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126
III. DETERMINING A DRUG'S ABUSE POTENTIAL
127
128
A.
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,
or
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
B.
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
3
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).
4
“Conference on Abuse Liability Assessment of CNS Drugs,”
Drug Alcohol and Dependence
, 70:3 Suppl. 2003.
4
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167
C.
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
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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
A.
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
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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
B.
Chemistry and Manufacturing
280
281
1.
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
7
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