# Presentation: 776125

## 		Abuse Liability Assessment and 	Drug Dependence:

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

**DIA ****	****Workshop **
**June 18, 2003**

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- CDER- CSS DIA Workshop

## 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.	Pfizer Global Research and Development, 		Worldwide Regulatory Affairs

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- CDER- CSS DIA Workshop

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

**  ****DIA Workshop **
**June 18, 2003**

## 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**

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## 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)**

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## 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**

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- CDER- CSS DIA Workshop

## Drug Classes Subject to Regulation under the CSA 

**Opioids**
**CNS depressants**
**CNS stimulants**
**Hallucinogens**
**Cannabinoids**
**Anabolic**** ****steroids**

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- CDER- CSS DIA Workshop

## 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**

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## 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)***

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- CDER- CSS DIA Workshop

## 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 **

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## 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**

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## Abuse Potential

**Chemical structure**
**Pharmaceutical characteristics**
**Ease of synthesis**
**Extractability**
**Solubility**
**CNS pharmacology**
**Receptor **
**Behavioral effects**

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- CDER- CSS DIA Workshop

## Abuse Liability Assessment Package of the NDA Includes

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

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## Pharmacology - Preclinical

**Neuropharmacological characterization**
**Receptor binding**
**Animal behavioral studies**
**Reinforcing effects (self-administration)**
**Discriminative effects (drug discrimination)**
**Physical dependence (withdrawal)**
**Tolerance**

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- CDER- CSS DIA Workshop

## Human Pharmacology

**Subjective effects - drug liking**
**Toxicity and performance impairment**
**Tolerance**
**Physical dependence**

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## 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)**

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## Scheduling CriteriaCII-CV Drugs

**Approved medical use**
**Relative potential for abuse**
**Dependence liability**

**21 USC 812 (b)**

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- CDER- CSS DIA Workshop

## 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**

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- CDER- CSS DIA Workshop

## Conclusions

**Abuse liability assessment  and drug scheduling are composites --based upon analysis of the chemistry, pharmacology, clinical considerations, and the public health risks following introduction of the drug to the general population  **
**Abuse or dependence potential can be best conceptualized as risks to be managed**
**Responsibility shared by FDA and DEA**

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- CDER- CSS DIA Workshop