tests in rabbits
and monkeys that used doses up to 500 times as high as the doses
received by the first group of volunteers,1 reportedly showed no signs
of toxicity.

However, after receiving injections of TGN1412, the six volunteers
became desperately ill, had multiple-organ failure, and were transferred
to an intensive care unit2 with what has been described as a cytokine
release syndrome.1 As of April 5, five of the volunteers had been
discharged from the hospital, and the other man appeared to be
recovering.2 This unexpected and devastating outcome is currently under
investigation by the relevant authorities under the supervision of the
United Kingdom Medicines and Healthcare Products Regulatory Agency
(MHRA), which originally approved the trial and its protocol. A
preliminary report has now been completed and released.1 The serious
injuries to these volunteers compel us to reassess the safety of such
clinical trials in general, particularly those involving healthy volunteers.

At some point in the development of every drug, the drug must be given
for the first time to humans in a phase 1 trial. Until now, such trials
have had a remarkably good safety record,3 reflecting both the extent of
the preclinical and animal testing that precedes them and the safeguards
built into their own designs. In particular, it is standard practice to
begin with very small doses, often orders of magnitude below those
determined to be nontoxic in animals and those expected to produce any
effect in humans. Doses are then increased slowly, as the experience at
lower doses is continually evaluated. Life-threatening toxic effects in
a phase 1 trial, such as those seen in the TeGenero study, are virtually
unheard of, although the tragic death of Jesse Gelsinger in a
gene-therapy trial at the University of Pennsylvania in 1999 certainly
highlighted the potential for harm.4 Why have most trials been free of
such incidents, and what can we do to enhance their safety even further?

System or human failures – such as errors in dosage, manufacturing, or
administration – are usually prevented by rigorous procedures for drug
preparation and administration. According to the MHRA’s preliminary
investigation, such errors do not appear to explain the life-threatening
toxic effects produced by this drug, implying that these effects were
produced by the drug itself.1

The toxicity of novel compounds falls into two broad categories. First,
toxic effects such as acute liver injury, leukopenia, cardiac
arrhythmia, or rash may be related to the new drug molecule itself but
unrelated to its intended mechanism of action. Considerable efforts are
made to identify these types of toxicity in vitro and through studies in
animals. However, our incomplete understanding of the mechanisms
underlying such toxicity and the limitations of animal models inevitably
mean that some potentially serious toxic effects go undetected in
preclinical screening, and sometimes even during the full development
process, and such drugs may reach the market, particularly if the toxic
effect is rare or occurs in only some subpopulations.

The second type of toxic effect results from the action of the drug on
its intended biologic target. Such effects are always unknown when a
target is “drugged” for the first time – and there must always be a
first time. It is fortunate that the first pharmaceutical antagonism of
beta-adrenergic receptors, histamine H2 receptors, and
angiotensin-converting enzyme in humans all proceeded satisfactorily.
Until these targets had been manipulated by drugs, many aspects of their
biology were unknown. New drugs of the same classes that are developed
subsequently, although still carrying the risk associated with new
molecules, may be administered with greater confidence because of the
knowledge base that has been built with previously studied drugs that
have similar action. But when a compound addressing a new biologic
target is tested for the first time in humans, much greater caution must
be exercised. Such caution should include avoidance of treating multiple
volunteers simultaneously or without a reasonably long interval between
them. The effects of very low doses in the first subject should be
monitored carefully for a period sufficient for the detection of both
immediate and later adverse effects before the drug is given to
additional volunteers. Had such a design been used in the TGN1412 study,
fewer volunteers would have been injured, because the serious toxic
effects would have been identified in the first volunteer.

In some cases, a phase 1 trial does not, in fact, represent the first
attempt to manipulate a particular biologic target – though the
researchers may be unaware of previous efforts. Clearly, we should not
be exposing people to such manipulation if it has been shown, in studies
in either humans or animals, to carry serious risks outweighing any
potential benefits. How would we respond if we were to learn that others
had abandoned CD28 agonists similar to TGN1412 because they produced an
overwhelming cytokine or immunologic response? This issue has become
more pressing as drug development, particularly of new biologic
compounds, has shifted to small biotechnology companies that lack the
massive “memory” of the large, integrated pharmaceutical companies that
have historically developed most drugs. Unfortunately, the companies
that generate early safety data consider them proprietary – a concern
that must somehow be reconciled with patients’ safety. Volunteers
rightly expect that we put their safety before competitive advantage,
and researchers have an ethical obligation to prevent the exposure of
additional volunteers to previously identified risks.

How can we improve the knowledge base for designing trials of new drugs
directed at novel targets and make it available to developers and
regulators when they are considering the safety of such trials? One
approach would be to ensure that all data from preclinical drug research
are held in a secure database, indexed by biologic target, and
accessible only by major regulatory authorities, which are used to
handling confidential data. Registration of trials and storage and
retention of such data in a format accessible to regulators – regardless
of what decision was made regarding continued development of the
molecule – would increase the safety of future studies. If this system
were designed not to be so intrusive as to inhibit innovation but
nonetheless to provide sufficient transparency, it would help to ensure
that safety lessons need not be relearned repeatedly. Indeed, it is
difficult to imagine how regulators can currently approve phase 1
studies without access to such data in a readily searchable format
during the review process.

The details of this trial, including such crucial facts as the dose,
rate of drug administration, planned number of doses, intervals between
doses, and even whether multiple doses were received by any volunteer,
were initially kept confidential under current laws in the United
Kingdom. The MHRA has now decided to release the details of the trial,
including its protocol,1 which makes clear that the intent was to study
four groups of eight volunteers with each group receiving progressively
higher doses; two volunteers in each group were to receive placebo. Only
the first group was studied. However, this incident once again raises
the question of whether such trials should be registered in an
accessible database such as ClinicalTrials.gov.5 There are fundamental
questions about which, if any, details of a clinical trial involving
volunteers should ever be confidential or whether safety and ethics
principles can be ensured only by an open, transparent process in which
such trials and protocols are registered in a public database. This
issue has become more urgent in the light of both this recent incident
and the migration of clinical trials to less developed countries, where
oversight may be less rigorous.

Although it is important to emphasize that most phase 1 studies have
been safe, it is equally important to ensure that lessons are learned
from this experience and systems put in place to minimize the risk of
recurrence. We must not squander the experience of the participants in
such trials by failing to share the knowledge gained with their help. We
have an opportunity to learn from events in the TeGenero study how to
improve early drug evaluation, and we clearly need to do so as we
develop more and more new compounds. Academia, the pharmaceutical and
biotechnology industries, and regulators must work together to prevent
such clinical-research nightmares from happening in the future.