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Assessing Abuse Liability During Drug Development: Changing Standards and Expectations KA Schoedel1 and EM Sellers1,2,3,4 As public health concerns have changed, regulatory expectations for assessing abuse liability of new central nervous system (CNS) drugs have increased. All CNS-active drugs with any properties indicating stimulant, depressant, hallucinogenic, or mood-elevating effects will require an evaluation of abuse liability. Abuse liability assessment involves the collection, analysis, and interpretation of data on chemistry and tampering, animal behavioral pharmacology, clinical trial adverse events (AEs), diversion and overdose, and potentially reinforcing (subjective) effects in recreational drug users. What is Abuse Liability?
Abuse potential has been defined as the ability of a drug to produce positive subjective or reinforcing effects, which is thought to be predictive of risk for “addiction.”1 Abuse liability from a regulatory and public health perspective refers not only to abuse potential, but also to all factors impacting the risk of misuse, abuse, or diversion. Such factors include therapeutic indication, availability, ease of synthesis, context of use, and risk for misuse or diversion. Abuse liability also includes the potential for negative outcomes resulting from abuse (e.g., addiction, overdose, or toxicity). Why is Assessing Abuse Liability Important?
The number of emergency department visits associated with drug abuse (as estimated by the Drug Abuse Warning Network in the United States)2 and reports from the United Nations (International Narcotics Control Board),3 as well as media and regulatory scrutiny associated with high-profile cases, underscore the increasing importance of prescription drug abuse. In recent years, while illicit drug use has stabilized or decreased, prescription drug abuse has increased.4 In 2005, 49% of the 1,449,154 emergency department visits reported to the Drug Abuse Warning Network involved pharmaceuticals alone or combined with alcohol/illicit substances.4
Regulatory Framework
Drugs of abuse are primarily controlled under the Single Convention on Narcotic Drugs, 1961, and the Convention on Psychotropic Substances, 1971 (refs. 5, 6), as well as the Convention Against the Illicit Traffic in Narcotic Drugs and Psychotropic Substances, 1988 (ref. 7). These international treaties include measures to maintain legitimate medical and scientific access while preventing diversion and trafficking. In the United States, the framework for control is regulated by the Controlled Substances Act and scheduling of drugs is determined by eight factors as a part of the New Drug Application approval process.8 The European Union classifies substances according to the United Nations Conventions. Specific European Union legislation on drug classification is limited to precursors (i.e., substances used in the illicit manufacture of controlled substances);9 however, information exchange, risk assessment, and control of new psychoactive substances are covered in a 2005 Council Decision10 (in addition to country-specific legislation). In Canada, substances with abuse liability are controlled under the Controlled Drugs and Substances Act.11 Abuse Liability Data Collection during CNS Drug Development
An overview of data required for an abuse liability evaluation by a regulatory authority prior to marketing approval is provided in Figure 1. The exact timing of the data collection will vary with the nature of the drug, as well as business decisions related to drug development. When “go/no-go” or therapeutic indication decisions are driven by abuse liability and scheduling concerns, abuse liability assessment should occur early in development, as soon as pharmacokinetics and safety data in humans are available (following studies of single- and multipleascending-dose tolerability). Abuse liability studies may also occur early in development when licensing, codevelopment, or other agreements depend on scheduling. In cases where
1Clinical Pharmacology Group, DecisionLine Clinical Research Corporation, Toronto, Ontario, Canada; 2Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada; 3Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 4Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. Correspondence: KA Schoedel (
[email protected])
Received 2 November 2007; accepted 28 November 2007; advance online publication 23 January 2008. doi:10.1038/sj.clpt.6100492 622
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development
Preclinical Structural similarity Binding/functional assays Microdialysis In vivo pharmacology
Clinical Phase I single- and multipleascending-dose studies: AE profile, PK, early PD
Clinical pharmacology • Human abuse liability study • PK: Onset/duration, metabolites • Drug/alcohol interactions • Neurocognitive/impairment
Clinical trial data • Abuse-related AEs • Discontinuation-emergent AEs • Overdose • Diversion
Nonclinical • Behavioral pharmacology (SA, DD) • Tolerance and sensitization • Physical dependence (chronic dosing)
Chemistry/formulation • Ease of synthesis • Precursors • Extractability • Routes of administration
Submission • Abuse evaluation (including all data) • Recommended schedule • Label • Risk management plan
Figure 1 Overview of abuse liability data collection during drug development. The exact order and nature of assessments will depend on what is observed at previous stages and the developer’s acceptable level of risk/control for a given indication. AE, adverse event; DD, drug discrimination; PD, pharmacodynamics; PK, pharmacokinetics; SA, self-administration.
scheduling and abuse liability are less in doubt, waiting until early phase III or late phase II permits evaluation of potential “signals” from earlier studies. However, most regulatory agencies will require these data with the final filing and the developer must consider the long time typically required for these studies. Methodological Guidance
A review of regulatory and other guidelines on abuse liability has been published elsewhere.12 Subsequently, the European Medicines Agency has issued a preclinical guidance for assessing dependence potential13 and Health Canada has published a comprehensive guidance on clinical assessment of abuse liability.14 There are currently no US Food and Drug Administration (FDA) guidelines on abuse liability assessment. Draft guidelines were initially prepared; however, they were subsequently withdrawn (they are available in ref. 12). A review article authored by FDA staff specifically on human abuse liability studies has recently been published.15 Controlled Substances Staff members have also presented at several conferences (some of which are available at http://www.fda.gov/CDER/Offices/CSS/presentations.htm and in refs. 16–18). In order to meet FDA requirements, nonclinical and clinical abuse liability data collection should be consistent with “best practices,” as outlined in this and other review articles.14,15,19–27 Medical reviews for recently approved drugs (available at Drugs@FDA)28 can also be helpful; although the abuse liability data are sometimes unavailable or difficult to find. In general, the FDA has the most structured and stringent requirements, and thus this article focuses on US regulatory expectations because meeting these standards will Clinical pharmacology & Therapeutics | VOLUME 83 NUMBER 4 | APRIL 2008
typically ensure adequate data for other regulatory agencies. The required clinical data are outlined briefly in the following sections. Required Clinical Data
The clinical data that contribute to the assessment of abuse liability include clinical trial adverse events (AEs), evidence of diversion or tampering, overdose, and the results of a human abuse liability study. Clinical AE monitoring
The few validated scales available for assessing abuse and/or dependence in clinical trials are specific to drug class and/or patient population and would require modification and validation in order to be useful. Therefore, clinical evaluation of abuse/dependence in healthy volunteers and patients is typically based on treatment-emergent “abuse-related” AEs observed in all clinical studies and those occurring upon discontinuation or taper of the drug (Table 1). These latter AEs assess whether a drug produces neuroadaptation (physical dependence) and a discontinuation syndrome. AEs occurring during the treatment phase of clinical studies can provide evidence of moodelevating, sedative, stimulant, or hallucinogenic properties. To be useful, AE data should ideally be prospectively collected based on predefined low-level (verbatim) terms of interest. Analyses should include summaries and listings of coded and verbatim events, as well as case narratives on AEs of interest. Narratives are essential for an understanding of the context of the AE reports and whether they represent signals of abuse potential. Drug “diversion” or tampering are evaluated by a 623
development Table 1 Abuse liability data collection in clinical trials Type of clinical trial data
Data collected
Comment
Euphoria/abuse-related AEs AEs that indicate mood elevation, depressant, stimulant, cognitive/motor impairment, or psychotomimetic effects (euphoric mood, sedation/somnolence, psychomotor hyperactivity, hallucination, feeling drunk, etc.)
MedDRA-coded AEs Verbatim terms (low-level clinical terms/descriptions) Case narratives
Can assess incidence of effects in all study patients Typically enroll low-risk populations (i.e., subjects with no abuse/dependence history) so signal detection is poor Magnitude of a relevant signal not established: difficult to compare across trials/compounds unless “head-to-head” Highly controlled environment: exclusion or withdrawal for “aberrant” behaviors or positive urine drug screens (UDSs) for drugs of abuse AE reports may not sensitive to detection of abuse risk: especially difficult to interpret without narratives
Discontinuation-emergent AEs AEs occurring during taper or after withdrawal that may indicate “physical dependence” or a discontinuation syndrome
MedDRA-coded AEs Verbatim terms Case narratives
Can assess incidence in all study patients Exiting scales may be drug class-specific: AE search lists may need refinement as nonclinical/clinical AE data become available Magnitude of signal indicating a “discontinuation syndrome” not established: difficult to compare across trials/compounds unless “head-to-head”
Overdose Cases of overdose that may indicate possible abuse and risk to public health associated with overdose
Incidence Case narratives
Incidence of overdose may be low and not necessarily associated with abuse. Overdose outcomes often confounded by disease, comorbidity, concomitant medications
Diversion/tampering Identification of diverted medication, discrepancies, taking more than allowed, or other drug-seeking behavior
Drug accountability Compliance Protocol deviations
Difficult to distinguish diversion from error or lost medication Study populations usually at low risk (no abuse/diversion history, UDS) Highly controlled environment
careful examination of drug accountability, compliance, and protocol deviation records to identify missing or lost medications, discrepancies, taking more of the drug than intended, and other drug-seeking or aberrant behaviors. In addition to spontaneous reporting or “open-ended” questions (e.g., “How are you feeling?”), structured assessments of CNS effects (e.g., visual analog scales, structured interview) may be more sensitive in detecting abuse-related effects, although they may be more difficult to implement in large-scale trials. Although these data represent essentially the only premarket opportunity to assess abuse and dependence risk in intended therapeutic populations, they have limitations and careful interpretation is warranted (Table 1). Human abuse liability study
The most effective strategy to assess drug abuse liability in humans is to compare the dose- and time-response profiles of subjective and pharmacologic effects of the investigational drug against placebo and comparator(s) with known abuse liability. These studies are typically single-dose, randomized, double-blind inpatient crossover studies in recreational drug users. Detailed study design and analysis considerations have been discussed previously12,14,15,24,27 and are summarized in Table 2. Current human abuse liability study methodology is scientifically robust, with high reproducibility and sensitivity in detecting subtle but important differences between drugs. Although a lack of effect in recreational drug users provides good evidence that the drug will not be abused, evidence of similarity to known drugs of abuse does not necessarily mean that the drug will be widely abused once on the market. Therefore, the results of a human abuse liability study should be interpreted in the context of all data pertinent to assessing abuse liability. 624
Which Drugs Require Abuse Liability Evaluation?
In the past, the extent of evaluation required was determined primarily using neurochemical criteria. If the drug was associated with targets of interest (γ-aminobutyric acid, μ-opioid, dopamine, etc.) or was of a certain class (opioids, benzodiazepines, cannabinoids, etc.), one could expect that a full evaluation would be needed, and if not, very few data were required. Increasing numbers of novel agents, as well as emerging abuse potential of some rather surprising drugs (e.g., κ-opioid agonists), have made the decisions more difficult. The US Controlled Substances Act refers to opioids, cannabinoids, sedatives, hallucinogens, and stimulants (and anabolic steroids, which are not discussed in this article). It is not difficult to determine whether a drug is an opioid or cannabinoid; however, the terms “sedative,” “hallucinogen,” and “stimulant” do not refer only to prototypical agents such as benzodiazepines, LSD or amphetamines but rather to any drug that shows evidence of these properties. Therefore, developers should assume that all centrally active drugs will require some evaluation of abuse potential if mood-elevating, stimulant, sedative, or hallucinogenic properties are observed in nonclinical or clinical studies (e.g., locomotor stimulation or depression, clinical AEs such as somnolence, hyperactivity, euphoric mood, hallucination, etc.). The Impact of Media and the Internet
The Internet and the media are now major sources of information on recreational drug use. There are numerous websites and chat rooms where information on drugs of abuse is shared, including trends, “trip reports,” tampering “recipes,” where to obtain drugs, and which drugs to abuse and how to abuse them (doses, routes of administration, potentiation of effects using combinations). This ability to rapidly disseminate knowledge VOLUME 83 NUMBER 4 | APRIL 2008 | www.nature.com/cpt
development Table 2 Overview of human abuse liability study design Parameter
Description/considerations
Subjects
Recreational drug use experience with class of interest No history of dependence or substance abuse treatment Pharmacologically qualified (distinguish test drug vs. placebo): Face validity Objective confirmation of history Avoid false negatives (non-drug users) Increased sensitivity/reduced noise to decrease risk of study failure Sample size typically 20–40: need sufficient power for all contrasts
Comparators Selection of comparators typically based on Highest appropriate schedule: for unscheduled status compare to IV or V Pharmacologic class/mechanism, if from an abused class Pharmacologic/side effects profile (for novel classes) Other considerations: Market competitor Pharmacokinetic similarity/biotransformation pattern Formulation Doses
Ideally two to three dose level: Dose response information and slope (dose-escalation pattern) Relevant to drug abusers Typical range of therapeutic → maximally tolerated
Measures
Visual analog scales: drug liking (overall, “at this moment”), take drug again, positive effects (good effects, high, etc.), negative effects (bad effects, feeling sick, etc.), class-specific effects, drug similarity Drug vs. money or other choice procedures Addiction Research Center Inventory (ARCI) Pharmacokinetics: assess exposure Objective: neurocognitive, pupillometry, vitals, observerrated scales
Challenges
Novel drugs: more difficult to select appropriate population/ comparator(s) Long half-life: incomplete washout, long study duration or nested parallel designs Outliers or “atypical” responses: difficult to interpret Methods improvement: many current scales are redundant and could be improved
confined to specific geographic areas. Now an Internet-savvy “pharmacologist” can disseminate knowledge about a new drug of abuse all over the globe within minutes. Current Regulatory Framework in the New Drug Abuse Environment
Regulatory expectations with respect to abuse liability have become more stringent in terms of the types of drugs subject to evaluation and the extent of data required. This is more likely related to changes in the context and environment of prescription drug abuse than to the intrinsic properties of the drugs themselves. Selected classes and historical patterns of abuse shaped the framing of current regulations; however, this framework did not fully anticipate the new patterns and extent of prescription drug abuse and the rapid, global dissemination of knowledge. Many older CNS drugs that were never evaluated for abuse liability would probably show significant potential for abuse using current methodological and public health standards. In the current environment, new CNS drugs are unlikely to escape detection by recreational drug users, since the populations at risk are now more widespread than the small geographical subsets or recreational drug “connoisseurs” of the past. Therefore, a more thorough premarket evaluation of abuse/ dependence potential provides some balance to uncontrolled information transfer via the Internet, by allowing dissemination through legitimate channels, such as product labeling and other educational tools. Conclusions and Outlook
Drug abuse liability is an important public health issue, often at least as important in terms of morbidity and mortality as other safety issues. Public health concerns have shifted and regulatory expectations for assessing abuse liability of new CNS drugs have increased. Now virtually any CNS-active drug with any properties suggestive of stimulant, depressant, hallucinogenic, or mood-elevating effects will require some abuse liability evaluation. Regulatory requirements to qualify for unscheduled status have also become more stringent, reflecting changing societal concerns and application of public health policies. Thus, providing an incomplete evaluation of abuse liability can delay drug development, regulatory review, and market approval. Comprehensive abuse liability data collection, analysis, interpretation, and dissemination through product labeling and education will help protect public health and maintain medical access to CNS drugs. Such an approved product will also help protect drug developers from postmarketing surprises and meet the obligations of their social contract.
influences the types and extent of abuse, drug abuse trends, and experimentation. In addition, many Internet pharmacies offer controlled substances without prescriptions.29,30 Other sources of information are product labels, which have become more detailed with respect to abuse/dependence liability, and direct-to-consumer advertisements. Many abusers read product labels and advertisements carefully, since they often contain information about whether products will cause a high or have other effects of interest. For example, a trip report on the website Erowid (http://www.erowid.org/splash.php)— “…has an interesting side effect…‘It may make you drowsy’ according to the label. This is true—” illustrates a case where the label had attracted the individual to experiment with the drug. This dramatically improved worldwide access to information increases the likelihood that new CNS drugs will be subject to experimentation by a potentially large number of abusers. It also makes containing “outbreaks” of abuse resulting from experimentation more difficult. In the past, drug abuse “fads” were usually
1. Calderon-Gutkind, S.N. The assessment of abuse liability: the regulatory perspective. (2003). 2. New Drug Abuse Warning Network. (2007).
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Conflict Of Interest EM Sellers is President and CEO of DecisionLine Clinical Research Corporation, and KA Schoedel is an employee of DecisionLine Clinical Research Corporation. © 2008 American Society for Clinical Pharmacology and Therapeutics
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