"Drug Abuse Liability Study: A Category Analysis"

Siddhartha Shaurabh, Lead Analyst with Beroe Inc
Drug Abuse Liability (DAL) assessment evaluates the likelihood of drug abuse or dependence on the prescribed drug and hence forms the core for safety pharmacology study in developing drugs for central nervous system (CNS). The drug abuse liability testing market is largely driven by global CNS therapeutics market which represents around 17 per cent of drugs in clinical trials in 2013. Considering drug abuse a major health concern, DAL, which was earlier confined to clinical phase, has been incorporated in pre-clinical stage by the regulatory bodies. The category managers at pharma companies employ a combination of CROs and academia at different stages of drug development to optimise spend on DAL testing. Also, DAL data, both at preclinical and clinical stages, would immensely help regulatory bodies in product labelling and drug scheduling recommendation with the hope of reducing its misuse and dependence.

Prescription drugs hold the chance to be misused or used for nonmedical reasons and can lead to physical dependence and withdrawal symptoms. The symptoms thus results are generally noticed in the drugs that affect the central nervous system. Such drugs are found to have abuse potential or abuse liability.

Drug abuse liability study has surfaced on the safety pharmacology space in recent years as a result of numerous safety guidelines and discussion documents from regulatory bodies in the US and Europe. Increasing incidents about prescription drug abuse and the withdrawal prospective of many common drugs have necessitated development of evaluation procedures (both non-clinical & clinical) like abuse liability testing.

In the last decade, Asia, Europe, and Australia indicated major trouble with opiate dependence, South America primarily was affected by cocaine addiction, and Africans were treated most often for the addiction to cannabis. Only in North America was drug habit disseminated relatively uniformly between the use of opiates, cannabis, cocaine, amphetamines, and other narcotics.

What types of prescription drugs are abused?
Three types of drugs are most often abused:
  • Opioids: generally prescribed for pain relief
  • CNS depressants: barbiturates and benzodiazepines prescribed for anxiety or sleep problems (often referred to as sedatives or tranquilizers)
  • Stimulants: prescribed for attention-deficit hyperactivity disorder (ADHD), the sleep disorder narcolepsy, or obesity.

Market Overview
Drug abuse liability study has its significance across Pharma, bio-pharma, agrochemicals, medical devices and cosmetics industry. Recently, higher incidents of drug abuse have led regulatory body to solicit assessment of the safety profile of NCEs particularly for all new CNS-active medicinal products (parents + metabolites) that can cross the blood brain barrier (BBB), interact with central targets and precipitate an abuse liability potential.

The estimated global market size for drug abuse liability study is around 1.5bn USD growing steadily at ~3 per cent. This market has a close impact with the CNS therapeutic area as all drug substance entering the CNS drug R&D space has to undergo abuse liability test.

There are three main types of studies that are typically employed to address abuse liability:
Drug discrimination -- This model is used to determine the properties of novel compounds with that of a known class of drugs or to determine if the novel compound can be distinguished. It is hence, used to identify the extent of similarity of the subjective effects of the new chemical entity to those of the known drugs of abuse, such as CNS stimulants or depressants.

Drug self-administration is a nonclinical model adopted to ascertain whether animals will work to get access to the direct injection of drugs. Administering the drug which induces the rewarding effect is the direct assessment of drug’s abuse liability. Amphetamine, morphine & cocaine are strongly positive in this test. Hence, it is used to directly measure the positive-reinforcing properties of the new chemical entity.

Drug dependence produces continued drug use in order to avoid negative feelings—physical or emotional—that occur when drug administration is stopped. Continued administration of a drug that produces dependence may be associated with the development of tolerance to the pharmacological effect of the drug. A positive signal in isolation doesn't necessarily indicate abuse potential. However, together with positive effects in the other assays, could contribute to the potential for abuse.

Exhibit:

Current service provision scenario in the market
Services in the drug abuse liability are provided by both academia and CROs. Service provision in the drug abuse liability testing could be 20-30% cheaper (could be even lesser depending on the particular area of interest) when done through academia but CROs are preferred due to two main reasons:
  • Speeds of completion- The work with the CROs are mainly business driven and customized as well. Hence, the focus is on the business outcome and timelines of client.
  • GLP Compliance- Most of the academia is non-GLP compliant and during the FDA reviews GLP compliance is mandatory. Hence, CROs are proactively chosen.
Though, academia and CROs are two separate entities but there can be subcontracting from CROs to academia due to
I. Greater scientific understanding on the subject by academia.
II. Better choice with protocol compliance & writing.
III. Interpretation of potential mechanisms of abuse.

However, CROs are mostly preferred for drug abuse liability studies due to the technology & expertise availability, regulatory compliance and capacity readiness. These CROs are also one stop shops for a battery of experiments required in abuse liability studies. As per pharma companies, it is more cost effective to rely on outside providers that can manage projects complexity and have an understanding of regulatory compliances.

Drug Abuse Liability Study: Compliance Scenario
The drug abuse liability testing is generally done as per GLP & non-GLP standard in the supply market greatly affecting the cost incurred & regulatory compliance requirement sought. However the quality of studies should be equivalent. Taking in to account a series of activities to evaluate the novel molecule with abuse potential, a two-tiered assessment is suggested by the regulatory body generally considered as Non-GLP (Tier1) or pharmacology & GLP (Tier2) or specific behavioral pharmacology studies.

Non-GLP Compliance:
  • Non-GLP studies are generally termed as tier1 study by regulatory body (EMA) and take in to account the testing of the novel molecule with abuse potential on account of chemical structure, PK/PD characteristics, pharmaceutical characteristics, etc.
  • Studies such as receptor-binding (in vitro), confirmation of binding & functional properties (in vivo) referred to under the first tier by European Medicines Agency as outlined under ICH S7A - largely need not meet the requirements of GLP.
GLP Compliance:
  • Studies for safety pharmacology are generally done with the GLP compliance which is largely considered as tier 2 studies as per regulatory body (EMA).
  • Specific behavioral pharmacology studies are done when the active substance has a novel mechanism of action & this is done on the basis of biochemical, pharmacological and clinical information already available through tier1 (non-GLP) test.
Market Practices:
Vendor Option: The service for drug abuse study is a very niche area and provided in the market by very few CROs and research oriented universities. Several independent consultants are also available in the market functioning in this space; however they again collaborate with same set of CROs for the service delivery.
  • CROs: These are the commercial services providers, having a greater understanding of the client’s requirement, regulatory practices & conformity (Good manufacturing practices (GMP) compliance) and proven expertise & experience.
  • Academia / University: These are the research centers with expertise of world leading disease scientists, technology experts, novel models etc. In abuse liability space, most of the academia is non-GMP compliant.
  • Consulting Firms: These are the group of Pharma consultants offering functional & regulatory affairs expertise and support services on the basis of their extensive experience & network of service providers.
Consulting firms are generally chosen for the abuse liability studies when a pharma company is planning to start these studies for very first time in order to understand the developing guidelines & standard operating procedure (SOP) and regulatory compliance. At the later stage they are not preferred because of their redundant use & added cost.

References
  • http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf
  • http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DrugSafetyandRiskManagementAdvisoryCommittee/UCM337158.pdf
  • http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/abus/abuse_liability_abusif_usage_clin-eng.php
  • http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM180770.pdf
  • http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM180785.pdf
  • http://www.toxicology.org/isot/rc/nesot/docs/07Alper.pdf
  • http://www.ncbi.nlm.nih.gov/pubmed/10519736
  • http://www.ncbi.nlm.nih.gov/pubmed/