Learning from the TGN1412 trial
BMJ 2006; 332 doi: https://doi.org/10.1136/bmj.38797.635012.47 (Published 23 March 2006) Cite this as: BMJ 2006;332:677
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Michael Goodyear says that whether we need to consider a parallel
drug testing process, using human tissues, needs careful consideration.
Surely the case for doing so is overwhelming, particularly in view of the
fact that human tissue company Asterand have a standard assay which could
have predicted the TGN1412 reaction - see
http://www.asterand.com/Asterand/NEWSEVENTS/2006PRESSRELEASES/4-17-
2006.aspx. The Government is making no investment into the increased
application of ethically-donated human tissue testing, so it is left to
small, struggling companies like Asterand to develop tests which would
benefit all of humanity, let alone the pharmaceutical industry, entirely
unaided.
Let us not forget that 92% of drugs fail in clinical trials, having
successfully passed through animal studies. Although they do not often
fail in such spectacular fashion as TGN1412, trial volunteers can
nevertheless be harmed or even killed by experimental drugs. Surely
they deserve better protection than 'proof of safety' in animals, which -
as thalidomide, eraldin, opren, clioquinol, isoprenaline, rezulin, Vioxx,
etc, etc. should have taught us - means very little for humans.
Competing interests:
None declared
Competing interests: No competing interests
As Crawford (1) points out, due to a problematic habit of
pharmaceutical companies not publishing details of their preclinical data,
at the time of the unfolding of this tragedy there was very little
information available in the public domain. Some months later, we are now
in a better position (2) to reassess this and address the questions raised
by Crawford and many others. Further correspondence is perhaps best
directed there.
The main sources of information are the release of the MHRA documents
and the interim report of the Expert Scientific Group (ESG). In addition a
large number of immunologists have since commented on the underlying
biology and pathology. I agree that the immune system is a highly complex
system, that may, like Pandora’s Box, react in unpredictable ways.
Furthermore there is a need to study it in the intact organism, rather
than isolated components, if we wish to reliably predict the effects of
interventions. With reference to Crawford’s specific questions about the
validity of murine models, we can now say that they were of limited
relevance, the primary data for the extrapolation to man being based on
non-human primates. However these also failed to reliably predict the
effects in man, as did ex-vivo experiments on human blood. For now, the
full explanation of the pathogenesis of the massive cytokine release
syndrome, or at least why it was confined to the experimental human
subjects remains a mystery.
Ultimately new drugs need to be tested in man, a critical event, as
Fuchs (3) points out, and whether we have placed an unjustified reliance
on animal testing, as Archibald implies, (4) and need to consider a
parallel process, using human tissues, needs careful consideration.
Adams’ (5) intriguing suggestion that new drugs should first be
tested on medical school professors (Otago or otherwise) raises important
issues as to whether the scientific and ethical review (which he suggests
was far from optimal) would be raised to a higher level under these
circumstances. One would like to think that those responsible for human
subject protection would use a similar standard to that which they would
demand for themselves.
Speirs (6) asks many relevant questions, which the ESG must address
if we wish to prevent a repetition of these events. Perhaps the most
important issue he raises is the interface of ethical and scientific
review. It is easy to believe (although we have no direct evidence to
date, and this must also be addressed) that the Human Subjects Committee
simply accepted on face value the review and assessment of risks presented
to them by the MHRA and the investigators. Unfortunately many now consider
that review inadequate, chiefly because of the lack of independent expert
assessment. This interface remains one hotly debated in the overall
governance of research ethics. It would be a mistake to see these as
separate processes, although no universally agreed model for their
integration has been adopted. Golec (7) argues that both processes should
be an integral part of protocol design well before the issues come before
a Human Subjects Committee.
Ariyanayagam (8) is right to question the current balance of
proprietary information over public interest and safety, to point out the
crisis in public confidence and the need for a more careful examination of
the potential risks and benefits to both individuals and society in
testing new drugs, issues also addressed by Khan (8). Khan also emphasises
the need for an open and collaborative approach to drug development, both
between companies and between companies and regulators, which is congruent
with the thrust of the World Health Organization’s Clinical Trials
Platform. (10) This is a theme that the ESG have also chosen to emphasise.
John (11) reminds us of the need to consider personal factors,
especially the pressures on clinicians and researchers to advance the
agenda, and the need to constantly keep the welfare of the patient or
subject paramount.
References
1. Crawford MA. TGN1412 - Did the striking nutritional contrasts
between the rats and men contribute to the disaster? 1 August 2006
2. Goodyear MD. Further lessons from the TGN1412 tragedy. BMJ. 2006
Aug 5;333(7562):270-1.
3. Fuchs D. Similarities and differences between men and mice 24
March 2006
4. Archibald KA. Safety testing in animals deserves scrutiny 31 March
2006
5. Adams DD. Ultimate basis of the TGN1412 disaster 3 April 2006
6. Speirs ASD. Governance of clinical research. 3 April 2006
7. Golec L. Integrating Scientific, Ethics and Research Process
Assessment into Protocol Design. 19th Graven Conference on the Physical
and Developmental Environment of the High Risk Infant: Human Factors and
Research in the NICU. University of South Florida 2006.
8. Ariyanayagam S. Harm Reduction in Human Experimentation – Time to
Revisit Research Governance. 27 March 2006
9. Khan SA. First do no harm: How safe are our clinical trials? 27
March 2006
10. http://www.who.int/ictrp/en/ (accessed August 11)
11. John SJ. Let us make Research More Personal - A Resident's Appeal
25 March 2006
Competing interests:
None declared
Competing interests: No competing interests
It is claimed that TGN1412 is a humanised monoclonal antibody that
binds, and is superagonistic to the CD28 receptor of the immune system's T
cells (1). "The
superagonistic properties of this agent means it fully activates T-cells
without the need for additional antigen-receptor stimulation. Superagonism
of these antibodies was found to be dependent on binding to a specific
part of the CD28 molecule. Once the investigators found antibodies with
these properties they wondered if they could be therapeutically useful in
stimulating the immune system in immunosuppressed patients as these
antibodies would be expected to crudely activate all T-cells
simultaneously" (2). It is important to know exactly what tests were
carried out in animals as there has been little detail given by Goodyear,
the manufacturer, nor the MHRA who only say no adverse reactions were
observed.(3).
The Te Genero Web Site states that “It has shown unique ex vivo and
in vivo T lymphocyte stimulatory capacity and therapeutic potential for a
number of autoimmune/inflammatory as well as oncological diseases” It
also states that
“Multiple preclinical results indicate that CD28-SuperMA® are capable of
inhibiting clinical signs, surrogate parameters and pathophysiological
characteristics of autoimmune/inflammatory diseases in a well-tolerated
fashion. ‘ Thus, TGN1412 is a novel approach to addressing the medical
need in chronic autoimmune/inflammatory diseases.”
The immune system is highly complex. Nutritional factors play a
significant part in the genesis of several chronic diseases, including
auto-immune disease and cancer .Diet also affects immunomodulatory
activities with different dietary lipids having quite opposite effects
(4). The diet of laboratory animals is low in fat. However fed a high
fat diet, marginal vascular dysfunction due to diabetes was found be
greatly exaggerated (5). Whilst it is plausible that the development of a
humanised monoclonal antibody might not be recognised in lower animals, no
stone should be left unturned in the search for the cause of the alleged
cytokine storm at Northwick Park. Apart from the species difference
between humans and the animals used for testing TGN1412, there would also
have been a huge difference in the background diets between the humans and
the test animals, and hence immune behaviour which should not be
overlooked in the search for answers. Indeed from what we know about the
cell membrane and the lipid domains for the receptors, the binding of
these antibodies to a specific part of the CD28 or indeed to other
molecules would be expected to be influenced by the membrane lipid domain
which will be very different in a human and a rat. The misinterpretation
of the use of COX2 inhibitors, associated with several deaths, also came
about because of a poor understanding of the dietary links to cell
behaviour.
Michael A Crawford.
1. Chia-Huey Lin, Thomas Kerkau, Christine Guntermann, Martin
Trischler, Niklas Beyersdorf, Yvonne Scheuring, Hans-Peter Tony, Christian
Kneitz, Martin Wilhelm, Peter Mueller, Thomas Huenig, Thomas Hanke (2004-
11-16). "Superagonistic Anti-CD28 Antibody TGN1412 as a Potential
Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic
Leukemia". Blood (ASH Annual Meeting Abstracts) 104 (11): Abstract 2519.
2. Wikipedia, the free encyclopedia, http://en.wikipedia.org
3. Michael Goodyear Learning from the TGN1412 trial, BMJ 2006; 332:
677-678.
4. Lee JY, Hwang DH. The modulation of inflammatory gene expression
by lipids: mediation through Toll-like receptors. Mol Cells. 2006;
21(2):174-85.
5. Holemans K, Gerber R, O'Brien-Coker I, Mallet A, van Bree R, van
Assche FA, Poston L.. Raised saturated-fat intake worsens vascular
function in virgin and pregnant offspring of streptozotocin-diabetic
rats., Br J Nutr. 2000;84(3):285-96
Competing interests:
None declared
Competing interests: No competing interests
Dear Madam,
Apart from its reckless design1, the TeGenero company's drug trial
disaster ultimately stems from a huge ignorance of the basic principles of
the pathogenesis of autoimmune diseases.2 A crucial fault in current
research is the loss of Burnet's forbidden clone theory of autoimmune
disease,3 which was proved for Graves' disease in my laboratory by
demonstration that the causative thyroid-stimulating autoantobodies in
individual patients contain only one of two possible light chain types and
therefore originate from a single lymphocyte by somatic V gene mutation.4
The clear objective in seeking curative therapy for autoimmune diseases is
to discover the pathogenic forbidden clone and selectively destroy it,
leaving the rest of the immunity system intact. The way to do this has
been pioneered in Belgium, in Dumont and Vassart's laboratory, by cloning
the autoantigen for Graves' disease.5 Attachment of a cytotoxic element,
such as 131I, could enable the forbidden clone to be selectively
destroyed. This is not necessary for Graves' disease where excellent
therapy is already available, but it shows a research pathway towards
specific immunotherapy for other autoimmune disease, such as rheumatoid
arthritis and the psychoses.
LATS protector6, the human-specific version of the thyroid-
stimulating autoantibodies is not active in guinea pigs and mice,
illustrating how a very small change in amino-acid sequence can hugely
change reactivity between man and laboratory animals. Incidently, the
infusion of LATS protector into humans, with the very slight risk of
transferring a latent noxious virus, was exemplary in using Otago Medical
School professors as subjects, rather than impecunious people.
TeGenero's attempt to develop treatment for autoimmune diseases by
trying to multiply mythical "regulatory T cells" with a monoclonal
antibody, should never have passed a competent scientific assessing
committee. Perhaps TGN1412 accidentally enabled T cells to attack host
histocompatibility antigens, for which they are very close to having
specificity.
DD Adams MD DSc FRACP
Faculty of Medicine, University of Otago,
Dunedin, New Zealand
References
1 Goodyear M. Learning from the TGN1412 trial. BMJ 2006; 332: 677-
678.
2. Adams DD, Knight JG. Principles of autoimmune disease:
pathogenesis, genetics and specific immunotherapy. J Clin Lab Immunol
2003; 52: 1-22.
3 Burnet FM. Autoimmune disease. BMJ 1959; 2: 645-640 and 720-725.
4 Knight JG, Laing P, Knight A, et al. Thyroid-stimulating
autoantibodies usually contain only Ć light chains: evidence for the
forbidden clone theory.
J Clin Endocrinol Metab 1986; 39: 826-832.
5 Costagliola S, Morganthaler N, Hoemann K, et al. Second generation
assay for TSH receptor antibodies has superior diagnostic sensitivity for
Graves' disease. J Clin Endocrinol Metab 1999; 84: 90-97
6 Adams DD, Fastier FN, Howie JB, Kennedy TH, Kilpatrick JA, Stewart
RDH. Stimulation of the human thyroid by infusions of plasma containing
LATS protector J Clin. Endocrinol Metab 1974; 39: 826-832.
Competing interests:
None declared
Competing interests: No competing interests
The tragic outcome of a Phase I clinical trial of TGN1412 at
Northwick Park Hospital raises many very important questions about the
conduct and governance of clinical trials in general and Phase I drug
studies in particular.
Was the hospital negligent in permitting this trial, which was flawed
in its design and had obvious risks? Was the Human Subjects Committee
failing in its duty when it approved the study? Should a commercial
company, in this case the US firm Parexel, be permitted to run a clinical
pharmacology research unit in a public hospital? Did the mechanism for
recruiting volunteers undergo adequate ethical scrutiny? Was the Informed
Consent form subjected to rigorous evaluation, in particular its statement
of potential risks and adverse effects? Was the financial reward offered
to the volunteers too great, and therefore likely to impair their
judgement regarding participation in the study? Were the investigators
properly trained in the conduct of Phase I studies? Were they adequately
supervised? These are extremely grave issues.
A poorly designed clinical trial is intrinsically unethical, because
it is unlikely to provide valid scientific information, thus making the
risk/benefit ratio unacceptably high. The most effective defence against
such trials is not bureaucratic decrees but an expert and fearless Human
Subjects Committee that includes scientists, ethicists, clinicians,
statisticians, lay persons, and coopted members appointed when special
expertise is required to evaluate a particular study proposal. Such
committees are vital not only for the protection of human subjects, but
for the status and reputation of science itself.
Competing interests:
None declared
Competing interests: No competing interests
Michael Goodyear comments that the tragic TGN1412 trial will probably
change the face of drug testing and that an independent inquiry is needed.
Patient safety group Europeans for Medical Progress agrees. We believe a
vital part of any inquiry should be a comparison of animal tests with
microdosing, human tissue tests and other state-of-the-art methods of
predicting human metabolism.
83% of GPs and over 200 MPs support such a scientific evaluation of
the best means to protect public health and safety: see
www.curedisease.net
Michael Goodyear is right that relative lack of severe toxicity in
animal models should never be construed as a guarantee of safety in man,
as the story of thalidomide should have taught us. TeGenero insists
monkeys and rabbits showed TGN1412 was safe. Monkeys and mice even showed
that Vioxx was cardioprotective. When will we learn?
Kathy Archibald
Director, Europeans for Medical Progress
PO Box 38604
London W13 0YR
info@curedisease.net
Competing interests:
None declared
Competing interests: No competing interests
1. Among the questions that arise from the human tragedy at Northwick
Park Hospital (1) are the following:
1 Is the design of the trial well thought through?
2 Should the Research Ethics Committee concerned have spotted the
potential risks to the volunteers?
With the benefit of hindsight it is easy to cast doubts on the
credibility of the researchers and those who form part of the research
regulatory system but the general consensus within the medical community
is that at a time of much distress to the casualties and their next of
kin, it would be inappropriate to be judgmental prior to the conclusions
of the investigations in to this unfortunate incident.
History reveals that contemporary society continues to benefit from
ethically sound and medically safe human experimentation. Against this
background, the Northwick Park tragedy offers an opportunity for
reflection for the scientific community. Such reflection should not be
directed towards apportioning blame but rather on harm reduction to
volunteers in the future unless of course negligence can be proven.
Questions around ‘staggered dosing’’ and other issues such as the
manner of recruitment are certainly the right ones to be raised but there
is a need for a detailed stock take, looking at the bigger picture at the
conduct of phase I trials as a whole with closer scrutiny (2,3).
Commercial sensitivity and the rules around intellectual property
rights however place limits on the extent to which the trials can be
subjected to ‘public’ scrutiny, although such right to confidentiality
have been called in to question already (4).
Clinical trials are designed to prevent harm, if not reduce harm but
never to cause harm or fatalities! The reality though is that any
cautionary approach involving the administration of a phase I trial drug
can only be aimed at harm minimization. It will be unrealistic to expect
zero health risk in these circumstances.
Good research is essential in the public interest but the incentive
offered to the volunteers to participate does pose an ethical question
that requires a debate, particularly in the light of the adverse events at
Northwick Park. Could it be argued that the financial incentives offered
and not altruism that motivate those volunteers? If so, could such offer
have clouded their judgment that led to participate? Do such financial
rewards render the volunteers vulnerable? In the event would such
financial incentives be considered ethical?
Payments to medical workforce for undertaking, recruiting and or
administering research at public organizations also raise ethical
questions (5).
Research Governance Systems require an urgent revisit if the public
confidence in the medical establishment, namely the research community is
to be restored.
Dr Sati Ariyanayagam
Consultant Physician – BH&R NHS Trust, Essex, UK
,br>Deputy Vice Chair – Eastern Region MREC
References:
1 Goodyear M, Learning from TGN 1412 trial, BMJ 2006; 332: 677 –678
2 Stewart PM, Improving Clinical Research, BMJ 2003; 327:999-1000
3 Bell J, Resuscitating Clinical Research in the United Kingdom, BMJ,
2003; 327:1041 - 1043
4 Ashcroft R, Pfeffer N, Ethics behind closed doors: do research ethics
committees need secrecy? BMJ 2001; 322:1294 -1296
5 Rao JN, Sant Cassia LJ, Ethics of undisclosed payments to doctors
recruiting patients in clinical trials, BMJ, 2002; 325:36 - 37
Competing interests:
None declared
Competing interests: No competing interests
Recently the first human trial of a new humanized monoclonal
superagonist TGN1412 of the CD28 T cell surface receptor [which received
the EU-Orphan drug designation on March 11, 2005](1) designed to mitigate
autoimmune and immunodeficiency disease has once again raise the concern
of drug safety in clinical trials. The six men who received the active
component rapidly developed catastrophic multisystem failure; the
remaining two, who received a placebo, were unharmed. At the time of going
to press, two remained in a critical condition (2). The study once again
raises many potential questions against our safer clinical trials. This
Phase I study involved the participation of healthy volunteers for a drug
used in autoimmune condition that raises the ethical concern. The
protocol for the trial also states that the dosing was staggered over a
relatively short period of time. Whenever a new drug of a newer class is
tested for the first time in human we should be vigilant enough to observe
any adverse event in the first volunteer before proceeding to the next.
Under no circumstances we should compromise over the drug safety be it
with respect to time or cost incurred by the clinical research
organizations.
The incident is an eye opener for all those involved in clinical
research. It’s always difficult to predict the drug safety of a newer
class in clinical trials though the drug passes the stringent safety tests
in pre-clinical studies. Safety of drugs in animals can never guarantee
the same for humans. What we need to practice is the strict vigilant
approach whenever the study involves such type of drugs. The hospitals
conducting such clinical trials needs to facilitate utmost care for the
volunteers that includes adjacent intensive care units to a clinical trial
center in case of life threatening conditions. When the drug enters the
Phase IV studies, due to limited experience, conservative estimates of the
overall merit seem preferable so that the prescriber will use the drug
critically. Subsequently, re-evaluation of the risk-to-benefit balance is
necessary as greater knowledge of efficacy and adverse effects is
acquired. It is possible to provide a general ‘principle of threes’(3)
structure for a merit assessment of drug safety based upon the concepts of
seriousness, duration and incidences as related to disease indication,
disease amelioration by a drug, and the adverse effects ascribed to the
medicine. This allows a rapid first comparison of medicines for a given
indication. .
On 16th March 2006, The Food and Drug Administration (FDA) and The
Critical Path Institute (C-Path) announced the formation of the Predictive
Safety Testing Consortium between C-Path and five of America’s largest
pharmaceutical companies to share internally developed laboratory methods
to predict the safety of new treatments before they are tested in humans
(4). The goal of the Predictive Safety Testing Consortium is to enable
pharmaceutical companies to share knowledge and resources. This will allow
the pharmaceutical companies to determine which of the lab tests that they
have developed individually should be recommended by the FDA to screen
drugs and better understand the potential side effects before the drugs
enter clinical testing in humans. Companies will share the details of the
methods that each has developed for specific kinds of tests and then
agrees to test another’s method to determine if it is reproducible. The
results of the comparison will be collected and summarized by C-Path for
submission to the FDA. Those methods that the FDA finds to be reliable and
reproducible will form the basis for agency-issued guidelines about which
safety tests should be used in the drug development process. An
initiative like this by FDA is needed for ensuring the pre clinical safety
of drugs.
We need to re-consider the basic fact that: First and foremost DO NO
HARM, which should be the basis of clinical research.
References:
1. TeGenero AG receives EU-orphan drug designation for Humanized
Agonistic Anti-CD28 Monoclonal Antibody TGN1412 for the treatment of B-
CLL. http://www.tegenero.com/documents/pr_tegenero_march_11_2005.pdf
(Accessed: 26th March 2006)
2. Learning from the TGN1412 trial (Editorial). BMJ 2006;332:677-678
.
3. Ralph Edwards, Bengt-Erick Wiholm, Carlos Martinez. Concepts in
Risk-Benefit Assessment. In : Drug Safety. Ralph Edwards, Marie Lindquist,
Ronald Meyboom, Sten Olsson Eds. Adis International, Auckland 2001;543.
4. FDA and the Critical Path Institute Announce Predictive Safety
Testing Consortium
Consortium Will Share Tests to Understand Safety of Potential New Drugs
Earlier. http://www.fda.gov/bbs/topics/news/2006/NEW01337.html (Accessed:
26th March 2006)
Competing interests:
None declared
Competing interests: No competing interests
Dear Sir
The effects of the TGN 1412 infusion seem to be very similar to the
effects on humans of the current strain of bird flu causing so much
anxiety. It also seems to mimic many of the symptoms and signs of the
1918-19 flu epidemic, which has also been traced to a bird flu origin.
It would be interesting to see if the knowledge gained about the
progression and subsequent management of the TGN 1412 trial could be of
value in the prevention and/or managemnet of any possible flu epidemic
which will occur if or when the bird virus manages to mutate to become
transmissable from human to human.
Sincerely
Dr Evan Lloyd
FRCP; FRCA.
Competing interests:
None declared
Competing interests: No competing interests
Of Mice and Men and Pandora: Looking Back? Moving Forwards
Of course Professor Goodyear was right to remind us that a lack of
severe toxicity in animal models should never be construed as a guarantee
of safety in man. These are inevitable limitations of animal studies. But
seat belts do not guarantee safety in cars; this is not an argument
against using them.
The parallel process which Professor Goodyear refers to involves
animals studies as well as alternative methods -- an entirely sensible
approach.
The conclusions of the Expert Scientific Group which looked in detail
at the role of animal experiments in the TGN1412 trial could not be more
clear-cut. They stated that:
Animal studies taking due regard of the three ‘Rs’ remain necessary
for many aspects of pre-clinical development of novel agents including
testing of ‘off-target’ and ‘on-target’ toxicity and understanding the
fundamental biology relevant to a new medicine and its target molecules in
the human. The key point we want to make is the importance of deciding
what can be learned from animal studies in the pre-clinical development of
a new medicine, and what limitations there might be when it comes to
predicting the response, and dose-response relationship, in humans.
Competing interests:
Represent almost all major research institutes in the UK to explain why well-regulated animal research is essential
Competing interests: No competing interests