# Presentation: 776124

## Abuse Liability and Drug Scheduling:The Role of the FDA  Deborah B. Leiderman, M.D.Director, Controlled Substance StaffCDER/FDA

**       ****January 30-31, 2002**

## Abuse Potential Assessment

**Federal Food, Drug and Cosmetic Act **
**(FD&C Act, 1938)**
**   ****Determination of Abuse Potential**
**   ****Labeling - Drug Abuse and Dependence Section**
**Controlled Substances Act (CSA, 1970)**
**   ****Scheduling**
**   ****Schedule I Protocols**
**   ****Estimates of  U.S. Medical Needs for Schedule I **
**and II Substances**

## NDA RequirementsUnder FD&C Act

**If potential for abuse exists, the following **_**must be included**_**: **
**All data pertinent to abuse of the drug**
**Proposal for scheduling under the Controlled Substances Act **
**Data on overdose**
**	****	****	****	****	****	**** ****21 CFR § 314.50 (5) (vii)**

## Controlled Substances Act (CSA) 1970

**  ****Provides a role for both DEA and DHHS**
**  ****Establishes legal procedures**
**  ****Scheduling based on scientifically verified and legally**
**  ****defensible data**
**  ****Legislatively scheduled Class I substances include **
**  ****heroin, LSD, marijuana**
**  ****Examples of Class II substances include cocaine,**
**  ****morphine, opium, oxycodone**

## Drug Classes Subject to Regulation (CSA) 

**Opioids**
**CNS Depressants**
**CNS Stimulants**
**Hallucinogens**
**Cannabinoids**
**Anabolic Steroids**

## CSA Mandate for DHHS

**“****If, at the time a NDA is submitted to the Secretary for any drug having a stimulant, depressant, or hallucinogenic effect on the central nervous system, it appears that such drug has an abuse potential, such information shall be forwarded by the Secretary to the Attorney General” **
**	****	****	****	****	****	****	****	**** ****-21 USC 811 (f)**
**  **

**	****	**** ****Delegation to FDA by Secretary, DHHS**
**	****	****	****	****	****	****	****	****-21 USC 5.10**

## Drug Scheduling Process

**FDA/DHHS performs scientific assessment and recommends initial schedule or change to DEA **
**DEA schedules drugs through rule-making**
**Schedule changes can be initiated by DEA, FDA, Congress, and by citizen or****	****sponsor petitions**
**Compliance with International Treaties**

## Levels of Drug Control

**Five Classes or Schedules Under CSA**

*** ******	******Schedule I:***** **
** ****Not approved in the U.S. **
** ****High abuse potential (most restrictive)**
** ****Special DEA license for research***** ******	***
***  ***
***  ******Schedules II-V:***** **
** ****Approved medical use in the U.S. **
** ****High (C-II) to limited (C-IV/V) physical or ****	****	****psychological dependence liability **

## Abuse Liability Assessment 

**Pre-IND, IND, and NDA Phases**
**Evaluation of All Data**
**Chemistry****	****	**
**Pharmacology (Animal and Human)**
**Pharmacokinetics & Pharmacodynamics**
**Adverse events reported in clinical trials  **
**Compare to a Pharmacologically Similar Substance**

## Abuse Potential

**Chemical Structure**
**Pharmaceutical Characteristics**
**Ease of synthesis**
**Extractability**
**Solubility**
**CNS Pharmacology**
**Receptor **
**Behavioral effects**

## Abuse Liability Assessment Package of the NDA Includes

**  ****Preclinical Pharmacology**
**  ****Human Pharmacology**
**  ****Clinical Trial Data**
**  ****CSA Scheduling Proposal                                             **
**  ****Data on Overdose         **

## Pharmacology - Preclinical

**Neuropharmacological Characterization**
**Receptor Binding**
**Animal Behavioral Studies**
**Reinforcing Effects (self-administration)**
**Discriminative Effects (drug discrimination)**
**Physical Dependence (withdrawal)**
**Tolerance**

## Human Pharmacology

**Subjective Effects - Drug Liking**
**Toxicity and Performance Impairment**
**Tolerance**
**Physical Dependence**

## Eight Factor Analysis (Required under CSA)

**Actual and potential for abuse**
**Pharmacology**
**Other current scientific knowledge**
**History and current pattern of abuse**
**Scope, duration and significance of abuse**
**Public health risk**
**Psychic or physiological dependence liability**
**If an immediate precursor of a controlled substance**** **
**	****	****	****	****	****	****	****21 USC 811(c)**

## Scheduling CriteriaCII-CV Drugs

**Approved Medical Use**
**Relative Potential for Abuse**
**Dependence Liability**

**21 USC 812 (b)**

## FDA and DEA Roles Under CSA

**FDA**
**Abuse Potential = Risk Assessment**
**Labeling of abuse/dependence risks **
**No control at level of prescriber, dispenser, or patient**
**DEA**
**Licenses CI-II manufacturers; sets quotas**
**Licenses prescribers**
**Law Enforcement**

## CONCLUSIONS

**Abuse liability assessment is a composite -based upon review of the chemistry, pharmacology, clinical considerations, and the public health risks following introduction of the drug to the general population.  **
**Abuse or dependence potential is a risk that needs to be managed.**
**Labeling and drug scheduling alone have limited impact.**

## Slide 18