FDA Open Public Hearing

1

• FDA Open Public Hearing
• May 5, 2008
• Beatrice Setnik, PhD
• Director, Scientific Business Development
• DecisionLine Clinical Research Corporation
• Toronto, Ontario, Canada
• Disclaimer
• DecisionLine provides consulting services and
  conducts clinical trials to assess abuse
  liability, drug interactions and tamperability
  for CNS active drugs.

2
Alcohol and Dose Dumping

• The term dose dumping is frequently used and
  often indiscriminately
• Describes accelerated drug release from modified
  release formulations (MRF)
• The term is non-quantitative and implies actual
  clinical importance
• Based historically on PK data for most CNS drugs
  PK is highly variable and there is a poor
  correlation of PK and PD
• Pharmacokinetic (PK) data do not predict
• Safety individual or risk to groups of patients
  
• Pharmacodynamic effects e.g. motor or cognitive
  impairment
• Efficacy
• Naltrexone cover often used with opioids (e.g.
  Palladone study)
• Statistically significant increase in mean plasma
  morphine levels (AUC0-24 ? 23 Cmax ?14.5)
  resulting from co-administration of morphine (60
  mg) naltrexone (300 mg) (Bashaw et al., 1995)
• Prevents gathering data on safety and PD data
• The clinical importance can only be determined if
  pharmacodynamic and safety measures are included
• Relevance to patient populations and drug abusers

3
Correlation of In Vitro and Clinical Data
Alcohol effects

• In vitro data not always correlated to clinical
  data
• e.g. OPANA ER
• In vitro data showed that oxymorphone was not
  released more rapidly in 500 mL of 0.1N HCl
  solutions containing ethanol (4, 20, and 40)
• Clinical data combining 40 mg OPANA ER and
  alcohol (4, 20 and 40) in healthy, fasted
  volunteers showed that with 40 ethanol
• Mean AUC (oxymorphone) was 13 higher (not
  statistically significant)
• Cmax was highly variable, increased on average by
  70 and up to 270 in individual subjects
• In vitro studies
• Inexpensive, quick
• Provide data on physical/chemical properties of
  formulation
• However, clinical studies
• Provide valuable information on pharmacokinetics
  and pharmacodynamic effects when various doses of
  alcohol are administered at various time, in
  relation to drug administration

4
Terminology

• Abuse deterrent and tamper resistant are
  often interchanged they are not equivalent.
• Tamper Resistant formulations can either
• Contain a controlled release caption that is not
  easily accessible
• Difficult to crush/chew/grind/dissolve
• Or when tampered with have physical/chemical
  properties that are not appealing for
  administration
• Prevention of snorting, injection, smoking, oral
  administration
• Addition of aversive/blocking agents (e.g.
  capsaicin)
• However, may contain an IR caption that may be
  abused when intact
• Abuse Deterrent formulations
• Means the formulation is designed without
  tampering to be less attractive for non-medicinal
  use, e.g. by decreasing the peak high, delaying
  the time of the peak effects or the rate of onset
  of effects or decreasing the overall effects
  (AUC)
• But in order to be effective, cannot be easily
  defeated

5
Summary

1. Experimental human studies and epidemiologic
   safety data are needed to address the clinical
   relevance of drug/alcohol interactions and dose
   dumping.
2. Determination of clinical importance requires the
   inclusion of sensitive clinical measures of
   safety and pharmacodynamic endpoints in
   pharmacokinetic studies
3. Dose dumping should only be used to describe
   situations where tampering results in a
   clinically important consequence
4. Criteria for clinical importance should be
   developed for target drug classes
5. Appropriate terminology and evidence is required
   to describe new formulation technologies designed
   to reduce tampering and abuse potential.