What has the TGN1412 incident done for the conduct of Phase I studies in Europe

1
What has the TGN1412 incident done for the
conduct of Phase I studies in Europe?

• Jeff Engelhardt, DVM, PhD, DACVP, FIATP
• Toxicology Executive Director
• Amgen
• Thousand Oaks, CA
• October 9, 2007

2
Reactionary Regulatory Guidance

• Pure Food and Drug Act - 1906
• Upton Sinclairs The Jungle
• Food, Drug, and Cosmetic Act - 1933
• Elixir sulfanilamide tragedy
• Required pre-market safety
• Kefauver-Harris Amendments - 1962
• Thalidomide
• Clinical studies supported by animal testing
• Special cases
• FIAU
• Testing of NRT inhibitors for hepatitis B in
  woodchucks

3
TGN1412 What happened

• CD28 agonist antibody
• Enhanced regulatory T cell activity
• T cell activation
• Standard repeated dose program in Cynomolgus
  monkey
• Transient increase in circulating T cells
• Low to moderate increases in IL-2, 5, and 6 but
  not IL-4, TNFa, or INFg
• No clinical signs suggestive of cytokine release
• Low level signals evident on retrospective
  analysis

4
TGN1412 What happened

• Six healthy male volunteers given TGN1412
  simultaneously in a Phase I study
• Systemic inflammatory response 90 min after dose
• Headache, myalgia, nausea, diarrhea, erythema,
  vasodilation, and hypotension
• Pulmonary infiltrates, renal failure, and DIC
  within 12-16 hr
• All survived with intensive cardiopulmonary
  support and dialysis for 1 month

5
The Cytokine and Regulatory Storm

• MHRA and BfArM GMP, GCP, and GLP auditors
  investigate clinical site and supporting studies
• CSM empanels an Expert Scientific Group on Phase
  One Clinical Trials chaired by Prof. Sir Gordon
  Duff
• The Duff Report returns assessment of study
  conduct and 22 recommendations on Phase I studies
  with higher risk medicinal products

6
The Cytokine and Regulatory Storm

• The European Commission charges the CHMP and SWP
  to develop new regulatory guidance to prevent a
  repeat of the tragedy

7
Requirements for First in Man Clinical Trials for
Potential High-Risk Medicinal Products

• Draft published as EMEA/CHMP/SWP/28367/2007
• Draft guidance emphasized non-clinical
  investigations as most critical
• Did not distinguish between biologics and small
  molecules
• Definition of high-risk would cover most
  innovative molecules
• Stamp of high risk on a molecule
• Proposed the use of MABEL
• Minimal anticipated biological effect level
• Concern for lack of harmonization across the
  member states relative to what constitutes
  high-risk

8
Requirements for First in Man Clinical Trials for
Potential High-Risk Medicinal Products

• EMEA workshop to finalize the guidance
• Rare occurrence
• 170 attendees
• gt200 pages of written comments from more than 60
  organizations or entities
• Authors from CHMP receptive to comments and
  critique of the draft
• Agreed to change scope and tone of the guidance
• Risk is a continuum

9
Adopted Guideline

• Guideline on strategies to identify and mitigate
  risks for first-in-human clinical trials with
  investigational medicinal products
  (EMEA/CHMP/SWP/294648/2007)
• Came into effect 1 Sep 2007
• Emphasis placed on clinical trial design and
  implementation

10
Timeline of Guidance Development

• 13 Mar 06 Phase I study started
• May 06 Preliminary report from MHRA
• Aug 06 Duff report released
• Oct 06 European Commission charge
• Jan 07 Development of guidance announced by SWP
  to EFPIA SAHG
• Mar 07 Draft adopted and released for
  consultation
• May 07 End of consultation period
• June 07 Finalization workshop
• 19 July 07 Adoption of guidance by CHMP
• 1 Sept 07 Guidance came into effect

11
What does this guidance mean for Sponsors?

• Intended to assist sponsors in the non-clinical
  to clinical transition
• Makes allowance for pre-IMPD meetings
• Covers nonclinical issues to consider prior to
  FTIM and design and conduct of Phase I for
  biologics and small molecules

12
Nonclinical factors to be considered

• Mode of action
• Nature of the target
• Relevance/reliability of animal models
• Surrogates of questionable value
• Studies in irrelevant species discouraged
• Disease models may be useful
• Starting dose
• NOAEL
• MABEL

13
MABEL vs. NOAEL

• MABEL is based on receptor occupancy, response
  curve, and exposure
• Relevant animal models
• Uses lower doses from PD studies
• No simple algorithm to calculate the MABEL
• NOAEL based on toxic effects
• Minimal effects may be present at NOAEL
• Receptor occupancy not considered
• Higher dose than MABEL (generally)
• When in doubt, use a lower dose

14
Clinical factors to be considered

• The higher the potential risks, the greater the
  precautionary measures that should be exercised
• Protocol should detail strategy to manage risk
• Specify plan to monitor for and manage likely
  adverse events and adverse reactions
• Nonclinical data and target liability

15
Clinical factors to be considered

• Further dose administration within each cohort
  should be sequential to mitigate risk
• Adequate observation period
• Dose increment for escalation should be guided by
  the nonclinical dose-response curve
• Identify clear stopping rules
• Immediate communication among sites
• FTIM should preferably be a single site

16
Summary

• Many key regulatory guidelines are developed in a
  reactionary manner
• Much of the FTIM guideline covers practices
  already in place in biotechnology and
  pharmaceutical companies
• If the Sponsor does not know a lot about the
  pathway or molecule, exercise more caution
• Phase I is all about safety
• Seek consultation as necessary

17
References

• EMEA/CHMP/SWP/294248/2007
• Hanke T. 2006. Lessons from TGN1412. Lancet.
  3681569-1570.
• Kenter MJ and Cohen AF. 2006. Establishing risk
  of human experimentation with drugs lessons from
  TGN1412. Lancet. 3681387-1391.
• Ohressner M, et al. 2006. Risk in drug trials.
  Lancet. 3682205-2206.
• Stebbings R, et al. 2007. Cytokine Storm in
  the Phase I trial of monoclonal antibody TGN1412
  Better understanding the causes to improve
  preclinical testing of immunotherapeutics. J
  Immunol. 1793325-3331.
• Suntharalingam G, et al. 2006. Cytokine storm
  in a Phase I trial of an anti-CD28 monoclonal
  antibody TGN1412. N Engl J Med. 3551018-1028.