FDA Regulatory Processes and Standards for Review and Approval of Opioid Analgesics: An Educational Primer and Conversation

February 10, 2009 Hilton Washington DC/Rockville Rockville, Maryland 20852

FDAs Involvement in Preventing Opioid Abuse presented by Michael Klein, PhD, Director Controlled Substance Staff, FDA/CDER

Controlled Substance Staff (CSS)

Located in the FDA/CDER Office of the Center Director (2000) Comprised of scientists, physicians & pharmacists Recommends scheduling and risk management, based upon NDA review of pharmacology, clinical effects, public health risks, and abuse/ misuse/ safety concerns Advises sponsors on abuse potential assessment (part of safety review) Responds to citizens petitions Provides an annual estimate of medical need of C-II drugs Reviews research protocols for C-I drugs Works with SAMHSA, NIH/NIDA, CDC, ASH Works with the DHHS & DOS on international issues related to United Nations activities
2

Food Drug & Cosmetics Act (FD&CA 1938)

FDA - Public Health Mission to ensure that Americans have access to safe and effective drug products
Safe and Effective under Labeled Conditions of Use Products Benefit Outweighs its Risk

Determine Abuse Potential

Labeling: Drug Abuse & Dependence Section Risk management recommendations

NDA Requirements Under FD&C Act

If potential for abuse exists, the following must be included in the NDA:

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)
4

Controlled Substances Act (CSA) 1970

Purpose to combat drug trafficking, comply with international treaties, and assure availability of controlled substances for legitimate medical use Establishes legal procedures and DHHS role Recommend scheduling Review and advise on Schedule I research protocols Provide an annual estimate of U.S. medical needs for Schedule I and II substances
5

Interactions with Review Groups

Office of New Drug Evaluation
Division of Anesthesia, Analgesia, and Rheumatology Products Division of Neurology Products Division of Psychiatry Products Division of Endocrine and Metabolic Products Division of Reproductive and Urologic Products Division of Gastroenterology Products Division of Cardiovascular and Renal Products Division of Nonprescription Products

Office of Surveillance and Epidemiology Center for Veterinary Medicine

6

Identifying the problem

Pre-Market Product Review

New Drug Review Investigational New Drug (IND)
Process by which a sponsor advances to next stage in drug development (clinical trials)
Animal Pharmacology and Toxicology Studies Manufacturing Information Clinical Protocols and Investigator Information

New Drug Application (NDA)

Formal application for approval of a new drug
8

Abuse Potential Assessment Data in NDA

Ability of a CNS-active drug to produce a reinforcing or positive psychic effect relative to a control Data correlates with and predictive of the risk of addiction
CSA Scheduling Proposal Chemistry Pre-clinical and Human Pharmacology Clinical Trial Data Data on Overdose Epidemiology Data (** If available)
9

Drug Abuse Assessment

Data on the drugs abuse potential can be obtained at critical times in the drug development process
Phase 1
Spontaneous Reports Performance Measures Physiology

Phase 2-3
Subjective Effects Discontinuation Drug Seeking Behavior

Preclinical
Biochemistry Global Pharmacology Animal Behaviors Structure

Phase 4
Post Marketing Adverse Effects Epidemiology Actual Abuse
10

Drug Scheduling

11

DHHS & DEA Roles in Scheduling

DHHS scientific-medical recommendation is binding on DEA with respect to scientific and medical determinations and whether a substance should not be controlled FDA evaluates the abuse potential of the drug and prepares a scheduling recommendation based on scientifically verified data
Seeks the advice of NIDA/NIH; interacts with SAMHSA After FDA approves the NDA, DEA finalizes scheduling Final decision making authority is delegated to DEA
12

Five Levels of Drug Control in CSA

Schedule I: Not approved in the U.S. High abuse potential (most restrictive) Lack of safety for use 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 13

Schedule II Drugs
OPIATES
Fentanyl 100-250 g/2mL 2.5-10 mg/patches Morphine 10mg/mL inj. 15-30 mg tabs MS Contin 15-200 mg tabs OxyContin 10-160 mg tabs Oxycodone comb. 5-10 mg tabs Hydrocodone Substance Hydromorphone 2-8 mg tabs Oxymorphone 1-1.5mg/mL inj. Secobarbital Amobarbital Pentobarbital

BARBITURATES

STIMULANTS
Cocaine Topical Solution 4%, 10%

Methamphetamine Amphetamine 5-30 mg caps & tabs

Methadone 5-40 mg tabs

Methylphenidate 5-54 mg caps & tabs 14

Schedule III-V Drugs

Schedule III
Codeine & Hydrocodone (comb.) Dihydrocodeine Buprenorphine Gamma hydroxybutyrate (GHB) Dronabinol Anabolic Steroids Alprazolam Diazepam Midazolam Quazepam

Schedule IV
Dextropropoxyphene Pentazocine Butorphanol Zaleplon Zolpidem Eszopiclone Sibutramine Modafinil

Schedule V
Codeine (comb.) Dihydrocodeine Diphenoxylate

OPIATES DEPRESSANTS STIMULANTS BENZODIAZEPINES OTHER

15

Managing the Risk of Abuse

16

Drug Scheduling Under CSA

Scheduling under the CSA does not manage all risks of misuse, abuse, and overdose of drugs Drug scheduling alone cannot address many challenges related to the modern health care system
Current patterns of medical practice Ease of access to information and drugs

CSA Regulations Require Registration and Vary with Schedules

17

Schedule I Registration Recordkeeping Distribution Restrictions Dispensing Limits Manufacturing Security Manufacturing Quotas Import/Export
Narcotic
Required

Schedule II
Required

Schedule III
Required

Schedule IV
Required

Schedule V
Required

Separate

Separate

Readily Retrievable Records Required Rx: written or oral Refills with MD's authorization Secure Storage No

Readily Retrievable Records Required Rx: written or oral Refills with MD's authorization Secure Storage No
(Some drugs limited by Schedule II)

Readily Retrievable Records Required OTC (Rx drugs limited to MD's order Secure Storage No
(Some drugs limited by Schedule II)

Order Forms

Order Forms

Research use only

Rx: written No Refills

Vault/Safe

Vault/Safe

Yes

Yes

(Some drugs limited by Schedule II)

Permit

Permit

Permit

Permit

Permit to import, declaration to export Mfr. Only

Reports to DEA
Mfr.& Distributor

Yes

Yes

Yes

Mfr. only

18

CSA-Regulated Entities
1. Drug Source (Manufacturer or Importer

2. Distributor

3. Health
care provider

4. Patient
19

Risk Management
Risk management is an extension of the product label Goals: Safe Use
Prevention of accidental overdose Prevention of unintended exposure Proper patient selection, Prevention of misuse and abuse

Risk management tools

To be discussed in detail in the following presentation

20

When is risk management considered for a drug with abuse potential?

CSA C ontrols

ng Clinica l Bene fits

Labeli

I nhe r e

nt Risk

21

When necessary to maintain a positive risk : benefit balance

a M k Ris

t n e m e g a n

ls o r t n o C CSA

s k s i R t n e r e h n I

g n i l e Lab s t i f e n e B l a c i n Cli
22

Conclusion
The evaluation of new drugs (NDAs) for abuse potential is based upon a comprehensive interdisciplinary scientific review Abuse potential evaluation and drug scheduling are a shared responsibility by DHHS and DEA If a drug has potential for abuse, appropriate abuserelated data must be included in the NDA for review Regulatory tools to prevent abuse include CSA scheduling and risk management programs See Food and Drug Administration Amendments Act of 2007 (FDAAA)
23