Transcript Adverse Preclinical Findings: Now What? July 2011

Adverse Preclinical
Events:
Now What?
tive (eHI)
Cynthia J. Davenport, Ph.D.
President
www.tigertox.com
PreClinical Discussion Group- San Diego, CA USA 26 July 2011
Adverse Preclinical Events:
Now what?
• Drug development = complex process
• Prediction of drug toxicity in humans is major challenge
• Toxicology studies designed to produce toxicity.
• Absence of toxicity may mean incorrect dose selection
and/or use of invalid nonclinical model.
• Can’t erase an adverse event
• Optimized preclinical dose selection is essential!
• Rare adverse events difficult to predict preclinically, and
generally require post-market surveillance
Agenda
Outline process for dealing with APEs to:
• Optimize chances of successful drug
development or
• Create a scientific basis for early termination of
development
No Single Answer for all
Problems
What are Adverse Preclinical
Events?
• Genetic Toxicity (e.g., aneuploidy, mutagenicity, chromosomal
rearrangements)
• Clinical signs (e.g., ataxia, morbidity, seizures)
• Safety Pharmacology Disturbances (e.g., QT prolongation,
respiratory distress, GI transit irregularities, seizures)
• Clinical Pathology/Hematology Changes (e.g., leukopenia, anemia,
enzymatic changes [ALT, AST, etc.])
• Immunological Toxicity (immuno-stimulation/-suppression)
• Morphological Toxicity (e.g., gross and histological pathology,
reproductive toxicity, developmental toxicity)
• Other
APEs can belong to >1 category
Process: How to Proceed?
• Assemble internal/external team of “experts”
• Increased focus by Regulators on safety-related issues.
Trending from passive to active surveillance (discovery,
preclinical through post-marketing)
Safety Signal Identification:
•Compare structure/adverse events (nonclinical and clinical) of
compounds with similar MOA and/or structure (published
literature, data bases, FOI, scientific community)
• Primary: patents, conference papers, case reports, journal articles,
correspondence, and theses
• Secondary: bibliographies, reviews, indexing and abstracting
services
• Tertiary: reference sourcebooks, textbooks
Process: How to Proceed?
Clinical/Epidemiological/Pharamcovigilance data
• Clinical trial database (ClinicalTrials.gov)
• Pharmacovigilance: FDA Sentinel system, the
Observational Medical Outcomes Partnership
(OMOP), and the eHealth Initiative (eHI)
• Epidemiologic data: information on disease and
disease population
• Text mining/analytics of social media channels and
call center notes
Process: How to Proceed?
Determine available options:
• Terminate development (e.g., unfavorable risk:benefit
ratio, budget, available backup[s], competition/time
to market)
• Outlicense (different indication, assume higher risks)
• Therapeutic indication
• More serious disease = higher risk tolerance
• Different therapeutic indication may require lower
dose
Process: How to Proceed?
• Issue resolution plan: objectives, time frame, budget,
potential exit points, responsibilities, bulk availability/timing,
etc.
• Availability of backup: start to develop (?); continue to work on
lead drug candidate (?)
• If class effect, screen backup(s)
• Contact Authorities if IND present and/or drug in clinical trials
(see guidelines)
• Agreement with Authorities to continue/terminate development.
• Option to publish results in peer-reviewed journals
• Risk evaluation/risk management may allow clinical development
to proceed until further risk evaluation possible based on quality
human data.
Adverse Preclinical Events:
What do I do now?
Imperatives:
• Identification and characterization of APE
• Risk evaluation and management
Application of Imperatives
Imperatives:
Identification and characterization of APE
• Identification: Recognition/assessment of suspected APE
 Increased risk of thyroid follicular tumors in 2-year
carcinogenicity study (mice)
• Characterization: Target Organ(s), Dose
(exposure)/response, severity, reversibility, ADME
 No genotoxicity, so tumors likely epigenetic (hormonal).
 4-week study:  T(4)UDP-GT (T4 uridine 5'diphosphoglucoronosyl transferase activity)
 13-week study:  T4,  TSH,  liver & thyroid weights.
Application of Imperatives
Imperatives
Hazard identification and characterization
Risk evaluation and risk management
• Risk Evaluation: MOA, relevance of finding for man, and safety ratios
 Drug induces UDP-GT   glucuronidation of T4  T4 excretion  
T4 serum levels   TSH  thyroid follicular cells  
thyroid follicular tumors.
 Humans less susceptible to hormonal imbalance.
  TSH (e.g., Hashimoto goiter)  benign thyroid hyperplasia or thyroid
adenoma.
 Safety ratio: at what multiple of the clinical dose does APE occur?
• Risk Management: implement precautions for use of drug in man
 Limit initial starting dose
 Monitor thyroid hormones and TSH in clinical studies to ensure changes
don't occur in man at therapeutic doses.
Risk Evaluation:
qualitative and quantitative
• Qualitative: determination of MoA necessary to assess
relevance to man
• Quantitative: calculation of safety ratio
• Exposure at NO(A)EL of most sensitive and relevant
preclinical species guides clinical starting dose
• Safety ratios especially important when APE not
species-specific or when MOA is not entirely clear
Quantitative Risk Evaluation
• Weight of evidence (WoE): analyses of multiple parameters
(e.g., therapeutic dose/safety margin, medical need, market
alternatives, severity and reversibility of toxicity, therapeutic
indication, dose/response, ADME/metabolites, early
biomarkers, age of target population, intended duration of
use, ethnicity, etc.)
• WoE evolves throughout product lifecycle.
• Safety ratio + WoE necessary to assess risk:benefit
• Greater benefit justifies higher risk (severe disease,
no/few therapeutic alternatives)
Risk Evaluation Using Weight of
Evidence (WoE) Analysis
Does MOA of drug candidate lead to observed APE?
No or partially
Is MOA potentially relevant for man?
Continue development
Sufficient safety factor?
Yes
No
MOA = mechanism of
action; APE = adverse
preclinical event
Continue development
with risk management
Development depends upon
further WoE analyses
Ettlin et al. J. Toxicol. Pathol. 2010; 23:189-211.
Risk Management:
precautions to minimize risk (1)
• Carefully monitor patients at increased risk
• Concurrent medications/drug interactions/comparator
studies
• Consider reproductive/developmental risk to WoCBP 1
• Careful selection of first dose/dose-escalation scheme in
humans
• Biomarker monitoring (e.g., serum chemistry, hematology,
urinary, EKG)
1
WoCBP = women of child-bearing potential
Risk Management:
precautions to minimize risk (2)
• Alerting health professionals/public (package insert,
training/education, PDR, product label, medication
guide)
• Proactive post-market surveillance program (REMS = risk
evaluation and mitigation strategy; RMP = risk
management plan; pharmacovigilance) – global scope
• Continuous assessment of risk:benefit by crossfunctional team throughout life cycle of drug
• Balanced communication of risk:benefit is essential in
our risk-adverse environment
Adverse Preclinical Events:
Now what?
Conclusion
• Drug development guidelines both necessary and
helpful, but challenges require sound scientific judgment
& experience
• Clear definition of MoA not always possible
• Key to meeting the challenge is identification,
characterization, risk evaluation, and risk management of
APE
MoA = mechanism of action; APE = adverse preclinical event.
References
• DrugBank. Version 3.0. Referenced 24 July 2011.
• Ettlin RA, et al. J. Toxicol. Pathol. 2010; 23:189-211.
• Eisenberg, PR. Integrating Risk Management Into Global
Drug Development -Opportunities and Challenges.
Plenary Session, DIA, Seoul, Korea 28 April 2011.
• Kupferberg, N. Drug Information Sources. Ohio State
University Library. 5 November 2010.
Cynthia J. Davenport, Ph.D.
www.tigertox.com
[email protected]
Questions and Discussion