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European Biopharmaceutical Review

Targeting Pain

Edgar H Adams and Vanesa Castillo at Covance examine the current perspectives on opioids, and review the challenges from Phase III to REMS

Opioids are effective agents in the armamentarium of treatment of acute and chronic pain and are generally well tolerated in carefully selected patients. However, the use of this therapeutic class is not without risks, and the potential for abuse and diversion are a real and present concern. Diversion, abuse and accidental overdoses have risen in the last 10 years despite significant efforts of prevention by pharmaceutical manufacturers, regulatory and enforcement agencies. This trend raises concern about optimal opioid medical use; therefore efforts by the US FDA are currently underway to prevent misuse and to improve prescribing habits (1,2).

Annually, healthcare practitioners in the US write more than 23 million Schedule II (C-II) prescriptions to approximately four million patients (3). Despite the impressive numbers of US opioid prescriptions, it is estimated that globally as many as five million individuals lack sufficient access to medications for pain control (4). As stated at the 2004 ‘Global Day on Pain’, “Although few people die of pain, many die in pain and many more live in pain” (5).

Within the US, some states limit or monitor access by scheduling or upscheduling some drugs. A large number of states have implemented prescription monitoring programmes to track the prescription of scheduled medications, and provide physicians with a tool to identify patients who may visit or obtain medication from multiple physicians (doctor shoppers). Unfortunately, these programmes are underused. In other instances, healthcare providers are concerned about addiction, lack the confidence to prescribe opioids, or are uneasy dealing with the regulatory and enforcement agencies charged with opioid oversight (6). Even in the US, it is generally accepted that, for many, pain symptoms are undertreated (6).

CURRENT PERSPECTIVES ON SCHEDULED DRUG USE IN THE US

In the US, the Controlled Substances Act (CSA) of 1970 charges the Drug Enforcement Agency (DEA), in conjunction with the FDA, with regulation of the production and distribution of controlled substances to limit their non-medical use. Essentially, the FDA determines whether there is sufficient scientific evidence to support scheduling, and makes a corresponding recommendation to the DEA. The DEA actually schedules the drug and is responsible for enforcement (6). Three basic questions guide how the DEA ‘schedules’ drugs (4):

  • Is there an established medical use for the product in the US?
  • Is there potential for abuse?
  • Does the drug cause physiological or psychological dependence?

Schedules provide for a closely monitored system of production and distribution, but may also have the unintended consequence of limiting legitimate medical use. Drugs with potential for abuse are placed into one of five ‘schedules’ (C-I to C-V) based on medical usefulness and abuse potential. Schedule 1 (C-I) drugs have the highest potential for abuse and no accepted medical use in the US, whereas Schedule 5 (C-V) have the lowest. To assess potential for abuse, drugs are evaluated on an eight-factor analysis that includes:

  • Actual potential for abuse
  • Pharmacological effect
  • State of current scientific knowledge regarding the drug
  • History and current pattern of abuse
  • Scope, duration and significance of abuse
  • Risk to public health
  • Psychological or physiological dependence and liability
  • Whether or not the substance is a precursor of an already controlled substance

When new safety issues arise after a drug is approved, the FDA, under the auspices of the FDA Amendments Act of 2007 (FDAAA), is authorised to require postapproval label changes, post-marketing studies, or risk evaluation and mitigation strategies (REMS) (7). The FDA is now exercising this authority to require an opioid class REMS, based on ‘new safety information’.

REMS processes and components are detailed in the 2007 FDAAA statute, and typically include components such as medication guides, a timetable for evaluation, and patient and physician education programmes. More complex components such as patient registries or specialised training may also be required. REMS are generally required to ensure the benefits of a drug under consideration continue to outweigh the risks. According to the statute, REMS should not be ‘unduly burdensome’ on patient access to medication or a burden to the healthcare delivery system (8).

CHALLENGES AND BEST PRACTICES FOR PRE- AND POST-APPROVAL OPIOID CLINICAL TRIALS

The conduct of opioid clinical trials presents particular challenges not typically encountered in clinical trials with nonscheduled therapeutics. In pre-approval scheduled drug studies (Phase II-IIIb), sponsors provide study drug to investigator sites; however, there are unique storage and shipping requirements, as well as stringent registration requirements for persons and institutions (such as hospitals and pharmacies) that may come into contact with the scheduled study drug. In contrast, for post-marketing trials, the scheduled study drug is not typically provided, so other measures are necessary for control.

In addition to federal drug regulations, there may also be state-specific obligations that investigators are required to follow, and which are subject to change. States may require that special licenses be held by the site and reports filed regularly detailing the study’s progress. Unfortunately, there is no centralised repository to find statecentric regulations, so this labour-intensive investigation should be factored into project planning timelines.

Sites that conduct studies with scheduled drugs must have a thorough knowledge of the risks involved with opioids, utilise standard operating procedures (SOPs), meet stringent practitioner registration guidelines and comply with specific storage requirements for pre-approval studies using scheduled drugs. DEA form 223 is a certificate of registration, and is obtained for each place of professional practice where controlled substances are manufactured, distributed or dispensed. If the investigator enrols patients in multiple settings, a DEA form 223 must be obtained for each location (9). Screening questionnaires employed during the feasibility process may help to identify more experienced sites.

Shipments of scheduled study drugs also present unique challenges. To ship a study drug, a DEA 222 form is required. Schedule II narcotics cannot be shipped overnight to a site without this form, having been previously sent by the site, which creates an auditable paper trail for each contact point through which a controlled substance passes. Study sites receive details for the study drug shipment, complete form DEA 222 and send by overnight courier to the study drug shipper. The shipper packages the study drug with its completed portion of the form, stating the number of packages, the size of each package, the name of the study drug inside the box, and the date it is shipped. The study drug is then stored in a secure location.

Table 1 outlines prerequisites and storage conditions for scheduled drugs. It must be verified that the study drug is located in a secure, locked storage cabinet or pharmacy are met. Clinical research associates (CRAs) must ask specific, probing questions of study staff during initiation and monitoring visits to assess compliance.

Table 1: Practitioner and storage requirements for conducting schedule II study protocols
Practitioner registration Requirements
Must meet DEA registration requirements Double-locked storage (highly recommended, though not a DEA requirement)
State licensure required (new registrations: 4-6 weeks, renewals: 4 weeks) Limited access
Registration of each physical location where the controlled substance is stored Proper DEA licensure
Interns, residents, staff physicians and mid-level practitioners may prescribe, dispense or administer controlled substance under the PI's DEA registration if doing so in the 'usual course of professional practice' DEA 222/223 Form process SOPs to govern site level, dispensing and return of study medication
C-II through C-V stored in a securely locked, substantially constructed cabinet, safe or steel cabinet equivalent to a US Government Class V security container List of study personnel who have access to study drug
Online applications available at www.deadiversion.usdoj.gove/drugreg Proper drug accountability

Diversion is a concern for both preapproval and post-marketing trials. Potential diversion is when a study drug is suspected of being used for a purpose other than what was intended. Examples include missing study drug or patient behaviours consistent with abuse or misuse. What constitutes potential diversion, and key measures for potential abuse with clients and investigators should both be established early in the planning phase of the study. For Phase II-IIIb studies, drug accountability logs account for pills that may be missing or lost. Before patients are enrolled, it should be determined how many missing pills warrant reporting to DEA or police so all staff can be trained on the requirements. For post-approval studies, the study design should include measures to capture abuse or misuse in the study design. Although these measures may be more indirect, examples include observation of aberrant behaviour such as euphoria, purposeful over-sedation, negative mood changes or withdrawal, or the appearance of intoxication. Patterns of use over time should be monitored for changes in the numbers of prescriptions per month or the primary purpose of taking medication.

If a site discovers that the study drug is missing, there should be a response plan, as quick implementation and documentation are critical. Stakeholder responsibilities are outlined in Table 2. Events at the study site should be reconstructed, including determination of the last time the study drug was accounted for. Sites need to inform the local police as well as the DEA. Detailed monitoring reports after every visit by the CRA should provide as much information as possible. Documentation of the exact number of kits, kit number and number of pills counted at the site streamlines the process when, or if, the study drug goes missing. Sponsors should provide sites with diversion reporting forms or tracking sheets that have all the requisite information to report to regulatory agencies and to identify trends.

Table 2: Stakeholder responsibility for missing study drug
Study site CRA Management
Contact CRA Contact manager immediately Notify client contact, AQ, medical monitor
Call police and file report Schedule study drug accountability and visit as soon as possible Determine if study drug tracking system needs to be updated
Perform 100 per cent IP accountability Provide management with all information for the latest drug accountability at site Forward documentation to client
Complete a DEA 106 form and move drug to another double-locked storage facility, if feasible Follow up with required steps Ensure all steps are being followed and proper documentation is in place

Measures to detect abuse or addiction should be incorporated in the study design and data collection instruments. In postmarketing studies, pill counts may not be feasible, but efforts to identify drug abuse are still necessary, and can be captured through patient questionnaires and physician assessments. Detailed checklists or screening instruments for investigators to use during the initial patient evaluation process can identify potential abuse behaviours, and it can be determined whether patients are able to take medication on schedule by incorporating diary compliance as part of the inclusion/exclusion screening. CRFs should be designed to assist sites and CRAs in identification of potential abuse and diversion.

OPIOID CLASS REMS

In February 2009, the FDA sent letters to brand and generic manufacturers of extended-release opioids giving notice that post-marketing REMS for their products will be required due to public health concerns over abuse, misuse and accidental deaths occurring in opioidnaïve patients (10). The FDA set a series of stakeholder meetings from February 2009 until May 2009 to meet with manufacturers, physicians, pharmacists, patients, advocacy groups and ‘interested’ medical organisations, in order to gather input on the design and implementation of a workable REMS programme that improves prescription through coordinated risk-management strategies. Subsequently, the FDA extended the comment period on the proposed REMS to October 2010, and stated that an advisory committee would be convened in the second quarter of 2010.

The proposed REMS post-marketing programme is unique among those required by the FDA because of the sheer scope, size and cost. It requires brand and generic manufacturers to devise jointly a single shared system (7). In contrast to other REMS plans instituted to date, this proposal must not only target patients for which opioids are prescribed, but should also address strategies to reach nonpatients or those who misuse or abuse the drugs and for whom an opioid prescription is not directly ordered. The challenging balance is to structure REMS postmarketing studies so that they protect public health without limiting legitimate patient access to pain medications and driving up the costs of care (11).

The ‘iPledge’ programme for isotrentinoin is the largest REMS programme conducted to date, and encompasses approximately one million prescriptions. The reach and scope of an opioid class REMS will represent a marked expansion of REMS, with an estimated 20 to 30 million prescriptions for extended release opioids (or 300 million prescriptions if all opioids are included). These actions will potentially create an enormous economic and clinical burden, so the stakes for successful development and implementation are high. Whatever solution is proposed, it needs to operate in real time so that patient access is maintained and detection of abuse or diversion occurs in a timely manner.

Components of an opioid class REMS will be built on a standardised REMS template and include many of the elements to assure safe use. Essential elements include clearly articulated goals, communication plans, medication guides, and an implementation system and timetable for submission of assessments.

The elements of safe use assure physician training and certification, including a schedule for recertification. Education for both physicians and patients is a major part of any REMS and includes proper prescribing practices, as well as elements regarding how to address abuse. An AMAdeveloped pain medication continuing medical education (CME) programme is currently available (12). Positive incentives are favoured by professional medical organisations, including a waiver of the DEA registration fee for those that complete a voluntary course and obtain training on pain management (12). Patients must register and provide documentation showing that they have been informed of the conditions of safe use. The implementation system verifies the number of registrants and identifies those receiving medication off-label (such as non-cancer pain for fentanyl and some modified release opioids).

Under a class REMS, opioids would be dispensed through certified pharmacies and practitioners; and only to patients who meet certain criteria. In the past, mandatory certification of prescribers and restricted distribution led to reduced access for some patients when clinicians shifted from prescribing Schedule II to Schedule III drugs (12). The REMS is likely to include some form of patient registration or more stringent patient monitoring to identify adverse reactions (7). The issues of compliance and compliance measures have yet to be addressed, but warrant consideration in any final plan.

The law for mandated assessments to evaluate REMS components under the FDAAA is very specific. The minimum is 18 months, three years and seven years after approval, but the FDA can mandate more frequent reporting if the need is sufficiently high or complex. Required REMS elements include surveys for understanding serious risks, reports on training and certification programmes, evaluation of REMS effectiveness, report on distributions and dispensing of medication guides, reports on failures to adhere to distribution and dispensing requirements, and what corrective actions are taken. It is likely an opioid class REMS will require more frequent reporting, probably at least every six months for key measures.

CONCLUSION

Opioids are an important tool for management of moderate to severe chronic pain, but the increase in diversion and abuse must be addressed. Implementation of an opioid class REMS has the potential to lead to improved patient management and reduced opioid abuse and diversion, thus maintaining an appropriate balance of risk and benefit. Given the size of an opioid class REMS, care must be taken not to place undue burden on stakeholders including physicians, pharmacists and patients. In light of the multiple examples where control policies have resulted in reductions in appropriate medical care, all REMS need careful evaluation (13).

References

  1. FDA, Opioid drugs and risk evaluation and mitigation strategies (REMS), available at: www.fda.gov/drugs/drugsafety/information
    bydrugClass/ucm163647.htm
    , accessed 31st July, 2009
  2. Katz NP, Adams EH and Chilcoat H, Challenges in the development of prescription opioid abuse-deterrent formulations, Clin J Pain 23(8): pp648-660, 2007
  3. Wechsler J, Safety and transparency shape drug development, Applied Clinical Trials 18(7): pp24-26, 2009
  4. Adams E and Castillo V, Opioids: Current perspective & challenges from Phase III to REMS, DIA Webinar, 14th July 2009, available at: www.diahome.org/DIAHOME/Education/FindEducationalOffering.aspx?productID=21023&eventType=Webinar, accessed 31st July, 2009
  5. Global day against pain, 11th October 2004, available at: www.iasp-pain.org/AM/Template.cfm?Section=Home&
    Template=/CM/ContentDisplay.cfm&ContentID=2899
    , accessed 4th August, 2009
  6. Katz NP, Adams EH, Benneyan JC et al, Foundations of opioid risk management, Clin J Pain 23(2): pp103-118, 2007
  7. Wechsler J, FDA leaders stress safety, transparency in drug development, Formulary, available at: http://formularyjournal.modernmedicine.com/formulary
    /Policy+News/FDA-leaders-stress-safety-transparencyin-drug-dev/ArticleStandard/Article/detail/611696
    , accessed 31st July, 2009
  8. Traynor K, Risk-management plan for opioid drugs proves slow going. 15th July 2009, available at: www.ashp.org/import/news/HealthSystemPharmacy
    News/newsarticle.aspx?id=3116
    . Accessed 31st July 2009
  9. DEA Diversion Control Manual, available at: www.deadiversion.usdoj.gov/pubs/
    manuals/pract/section2.htm
    , accessed 31st July 2009
  10. Van Arnum P, FDA seeks to establish REMS for opioid drugs, PharmTech.com, available at: http://pharmtech.findpharma.com/pharmtech/
    Ingredients/FDA-Seeks-to-Establish-REMS-for-Opioid-
    Drugs/ArticleStandard/Article/detail/580865
    , accessed 31st July 2009
  11. Pinney Associates, Classwide Opioid REMS: A good idea, implement carefully, available at: www.reuters.com/article/pressRelease/idUS197711+26-May-2009+PRN20090526, accessed 31st July 2009
  12. Letter to FDA Commissioner dated 30th June 2009, available at: www.ama-assn.org/amal/pub/upload/mm/
    399/administration_opioids_REMS_signon-letter.pdf
    , accessed 31st July 2009
  13. Adams EH, The unintended consequences of good intentions, Poster presented at the 25th International Conference on Pharmacoepidemiology, Providence, RI 18th August 2009

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Edgar Adams, ScD, is Executive Director, Epidemiology, Periapproval Services at Covance. He is responsible for providing scientific and technical leadership in epidemiology and risk management. Edgar has more than 15 years’ experience consulting on the design and implementation of risk management plans including RiskMAPs and REMS. He was a Commissioned Officer in the US Public Health Service, and served as the Chief Epidemiologist at the National Institute on Drug Abuse. Edgar was the US representative to the Pompidou Group of Experts in Epidemiology within the Council of Europe. Edgar has a BS in Pharmacy (Fordham), an MS in Pharmacology (Purdue) and an ScD from Johns Hopkins School of Public Health.

Vanesa Castillo is a Project Director within the Clinical Operations Department at Covance Periapproval Services. She serves as operational leader for domestic and international projects. Vanesa has a wide range of research and management experience in the CRO and pharmaceutical industries. Vanesa has accumulated extensive experience in the management and direction of clinical trials in several therapeutic areas including oncology, genitourinary, dermatology, musculoskeletal, mental disorders, infections/parasitic disease, CNS (pain management) and immunology.

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