Klein OpioidEducationConferenceFDA013009

 

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

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

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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 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 ensure that Americans have to access to safe and effective drug products

 – Safe and Effective under Labeled Conditions of Use

 – Product’s Benefit Outweighs its Risk

• Determine Abuse Potential  – Labeling: Drug Abuse & Dependence Section  – Risk management recommendations

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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

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Interactions with Review Groups • Office of New Drug Evaluation  – Division of Anesthesia, Analgesia, and Rheumatology Rheumatology Products  – Division of Neurology Products  – Products  – Division Division of of Psychiatry Endocrine and Metabolic Products  – Division of Reproductive and Urologic Products Gastroenterol Gastroenterology ogy Products  –  – Division Division of of Cardiovascular and Renal Products  – Division of Nonprescription Products

and Epidemiology •• Office CenterofforSurveillance Veterinary Medicine 6

 

Identifying the problem

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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  – Animal Pharmacology and Toxicology Toxicology Studies Studies  – Manufacturing ng Information Clinical Protocols and Investigator Information  – Manufacturi

 – New Drug Application (NDA) • Formal application for approval of a new drug 8

 

 Abuse Potential Assessment Data in NDA ∙

 Ability of a psychic CNS-active drug to produce a reinforcing or  positive 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)  

 

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Drug Abuse Assessment Data on the drug’s abuse potential can be obtained at critical times in the drug development process Phase 1 Spontaneous Reports Performance Measures Physiology

Preclinical Biochemistry Global Pharmacology Animal Behaviors Structure

Phase 2-3 Subjective Effects Discontinuation Drug Seeking Behavior 

Phase 4 Post Marketing Adverse Effects Epidemiology Actual Abuse 10

 

Drug Scheduling

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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 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 BARBITURATES Fentanyl 100-250 µg/2mL 2.5-10 mg/patches

STIMULANTS Cocaine Topical Solution 4%, 10%

Morphine 10mg/mL inj. 15-30 mg tabs MS Contin 15-200 mg tabs

Hydrocodone Substance

OxyContin 10-160 mg tabs

Hydromorphone 2-8 mg tabs

Oxycodone comb. 5-10 mg tabs

Oxymorphone 1-1.5mg/mL inj.

Methadone 5-40 mg tabs

Secobarbital

Methamphetamine Amphetamine

Amobarbital Pentobarbital

5-30 mg caps & tabs

Methylphenidate 5-54 mg caps & tabs14

 

Schedule III

Schedule III-V Drugs Schedule IV

Codeine & Hydrocodone (comb.) Dihydrocodeine Buprenorphine

Dextropropoxyphene Pentazocine Butorphanol

Schedule V Codeine (comb.) Dihydrocodeine Diphenoxylate

Zaleplon Gamma hydroxybutyrate (GHB) Dronabinol

Zolpidem Eszopiclone Sibutramine

OPIATES

Modafinil

DEPRESSANTS STIMULANTS

Alprazolam Diazepam

BENZODIAZEPINES

Midazolam Quazepam

OTHER

Anabolic Steroids

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Managing the Risk of Abuse

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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   of access to information and drugs − Ease

 

• CSA Regulations Require Registration and Vary with Schedules 17

 

Schedule I

Schedule II

Schedule III

Schedule IV

Schedule V

Registration

Required

Required

Required

Required

Required

Recordkeeping

Separate

Separate

Readily Retrievable

Readily Retrievable

Readily Retrievable

Distribution Restrictions

Order Forms

Order Forms

Records Required

Records Required

Records Required

Dispensing Limits

Research use only

Rx: written No Refills

Rx: written or oral Refills with MD's authorization

Rx: written or oral Refills with MD's authorization

OTC (Rx drugs limited to MD's order 

Vault/Safe

Vault/Safe

Secure Storage

Secure Storage

Secure Storage

No

No

No

Yes

Yes

(Some drugs limited by Schedule II)

(Some drugs limited by Schedule II)

(Some drugs limited by Schedule II)

Manufacturing Security Manufacturing Quotas

Permit to import,

Import/Export Narcotic

Reports to DEA Mfr.& Distributor 

Permit

Permit

Permit

Permit

declaration to export

Yes

Yes

Yes

Mfr. only

Mfr. Only

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CSA-Regulated Entities 1. Drug Source

2. Distributor 

(Manufactu (Manufacturer rer or  Importer 

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

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When is risk management considered for a drug with abuse potential? C S S A    C o  on   t r  r o  oll   s  

La b  b e  e ll  ii  ng  C l  l i  in   i c c  a a  ll  B e  e ne f  f ii  t  t s

I nhe rr  e e  nt  R ii  sk s

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When necessary to maintain a positive risk : benefit balance

 m e n t  e  g  a  n  a  M M    s k  R i s  s  o l s  r o  t r  C SA  SA C  C o n  g  n  i n  l i

 L a b e  s  s    t t  i   i  f  e  B e n  C l  ii  n n i  c c a l   l 

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

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Conclusion • The evaluation of new drugs (NDAs) for abuse potential is based upon a comprehensive comprehensive interdisciplinary scientific review •  Abuse potential potential evaluation a and nd drug schedu scheduling ling are a shared responsibility responsibility by DHHS and DEA • If a drug has potential for abuse, appropriate abuse abuse-related 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 Amendment Amendments s Act of 2007 (FDAAA) 23