Design and Operational Challenges when Executing Opioid ...

Volume 7 Issue 542 Journal for Clinical Studies

Therapeutics

Design and Operational Challenges when Executing Opioid Clinical Trials: Lessons Learned

Patients requiring chronic opioid administration frequently have complex medical conditions and are heterogeneous with respect to unpredictable individual differences in potency, effectiveness, and adverse effects. Consequently, pain assessments in patients requiring chronic opioid administration are highly challenging, even with the use of well-validated tools. Opioid abuse with prescription opioids is a prevalent and increasing issue. In the United States, the FDA has highlighted this issue and mandated that new opioid formulations are assessed for ‘tamper-resistance.’

Diversion of opioids is a frequent issue within the clinical trial setting. This problem occurs across different countries, at multiple investigative sites, and varies by study subjects and study staff. Potential patients for opioid analgesia trials have complex characteristics, and current study designs are highly restrictive and unattractive with regard to eligibility criteria, requirements for a placebo arm, and schedule of events. Pro-active operational risk mitigation and planning can increase compliance and quality of study data, and protect patients and the wider community from the damaging effects of opioid diversion.

Pain is a ubiquitous consequence of a wide range of injuries, surgeries, and medical conditions as diverse as cancer, low-back pain, and restless leg syndrome.1-7 Both acute and chronic pain can be extremely debilitating clinical conditions, and there is an ever-present need for analgesic medication. This paper reviews the multiple study designs and operational challenges in executing clinical trials for new opioid analgesics under development, and suggests some solutions to these challenges.

The opium poppy produces benzylisoquinoline alkaloids (opiates) that are important medicinal compounds, including the analgesics morphine, codeine, and thebaine, which is used in the synthesis of various semi-synthetic opioid analgesics.8.9 These synthesised compounds include hydrocodone, oxycodone, hydromorphone, and oxymorphone. Most opioids used in clinical practice exert their influence via mu opioid receptors. While a single mu opioid receptor gene has been identified, the mechanism of alternate splicing results in multiple proteins that constitute these receptors.10 The range of opioid medications and opioid receptors can lead to unpredictable differences in individuals in potency, effectiveness, and adverse effects,11 one feature that complicates the interpretation and generalisability of results from a given clinical trial. This also makes it extremely important to individualise therapy for every patient in pain.11

Pain assessment itself is not straightforward: as Joffe et al. observed, “To effectively treat pain, it must be detected and quantified using a validated assessment tool”.12 Assessing pain becomes even more challenging when an individual, who is almost certainly experiencing severe pain, is unable to self-report the pain: examples include individuals in cardiovascular intensive care units and medical/surgical/trauma units.13

We have analysed opioid data from an internal, proprietary, illustrative database using de-identified, aggregated data from many sources. It is within the context of the complexities just described that the following results and discussions are presented. MethodsA proprietary, illustrative database using de-identified, aggregated data, including opioid analgesia data from many sources, was used for the analysis. A leadership survey was given to researchers of opioid analgesia and interviews were conducted with them following the format of the questionnaire to yield ‘lessons learned.’ The database was classified by type of pain (acute – 34%; chronic – 66%) and by age (paediatric – 20%; adult – 80%). This research had three main objectives: to determine the main areas of operational execution within analgesia trials investigating opioids that create major challenges; to analyse internal organisational data relating to quality and clinical study monitoring, thus examining trends in operational delivery challenges; and to recommend key areas of risk mitigation and improvement in operational delivery for future opioid trial conduct.

Three key areas of data pertaining to operational delivery were examined:• Surveys of leadership teams governing the studies.

Interviews and questionnaires were conducted with medical advisors and clinical project managers executing the programmes. The areas of feedback elicited pertained to the participant population chosen, recruitment and retention, opioid diversion (study drug being ‘diverted’ from its intended use in the trial), study design, site experience and logistics, and risk management.

• Clinical monitoring reviews and quality assurance audits. Records and reports were examined that specifically pertained to critical and major protocol deviations, violations and audit findings within the following categories: eligibility, compliance, opioid accountability, site security, and opioid diversion.

Characteristics examined included study design, participant population, recruitment and retention,

Journal for Clinical Studies 43www.jforcs.com

site experience, logistics, opioid diversion, and risk management.

The leadership survey was provided to study personnel via a paper questionnaire and interviews were conducted with these individuals following the format of the questionnaire. The opportunity was taken by the interviewers to elicit as much detail as possible pertaining to the areas outlined and to encourage objective reflection on areas where the operational execution was both successful and deficient.

ResultsThe leadership survey response rate was 52% for the identified studies.

Study DesignOf the total respondents, 75% identified issues with study inclusion/exclusion criteria leading to high screen failure rate. These criteria included pain severity required for entry into the trial, exclusionary medical conditions, and excluded medication at screening identified in urine drug analyses. Inclusion of a placebo arm in the study also proved problematic (with participants not wishing to take the chance of being randomised to that treatment arm). Lengthy and cumbersome study procedures were also identified as problematic, as discussed next.

Patient Population, Recruitment, and RetentionOf the total respondents, 58% identified issues with participants in the screening/enrolment period that were related to lengthy and cumbersome procedures, such as dose titration and diary completion. These issues led to high screen failure and poor adherence. Of these 58%, 33% reported issues with washout of current medication causing ‘pain flare’ and high screen failure rates.

Of the total respondents, 58% (same number) of total respondents identified low recruitment as an issue. Of these, 71% identified the complex schedule of assessments, and 60% identified lack of interest in placebo-controlled trials. Of the total respondents, 25% identified high recruitment as an issue, mainly due to the overall poor quality of data generated at the high-recruiting sites.

With regard to participant retention, 17% of the total respondents identified retention as problematic due to cumbersome schedules and visits, which led to participant disinterest. For adherence, 67% of total respondents identified issues with participant adherence. Of these, 75% identified diary completion, 50% attending scheduled visits, and 50% adhering to dosing and rescue medication requirements.

Site Experience and LogisticsOf the total respondents, 75% identified regulatory hurdles. In the Unites States (US), Drug Enforcement Agency licensure is different from state to state. In the European Union (EU) and India there are specific relevant

regulations for opioid use in some EU countries and India. Additionally, 41% stated that these issues had an impact on the recruitment due to delays in regulatory start-up.

The overall majority of the total respondents, 56%, reported that more experienced sites that had participated in multiple opioid trials appeared to recruit participants with more robust profiles and better safety oversight than less experienced sites.

One-third of the respondents identified issues with site security that were mainly related to non-reconciled drug or drug/rescue medication unaccountably removed from the site storage area.

Risk Management83% of participants confirmed development of a risk management plan and the major risks identified were related to participant recruitment, identification of qualified sites, and opioid drug diversion.

Study Drug DiversionOf the total respondents, 42% identified opioid diversion as an issue. The majority of issues pertained to opioid diversion by participants, but this behaviour was also exhibited by site staff. Of these, 80% identified diversion occurring at multiple sites across the study, and 80% identified participants enrolling at multiple sites, hence having the chance of being given more study drug (if randomised to more than one drug treatment arm).

Lessons LearnedLessons learned are presented in Table 1. These came from feedback in the leadership survey in a section where medical advisors and clinical project managers were invited to provide their comments.

Discussion and ConclusionsAnalysis of the three main sources of available data confirms there are many challenges associated with conducting opioid trials:• Opioid diversion is frequently encountered,

particularly with immediate release formulations. Diversion has been encountered with subjects, site staff, and from physical breach of opioid storage. This has major implications for study quality, safety of subjects, and contribution to the social impact of illegal narcotic use in the community.

• Ensuring compliance is challenging at a subject and site level. At the subject level, diary requirements are onerous, therefore eligibility and endpoints can be significantly impacted. At a site level, challenges with compliance pertain to accountability of opioid and rescue medication. This process is required to be rigorous as this is a key regulatory and safety requirement.

• Study design currently creates significant barriers to recruiting subjects. These include: strict entry criteria, placebo control, requirement for washout of concomitant analgesics prior to enrolment, complex

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Volume 7 Issue 544 Journal for Clinical Studies

schedules requiring cumbersome dose titration, and diary commitments.

Many studies combine these elements, which leads to considerable challenges in operational delivery within required timelines.

As the burden of unmet need concerning the management of acute and chronic painful conditions continues and increases, it is incumbent upon commercial analgesic sponsors in collaboration with third-party contract research organisations to ensure opioid studies are conducted to robust standards in order to accurately assess efficacy and safety. Sub-standard operational execution can lead to considerable issues pertaining to the safety of subjects on study drug and protection of overall public health. Proactive operational risk mitigation that includes the areas identified in this paper can maximise the safety and efficiency of future opioid clinical trials.

References

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Kremena Ilcheva, MD, is Director of Clinical Project Management, Quintiles. She has worked as an electrophysiologist specializing in Sleep Medicine, and the diagnosis and treatment of epilepsy. At Quintiles she has lead a team responsible for international studies within neurology,

anti-infective, respiratory, and women’s health, including implementation and management of a risk-based monitoring model.

Cathy Vanbelle, RN, is Global Director of Strategic Planning, CNS Therapeutics, Quintiles. She has 23 years of experience in conducting and supporting clinical trials. She is especially qualified in the fields of neurology, immunology, infectious diseases, psychiatry, and stem cell transplantation

(hematology oncology). A registered pediatric nurse, she worked for 10 years on a pediatric bone marrow transplantation ward. Email: [email protected]

Dominic Bowers, MBChB, MRCA, Dip Pharm Med, is an independent medical consultant with the Harten Group. He has over eight years of experience within clinical development and governance of sponsor-led clinical trials. He has broad experience within the acute care and pain

management, internal medicine, and immunology therapeutic areas. At the time of this paper’s presentation he was a Medical Director at Quintiles.

Lynne Hughes, PhD, is Vice President and Global Head, Centres of Excellence for Neurology, Autism, and Acute Care & Pain, Quintiles. She has worked in clinical research for 30 years in both Europe and the United States, and been involved to varying extents in the development of

every neurology product on the market today.Email: [email protected]

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