1. Part III
Lessons from TGN1412

2. TGN1412 “A Watershed Incident” Fiona Godlee, Editor BMJ
A line in the sand?
A cautionary tale from Waltham MA

3. Hell of human guinea pigs
How the drug trial horror unfolded
By MICHAEL SEAMARK, Daily Mail 17th March 2006
We saw human guinea pigs explode
Victims tearing at shirts
By NICK PARKER, EMMA MORTON and JACQUI THORNTON
16th March 2006

4. Peer Review Wood AJ, Darbyshire J.
Injury to research volunteers--the clinical-research nightmare. N Engl J Med May 4;354(18):
Ho MW, Cummins J.
London Drug Trial Catastrophe – Collapse of Science and Ethics: Postmortem on the TGN1412 disaster
Science in Society Summer 30: 44-5

5. 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.

6. 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”

7. 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.”

8. TGN1412

9. CD28 T Cell Receptor SuperAgonist Humanised IgG4 Monoclonal Antibody
TGN 1412
CD28 T Cell Receptor SuperAgonist
CD28
Humanised IgG4 Monoclonal Antibody

10. TGN 1412
By-passes Costimulation by
Antigen Presenting Cell

11. TGN 1412 First Time in Man Phase I March 13 2006
8 Subjects in first cohort
Healthy Male Volunteers
2 Placebo
6 Active
All 8 treated in rapid succession
Dose based on NOAEL
$4,000

12. TGN 1412 No Observed Adverse Effect Level
Primates tested up to 50mg/kg (NOAEL)
Clinical testing started at 0.1mg/kg
1/500 NOAEL
(NOAEL ≠ Pharmacologically effect)
0.3 – 5.0mg/kg

13. TGN 1412 Rapid onset Testing continued Multiple Organ Failure
Cytokine Release Syndrome
Angioedema
Testing continued
Multiple Organ Failure
All subjects admitted to ICU
Prolonged immunosuppression
1 still hospitalised, dry gangrene

14. Medicines and Healthcare Products Agency
TGN 1412
Medicines and Healthcare Products Agency
(MHRA)
Suspended CTA
Immediate Inquiry
Released
protocol, review and inquiry
UK Government announces expert inquiry
No review of ethical review to date

15. Expert Inquiry (Terms of Reference)
TGN 1412
Expert Inquiry (Terms of Reference)
What may be necessary in transition from pre-clinical 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 (August)
Minutes of meetings and interim findings to be made public

16. 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

19. 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

20. 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 (Maccaca)
Transparency in Development
Publishing preclinical work
Transparency of Reviews
Response to Disasters

21. 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 was 5mg/kg)

22. 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

23. 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
Private collection Oil on canvas

24. 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

25. The Relevance of Animal Testing?
Bhogal N, Combes R.
TGN1412: time to change the paradigm for the testing of new pharmaceuticals. Altern Lab Anim May;34(2):225-3
Fund for the Replacement of Animals in Medical Experiments

26. The normal co-stimulatory mechanism of T-cell activation
TGN1412 recognises single CD28 on receptor
Bhogal, Combes 2006

27. CD28 monomer and corresponding TGN1412 binding epitope
3-D model of CD28 extracellular domain
TGN1412 binding epitope circled
Bhogal, Combes 2006

28. Conservation of amino acid sequences of CD28.
Substitution of Glutamate (E) in Macacca mulatta (Rhesus) for Glycine (G) in human, could have profound conformal implications, and hence affect affinity binding and downstream effects.
Bhogal, Combes 2006

29. The Relevance of Animal Testing
Need to establish validity
Staggered timing
Microdosing
Ex-vivo

30. Learning from Mistakes
We have been assured repeatedly that proper procedures were followed, when the 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. CMAJ In press

31. "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

32. Part IV
Moving Forward?

33. Moving Forward? Adaptation in a Changing World
Regulation and ethics always lags behind technology
Transparency
Governance
Support

34. Moving Forward? Transparency
One of the biggest threats to research integrity
Trust and confidence can only be restored by a guaranty of transparency

35. 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

36. Clinical trial registration: transparency is the watchword
Sim I et al. May 20th 2006

37. Opening Address to World Health Assembly, May 2005
"We are ready to move forward with an International Clinical Trials Registry. This will do much to strengthen the research process and its ability to win public trust"
Dr Jong-wook Lee
WHO Director-General
died May 22
I Sim

38. Restoring Normative Values
Robert K Merton
( )
CUDOS

39. Moving Forward? Adaptation in a Changing World
Regulation and ethics always lags behind technology
Transparency
Governance
Support

40. Michael K Walsh, John J McNeil and Kerry J Breen
Improving the governance of health research
MJA 2005; 182: 468–471

42. Summary Research ethics has come a long way
In many ways it is unworkable, and unable to adapt
The whole scientific endeavour has come off the rails
Collaboration must replace competition
The process must be transparent and accountable
Responsible research is a collective culture

43. A Fundamental Cultural Shift is required to move from Competition to Collaboration, and from Secrecy to Transparency, if we are to move forward and restore Normative Values to Science, and Ethical Integrity to Research

44. Medical hubris...has overvalued the state of our knowledge and failed to acknowledge the extent of our ignorance
McCormick J. Medical hubris and the public health: the ethical dimension.
J Clin Epidemiol :619