Bench to Bedside A Curious Tail of Elephants, Rodents and other Primates or Bedside to Bench?...

Bench to BedsideBench to BedsideAA

Curious Tail of Elephants, Curious Tail of Elephants, Rodents and other PrimatesRodents and other Primates

or Bedside to Bench? or Bedside to Bench?

Michael GoodyearMichael Goodyear

Department of Medicine,Department of Medicine,Queen Elizabeth II Health Sciences Centre, Queen Elizabeth II Health Sciences Centre,

Dalhousie University, Halifax,Dalhousie University, Halifax,Nova Scotia, CanadaNova Scotia, Canada

MSMR Waltham MA, June 2007MSMR Waltham MA, June 2007

“If you have cancer and you're a mouse, we can take good care of you"

Judah FolkmanNY Times May 1988

Animal Welfare better than Animal Welfare better than People’s?People’s?

““The current situation in which national oversight of The current situation in which national oversight of research involving animals is far more effective and research involving animals is far more effective and independent than that for research involving humans independent than that for research involving humans would we believe be profoundly upsetting to the would we believe be profoundly upsetting to the Canadian people”.Canadian people”.

The Governance of Health Research Involving Human The Governance of Health Research Involving Human

SubjectsSubjects. . Law Commission of Canada, 2000.Law Commission of Canada, 2000.

Learning ObjectivesLearning Objectives

• I: The Bad News: The corruption I: The Bad News: The corruption of scienceof science

• II: Learning from disasters: The II: Learning from disasters: The story of TGN1412story of TGN1412

• III: The Good News: Approaching III: The Good News: Approaching transparencytransparency

SummarySummary

Part IPart I

The Bad News: The Bad News:

The corruption of scienceThe corruption of science

The Collapse of Scientific The Collapse of Scientific IntegrityIntegrity

• The ongoing crisis in public The ongoing crisis in public confidence and trustconfidence and trust

• The corrosion of the evidence base The corrosion of the evidence base in EBMin EBM

• Ongoing concernsOngoing concerns

Declaration of HelsinkiDeclaration of HelsinkiWORLD 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.

RosiglitazoneRosiglitazone

Class: Thiazolidinedione

May 21, 2007May 21, 2007

Rosiglitazone and Cardiovascular RiskRosiglitazone and Cardiovascular Risk

Bruce M. Psaty, M.D., Ph.D., and Curt D. Bruce M. Psaty, M.D., Ph.D., and Curt D. Furberg, M.D., Ph.D.Furberg, M.D., Ph.D.

Cardiovascular Health Research Unit, Departments of Medicine, Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Services, University of Washington, Epidemiology, and Health Services, University of Washington, and the Center for Health Studies, Group Health, Seattle; and and the Center for Health Studies, Group Health, Seattle; and the Division of Public Health Sciences, Wake Forest University, the Division of Public Health Sciences, Wake Forest University,

Winston-Salem, NCWinston-Salem, NC


The The possibilitypossibility of cardiovascular of cardiovascular benefitbenefit associated with the use of rosiglitazone seems associated with the use of rosiglitazone seems remoteremote. . In view of the potential cardiovascular risks In view of the potential cardiovascular risks and in the absence of evidence of other health and in the absence of evidence of other health advantages, advantages, except for laboratory measuresexcept for laboratory measures of of glycemic control, the rationale for prescribing glycemic control, the rationale for prescribing rosiglitazone at this time is unclear. rosiglitazone at this time is unclear. Unless new data provide a different picture of Unless new data provide a different picture of the risk–benefit profile, the risk–benefit profile, regulatory action by regulatory action by the Food and Drug Administration (FDA) the Food and Drug Administration (FDA) is now warrantedis now warranted. .


During the market life of rosiglitazone, During the market life of rosiglitazone, tens of millions of prescriptions for the tens of millions of prescriptions for the drug have been written for patients with drug have been written for patients with type 2 diabetes. type 2 diabetes.

Rosiglitazone represents Rosiglitazone represents a major failure a major failure of the drug-use and drug-approval of the drug-use and drug-approval processes in the United Statesprocesses in the United States..

RosiglitazoneRosiglitazonePhysicians who chose to prescribe Physicians who chose to prescribe rosiglitazone focused on the rosiglitazone focused on the single single dimensiondimension of glycemic control. of glycemic control.The underlying assumption represents a The underlying assumption represents a kind of kind of linear "physiological" argumentlinear "physiological" argument: : high levels of glycated hemoglobin increase high levels of glycated hemoglobin increase risk, so a reduction in glycated hemoglobin risk, so a reduction in glycated hemoglobin will will automatically translate into improved automatically translate into improved health outcomeshealth outcomes for patients. for patients. Many physicians did not require Many physicians did not require proof of proof of health benefitshealth benefits as a criterion for selecting as a criterion for selecting rosiglitazone as a therapy for type 2 rosiglitazone as a therapy for type 2 diabetes.diabetes.


Had practicing physicians required this Had practicing physicians required this higher standardhigher standard, they would have been at a , they would have been at a loss for evidence from large, long-term trials.loss for evidence from large, long-term trials.

Rosiglitazone was Rosiglitazone was approvedapproved on the basis of on the basis of short-term studiesshort-term studies of the of the surrogate end pointsurrogate end point of glycemic control. of glycemic control.

The use of surrogate end points in the The use of surrogate end points in the drug-approval process has been drug-approval process has been problematicproblematic


RofecoxibRofecoxib, whose biologic actions , whose biologic actions early on suggested the possibility of early on suggested the possibility of both gastrointestinal benefit and both gastrointestinal benefit and cardiovascular harm, cardiovascular harm, represented a represented a similar regulatory failuresimilar regulatory failure to insist to insist on large trials of public health on large trials of public health importance in a timely fashion. importance in a timely fashion.

Rofecoxib

Class: COX-2 Inhibitor

Pharmacoeconomics

After Sanctions, Doctors Get Drug Company Pay Gardiner Harris and Janet RobertsJune 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 One of Dr. Abuzzahab’s patients was David Olson, whom the psychiatrist the psychiatrist tried repeatedly to recruit for clinical tried repeatedly to recruit for clinical trialstrials. Drug makers paid Dr. Abuzzahab thousands of . Drug makers paid Dr. Abuzzahab thousands of dollars for every patient he recruited. In July 1997, dollars for every patient he recruited. In July 1997, when when Mr. Olson again refusedMr. Olson again refused to be a test subject, Dr. to be a test subject, Dr. Abuzzahab Abuzzahab discharged him from the hospitaldischarged him from the hospital even though even though he was suicidal, records show. he was suicidal, records show. Mr Olson committed suicideMr Olson committed suicide two weeks later.two weeks later.

From 1997 to 2005, at least From 1997 to 2005, at least 103 doctors who had been 103 doctors who had been disciplined or criticized by the state medical board disciplined or criticized by the state medical board received a total of $1.7 million from drug makers.received a total of $1.7 million from drug makers. The The median payment over that period was $1,250; the largest median payment over that period was $1,250; the largest was $479,000. was $479,000.

Part IIPart II

Learning from disasters:Learning from disasters:

The story of TGN1412 The story of TGN1412 Is animal testing still Is animal testing still

relevant?relevant?

Pharmacological Pharmacological EvolutionEvolution

• Switching from classic chemical Switching from classic chemical pharmacology to biologicalpharmacology to biological– Loss of classic dose-response paradigmsLoss of classic dose-response paradigms

• Humanisation of antibodiesHumanisation of antibodies– Intra-species variationIntra-species variation– Immunogenicity in animals, Immunogenicity in animals,

neutralisation and masking of toxicityneutralisation and masking of toxicity

• Increasing uncertainty Increasing uncertainty

Safety in Phase ISafety in Phase I First-in-Man Trials First-in-Man Trials

• Repeated reassurancesRepeated reassurances– Orme M et al.Orme M et al. Br J Clin Pharmacol 1989 27: Br J Clin Pharmacol 1989 27:

125125• Mild 6.9%Mild 6.9%• Moderate 0.55%Moderate 0.55%• Serious 0.04%Serious 0.04%

– Sibille M et al.Sibille M et al. Eur J Clin Pharmacol 1986 Eur J Clin Pharmacol 1986 20: 24320: 243

– Lutfullin AJ et al.Lutfullin AJ et al. Int J Clin Pharmacol Ther Int J Clin Pharmacol Ther 2005 43: 2172005 43: 217• Severe 0.2% Severe 0.2%

– BUT: None were biological trialsBUT: None were biological trials

Learning OpportunitiesLearning Opportunities

• TGN1412 and Cytokine Release TGN1412 and Cytokine Release SyndromeSyndrome

• Natalizumab and PNatalizumab and Progressive rogressive Multifocal Leukoencephalopathy Multifocal Leukoencephalopathy ((PML)PML)

TGN1412TGN1412

““A Watershed Incident”A Watershed Incident”

Fiona Godlee, Editor BMJFiona Godlee, Editor BMJ

A line in the sand?A line in the sand?

A cautionary tale from Waltham MA

VOLUME 332 25 MARCH 2006 677-8VOLUME 332 25 MARCH 2006 677-8

Learning from the TGN1412 trialLearning from the TGN1412 trialThis experience should foster an open culture in This experience should foster an open culture in

medical researchmedical research


Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, CanadaCanada

Hell of human guinea pigsHow the drug trial horror unfoldedBy MICHAEL SEAMARK17th March 2006

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

Myfanwy Marshall, 35, whose boyfriend is critically ill, said the normally healthy 28-year-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: 566-717 March 2007 334: 566-7

““We Saw human guinea pigs explode”:We Saw human guinea pigs explode”:Newspaper coverage of adverse events in the Newspaper coverage of adverse events in the

TGN14412 trialTGN14412 trial

Stobbart L, Murtagh MJ, Rapley T et al.Stobbart L, Murtagh MJ, Rapley T et al.

Institute of Health and Society, Newcastle University, Newcastle Institute of Health and Society, Newcastle University, Newcastle upon Tyneupon Tyne

Peer ReviewPeer Review

•Wood AJ, Darbyshire J.Wood AJ, Darbyshire J.

Injury to research volunteers--the clinical-Injury to research volunteers--the clinical-research research nightmarenightmare..

N Engl J Med. 2006 May 4;354(18):1869-71N Engl J Med. 2006 May 4;354(18):1869-71

•Ho MW, Cummins J.Ho MW, Cummins J.

London Drug Trial Catastrophe – London Drug Trial Catastrophe – Collapse of Collapse of Science and EthicsScience and Ethics: Postmortem on the : Postmortem on the TGN1412 TGN1412 disasterdisaster

Science in Society. 2006 Summer 30: 44-5Science in Society. 2006 Summer 30: 44-5

• Liedert B, Bassus S, Schneider U et al.Liedert B, Bassus S, Schneider U et al. Safety of phase I clinical trials with Safety of phase I clinical trials with monoclonal antibodies in Germany – the monoclonal antibodies in Germany – the regulatory requirements viewed in the regulatory requirements viewed in the aftermath of the TGN1412 aftermath of the TGN1412 disasterdisaster

International Journal of Clinical International Journal of Clinical Pharmacology and Therapeutics 2007 45(1) Pharmacology and Therapeutics 2007 45(1) 1-91-9

The Elephant in the RoomThe Elephant in the Room

EditorialEditorial

14 December 200614 December 2006

Less satisfactory is the Government’s Less satisfactory is the Government’s failure so far to hold anybody failure so far to hold anybody accountable for the Northwick Park accountable for the Northwick Park incident. The MHRA exonerated both incident. The MHRA exonerated both itself and Parexel.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.”

TGN1412TGN1412

TGN 1412TGN 1412

CD28 T Cell Receptor CD28 T Cell Receptor SuperAgonistSuperAgonist

Humanised IgG4 Mouse anti-Human CD28 Monoclonal Antibody

CD28

TGN 1412TGN 1412

• CD28 – CD28 – – Costimulatory receptor on CD4+ and Costimulatory receptor on CD4+ and

CD8+ T CellsCD8+ T Cells

• Requires costimulation from T cell Requires costimulation from T cell antigen receptor (TCR) to activate T antigen receptor (TCR) to activate T helper cellshelper cells

• TGN1412 bypasses TCR and activates TGN1412 bypasses TCR and activates T cells irrespective of TCR specificity T cells irrespective of TCR specificity

TGN 1412TGN 1412

• By-passes Costimulation byBy-passes Costimulation by

Antigen Presenting CellAntigen Presenting Cell

TGN 1412TGN 1412Phase I First Time in ManPhase I First Time in Man

• $4,000 Incentive $4,000 Incentive • March 13 2006 08.00March 13 2006 08.00• 8 Subjects in first dose level cohort8 Subjects in first dose level cohort

– Healthy Male Volunteers, Age 26 (19-34)Healthy Male Volunteers, Age 26 (19-34)•2 Placebo – hidden allocation2 Placebo – hidden allocation•6 Active6 Active

• All 8 treated in rapid successionAll 8 treated in rapid succession– 3-6 min ivi3-6 min ivi

• Dose based on Dose based on NOAELNOAEL

TGN 1412TGN 1412

NOAEL:NOAEL:

NNo o OObserved bserved AAdverse dverse EEffect ffect LLevelevel

• Primates tested up to 50mg/kg Primates tested up to 50mg/kg – (NOAEL)(NOAEL)

• Clinical testing started at 1/500 Clinical testing started at 1/500 NOAEL NOAEL – 0.1mg/kg0.1mg/kg

TGN 1412TGN 1412

• BUTBUT::

NOAELNOAEL

≠ ≠

PPharmacological effect (NOEL)harmacological effect (NOEL)(0.3 – 5.0mg/kg)(0.3 – 5.0mg/kg)

• Therefore:Therefore:– Treated close to Effect Level Treated close to Effect Level

(0.1mg/kg)(0.1mg/kg)

TGN 1412TGN 1412

EffectsEffects

• Rapid onset Rapid onset – Cytokine Release SyndromeCytokine Release Syndrome– AngioedemaAngioedema

Testing continuedTesting continued

• Multiple Organ FailureMultiple Organ Failure

• All subjects admitted to ICUAll subjects admitted to ICU

• Prolonged immunosuppressionProlonged immunosuppression

TGN 1412TGN 1412

TreatmentTreatment

• Life supportLife support

• High dose steroidsHigh dose steroids

• Daclizumab (anti-IL2 receptor Daclizumab (anti-IL2 receptor antagonist)antagonist)

TGN 1412TGN 1412

Amputations for dry gangreneAmputations for dry gangrene

TGN 1412TGN 1412

CurrentlyCurrently

•Loss of memoryLoss of memory

•Inability to concentrateInability to concentrate

•HeadachesHeadaches

•UlcersUlcers

TGN 1412TGN 1412

Medicines and Healthcare Products AgencyMedicines and Healthcare Products Agency(MHRA)(MHRA)

• Suspended CTASuspended CTA• Immediate InquiryImmediate Inquiry• ReleasedReleased

– protocol, review and inquiryprotocol, review and inquiry• Reports April 5, May 25Reports April 5, May 25

• FIM Immunomodulation trials on indefinite holdFIM Immunomodulation trials on indefinite hold

UK Government announced independent expert inquiryUK Government announced independent expert inquiry

No review of ethical reviewNo review of ethical review

TGN 1412TGN 1412

Expert Inquiry (Terms of Reference)Expert Inquiry (Terms of Reference)• What may be necessary in transition from pre-What may be necessary in transition from pre-

clinical to first-in-man Phase 1 studies, clinical to first-in-man Phase 1 studies, specifically:specifically:

– Biological molecules with novel mechanisms of action Biological molecules with novel mechanisms of action – New agents with highly species-specific action New agents with highly species-specific action – New drugs for immune system targets New drugs for immune system targets

• Interim report within 3 months, final in 6 Interim report within 3 months, final in 6 • Minutes of meetings and interim findings to be Minutes of meetings and interim findings to be

made public made public

TGN 1412TGN 1412Expert Scientific Group Expert Scientific Group

InquiryInquiry

ChairChair

Professor Sir Gordon DuffFlorey Professor of Molecular Medicine

University of Sheffield

Expert Scientific GroupExpert Scientific Group

Phase One Clinical TrialsPhase One Clinical Trials

Interim ReportInterim Report

2525thth July 2006 July 2006

Final ReportFinal Report

3030thth November 2006 November 2006

VOLUME 333 5 AUGUST 2006 270-1VOLUME 333 5 AUGUST 2006 270-1

Further lessons from the TGN1412 Further lessons from the TGN1412 tragedytragedy

New guidelines call for a change in the culture New guidelines call for a change in the culture of researchof research


Department of Medicine, Dalhousie University, Halifax, Nova Department of Medicine, Dalhousie University, Halifax, Nova Scotia, CanadaScotia, Canada

Further LessonsFurther Lessons

• Common sense, avoiding blameCommon sense, avoiding blame• A retreat from blind process to judiciousnessA retreat from blind process to judiciousness

– Stopping the clockStopping the clock• Recognises the problem of increasing Recognises the problem of increasing

commercialisation, and lack of experience and commercialisation, and lack of experience and planningplanning

• Places onus on sponsor to demonstrate needPlaces onus on sponsor to demonstrate need• Places openness above proprietary interestsPlaces openness above proprietary interests• While constrained by narrow remit, needs to draw While constrained by narrow remit, needs to draw

attention to broader issuesattention to broader issues• Failed to identify the elephant in the roomFailed to identify the elephant in the room• Why are we asking these questions now?Why are we asking these questions now?

Testing Antibody Therapies:Testing Antibody Therapies:

Position PaperPosition Paper

April 2006April 2006

Had previously warned of Had previously warned of possibility in November 2005 - possibility in November 2005 -

Early Stage Clinical Trial TaskforceEarly Stage Clinical Trial Taskforce

July 2006July 2006

1. On-line August 141. On-line August 14

Volume 355:1018-1028Volume 355:1018-1028 September 6September 611, 2006, 2006 Number 10Number 10 Cytokine Storm in a Phase 1 Trial of the Cytokine Storm in a Phase 1 Trial of the Anti-CD28 Monoclonal Antibody TGN1412Anti-CD28 Monoclonal Antibody TGN1412

Ganesh Suntharalingam, F.R.C.A., Meghan R. Ganesh Suntharalingam, F.R.C.A., Meghan R. Perry, M.R.C.P., Stephen Ward, F.R.C.A., Perry, M.R.C.P., Stephen Ward, F.R.C.A.,

Stephen J. Brett, M.D., Andrew Castello-Cortes, Stephen J. Brett, M.D., Andrew Castello-Cortes, F.R.C.A., Michael D. Brunner, F.R.C.A., and F.R.C.A., Michael D. Brunner, F.R.C.A., and

Nicki Panoskaltsis, M.D., Ph.D.Nicki Panoskaltsis, M.D., Ph.D. Department of Intensive Care Medicine, Northwick Park and St. Department of Intensive Care Medicine, Northwick Park and St.

Mark's Hospital, Watford Rd., Harrow, London HA1 3UJ, United Mark's Hospital, Watford Rd., Harrow, London HA1 3UJ, United Kingdom Kingdom

http://content.nejm.org/cgi/content/short/355/10/1029?query=nextarrow

Event times for 8 healthy volunteers in TGN1412 study13 March 2006

Volunteer Allocation Time of i.v. Time to ICU

A TG 8.4mg 08:00 16 hrs B Placebo 08:10 C TG 6.8mg 08:20 15.5hrs D TG 8.8mg 08:30 16hrs E TG 8.2mg 08:40 12hrs F TG 7.2mg 08.50 16hrs G TG 8.2mg 09:00 16hrs H Placebo 09:10

Cytokine Release D1-5Cytokine 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 FIM trials with high risk agents will require input from an Expert Advisory Group prior to input from an Expert Advisory Group prior to CTA applicationCTA application

Feb 7 2007Feb 7 2007

•Convened “Convened “Lessons from TGN-1412Lessons from TGN-1412” ” Conference, and Implementation CommitteeConference, and Implementation Committee

•Developing accreditation of investigators Developing accreditation of investigators and sites and sites

•Developed guidance through EMEADeveloped guidance through EMEA

GUIDELINE ON REQUIREMENTS GUIDELINE ON REQUIREMENTS FOR FOR

FIRST-IN-MAN CLINICAL TRIALS FIRST-IN-MAN CLINICAL TRIALS FOR POTENTIAL HIGH-RISK FOR POTENTIAL HIGH-RISK

MEDICINAL PRODUCTSMEDICINAL PRODUCTS

London, March 2007London, March 2007

Recommendations (Recommendations (11))

Expert Group: 22 RecommendationsExpert Group: 22 Recommendations- - Safety and Good ScienceSafety and Good Science - -

1.1. Preclinical and early clinical developmentPreclinical and early clinical development

2.2. Preparation and review of clinical trials Preparation and review of clinical trials applicationsapplications

3.3. Determining and administering the initial Determining and administering the initial dose in humansdose in humans

4.4. The clinical environment for first-in-man The clinical environment for first-in-man studiesstudies

5.5. Developing expertiseDeveloping expertise


1.1. Preclinical and early clinical developmentPreclinical and early clinical development

• Development must be on case by case basis, Development must be on case by case basis, and risk basedand risk based

• Regulatory process to be reviewed regularlyRegulatory process to be reviewed regularly• All preclinical and Phase I data must be All preclinical and Phase I data must be

available and sharedavailable and shared• Presubmission should include expert Presubmission should include expert

consultationconsultation


2.2. Preparation and review of clinical trials Preparation and review of clinical trials applicationsapplications

• Timelines must be flexibleTimelines must be flexible


3.3. Determining and administering the initial Determining and administering the initial dose in humans dose in humans

• Dose selection must go beyond NOEL and Dose selection must go beyond NOEL and NOAELNOAEL

• Minimal Anticipated Biological Effect Level Minimal Anticipated Biological Effect Level (MABEL)(MABEL)

• If preclinical models provide little If preclinical models provide little information – err on side of cautioninformation – err on side of caution

• Use Slow infusionsUse Slow infusions• Design must be justified scientifically and Design must be justified scientifically and

statisticallystatistically


3. (Cont’d.)3. (Cont’d.)

• Agents should not be administered to more Agents should not be administered to more than one subject simultaneouslythan one subject simultaneously

• Choice of healthy volunteers must be Choice of healthy volunteers must be justifiedjustified


4.4. The clinical environment for first-in-man The clinical environment for first-in-man studiesstudies

• PIs must be highly qualifiedPIs must be highly qualified

• Contingency plans for SAEs must be in placeContingency plans for SAEs must be in place

• FIM studies should take place in specialised FIM studies should take place in specialised centrescentres


5.5. Developing expertiseDeveloping expertise

• Specialised training of investigators is Specialised training of investigators is needed together with development of needed together with development of specialist centresspecialist centres


• Many issues were raised that were Many issues were raised that were outside the remit of the committeeoutside the remit of the committee– ConsentConsent– CommunicationCommunication– InsuranceInsurance– Research Ethics CommitteesResearch Ethics Committees– Follow up of subjectsFollow up of subjects

• Recommend these be investigatedRecommend these be investigated

Recommendations 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

• Attempt to implement recommendationsAttempt to implement recommendations• Relevance of animal models must be Relevance of animal models must be

justifiedjustified• IDMSCIDMSC

Criticised as weakCriticised as weak

Draft GuidelineConsultation to May 23

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 guidelineDrugResearcher.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 The American Journal of Bioethics, Volume 7 Issue 2

2007 76-812007 76-81

Money and Distorted Ethical Judgments Money and Distorted Ethical Judgments about Research: Ethical Assessment about Research: Ethical Assessment

of the TeGenero TGN1412 Trialof the TeGenero TGN1412 Trial

Ezekiel J. Emanuel; Franklin G. MillerEzekiel J. Emanuel; Franklin G. Miller Department of Clinical Bioethics, National Institutes of Health, Department of Clinical Bioethics, National Institutes of Health,

BethesdaBethesda

ResponsesResponses• Risk, Judgment and Fairness in Research Incentives Risk, Judgment and Fairness in Research Incentives 82 – 8382 – 83

Benjamin HaleBenjamin Hale• Evaluation of Research Design by Research Ethics Evaluation of Research Design by Research Ethics

Committees: Misleading Reassurance and the Need for Committees: Misleading Reassurance and the Need for Substantive Reforms Substantive Reforms 84 – 8684 – 86Howard MannHoward Mann

• Money Matters Money Matters 86 – 8886 – 88Toby Schonfeld; Bruce Gordon; Jean Amoura; Joseph Spencer BrownToby Schonfeld; Bruce Gordon; Jean Amoura; Joseph Spencer Brown

• Money, Advertising and Seduction in Human Subjects Money, Advertising and Seduction in Human Subjects ResearchResearch88 – 9088 – 90Trisha B. PhillipsTrisha B. Phillips

• Ethical Flaws in the TeGenero Trial Ethical Flaws in the TeGenero Trial 90 – 9290 – 92Adil Shamoo; Elizabeth WoecknerAdil Shamoo; Elizabeth Woeckner

• Faulty Premise, Premature Conclusion: That Money Was Faulty Premise, Premature Conclusion: That Money Was Extraneous to the Research Ethics of the TGN1412 Study Extraneous to the Research Ethics of the TGN1412 Study 93 – 93 – 9494Bethany SpielmanBethany Spielman

Allied Research International is always recruiting for normal healthy study Allied Research International is always recruiting for normal healthy study participants for our phase I and bioequivalence studies. We conduct our participants for our phase I and bioequivalence studies. We conduct our studies in a cheerful, safe, and respectful environment. Our meals are second studies in a cheerful, safe, and respectful environment. Our meals are second to none and to none and …now with 100% more …now with 100% more pool tablespool tables!!

$950

Swiss Cheese Model of Patient Safety (Reason)

Lessons to be learnt fromLessons to be learnt from TGN 1412 ( TGN 1412 (11))

• RecruitmentRecruitment– Financial IncentivesFinancial Incentives

• Adequacy of InformationAdequacy of Information

• Choice of Subject in Phase IChoice of Subject in Phase I

• Number of SubjectsNumber of Subjects

• Timing of AdministrationTiming of Administration


• RecruitmentRecruitment

• Adequacy of InformationAdequacy of Information– ConsentConsent

• Choice of Subject in Phase IChoice of Subject in Phase I– Healthy volunteersHealthy volunteers

• Number of SubjectsNumber of Subjects

• Timing of AdministrationTiming of Administration


• Sources of Information ReviewedSources of Information Reviewed– Regulatory ReviewRegulatory Review– Ethical ReviewEthical Review

• Place of Independent Expert ReviewPlace of Independent Expert Review

• Relevance of Preclinical TestingRelevance of Preclinical Testing– Interspecies difference (Macaca)Interspecies difference (Macaca)

• Transparency in DevelopmentTransparency in Development– Publishing preclinical workPublishing preclinical work

• Transparency of Reviews Transparency of Reviews

• Response to DisastersResponse to Disasters


• Caution inCaution in– developing immunomodulatorsdeveloping immunomodulators– agonistsagonists– bypassing regulatory mechanisms (super)bypassing regulatory mechanisms (super)

• Assumptions about Dose-ResponseAssumptions about Dose-Response– non-linearnon-linear– bell shaped bell shaped

•(optimum dose in Macaca was 5mg/kg)(optimum dose in Macaca was 5mg/kg)


• Homology may not mean affinityHomology may not mean affinity

• Affinity may not translate Affinity may not translate downstream downstream

• Even monoclonals are not specificEven monoclonals are not specific

• Standards for preclinical testingStandards for preclinical testing

• Avoid check-box mentalityAvoid check-box mentality


The Immune The Immune System is a System is a Capricious Capricious Pandora’s Box! Pandora’s Box!

Pandora 1898. John William WaterhouseBritish Pre-Raphaelite (1849-1917)Private collection, Oil on canvas


• Relationships with industryRelationships with industry

• Adequacy of training of staffAdequacy of training of staff

• Adequacy of facilitiesAdequacy of facilities

• Adequacy of liability insuranceAdequacy of liability insurance

Plan for the worst, hope for the Plan for the worst, hope for the bestbest

The Relevance of Animal TestingThe Relevance of Animal Testing

Altern Lab Anim. 2006 May;34(2):225-3Altern Lab Anim. 2006 May;34(2):225-3

TGN1412: time to change the paradigm TGN1412: time to change the paradigm for the testing of new pharmaceuticalsfor the testing of new pharmaceuticals

Bhogal N, Combes R Bhogal N, Combes R

Fund for the Replacement of Animals in Medical Experiments

Focus On Alternatives


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 ReceptorCD28 Receptor

a) CD28 monomer and corresponding TGN1412 binding epitopeb) 3-D model of CD28 extracellular domainTGN1412 binding epitope ( C’’D loop ) circled – 6 AAs

Bhogal, Combes 2006

Macaca mulatta (Rhesus)Macaca fasicularis (Cynomulgus)

Mus musculus

Sylvilagus audubonii

Rattus rattus

Bhogal, Combes 2006

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.

2007 Apr 1;109(7):2968-772007 Apr 1;109(7):2968-77 Physiologic and aberrant regulation Physiologic and aberrant regulation

of memory T-cell trafficking by the of memory T-cell trafficking by the costimulatory molecule CD28costimulatory molecule CD28

Mirenda V, Jarmin SJ, David R, Dyson J, Mirenda V, Jarmin SJ, David R, Dyson J, Scott D, Gu Y, Lechler RI, Okkenhaug K, Scott D, Gu Y, Lechler RI, Okkenhaug K,

Marelli-Berg Federica MMarelli-Berg Federica M.. Department of Immunology, Division of Medicine, Department of Immunology, Division of Medicine, Imperial College London, Hammersmith Campus, Imperial College London, Hammersmith Campus, London, United KingdomLondon, United Kingdom

How Clean is Your Lab?How Clean is Your Lab?

• Memory helper T cells react differently Memory helper T cells react differently to TGN1412 than do Ag naïve T cells to TGN1412 than do Ag naïve T cells

• Humans have up to 50% T cells Humans have up to 50% T cells activated (memory)activated (memory)

• Laboratory animals have few memory T Laboratory animals have few memory T cells due to rearing conditionscells due to rearing conditions

• CD28 activated memory T cells migrate CD28 activated memory T cells migrate into extra-lymphoid tissues causing into extra-lymphoid tissues causing damage, naïve T cells do notdamage, naïve T cells do not

Why use inbred pathogen free animals to Why use inbred pathogen free animals to test drugs to be used on outbred pathogen test drugs to be used on outbred pathogen exposed people?exposed people?

Activated T cells susceptible to over Activated T cells susceptible to over stimulation if isolated from costimulatory stimulation if isolated from costimulatory requirements of antigen specificityrequirements of antigen specificitySharpe AH, Abbas AKSharpe AH, Abbas AKNEJM NEJM 2006 Sep 7;355(10):973-5. 2006 Sep 7;355(10):973-5.

National Institute for Biological Standards and National Institute for Biological Standards and

ControlControl

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 2007ESG Final Report

TGN1412 TGN1412Evoked EvokedActivation 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, whether "The relevance of animal testing, whether artificially created disease models or artificially created disease models or healthy animals for toxicology, has to be healthy animals for toxicology, has to be very seriously questioned for testing of very seriously questioned for testing of human-specific biologic drugs. That's one human-specific biologic drugs. That's one of the of the key lessonskey lessons of TGN1412." of TGN1412." Dr David GloverDr David GloverNature Biotechnology Vol 25(5) May 2007 485


All reports were highly critical of All reports were highly critical of limitations of animal tests in limitations of animal tests in predicting biological and predicting biological and pharmacological effects in humanspharmacological effects in humans


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

ChairSir David Weatherall

Regius Professor of Medicine, Oxford UniversityDirector, 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 PrimatesNon-human Primates

• Keep to a minimumKeep to a minimum

• Only where absolutely necessaryOnly where absolutely necessary

• Optimise careOptimise care

• Only in centres of excellenceOnly in centres of excellence

• Details on welfare should be in Details on welfare should be in publicationspublications

• Encourage alternativesEncourage alternatives

Learning from MistakesLearning from Mistakes

• We have been assured repeatedly that proper We have been assured repeatedly that proper procedures were followed, when the real question is procedures were followed, when the real question is whether they were the right procedures.whether they were the right procedures.

Goodyear M. BMJ March 25Goodyear M. BMJ March 25thth 2006 2006

• Nor will a collective claim of ‘not-guilty’ likely lead to Nor will a collective claim of ‘not-guilty’ likely lead to understanding and correctionunderstanding and correction

Goodyear M. 2006Goodyear M. 2006

Potentially Incompatible Goals at F.D.A. Potentially Incompatible Goals at F.D.A. GARDINER HARRISGARDINER HARRISJune 11, 2007June 11, 2007

Safety and speed are the yin and yang of drug Safety and speed are the yin and yang of drug regulation. Patients want immediate access to regulation. Patients want immediate access to breakthrough medicines but also want to believe the breakthrough medicines but also want to believe the drugs are safe.drugs are safe.

These goals can be incompatible. Race a drug to These goals can be incompatible. Race a drug to market and much is likely to remain unknown when market and much is likely to remain unknown when patients take it. Test a drug thoroughly to assess all patients take it. Test a drug thoroughly to assess all possible risks and its release may be delayed by possible risks and its release may be delayed by years.years.

Health Research buckles under burden of red tapeHealth Research buckles under burden of red tapeTony TysomeTony Tysome5 May 20075 May 2007

Academics have called for urgent action to end the Academics have called for urgent action to end the "bureaucratic nightmare" that is currently stifling vital "bureaucratic nightmare" that is currently stifling vital health-related research across the UK. health-related research across the UK. Thousands of researchers who are conducting studies Thousands of researchers who are conducting studies involving the National Health Service are struggling to cope involving the National Health Service are struggling to cope with red tape designed to regulate the quality of their work with red tape designed to regulate the quality of their work and protect hospital patients. and protect hospital patients. Research proposals are being held up or dropped altogether Research proposals are being held up or dropped altogether because of the time and costs involved in gaining approval because of the time and costs involved in gaining approval from the governance and ethics committeesfrom the governance and ethics committees

The Fall OutThe Fall Out

• Virtual shut down of phase I testing Virtual shut down of phase I testing in UKin UK

• Migration to less regulated Migration to less regulated environments (US)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 IIIPart III

The Good News: The Good News:

Approaching Approaching transparency transparency

Moving ForwardMoving Forward• Response to TGN1412Response to TGN1412

– This tragedy creates one more imperative for an This tragedy creates one more imperative for an openopen culture in medical research, a culture that many culture in medical research, a culture that many fear is increasingly losing its wayfear is increasingly losing its way Goodyear M. BMJ March 25Goodyear M. BMJ March 25thth 2006 2006

His call for a culture of greater His call for a culture of greater opennessopenness in medical in medical research is, I think, both powerful and timelyresearch is, I think, both powerful and timelyGunn A USA TODAY March 27Gunn A USA TODAY March 27thth 2006 2006

– Maximum Maximum transparencytransparency to reaffirm trust in clinical to reaffirm trust in clinical trials and their regulation. Commercial confidentiality trials and their regulation. Commercial confidentiality should not obstruct independent scrutinyshould not obstruct independent scrutiny Lancet March 25Lancet March 25thth 2006 2006

Moving ForwardMoving Forward

• There is focus on There is focus on sharing sharing of information relevant to safety… of information relevant to safety… regulatory authorities should expedite the collection of regulatory authorities should expedite the collection of information from information from unpublishedunpublished pre-clinical studies…in the pre-clinical studies…in the interests of safety, we believe that the ultimate goal should interests of safety, we believe that the ultimate goal should be an be an open accessopen access database database

Expert Scientific Group Dec 2006Expert Scientific Group Dec 2006

Clinical trial registration:Clinical trial registration:

Transparency is the watchwordTransparency is the watchword

Sim I et al. May 20Sim I et al. May 20thth 2006 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-General(died May 22 2006)

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

I Sim

January 2, 2007; 176 (1).January 2, 2007; 176 (1).

Free access to medical Free access to medical information: A moral right?information: A moral right?


Department of Medicine, Dalhousie Department of Medicine, Dalhousie University, Halifax, NSUniversity, Halifax, NS

May 2007 54: 331-335May 2007 54: 331-335

Reporting research results: A Reporting research results: A moral obligation for all moral obligation for all

researchersresearchers

David MoherDavid MoherDepartment of Pediatrics, Epidemiology & Community Department of Pediatrics, Epidemiology & Community

Medicine, University of Ottawa, Children's Hospital Eastern Medicine, University of Ottawa, Children's Hospital Eastern Ontario Research Institute, Ottawa, Ontario, CanadaOntario Research Institute, Ottawa, Ontario, Canada

May 2007 54: 380-388May 2007 54: 380-388

Publication bias in the medical Publication bias in the medical literature: literature:

A review by a Canadian Research A review by a Canadian Research Ethics BoardEthics Board

Hall R, de Antueno C, Webber AHall R, de Antueno C, Webber A Dalhousie University and the Capital District Health Authority, Dalhousie University and the Capital District Health Authority,

Halifax, Nova Scotia, CanadaHalifax, Nova Scotia, Canada

•44% Publication rate •Phase III/IV >I/II•Pharmaceutical Industry<Grant•Significant >Insignificant

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 The ICMJE recognizes the potential benefit of having information about information about preliminarypreliminary trials in the public domain, trials in the public domain, because these studies can guide future research or signal because these studies can guide future research or signal safety concerns. safety concerns.

The ICMJE is The ICMJE is expanding the definitionexpanding the definition of the types of trials of the types of trials that must be registered to include these preliminary trials that must be registered to include these preliminary trials and adopts the and adopts the WHO’s definitionWHO’s definition of clinical trial: of clinical trial: ““any research study that prospectively any research study that prospectively assignsassigns human human participants or groups of humans to one or more health-participants or groups of humans to one or more health-related interventions to evaluate the effects on health related interventions to evaluate the effects on health outcomes”outcomes”

June 2007June 2007

The ICMJE will The ICMJE will notnot consider results posted in the register consider results posted in the register as as previous publicationprevious publication if the results are presented in the if the results are presented in the form of a brief, structured abstract or table.form of a brief, structured abstract or table.

The ICMJE favors a standard abstract format for results The ICMJE favors a standard abstract format for results reporting, and the CONSORT group’s guidelines for reporting, and the CONSORT group’s guidelines for abstracts related to trials may be one such option.abstracts related to trials may be one such option.

The ICMJE believes that parties should consider The ICMJE believes that parties should consider requiring requiring the depositionthe deposition of such an abstract in the registry of such an abstract in the registry 24 24 months after closure of data collectionmonths after closure of data collection if results are not if results are not published in a peer-reviewed venue by that time.published in a peer-reviewed venue by that time.

June 2007June 2007

Summary (Summary (11))

• Left to its own devices research will not Left to its own devices research will not advance the welfare of peopleadvance the welfare of people

• Blind repetition of worn ways of doing Blind repetition of worn ways of doing things inevitably invites disasterthings inevitably invites disaster

• What we have learnt is the need for What we have learnt is the need for collaboration and sharingcollaboration and sharing

• Registration represents one way of creating Registration represents one way of creating openness in scienceopenness in science

• Responsible research is a collective cultureResponsible research is a collective culture

Summary (Summary (22))

• Ethics and regulations always lag Ethics and regulations always lag behind technologybehind technology

• Biological agents and in particular Biological agents and in particular humanised agents require a new humanised agents require a new paradigm for testingparadigm for testing

• Animal testing may be limited in Animal testing may be limited in valuevalue

Thank you!

Bench to Bedside A Curious Tail of Elephants, Rodents and other Primates or Bedside to Bench?...

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