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Injury to Research Volunteers — The

Clinical-Research Nightmare

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

Ch.B.

 

 

 

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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.

 

 

Source Information

 

Dr. Wood is a professor of medicine and pharmacology

at Vanderbilt University School of Medicine,

Nashville. Dr. Darbyshire is the director of the

Clinical Trials Unit of the Medical Research Council,

London.

 

An interview with Dr. Wood can be heard at

www.nejm.org.

 

References

 

1. Press release of the Medicine and Healthcare

Products Regulatory Agency. Latest findings on

clinical trial suspension. April 5, 2006. (Accessed

April 13, 2006, at

http://www.mhra.gov.uk/home/idcplg?IdcService=SS_GET_PAGE & useSecondary=true & ssDo\

cName=CON2023515 & ssTargetNodeId=389.)

 

2. North West London Hospitals press statements.

(Accessed April 13, 2006, at

http://www.nwlh.nhs.uk/news/item.cfm?id=97.)

3. Stein CM. Managing risk in healthy subjects

participating in clinical research. Clin Pharmacol

Ther 2003;74:511-512. [CrossRef][iSI][Medline]

4. Raper SE, Chirmule N, Lee FS, et al. Fatal

systemic inflammatory response syndrome in an

ornithine transcarbamylase deficient patient following

adenoviral gene transfer. Mol Genet Metab

2003;80:148-158. [CrossRef][iSI][Medline]

5. Drazen JM, Wood AJJ. Trial registration report

card. N Engl J Med 2005;353:2809-2811. [Full Text]