A First-in-Man Phase 1 Clinical Trial

Quality & Compliance
A First-in-Man Phase 1 Clinical Trial
A Tragic Ending leads to a New Guideline
By Lorna Speid, PhD, RAC
T
Research Subject
Safety Series Part 1
he injury of six healthy volunteer research
subjects during a first-in-man phase 1
clinical trial at Northwick Park research
center in 2006 sent shock waves throughout
the pharmaceutical community and the general
public worldwide. Many people, including those
involved in the drug development process and
clinical research, believed something was clearly
amiss with the system for assessing clinical trials
if this type of event could occur. Answers were
demanded about what went wrong and what
would need to change in the way clinical trials
are conducted. In the aftermath of this event,
there was an extensive investigation and report,1
and a new guideline2 was issued. Scientists have
discussed at length the physiological and scientific
issues involved.1,3,5 Project teams working on New
Chemical Entities can learn important lessons
from reviews and investigations of this event.1
This series of articles examines some of the
issues regulatory affairs professionals on a project
team must be able to handle on a day-to-day
basis. It looks at the TeGenero clinical trial and
its implications. This clinical trial resulted in
significant harm to six healthy volunteers and
may have changed the landscape of, at least, firstin-man clinical trial conduct for the foreseeable
future. Part 1 of this three-part series reviews
the guideline issued by EMEA as a result of this
experience.2 Although the guideline was issued by
European authorities, the principles are applicable
anywhere first-in-man studies are conducted.
The second article will examine lessons learned
from this tragedy. In Part 3, the informed consent
process will be discussed; we will consider how
it must be designed and used to ensure research
subjects are able to make truly informed decisions
when considering participating in a clinical trial.
Phase 1 Clinical Trials:
TGN1412 (TeGenero)
As is typical for clinical studies, several organizations were involved in conducting this clinical trial to evaluate TGN1412, a first-in-man
monoclonal antibody. The sponsor—in this case
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TeGenero (Germany)—is ultimately responsible for the oversight of all aspects of the clinical trial. The drug product manufacturer was
Boehringer Ingelheim, and the phase 1 unit based
at London’s Northwick Park Hospital was run
by PAREXEL, a Clinical Research Organization.
TGN1412 was being developed for the treatment
of rheumatoid arthritis, leukaemia and multiple
sclerosis. It was administered by injection over
a period of minutes, rather than a slow infusion
over several hours, as may have been advisable.
TeGenero filed a phase 1 clinical trial application for the compound with the UK Medicines
and Healthcare products Regulatory Agency
(MHRA) in early 2006. MHRA cleared the
application without identifying any major issues.
On 13 March 2006, eight healthy male volunteers participated in the double-blind, randomized, placebo-controlled phase 1 safety study of
TGN1412. Two volunteers received placebo and
the other six subjects received TGN1412. The
study drug was a recombinantly expressed, humanized super-agonist monoclonal antibody.1,3,4,5
The six subjects receiving the active molecule
were dosed within 10 minutes of one another.
Within 90 minutes, all six experienced systemic
inflammatory responses that caused their main
body organs to collapse. This syndrome was characterized by a rapid induction of proinflammatory
cytokines, accompanied by headache, myalgias,
nausea, diarrhea, erythema, vasodilatation and
hypotension. Within 12 to 16 hours following
infusion, the subjects became critically ill with
pulmonary infiltrates and lung injury, renal failure and disseminated intravascular coagulation.
Severe and unexpected depletion of lymphocytes
and monocytes occurred within 24 hours of
infusion. Cardiopulmonary support (including
dialysis), high-dose methylprednisolone and an
anti–interleukin-2 receptor antagonist antibody
were required. All six volunteers in the treatment
group had multiorgan failure with an unknown
mechanism and an unpredictable severity. They
were admitted to the on-site critical care unit
at Northwick Park and St. Mark’s Hospital, a
National Health Service (NHS) hospital.
Fortunately, all six research subjects survived,
but it is anticipated that they will suffer longterm sequellae as a result of irreversible damage
to their immune systems. They may have an
increased lifetime susceptibility to various types
of cancers. This is a tragedy for volunteers who
were clearly healthy when they entered the clinical trial.
The regulatory affairs professional plays
an important role in ensuring that the EMEA
guideline2 and Expert Report1 recommendations
are implemented in first-in-man studies involving high-risk molecules. In fact, many of these
recommendations would serve companies well in
clinical programs in general.
The new guideline2 is reviewed below; it
reflects many of the findings from the investigation1 conducted following the TeGenero incident.
Guideline Review
The guideline encompasses many areas of development covered in more detail in other guidelines. For instance, it references International
Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals
for Human Use (ICH) guidelines that must be
considered during the development program.6-15
The guideline emphasizes that it is not applicable
to gene and cell therapies. It was issued to address
issues to be considered in working with novel
compounds classified as high risk.
After extensive investigation, the Committee
on Human Medicinal Products (CHMP) determined that TeGenero had complied with all
applicable regulatory guidelines. Since the incident occurred despite that compliance, additional
guidance on high-risk molecules was deemed to
be appropriate.
The guideline captures important concepts
and rules of drug development that many companies should be following routinely, regardless of
the type of molecule being developed. Although
the guideline does not cover much new material, it
summarizes the types of issues to be considered in
moving a potentially high-risk medicinal product
through the development pathway and into the
clinic. It recognizes the challenges of integrating
the different decisions that need to be made about
a compound moving through the early stages of
development.
The regulatory professional on the project
team is often more familiar than most with these
concepts, and should be confident enough to voice
concerns when decisions do not take them into
account. In this respect, the guideline will assist
the regulatory professional make the arguments on
these matters. In effect, it provides a crash course
in good drug development practice, which will be
particularly helpful to small companies or those
new to drug development. For large pharmaceutical manufacturers, this guideline will be helpful,
but that environment is likely to have more checks
and balances, and therefore more opportunities to
address the issues identified in the report and the
guideline.
Definition of High-Risk Molecules
High-risk molecules are those that fulfill any of
the following criteria:
• present the potential for serious adverse
reactions in first-in-man studies
• target the immune system
• have a mechanism of action that
bypasses normal physiological control
mechanisms, e.g., CD3 or CD28 supra
agonists
• are novel fusion proteins
• are bi-specific antibodies
• present difficulties in quantifying or
predicting risks from animal studies
and animal models due to speciesspecific responses, or difficulties in
reproducing the human situation in
animal studies
Mode of Action of High-Risk Molecules
There is concern about the mode of action and
the difficulties of predicting the dose response
curve for high-risk molecules. In situations where
the molecule is able to act on many targets in an
unpredictable way, constructing the dose finding
curve may be difficult. This results in higher risks
to research subjects for first-in-man studies.
“Mode of action
Consideration should be given to the
novelty, plausibility and extent of knowledge
of the proposed mode of action. This
includes the nature and intensity (extent,
amplification, duration, reversibility) of the
effect of the active substance on the target
and the type of dose response (linear, nonlinear, U-shaped, bell-shaped). Previous
exposure of human beings to compounds
that have related biological mechanisms
should also be considered.
For example, the following mechanisms
could be considered as high risk:
− A pleiotropic mechanism, e.g.,
leading to various physiological
effects, or targets that are
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ubiquitously expressed, as often seen
in the immune system,
− A mechanism that bypasses
physiological control mechanisms,
e.g., CD3 or CD28 (supra-) agonists.”
[Extracted from Guideline 2]
Predictive Value of Animal Studies
The relevance of animal models is a particular
concern for high-risk molecules, as is scale-up to
appropriate species for Good Laboratory Practice
toxicology studies. If the molecule does not
produce the same dose effects in the species as it
will in man, observed animal responses may not
accurately predict the types of adverse responses
that could be observed in man or the doses at
which they might occur. These molecules must
be considered high risk because it is impossible
to predict the responses they will elicit in
research subjects. More caution must therefore
be exercised when conducting these studies.
“Relevance of animal models
The Sponsor should compare the available
animal species to humans taking into
account the target, its structural homology,
distribution, signal transduction pathways
and the nature of pharmacological effects.
If available animal models are of limited
relevance to study properly the pharmacological and toxicological effects of the medicinal
product, it should be considered as highrisk.” [Extracted from Guideline 2]
Demonstrating a Link Between
Material in Toxicology Studies
and Clinical Trials
Demonstrating a link between the material
used in the GLP toxicology studies and that
used in clinical studies is critical. For instance,
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April 2008
differences in the amounts and/or types of
impurities in the material used in toxicology
studies and the material used in clinical trials
reduce the predictive ability of the GLP toxicology studies. One way of ensuring a link by
manufacturing sufficient amounts of material
for both the GLP toxicology studies and the
first clinical study in the same batch.
Selecting Doses for
First-in-Man Studies
Methods needed to determine first-in-man studies for high-risk molecules may be different from
those used to determine the starting dose for
other molecules. The guideline2 and the official
investigation report1 suggest some methods for
calculating starting doses.
“4.3.6 Calculation of the first dose in man
In general, the calculation of the first dose
in man is based on No Observed Adverse
Effect Level (NOAEL) determined in nonclinical safety studies performed in the most
sensitive and relevant animal species, adjusted
with allometric factors or on the basis of
pharmacokinetics. The relevant dose is then
reduced/adjusted by appropriate safety factors
according to the particular aspects of the
molecule and the design of the clinical trials.
For high-risk medicinal products, an
additional approach to dose calculation should
be taken. The use of ‘Minimal Anticipated
Biological Effect Level’ (MABEL) approach is
recommended. The MABEL is the anticipated
dose level leading to a minimal biological
effect level in humans. Safety factors are
usually applied for the calculation of the first
dose in man from MABEL.
The calculation of MABEL should
utilise all relevant in vitro and in vivo available
information from pharmacodynamic/
pharmacokinetic data such as:
i) receptor binding and receptor
occupancy studies in vitro in target
cells from human and the relevant
animal(s) species and in vivo in the
relevant animal species.
ii) concentration-response curves in
vitro in target cells from human
and the relevant animal(s) species
and dose response in vivo in the
relevant animal species.
iii) exposures at pharmacological doses
in the relevant species.
The above data should be integrated
in a PK/PD modelling approach for the
determination of the MABEL. In order
to further limit the potential for adverse
reactions in humans, safety factors should
be applied in the calculation of the first dose
in man from the MABEL. These should
take into account criteria of risks such as the
novelty of the active substance, its biological
potency and its mode of action, the degree
of species specificity, and the shape of the
dose-response curve. The safety factors used
should be justified.
When the methods of calculation (e.g.
NOAEL, MABEL) give different estimations
of the first dose in man, the lowest value
should be used.” [Extracted from Guideline 2]
Level of Acceptable Risk
Research subjects must not be exposed to
undue risk. Preclinical work must demonstrate
an acceptable level of risk. This requirement is
not new; all clinical research carries some risk.
However, healthy volunteers in a phase 1 trial
will not experience any benefit from taking
the drug, therefore the level of risk must be
very small.
Regulatory Standards and Compliance
Good Manufacturing Practices (GMPs) must
be followed in manufacturing the material to be
administered to research subjects. For US-based
companies following a graded GMP strategy
as development progresses, discussions with
European regulatory authorities may be required
to ensure that GMP standards being followed for
the phase 1 studies are acceptable.
The guideline emphasizes the need to
achieve a high level of quality characterization
before the phase 1 study. This implies that
analytical methods will be developed and
validated prior to the start of toxicology studies.
The molecule or compound will also require
significant scientific characterization in advance
of the first-in-man phase 1 study. Companies
focused on developing biological agents may
tend to try following a graded approach in the
application of GMPs and Good Laboratory
Practices. Had TeGenero not been highly
compliant in these areas, it would have been
difficult to determine whether the events that
occurred were due to the quality of the material
used, immune responses or other factors. The
apparent high level of compliance with GLP,
GMP and GCP standards made it easier to
identify the pharmacological issues that may
have contributed to the adverse events.
Target Organ Toxicity Elucidation
Good Laboratory Practice (GLP) toxicology
studies should demonstrate target organ toxicities
to enable the patient study(-ies) to include
appropriate safety monitoring. This may be
difficult if the compound cannot be administered
to animals in large amounts, e.g., if humanized
molecules are used. In such a case, discussion
with the regulatory agency may be appropriate
to determine whether special animal toxicology
models should be developed to study mechanisms
of toxicity before first-in-man studies can begin.
Choice of Research Subject Population
The population to be studied should be selected
carefully. For a novel immunomodulator, patients
may be more appropriate than healthy volunteers.
A healthy immune system may overreact to the
administration of immunomodulators, resulting
in collapse or attack on the body systems.
Facilities for Conducting Studies of
High-Risk Molecules
The guideline2 and the investigation1 highlighted
the fact that the TeGenero study was conducted
in a hospital facility with expert emergency
physicians and other staff who may have saved
the participants’ lives. First-in-man studies
should take place in appropriately staffed and
equipped medical facilities, even for healthy
volunteer studies. Healthy volunteer units
without medical facilities in close proximity to
the research unit should be avoided for studies
involving high-risk medicinal products.
Dosing High-Risk Molecules
It is important to proceed cautiously with dose
escalation after starting at the lowest feasible dose.
Adequate intervals must be left between
dosing research subjects. In the TeGenero study
all subjects were dosed within 10 minutes of one
another. This left little room for dose adjustment or
study termination when problems became evident
approximately 90 minutes after dosing began.
High-risk molecules need to include rules
for stopping dosing (stopping rules) that should
be pre-agreed with the health authority and
activated as conditions require. Stopping rules
should detail appropriate steps to be taken in
the event of various eventualities.
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Safety Monitoring During the Study
Research subjects in whom high-risk molecules
are being studied should remain on site for the
study’s duration. They also should be monitored
after leaving the facility for a sufficient period of
time after dosing to detect any delayed responses.
It may be appropriate to establish an
independent drug safety monitoring board to
oversee the safety of studies involving highrisk medicinal products. A monitoring plan
should be developed for the study that includes
a risk management plan, which should identify
the likely risks and how each of them will
be mitigated during the clinical trial. This
monitoring plan should be communicated to
study physicians and nurses, and to emergency
personnel who will be on standby during the
clinical trial. Mechanisms for safety reporting
should be in place before the study begins.
Conclusion
As the pharmaceutical industry and research institutions seek to address as yet unmet medical needs,
molecules of a type not previously studied in man
may be created. These molecules may need to be
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April 2008
classified as high risk, depending upon the ease with
which they can be studied in animals, as well as the
type of reactions they may elicit in the human body.
Where they are classified as high risk, care must be
taken to ensure that risks to research subjects are
appropriately controlled. Adherence to the current
guideline will help reduce the potential for another
incident like TeGenero. It is hoped the guideline will
be dynamic since additional guidance may be needed
or updates made as more experience is gained with
high-risk molecules. Although the guideline was
issued in Europe, and the US and Japan do not yet
have their own versions, the recommendations it
contains may be relevant for studies conducted elsewhere. On the contrary, because the pharmaceutical
industry is involved in global product development,
what happens in Europe impacts drug development
programs designed in the US and elsewhere.
REFERENCES
1. Expert Scientific Group on Phase One Clinical Trials.
Final Report, 30 November 2006.
2. Guideline for Requirements for First in Man Clinical
Trials for Potential High Risk Medicinal Products.
Committee for Medicinal Products for Human Use
(CHMP).EMEA /CHMP/SWP/28367/2007. Corr.23
May 2007.
Suntharalingam G, Perry MR, Ward S, Brett SJ,
Costello-Cortes A, Brunner MD, Panoskaltsis N.
“Cytokine Storm in a Phase 1 Trial of the Anti-CD28
Monoclonal Antibody TGN1412.” N Engl J Med,
2006; 356(10): 1018-1028.
4. TGN1412 investigator’s brochure. Wurzburg,
Germany: TeGenero Immunotherapeutics, 2005.
Accessed 11 August 2006. www.mhra.gov.uk/home/
idcplg?IdcService=GET_FILE&dDocName=CON202351
8&RevisionSelectionMethod=LatestReleased.
5. Investigations into adverse incidents during clinical trials of TGN1412. London: Medicines and Healthcare
products Regulatory Agency (MHRA), 2006.
Accessed 11 August 2006. www.mhra.gov.uk/home/
idcplg?IdcService=GET_FILE&dDocName=CON202382
1&RevisionSelectionMethod=LatestReleased .
6. “Non-Clinical Safety Studies For The Conduct Of
Human Clinical Trials For Pharmaceuticals.” (ICH
M3), CPMP/ICH/286/95.
7. “Preclinical safety evaluation of biotechnology-derived
pharmaceuticals.” (ICH S6) CPMP/ICH/302/95,
8. “The Non-clinical Evaluation of the Potential for
delayed Ventricular Repolarization (QT Interval
Prolongation) by Human Pharmaceuticals.” (ICH
S7B) CPMP/ICH/423/02.
9. “Safety pharmacology studies for human
pharmaceuticals.” (ICH S7A) CPMP/ICH/539/00.
Quality aspects.
10. EUDRALEX—Volume 4—Medicinal Products for
3.
11. 12. 13. 14. 15. Human and Veterinary Use: Good Manufacturing
Practice. “Annex 13: Manufacture of Investigational
Medicinal Products.”
Guideline on Virus Safety Evaluation of Biotechnological
Investigational Medicinal Products—Draft. EMEA/
CHMP/BWP/398498/2005-corr.
Guideline on the Requirements to the Chemical and
Pharmaceutical Quality Documentation concerning
Investigational Medicinal Products in Clinical Trials.
CHMP/QWP/185401/2004.
Guideline for Good Clinical Practice. (ICH
E6), CPMP/ICH/135/95.
General Considerations for Clinical Trials,
(ICH E8) CPMP/ICH/291/95.
EUDRALEX—Vol 10—Clinical trials. In particular:
Chapter I: Application and Application Form and
Chapter II: Monitoring and Pharmacovigilance.
AUTHOR
Lorna Speid, PhD, RAC, is President of Speid & Associates
Inc. (www.sndtm.com) a regulatory affairs and drug development consultancy based in San Diego. She can be reached at
[email protected] or at +1 858 793 1295.
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