Transcript Through the Looking Glass: Reflections of a Research Ethicist or

Bench to Bedside
A
Curious Tail of Elephants,
Rodents and other Primates
or Bedside to Bench?
Michael Goodyear
Department of Medicine,
Queen Elizabeth II Health Sciences Centre,
Dalhousie University, Halifax,
Nova Scotia, Canada
MSMR Waltham MA, June 2007
“If you have cancer and
you're a mouse, we can
take good care of you"
Judah Folkman
NY Times May 1988
Animal Welfare better than
People’s?
“The
current situation in which national oversight of
research involving animals is far more effective and
independent than that for research involving humans
would we believe be profoundly upsetting to the
Canadian people”.
The Governance of Health Research Involving Human
Subjects. Law Commission of Canada, 2000.
Learning Objectives
• I: The Bad News: The corruption of
science
• II: Learning from disasters: The story
of TGN1412
• III: The Good News: Approaching
transparency
Summary
Part I
The Bad News:
The corruption of science
The Collapse of Scientific Integrity
•
•
•
The ongoing crisis in public confidence
and trust
The corrosion of the evidence base in
EBM
Ongoing concerns
Declaration of Helsinki
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
1964
16. Every medical research project involving human
subjects should be preceded by careful assessment
of predictable risks and burdens in comparison with
foreseeable benefits to the subject or to others
18. Medical research involving human subjects
should only be conducted if the importance of the
objective outweighs the inherent risks and burdens
to the subject
Vera Hassner Sharav, M.L.S.
Rosiglitazone
Class: Thiazolidinedione
May 21, 2007
Rosiglitazone and Cardiovascular Risk
Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg,
M.D., Ph.D.
Cardiovascular Health Research Unit, Departments of Medicine,
Epidemiology, and Health Services, University of Washington, and
the Center for Health Studies, Group Health, Seattle; and the
Division of Public Health Sciences, Wake Forest University, WinstonSalem, NC
Rosiglitazone
The possibility of cardiovascular benefit
associated with the use of rosiglitazone seems
remote.
In view of the potential cardiovascular risks and
in the absence of evidence of other health
advantages, except for laboratory measures of
glycemic control, the rationale for prescribing
rosiglitazone at this time is unclear.
Unless new data provide a different picture of
the risk–benefit profile, regulatory action by
the Food and Drug Administration (FDA) is
now warranted.
Rosiglitazone
During the market life of rosiglitazone, tens of
millions of prescriptions for the drug have been
written for patients with type 2 diabetes.
Rosiglitazone represents a major failure of
the drug-use and drug-approval processes
in the United States.
Rosiglitazone
Physicians who chose to prescribe rosiglitazone
focused on the single dimension of glycemic
control.
The underlying assumption represents a kind of
linear "physiological" argument: high levels of
glycated hemoglobin increase risk, so a
reduction
in
glycated
hemoglobin
will
automatically translate into improved health
outcomes for patients.
Many physicians did not require proof of health
benefits as a criterion for selecting rosiglitazone
as a therapy for type 2 diabetes.
Rosiglitazone
Had practicing physicians required this higher
standard, they would have been at a loss for
evidence from large, long-term trials.
Rosiglitazone was approved on the basis of
short-term studies of the surrogate end point of
glycemic control.
The use of surrogate end points in the
drug-approval
process
has
been
problematic
Rosiglitazone
Rofecoxib, whose biologic actions early
on suggested the possibility of both
gastrointestinal benefit and cardiovascular
harm,
represented
a
similar
regulatory failure to insist on large trials
of public health importance in a timely
fashion.
Rofecoxib
Class: COX-2 Inhibitor
Pharmacoeconomics
After Sanctions, Doctors Get Drug Company Pay
Gardiner Harris and Janet Roberts
June 3, 2007
A decade ago the Miinesota Board of Medical Practice
accused Dr. Faruk Abuzzahab of a “reckless, if not
willful, disregard” for the welfare of 46 patients, 5 of
whom died in his care or shortly afterward. The board
suspended his license for seven months and restricted
it for two years after that.
But Dr. Abuzzahab, a Minneapolis psychiatrist, is still
overseeing the testing of drugs on patients and is
being paid by pharmaceutical companies for the work.
At least a dozen have paid him for research or
marketing since he was disciplined.
One of Dr. Abuzzahab’s patients was David Olson, whom the
psychiatrist tried repeatedly to recruit for clinical trials. Drug
makers paid Dr. Abuzzahab thousands of dollars for every patient
he recruited. In July 1997, when Mr. Olson again refused to be a
test subject, Dr. Abuzzahab discharged him from the hospital even
though he was suicidal, records show. Mr Olson committed suicide
two weeks later.
From 1997 to 2005, at least 103 doctors who had been disciplined
or criticized by the state medical board received a total of $1.7
million from drug makers. The median payment over that period
was $1,250; the largest was $479,000.
Part II
Learning from disasters:
The story of TGN1412
Is animal testing still relevant?
Pharmacological Evolution
• Switching from classic chemical
pharmacology to biological
– Loss of classic dose-response paradigms
• Humanisation of antibodies
– Intra-species variation
– Immunogenicity in animals, neutralisation and
masking of toxicity
• Increasing uncertainty
Safety in Phase I
First-in-Man Trials
• Repeated reassurances
– Orme M et al. Br J Clin Pharmacol 1989 27: 125
• Mild 6.9%
• Moderate 0.55%
• Serious 0.04%
– Sibille M et al. Eur J Clin Pharmacol 1986 20:
243
– Lutfullin AJ et al. Int J Clin Pharmacol Ther
2005 43: 217
• Severe 0.2%
– BUT: None were biological trials
Learning Opportunities
• TGN1412 and Cytokine Release Syndrome
• Natalizumab and Progressive Multifocal
Leukoencephalopathy (PML)
TGN1412
“A Watershed Incident”
Fiona Godlee, Editor BMJ
A line in the sand?
A cautionary tale from Waltham MA
VOLUME 332 25 MARCH 2006 677-8
Learning from the TGN1412 trial
This experience should foster an open culture in
medical research
Michael Goodyear
Department of Medicine, Dalhousie University, Halifax, Nova Scotia,
Canada
Hell of human guinea pigs
How the drug trial horror unfolded
By MICHAEL SEAMARK
17th March 2006
We saw human guinea pigs explode
Victims tearing at shirts
By NICK PARKER, EMMA MORTON and JACQUI THORNTON
16th March 2006
Myfanwy Marshall, 35, whose boyfriend is
critically ill, said the normally healthy 28year-old barman's face was so puffed, he
"looks like the Elephant Man ". He
looks like a monster.
One victim was named as
Ryan Flanagan, 21, a
student from Highbury,
north London. His family
was told that he could not
breathe and that his head
had swollen to three
times its normal size.
17 March 2007 334: 566-7
“We Saw human guinea pigs explode”:
Newspaper coverage of adverse events in the TGN14412
trial
Stobbart L, Murtagh MJ, Rapley T et al.
Institute of Health and Society, Newcastle University, Newcastle upon
Tyne
Peer Review
• Wood AJ, Darbyshire J.
Injury to research volunteers--the clinicalresearch nightmare.
N Engl J Med. 2006 May 4;354(18):1869-71
• Ho MW, Cummins J.
London Drug Trial Catastrophe – Collapse of
Science and Ethics: Postmortem on the TGN1412
disaster
Science in Society. 2006 Summer 30: 44-5
• Liedert B, Bassus S, Schneider U et al.
Safety of phase I clinical trials with monoclonal
antibodies in Germany – the regulatory
requirements viewed in the aftermath of the
TGN1412 disaster
International Journal of Clinical Pharmacology
and Therapeutics 2007 45(1) 1-9
The Elephant in the Room
Editorial
14 December 2006
Less satisfactory is the Government’s
failure so far to hold anybody accountable
for the Northwick Park incident. The
MHRA exonerated both itself and Parexel.
Loxodonta africana
SUN: A VOLUNTEER who escaped the drug test
disaster told last night how he saw six healthy young
men turn into wailing wrecks within minutes.
Human guinea pig Raste Khan — who did not know he
had been given a harmless placebo in the test — said it
was like a horror film unfolding before his eyes.
Cavia porcellus
Homo sapiens
RASTE KHAN
“The test ward turned into a living hell minutes after we
were injected. The men went down like dominoes.
First they began tearing their shirts off complaining of
fever, then some screamed out that their heads felt like
they were about to explode”
“After that they started fainting, vomiting and writhing
around in their beds”
“It was terrifying because I kept expecting it to happen
to me at any moment. But I felt fine and didn’t know
why. An Asian guy next to me started screaming and his
breathing went haywire as though he was having a
terrible panic attack”
RASTE KHAN
“They put an oxygen mask on him but he kept
tearing it off, shouting ‘Doctor, doctor, please
help me!’ He started convulsing, shouting that
he was getting shooting pains in his back.”
TGN1412
TGN 1412
CD28 T Cell Receptor SuperAgonist
CD28
Humanised IgG4 Mouse anti-Human CD28
Monoclonal Antibody
TGN 1412
• CD28 –
– Costimulatory receptor on CD4+ and CD8+ T
Cells
• Requires costimulation from T cell antigen
receptor (TCR) to activate T helper cells
• TGN1412 bypasses TCR and activates T
cells irrespective of TCR specificity
TGN 1412
• By-passes Costimulation by
Antigen Presenting Cell
TGN 1412
Phase I First Time in Man
• $4,000 Incentive
• March 13 2006 08.00
• 8 Subjects in first dose level cohort
– Healthy Male Volunteers, Age 26 (19-34)
• 2 Placebo – hidden allocation
• 6 Active
• All 8 treated in rapid succession
– 3-6 min ivi
• Dose based on NOAEL
TGN 1412
NOAEL:
No Observed Adverse Effect Level
• Primates tested up to 50mg/kg
– (NOAEL)
• Clinical testing started at 1/500 NOAEL
– 0.1mg/kg
TGN 1412
• BUT:
NOAEL
≠
Pharmacological effect (NOEL)
(0.3 – 5.0mg/kg)
• Therefore:
– Treated close to Effect Level (0.1mg/kg)
TGN 1412
Effects
• Rapid onset
– Cytokine Release Syndrome
– Angioedema
Testing continued
• Multiple Organ Failure
• All subjects admitted to ICU
• Prolonged immunosuppression
TGN 1412
Treatment
• Life support
• High dose steroids
• Daclizumab (anti-IL2 receptor antagonist)
TGN 1412
Amputations for dry gangrene
TGN 1412
Currently
• Loss of memory
• Inability to concentrate
• Headaches
• Ulcers
TGN 1412
Medicines and Healthcare Products Agency
(MHRA)
• Suspended CTA
• Immediate Inquiry
• Released
– protocol, review and inquiry
• Reports April 5, May 25
• FIM Immunomodulation trials on indefinite hold
UK Government announced independent expert inquiry
No review of ethical review
TGN 1412
Expert Inquiry (Terms of Reference)
• What may be necessary in transition from preclinical to first-in-man Phase 1 studies,
specifically:
– Biological molecules with novel mechanisms of action
– New agents with highly species-specific action
– New drugs for immune system targets
• Interim report within 3 months, final in 6
• Minutes of meetings and interim findings to be
made public
TGN 1412
Expert Scientific Group Inquiry
Chair
Professor Sir Gordon Duff
Florey Professor of Molecular Medicine
University of Sheffield
Expert Scientific Group
Phase One Clinical Trials
Interim Report
25th July 2006
Final Report
30th November 2006
VOLUME 333 5 AUGUST 2006 270-1
Further lessons from the TGN1412
tragedy
New guidelines call for a change in the culture of
research
Michael Goodyear
Department of Medicine, Dalhousie University, Halifax, Nova Scotia,
Canada
Further Lessons
• Common sense, avoiding blame
• A retreat from blind process to judiciousness
– Stopping the clock
• Recognises the problem of increasing commercialisation,
•
•
•
•
•
and lack of experience and planning
Places onus on sponsor to demonstrate need
Places openness above proprietary interests
While constrained by narrow remit, needs to draw
attention to broader issues
Failed to identify the elephant in the room
Why are we asking these questions now?
Testing Antibody Therapies:
Position Paper
April 2006
Had previously warned of
possibility in November 2005 -
Early Stage Clinical Trial Taskforce
July 2006
Volume 355:1018-1028 September 61, 2006 Number 10
Cytokine Storm in a Phase 1 Trial of the
Anti-CD28 Monoclonal Antibody TGN1412
Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry,
M.R.C.P., Stephen Ward, F.R.C.A., Stephen J.
Brett, M.D., Andrew Castello-Cortes, F.R.C.A.,
Michael D. Brunner, F.R.C.A., and Nicki
Panoskaltsis, M.D., Ph.D.
Department of Intensive Care Medicine, Northwick Park and St. Mark's
Hospital, Watford Rd., Harrow, London HA1 3UJ, United Kingdom
1. On-line August 14
Event times for 8 healthy volunteers in TGN1412 study
13 March 2006
Volunteer
Allocation
Time of i.v.
Time to ICU
A
B
C
D
E
F
G
H
TG 8.4mg
Placebo
TG 6.8mg
TG 8.8mg
TG 8.2mg
TG 7.2mg
TG 8.2mg
Placebo
08:00
08:10
08:20
08:30
08:40
08.50
09:00
09:10
16 hrs
15.5hrs
16hrs
12hrs
16hrs
16hrs
ICU
Cytokine Release D1-5
Report of the Working Party on Statistical Issues
in First-in-Man studies
Royal Statistical Society
March 2007
Central Committee on Research inv. Human Subjects
• FIM trials with high risk agents will require
input from an Expert Advisory Group prior to
CTA application
Feb 7 2007
• Convened “Lessons from TGN-1412”
Conference, and Implementation Committee
• Developing accreditation of investigators and
sites
• Developed guidance through EMEA
GUIDELINE ON REQUIREMENTS
FOR
FIRST-IN-MAN CLINICAL TRIALS
FOR POTENTIAL HIGH-RISK
MEDICINAL PRODUCTS
London, March 2007
Recommendations (1)
Expert Group: 22 Recommendations
- Safety and Good Science -
1. Preclinical and early clinical development
2. Preparation and review of clinical trials
3.
4.
5.
applications
Determining and administering the initial
dose in humans
The clinical environment for first-in-man
studies
Developing expertise
Recommendations (2)
1. Preclinical and early clinical development
•
•
•
•
Development must be on case by case basis, and
risk based
Regulatory process to be reviewed regularly
All preclinical and Phase I data must be available
and shared
Presubmission should include expert
consultation
Recommendations (3)
2. Preparation and review of clinical trials
applications
•
Timelines must be flexible
Recommendations (4)
3.
Determining and administering the initial dose
in humans
•
Dose selection must go beyond NOEL and
NOAEL
Minimal Anticipated Biological Effect Level
(MABEL)
If preclinical models provide little information –
err on side of caution
Use Slow infusions
Design must be justified scientifically and
statistically
•
•
•
•
Recommendations (5)
3. (Cont’d.)
• Agents should not be administered to more than
•
one subject simultaneously
Choice of healthy volunteers must be justified
Recommendations (6)
4. The clinical environment for first-in-man studies
•
•
•
PIs must be highly qualified
Contingency plans for SAEs must be in place
FIM studies should take place in specialised
centres
Recommendations (7)
5.
Developing expertise
•
Specialised training of investigators is needed
together with development of specialist centres
Recommendations (8)
• Many issues were raised that were outside
the remit of the committee
– Consent
– Communication
– Insurance
– Research Ethics Committees
– Follow up of subjects
• Recommend these be investigated
Recommendations
• Statistical expertise must be available
• All parties must be adequately insured
• There should be agreed guides for
•
•
•
classifying risk
In vitro studies with human tissue
should be part of preclinical
development
Risk should be numerical not verbal
No healthy volunteers in high risk
trials
Draft Guideline
Consultation to May 23
• Attempt to implement recommendations
• Relevance of animal models must be
justified
• IDMSC
Criticised as weak
Vol 25(5) May 2007 485
Critics pan timid European response to
TeGenero disaster
“EMEA’s record on enforcement is tenuous”
EMEA ‘passing the buck’ with clinical trial guideline
DrugResearcher.com March 29 2007
An exercise in regulatory face-saving or a genuine
attempt to improve safety?
Pharmaceutical Executive Europe May 1 2007
“At stake is the credibility of the healthcare sector”
The American Journal of Bioethics, Volume 7 Issue 2
2007 76-81
Money and Distorted Ethical
Judgments about Research: Ethical
Assessment of the TeGenero
TGN1412 Trial
Ezekiel J. Emanuel; Franklin G. Miller
Department of Clinical Bioethics, National Institutes of Health,
Bethesda
Responses
• Risk, Judgment and Fairness in Research Incentives 82 – 83
•
•
•
•
•
Benjamin Hale
Evaluation of Research Design by Research Ethics Committees:
Misleading Reassurance and the Need for Substantive Reforms
84 – 86
Howard Mann
Money Matters 86 – 88
Toby Schonfeld; Bruce Gordon; Jean Amoura; Joseph Spencer Brown
Money, Advertising and Seduction in Human Subjects Research
88 – 90
Trisha B. Phillips
Ethical Flaws in the TeGenero Trial 90 – 92
Adil Shamoo; Elizabeth Woeckner
Faulty Premise, Premature Conclusion: That Money Was
Extraneous to the Research Ethics of the TGN1412 Study 93 – 94
Bethany Spielman
Allied Research International is always recruiting for normal healthy study participants
for our phase I and bioequivalence studies. We conduct our studies in a cheerful, safe,
and respectful environment. Our meals are second to none and …now with 100%
more pool tables!
$950
Swiss Cheese Model of
Patient Safety (Reason)
Lessons to be learnt from
TGN 1412 (1)
• Recruitment
– Financial Incentives
• Adequacy of Information
• Choice of Subject in Phase I
• Number of Subjects
• Timing of Administration
Lessons to be learnt from
TGN 1412 (1)
• Recruitment
• Adequacy of Information
– Consent
• Choice of Subject in Phase I
– Healthy volunteers
• Number of Subjects
• Timing of Administration
Lessons to be learnt from
TGN 1412 (2)
• Sources of Information Reviewed
– Regulatory Review
– Ethical Review
• Place of Independent Expert Review
• Relevance of Preclinical Testing
– Interspecies difference (Macaca)
• Transparency in Development
– Publishing preclinical work
• Transparency of Reviews
• Response to Disasters
Lessons to be learnt from
TGN 1412 (3)
• Caution in
– developing immunomodulators
– agonists
– bypassing regulatory mechanisms (super)
• Assumptions about Dose-Response
– non-linear
– bell shaped
• (optimum dose in Macaca was 5mg/kg)
Lessons to be learnt from
TGN 1412 (4)
• Homology may not mean affinity
• Affinity may not translate downstream
• Even monoclonals are not specific
• Standards for preclinical testing
• Avoid check-box mentality
Lessons to be learnt from
TGN 1412 (4)
The Immune System
is a Capricious
Pandora’s Box!
Pandora 1898.
John William Waterhouse
British Pre-Raphaelite (1849-1917)
Private collection, Oil on canvas
Lessons to be learnt from
TGN 1412 (5)
• Relationships with industry
• Adequacy of training of staff
• Adequacy of facilities
• Adequacy of liability insurance
Plan for the worst, hope for the best
The Relevance of Animal Testing
Altern Lab Anim. 2006 May;34(2):225-3
TGN1412: time to change the paradigm
for the testing of new pharmaceuticals
Bhogal N, Combes R
Focus On Alternatives
Fund for the Replacement of Animals in Medical Experiments
The Relevance of Animal Testing
Toxicology in Vitro 2007 Mar 1
Immunostimulatory antibodies:
Challenging the drug testing paradigm
Bhogal N, Combes R
Information provided to regulatory authorities on
epitope homology differs substantially from what is
known
a) The normal co-stimulatory mechanism of T-cell activation
b) TGN1412 recognises single CD28 on receptor
Bhogal, Combes 2006
CD28 Receptor
a) CD28 monomer and corresponding TGN1412 binding epitope
b) 3-D model of CD28 extracellular domain
TGN1412 binding epitope ( C’’D loop ) circled – 6 AAs
Bhogal, Combes 2006
Rattus rattus
Sylvilagus audubonii
Mus musculus
Macaca mulatta (Rhesus)
Macaca fasicularis (Cynomulgus)
Conservation of amino acid
sequences of CD28.
Substitution of Glutamate (E)
in Macaca mulatta (Rhesus) for
Glycine (G) in human, could
have profound conformal
implications, and hence affect
affinity binding and
downstream effects.
Bhogal, Combes 2006
2007 Apr 1;109(7):2968-77
Physiologic and aberrant regulation of
memory T-cell trafficking by the
costimulatory molecule CD28
Mirenda V, Jarmin SJ, David R, Dyson J,
Scott D, Gu Y, Lechler RI, Okkenhaug K,
Marelli-Berg Federica M.
Department of Immunology, Division of Medicine,
Imperial College London, Hammersmith Campus,
London, United Kingdom
How Clean is Your Lab?
• Memory helper T cells react differently to
TGN1412 than do Ag naïve T cells
• Humans have up to 50% T cells activated
(memory)
• Laboratory animals have few memory T
cells due to rearing conditions
• CD28 activated memory T cells migrate
into extra-lymphoid tissues causing
damage, naïve T cells do not
Why use inbred pathogen free animals to test
drugs to be used on outbred pathogen exposed
people?
Activated T cells susceptible to over stimulation if
isolated from costimulatory requirements of
antigen specificity
Sharpe AH, Abbas AK
NEJM 2006 Sep 7;355(10):973-5.
National Institute for Biological Standards and
Control
NIBSC scientists replicate trial results:
In vitro tests with human immune cells and TGN1412 produced
polyclonal expansion and cytokine release
Higher doses, as used in the preclinical studies did not produce
this response. The dose given to the volunteers was the
maximum immunostimulatory dose.
Non-human primate cells did not show a similar effect, nor were
there any adverse effects in-vivo
Inglis S. December 2007
ESG Final Report
TGN1412
TGN1412
Evoked
Evoked
Activation
Proliferation
______________________________________
Human
++++
++++
PBMC
______________________________________
Macaca
++
PBMC
______________________________________
PBMC: Peripheral Blood Mononuclear Cells
Mehrishi J, Szabo M, Bakacs T. Vaccine 2007 25(18) 3517
The Relevance of Animal Testing
"The relevance of animal testing, whether
artificially created disease models or healthy
animals for toxicology, has to be very seriously
questioned for testing of human-specific biologic
drugs. That's one of the key lessons of
TGN1412."
Dr David Glover
Nature Biotechnology Vol 25(5) May 2007 485
The Relevance of Animal Testing
All reports were highly critical of
limitations of animal tests in predicting
biological and pharmacological effects in
humans
The Relevance of Animal Testing
Academy of Medical Sciences/ Medical Research
Council/ Royal Society/ Wellcome Trust
Study into the use of Non-human Primates (NHP) in
Research
12 December 2006
Chair
Sir David Weatherall
Regius Professor of Medicine, Oxford University
Director, Institute of Molecular Medicine
“To examine the scientific basis for
recent, current and future use of
non-human
primates
within
biological and medical research”
Non-human Primates
• Keep to a minimum
• Only where absolutely necessary
• Optimise care
• Only in centres of excellence
• Details on welfare should be in
publications
• Encourage alternatives
Learning from Mistakes
• We have been assured repeatedly that proper procedures
were followed, when the real question is whether they were
the right procedures.
Goodyear M. BMJ March 25th 2006
• Nor will a collective claim of ‘not-guilty’ likely lead to
understanding and correction
Goodyear M. 2006
Potentially Incompatible Goals at F.D.A.
GARDINER HARRIS
June 11, 2007
Safety and speed are the yin and yang of drug regulation.
Patients want immediate access to breakthrough medicines
but also want to believe the drugs are safe.
These goals can be incompatible. Race a drug to market
and much is likely to remain unknown when patients take
it. Test a drug thoroughly to assess all possible risks and its
release may be delayed by years.
Health Research buckles under burden of red tape
Tony Tysome
5 May 2007
Academics have called for urgent action to end the
"bureaucratic nightmare" that is currently stifling vital
health-related research across the UK.
Thousands of researchers who are conducting studies
involving the National Health Service are struggling to cope
with red tape designed to regulate the quality of their work
and protect hospital patients.
Research proposals are being held up or dropped
altogether because of the time and costs involved in
gaining approval from the governance and ethics
committees
The Fall Out
• Virtual shut down of phase I testing in UK
• Migration to less regulated environments
(US)
"Is there any point to which you would
wish to draw my attention?"
"To the curious incident of the dog in
the night-time."
"The dog did nothing in the night-time."
"That was the curious incident,"
remarked Sherlock Holmes.
Conan-Doyle A. Silver Blaze 1892
Part III
The Good News:
Approaching transparency
Moving Forward
• Response to TGN1412
– This tragedy creates one more imperative for an open
culture in medical research, a culture that many fear is
increasingly losing its way
Goodyear M. BMJ March 25th 2006
His call for a culture of greater openness in medical
research is, I think, both powerful and timely
Gunn A USA TODAY March 27th 2006
– Maximum transparency to reaffirm trust in clinical trials
and their regulation. Commercial confidentiality should not
obstruct independent scrutiny
Lancet March 25th 2006
Moving Forward
• There is focus on sharing of information relevant to safety…
regulatory authorities should expedite the collection of information
from unpublished pre-clinical studies…in the interests of safety, we
believe that the ultimate goal should be an open access database
Expert Scientific Group Dec 2006
Clinical trial registration:
Transparency is the watchword
Sim I et al. May 20th 2006
Opening Address to World
Health Assembly, May 2005
"We
are
ready
forward
with
to
move
an
International Clinical Trials
Dr Jong-wook Lee
WHO Director-General
(died May 22 2006)
Registry. This will do much
to strengthen the research
process and its ability to win
public trust"
I Sim
January 2, 2007; 176 (1).
Free access to medical information: A
moral right?
Michael Goodyear
Department of Medicine, Dalhousie
University, Halifax, NS
May 2007 54: 331-335
Reporting research results: A moral
obligation for all researchers
David Moher
Department of Pediatrics, Epidemiology & Community Medicine,
University of Ottawa, Children's Hospital Eastern Ontario Research
Institute, Ottawa, Ontario, Canada
May 2007 54: 380-388
Publication bias in the medical
literature:
A review by a Canadian Research
Ethics Board
Hall R, de Antueno C, Webber A
Dalhousie University and the Capital District Health Authority, Halifax,
Nova Scotia, Canada
•44% Publication rate
•Phase III/IV >I/II
•Pharmaceutical Industry<Grant
•Significant >Insignificant
WHO
http://www.who.int/ictrp/en/
May 4 2007
Results reporting
Once a trial is registered, full transparency and
accountability requires that all of the trial's results be
made available to the public in a timely manner.
The ICMJE recognizes the potential benefit of having
information about preliminary trials in the public domain,
because these studies can guide future research or signal
safety concerns.
The ICMJE is expanding the definition of the types of trials
that must be registered to include these preliminary trials
and adopts the WHO’s definition of clinical trial:
“any research study that prospectively assigns human
participants or groups of humans to one or more healthrelated interventions to evaluate the effects on health
outcomes”
June 2007
The ICMJE will not consider results posted in the register
as previous publication if the results are presented in the
form of a brief, structured abstract or table.
The ICMJE favors a standard abstract format for results
reporting, and the CONSORT group’s guidelines for
abstracts related to trials may be one such option.
The ICMJE believes that parties should consider requiring
the deposition of such an abstract in the registry 24
months after closure of data collection if results are not
published in a peer-reviewed venue by that time.
June 2007
BMJ 2007;334:1080
Copyright ©2007 BMJ Publishing Group Ltd.
Summary (1)
• Left to its own devices research will not advance
•
•
•
•
the welfare of people
Blind repetition of worn ways of doing things
inevitably invites disaster
What we have learnt is the need for
collaboration and sharing
Registration represents one way of creating
openness in science
Responsible research is a collective culture
Summary (2)
• Ethics and regulations always lag behind
technology
• Biological agents and in particular
humanised agents require a new paradigm
for testing
• Animal testing may be limited in value
Thank you!