part iii lessons from tgn1412. tgn1412 “a watershed incident” fiona godlee, editor bmj a line in...

Part III

Lessons from TGN1412

TGN1412

“A Watershed Incident”

Fiona Godlee, Editor BMJ

A line in the sand?

A cautionary tale from Waltham MA

Hell of human guinea pigsHow the drug trial horror unfoldedBy MICHAEL SEAMARK, Daily Mail 17th March 2006

We saw human guinea pigs explodeVictims tearing at shirtsBy NICK PARKER, EMMA MORTON and JACQUI THORNTON 16th March 2006

Peer Review

• Wood AJ, Darbyshire J.

Injury to research volunteers--the clinical-research 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

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.

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.”

TGN1412TGN1412

TGN 1412

CD28 T Cell Receptor SuperAgonist

Humanised IgG4 Monoclonal Antibody

CD28

TGN 1412

• By-passes Costimulation by

Antigen Presenting Cell

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

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

TGN 1412

• Rapid onset – Cytokine Release Syndrome

– Angioedema

• Testing continued• Multiple Organ Failure• All subjects admitted to ICU• Prolonged immunosuppression• 1 still hospitalised, dry gangrene

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

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

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 (Maccaca)

• 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 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

Lessons to be learnt from TGN 1412 (4)

The Immune System is a Capricious Pandora’s Box!

Pandora 1898. John William WaterhouseBritish Pre-Raphaelite1849-1917Private 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?

Bhogal N, Combes R.

TGN1412: time to change the paradigm for the testing of new pharmaceuticals.Altern Lab Anim. 2006 May;34(2):225-3

Fund for the Replacement of Animals in Medical Experiments

a) The normal co-stimulatory mechanism of T-cell activation b) TGN1412 recognises single CD28 on receptor

Bhogal, Combes 2006

a) CD28 monomer and corresponding TGN1412 binding epitopeb) 3-D model of CD28 extracellular domainTGN1412 binding epitope circled

Bhogal, Combes 2006

Bhogal, Combes 2006

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.

The Relevance of Animal Testing

• Need to establish validity

• Staggered timing

• Microdosing

• Ex-vivo

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

"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 IV

Moving Forward?

Moving Forward?

• Adaptation in a Changing World

– Regulation and ethics always lags behind technology

• Transparency

• Governance

• Support

Moving Forward?

• Transparency– One of the biggest threats to research

integrity

– Trust and confidence can only be restored by a guaranty of 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 timelyGunn 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

Clinical trial registration: transparency is the watchword

Sim I et al. May 20th 2006

"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"

"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 LeeWHO Director-Generaldied May 22

Opening Address to World Opening Address to World Health Assembly, May 2005Health Assembly, May 2005

I Sim

Robert K Merton (1910-2003)

Restoring Normative Values

CUDOS

Moving Forward?

• Adaptation in a Changing World

– Regulation and ethics always lags behind technology

• Transparency

• Governance

• Support

Michael K Walsh, John J McNeil and Kerry J BreenImproving the governance of health researchMJA 2005; 182: 468–471

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

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

Medical hubris...has overvalued the state of our knowledge and failed to acknowledge the extent of our ignoranceMcCormick J. Medical hubris and the public health: the ethical dimension.J Clin Epidemiol. 1996 49:619