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Guidance for Industry

Assessment of Abuse Potential

of Drugs

DRAFT GUIDANCE

This guidance document is being distributed for comment purposes only.

Comments and suggestions regarding this draft document should be submitted within 60 days of

publication in the

Federal Register

of the notice announcing the availability of the draft

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments

should be identified with the docket number listed in the notice of availability that publishes in

the

Federal Register

For questions regarding this draft document contact Corinne Moody at 301-796-5402.

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

January 2010

Clinical Medical

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Guidance for Industry

Assessment of Abuse Potential

of Drugs

Additional copies are available from:

Office of Communications

Division of Drug Information

Center for Drug Evaluation and Research

Food and Drug Administration

10903 New Hampshire Avenue

Bldg. 51, rm. 2201

Silver Spring, MD 20993-0002

Phone: 301-796-3400; Fax: 301-847-8714

http://www.fda.gov/cder/guidance/index.htm

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

January 2010

Clinical Medical

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TABLE OF CONTENTS

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 2

III. DETERMINING A DRUG'S ABUSE POTENTIAL .................................................... 4

A. Definitions.......................................................................................................................................4

B. When Should an Abuse Potential Assessment Be Submitted to FDA?.....................................4

C. What Should Be Included in an Abuse Potential Submission?..................................................5

IV. APPROACHES AND METHODS FOR ABUSE POTENTIAL ASSESSMENTS.... 6

A. Preclinical Screening .....................................................................................................................6

B. Chemistry and Manufacturing .....................................................................................................7

C. Animal Behavioral Pharmacology Studies..................................................................................9

D. Application of Good Laboratory Practice (GLP) .....................................................................12

E. Pharmacokinetics/Pharmacodynamics......................................................................................12

HUMAN LABORATORY STUDIES ........................................................................... 12

A. Human Abuse Potential Study in Recreational Drug Users .................................................... 13

B. Related Pharmacology Studies ...................................................................................................16

C. Clinical Trial Data Relative to Abuse Potential Assessments..................................................17

VI. POSTMARKET EXPERIENCE/DATA ...................................................................... 18

VII. LABELING AND DRUG SCHEDULING ................................................................... 19

ABBREVIATIONS..................................................................................................................... 20

BIBLIOGRAPHY....................................................................................................................... 21

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Contains Nonbinding Recommendations

Draft – Not for Implementation

Guidance for Industry

Assessment of Abuse Potential of Drugs

This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current

thinking on this topic. It does not create or confer any rights for or on any person and does not operate to

bind the FDA or the public. You can use an alternative approach if the approach satisfies the

requirements of the applicable statutes and regulations. If you want to discuss an alternative approach,

contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate

FDA staff, call the appropriate number listed on the title page of this guidance.

INTRODUCTION

17 This guidance is intended to assist sponsors who are developing drug products with the potential

18 for abuse that may need to be scheduled under the Controlled Substances Act (21 U.S.C. 811(b),

19 811(c)). Examples of products that are addressed in this guidance include new molecular entities

20 and new dosage forms of drug substances already controlled under the Controlled Substances

21 Act (21 U.S.C. 812(c)). Drugs with abuse potential generally include drugs that affect the

22 central nervous system, drugs that are chemically or pharmacologically similar to other drugs

23 with known abuse potential, and drugs that produce psychoactive effects such as sedation,

24 euphoria, or mood change.

26 Specifically, the guidance discusses the following:

•

The definition of

abuse potential

•

Information on submitting an abuse potential assessment, including a proposal for

scheduling

•

A description of what constitutes an adequate abuse potential assessment

•

Information for sponsors performing an assessment, including (1) the design and conduct

of appropriate studies and investigations and (2) general administrative recommendations

for submitting a proposal for scheduling

36 FDA’s guidance documents, including this guidance, do not establish legally enforceable

37 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should

38 be viewed only as recommendations, unless specific regulatory or statutory requirements are

39 cited. The use of the word

should

in Agency guidances means that something is suggested or

40 recommended, but not required.

This guidance has been prepared by the Controlled Substance Staff (CSS) in the Center for Drug Evaluation and

Research (CDER) at the Food and Drug Administration.

Comprehensive Drug Abuse Prevention and Control Act of 1970, H.R. Rep. No. 91-1444, 91st Cong., Sess. 1

(1970), reprinted in 1970 U.S.C.C.A.N. 4566, 4603.

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Contains Nonbinding Recommendations

Draft — Not for Implementation

II.

BACKGROUND

45 The purpose of scheduling substances under the CSA is to minimize abuse and diversion while

46 affording appropriate therapeutic access. Each schedule under the Controlled Substances Act

47 includes a set of regulations that are most restrictive for the Schedule I and II substances and are

48 relatively less restrictive for the Schedule III to V drugs, respectively. Drugs in Schedule I have

49 no accepted medical use in the United States. Depending on the Schedule (II-V), controls may

50 include manufacturing and production quotas, varying degrees of manufacturing and distribution

51 site security requirements, dispensing and prescribing limitations, a range of record-keeping and

52 reporting requirements, and import/export regulations. Prescribers, dispensers, drug

53 manufacturers, and distributors are required to register with the Drug Enforcement

54 Administration (DEA).

56 Before a drug with a potential for abuse is controlled under the Controlled Substances Act

57 (CSA), the Secretary, Department of Health and Human Services (HHS), must make a

58 recommendation for scheduling under the CSA to the DEA. The regulatory responsibilities for

59 this process are described in 21 U.S.C. 811 and 812, as well as in 21 CFR parts 1300-1316.

61 Under 21 U.S.C. 811(b) of the CSA, the Secretary of HHS is required to consider, in a scientific

62 and medical evaluation, eight factors determinative of control under the CSA. Following

63 consideration of the eight factors, the Secretary must make three findings and a recommendation

64 for scheduling a substance in the CSA. The eight factors are set out in 21 U.S.C. 811(c) as

65 follows:

67 1. Its actual or relative potential for abuse

69 2. Scientific evidence of the drug's pharmacological effects

71 3. The state of current scientific knowledge regarding the drug or other substance

73 4. Its history and current pattern of abuse

75 5. The scope, duration, and significance of abuse

77 6. What, if any, risk there is to the public health

79 7. Its psychic or physiological dependence liability

81 8. Whether the substance is an immediate precursor of a substance already controlled.

83 The findings relate to a substance's abuse potential, legitimate medical use, and safety or

84 dependence potential, which are factors considered in scheduling drugs under 21 U.S.C. 812.

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Contains Nonbinding Recommendations

Draft — Not for Implementation

86 When a sponsor submits a new drug application (NDA) to the FDA for review, if the drug has a

87 potential for abuse, the sponsor must submit “a description and analysis of studies or information

88 related to abuse of the drug, including a

proposal for scheduling

(emphasis added) under the

89 Controlled Substances Act.” (21 CFR 314.50(d)(5)(vii)). In addition, a description must be

90 submitted “of any studies related to overdosage, . . . including information on dialysis, antidotes,

91 or other treatments, if known” (id.).

1. The Controlled Substance Staff evaluates the drug’s abuse potential. The Controlled

Substance Staff prepares a scientific analysis, including a recommendation for

scheduling, based on a scientific and medical evaluation of all relevant and available data

(including the public health risk and the sponsor’s proposal for scheduling), as required

by the CSA.

2. FDA provides the analysis to the National Institute on Drug Abuse (NIDA) for review

100

and comment, as described in the Memorandum of Understanding (MOU) of March 8,

101

1985 (50 FR 9518-20).

102

103

3. The FDA analysis is reviewed and approved by the Office of Chief Counsel, the Center

104

Director, and the FDA Commissioner.

105

106

4. FDA then forwards the FDA proposed scheduling recommendation to the Assistant

107

Secretary for Health, who makes the HHS recommendation for scheduling that is

108

transmitted to the DEA.

109

110

5. In accepting the HHS recommendation to schedule a drug, DEA publishes a notice of

111

proposed rulemaking in the Federal Register wherein DEA proposes scheduling,

112

describes the proposal and requests comments from the public. After the comment period

113

(usually of 30 to 60 days) has expired, DEA reviews any comments, objections, and

114

requests for a hearing that they have received, and publishes another FR notice, either

115

finalizing the scheduling action with an effective date or responding to the objections and

116

hearing requests.

117

118 If the DEA determines that a drug requires scheduling, the sponsor must follow specific

119 regulations related to drug labeling, manufacturing, storage, ordering, prescribing and

120 dispensing. See generally 21 CFR parts 1300-1316. Sponsors are encouraged to contact the

121 DEA early in the drug development process if they believe their drug may have abuse potential

122 and may be controlled and to discuss with the DEA issues related to CSA researcher registration

123 requirements, quotas, and other rules and regulations that concern controlled substances that may

124 be relevant to their product.

125

Contains Nonbinding Recommendations

Draft — Not for Implementation

126

III. DETERMINING A DRUG'S ABUSE POTENTIAL

127

128

Definitions

129

130 The Controlled Substances Act refers to the assessment of “potential for abuse,” “addiction

131 sustaining liability,” and “dependence” 21 U.S.C. 802(1),(9),(18),(29). The Controlled

132 Substances Act does not define these terms.

Abuse potential

and

addiction-sustaining,

abuse

133

liability,

can be understood to encompass similar concepts and, as such, are often used

134 interchangeably.

3,4

135

136

Abuse potential

refers to a drug that is used in nonmedical situations, repeatedly or even

137 sporadically, for the positive psychoactive effects it produces. These drugs are characterized by

138 their central nervous system (CNS) activity. Examples of the psychoactive effects they produced

139 include sedation, euphoria, perceptual and other cognitive distortions, hallucinations, and mood

140 changes. Drugs with abuse potential often (but not always) produce psychic or physical

141 dependence and may lead to the disorder of

addiction.

142

143 The concept of

abuse potential

encompasses all the properties of a drug, including, for example,

144 chemical, pharmacological, and pharmacokinetic characteristics, as well as fads in usage and

145 diversion history.

146

147

Addiction

is defined as a chronic, neurobiological disorder with genetic, psychosocial, and

148 environmental aspects, characterized by one or more of the following: impaired control over

149 drug use, compulsive use, continued use despite harm, and craving (American Academy of Pain

150 Medicine, American Pain Society, and American Society of Addiction Medicine consensus

151 document, 2001).

152

153

When Should an Abuse Potential Assessment Be Submitted to FDA?

154

155 A sponsor must submit in the NDA an assessment of studies and other information related to the

156 potential abuse of a drug and include a

proposal for scheduling

if the drug affects the central

157 nervous system (CNS), is chemically or pharmacologically similar to other drugs with known

158 abuse potential, or produces psychoactive effects such as sedation, euphoria, and mood changes.

159 See 21 CFR 314.50(d)(5)(vii).

160

161 An assessment of abuse potential may be needed for new drugs, including new molecular entities

162 (NME). An abuse potential assessment might also be necessary for a marketed drug product that

163 presents an unexpected adverse event profile that includes events that are related to abuse

164 potential or that is being re-evaluated for a new route of administration that could affect the

165 abuse potential of the drug.

166

See the DEA Web site for the schedules of drugs, contact information, pertinent information regarding the

Controlled Substances Act, and related topics (http://www.deadiversion.usdoj.gov).

“Conference on Abuse Liability Assessment of CNS Drugs,”

Drug Alcohol and Dependence

, 70:3 Suppl. 2003.

Contains Nonbinding Recommendations

Draft — Not for Implementation

167

What Should Be Included in an Abuse Potential Submission?

168

169 The abuse potential assessment must be submitted as a section of the NDA or a supplement. The

170 section must contain all pertinent preclinical, pharmacological, chemistry, biochemical, human

171 laboratory, and clinical studies, drug formulation data, and a proposal for scheduling, if

172 appropriate (21 CFR 314.50(d)(5)(vii)). The abuse potential section should also include

173 proposed labeling that describes the drug’s abuse potential and dependence liability.

174

175 The Controlled Substance Staff evaluates all abuse-related data to help FDA review divisions to

176 determine the suitability of a drug’s label and labeling and accordingly may make additional

177 recommendations to the sponsor that relate to the CSS evaluation.

178

179 Contents of an abuse potential section include the following:

180

181

For NMEs, the NDA should include an abuse potential section with the following:

182

183

1. A summary, interpretation, and discussion of abuse potential data provided in the NDA

184

2. A proposal and rationale for placing (or not placing) a drug into a particular schedule of

185

the Controlled Substances Act

186

3. All primary data related to the abuse potential characterization of the drug, organized

187

under the following subheadings:

188

189

a. Chemistry

190

b. Preclinical Pharmacology

191

c. Animal Behavioral and Dependence Pharmacology

192

d. Pharmacokinetics/Pharmacodynamics

193

e. Human Abuse Potential Laboratory Studies

194

f. Clinical Trial Data Relative to Abuse and Dependence Potential

195

g. Integrated Summaries of Safety and Efficacy

196

h. Foreign Experience with the Drug (Adverse Events, Abuse Potential, Marketing

197

and Labeling)

198

199

4. Electronic submissions

200

201

For an NDA submitted in electronic format, the common technical document (CTD) should

202

address points 1, 2, and 3a-h (above) under the appropriate Modules 1, 2, 3, 4 and 5. These

203

sections should contain links to the summary of abuse data in Module 2 and the proposal for

204

scheduling and product labeling in Module 1. The data and studies supporting sections 3 a-g

205

(above) should be placed in the appropriate sections of the CTD: Chemistry (Module 3),

206

preclinical and animal pharmacology (Module 4), pharmacokinetics/pharmacodynamics

207

(Modules 4 and 5), human abuse and clinical studies (Module 5), and integrated summaries

208

of safety and efficacy (Module 5). Foreign experience has no specific designated location,

209

but would fit most appropriately under Module 5, postmarket experience.

210

211

5. Paper submissions

212

Contains Nonbinding Recommendations

Draft — Not for Implementation

213

An NDA that will be submitted in paper form should contain the above listed information

214

clearly identified as an abuse potential section.

215

216 The scientific overview of the drug’s pharmacological activity should include consideration of

217 the drug’s pharmacology, a description of its chemical structure and class, its profile of

218 biochemical activity, its pharmacokinetics and metabolism, the production of any active

219 metabolites (and their pharmacological activity profile), and a description of any adverse

220 reactions.

221

222 Sponsors are encouraged to consult with the Controlled Substance Staff through the appropriate

223 FDA centers, offices, or divisions responsible for the overall review of the application about the

224 design of studies and data to be included in an abuse potential section. Discussions between the

225 Controlled Substance Staff and sponsors regarding the proposed studies and data can facilitate

226 adequate data submission and full characterization of the abuse potential of the drug substance or

227 product.

228

229

230

IV. APPROACHES AND METHODS FOR ABUSE POTENTIAL ASSESSMENTS

231

232 A variety of approaches that can be used to assess the abuse potential of a drug product are

233 discussed in the following sections of the guidance.

234

235

Preclinical Screening

236

237 In vitro receptor binding studies are an important part of the preclinical screening of new drugs

238 with abuse potential because they are very useful in interpreting the results of other animal and

239 human studies, as well as in the planning of future investigations.

240

241 In vitro binding studies should be conducted to determine the pharmacological site of action of

242 the drug and active metabolites in the brain (e.g., receptor, transporter, ion-gated channel

243 system). Novel drug mechanisms of action may be associated with previously unrecognized

244 abuse potential in humans.

245

246 Although a drug may have a single high-affinity site, it is important that direct and indirect

247 actions and effects of the drug on other neurotransmitter systems associated with abuse potential

248 be assayed. Examples of neurotransmitter systems of interest include the following:

249

250

•

Dopamine

251

•

Norepinephrine

252

•

Serotonin

253

•

Gamma-aminobutyric acid (GABA)

254

•

Acetylcholine

255

•

Opioid

256

•

N-methyl-D-aspartate (NMDA)

257

•

Cannabinoid

258

Contains Nonbinding Recommendations

Draft — Not for Implementation

259 The application of general scientific principles, including the use of appropriate regional brain

260 tissue, positive controls, and internal standards, should be ensured. High selectivity radioligands

261 should be used whenever they are available. Binding sites can also be analyzed using

262 complementary DNA (cDNA), encoding a specific receptor that is expressed in a homogeneous

263 system.

264

265 In vivo binding techniques, such as positron emission tomography (PET) or single photon

266 emission computed tomography (SPECT), can also provide information about the localized

267 action of drugs. Studies using these techniques can contribute important information about the

268 whole body pharmacokinetic and pharmacodynamic properties of the drug in question.

269

270 Knowledge of the binding profile may suggest which functional in vitro assays can help

271 determine whether the drug is an agonist, antagonist, partial agonist, or mixed agonist-antagonist

272 at specific binding sites. Based on the biochemical pharmacology, behavioral tests relevant to

273 the specific mechanism of action will be more apparent.

274

275 Receptor binding data should be submitted as a part of the pharmacology-toxicology section of

276 the NDA and should also be included in, or hyperlinked to, the abuse potential assessment

277 section of the NDA.

278

279

Chemistry and Manufacturing

280

281

Consideration of Chemistry Data

282

283

Data from the chemistry, manufacturing, and controls (CMC) section of the NDA that are

284

relevant to the abuse potential of the drug under investigation should be submitted as part

285

of, or be hyperlinked to, the abuse potential section. The assessment of abuse potential

286

should include information related to the synthesis of the drug, data on the physical and

287

chemical properties of the substance and proposed drug product, and data related to

288

alternate synthetic pathways and drug characteristics, including yields and impurity

289

profiles.

290

291

In addition to the information submitted as part of the CMC section of the NDA, the

292

abuse potential assessment should include an evaluation of the physicochemical

293

properties of the drug substance and product. Information on extractability and solubility

294

of a drug is relevant to the drug’s abuse potential and should be addressed.

295

296

Assessment of such data is especially relevant when the new drug product is a new

297

formulation of a drug substance, such as a 505(b)(2) NDA submission, of recognized

298

abuse potential, that presents additional safety concerns. Examples of drugs with the

299

highest relative abuse potentials can be found in Schedule II (see 21 CFR 1308.12 for the

300

most current listing). Additional information on the ease or risk of extraction of the drug

301

substance, that is, the active pharmaceutical ingredient (API), from the product

302

formulation should be obtained. In particular, sustained- or extended-release

303

formulations and transdermal systems (patches or mechanical devices containing drugs)

304

that are expected to contain large quantities of a controlled substance should be assessed

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