# Presentation: 586405

## 		Abuse Liability Assessment and 	Drug Dependence:

***Scientific and Regulatory Considerations ***
***in Drug Development***

**DIA ****	****Workshop **
**June 16, 2004**

## SpeakersDeborah B. Leiderman, M.D., M.A.	Director, Controlled Substance Staff (CSS), 		CDER, FDASilvia Calderon, Ph.D.	Team Leader, CSS, CDER, FDA Robert S. Mansbach, Ph.D.	Neurocrine Biosciences, Inc.

## Abuse Liability Assessmentand Drug Scheduling:An OverviewDeborah B. Leiderman, M.D

**  ****DIA Workshop **
**June 16, 2004**

## 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 under the 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**** *****(Single Convention on Narcotic Drugs, Psychotropic Convention)***

## 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**
**Regulates prescribers, dispensing pharmacies**
**Law enforcement**

## Conclusions

**Abuse liability Assessment/Drug Scheduling based upon composite analysis of chemistry, pharmacology, clinical data, and the public health risk following drug introduction to the general population  **
**Abuse or dependence potential = risk to be managed**
**Responsibility shared by FDA and DEA**