药品风险管理中的案例历史外文文献英文

Drug and Alcohol Dependence 105S 2009 S42 S55 Contents lists available at ScienceDirect Drug and Alcohol Dependence journal homepage Case histories in pharmaceutical risk management Cynthia G McCormicka Jack E Henningfi eldb c J David Haddoxd Sajan Varughesee Anders Lindholme Susan Rosene Janne Wisself Deborah Waxmanf Lawrence P Carterf Vickie Seegerg Rolley E Johnsong aMcCormick Consultation LLC 9127 Friars Road Bethesda MD 20817 USA bPinney Associates Inc 3 Bethesda Metro Center Suite 1400 Bethesda MD 20814 USA cDepartment of Psychiatry and Behavioral Sciences The Johns Hopkins University School of Medicine 600 North Wolfe Street Meyer 3 142 Baltimore MD 21287 USA dHealth Policy Purdue Pharma L P One Stamford Forum Stamford CT 06901 USA eShire Pharmaceuticals 725 Chesterbrook Blvd Wayne PA 19087 USA fJazz Pharmaceuticals 3180 Porter Drive Palo Alto CA 94087 USA gReckitt Benckiser Pharmaceuticals Inc 10710 Midlothian Turnpike Suite 430 Richmond VA 23235 USA a r t i c l ei n f o Article history Received 4 June 2009 Received in revised form 19 August 2009 Accepted 19 August 2009 Available online 19 September 2009 Keywords Abuse liability Regulation Post marketing surveillance Risk management REMS Medications Opioids Oxycodone Buprenorphine Amphetamine Methylphenidate Sodium oxybate Lisdexamfetamine Food and Drug Administration a b s t r a c t The development and implementation of programs in the U S to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration FDA sincethemid1990s Thispaperprovidesfourcasehistoriesofriskmanagementandpost marketing surveillance programs utilized recently to address problems associated with possible abuse dependence and diversion The pharmaceutical sponsors of each of these drugs were invited to present their pro grams and followed a similar template for their summaries that are included in this article The drugs and presenting companies were OxyContin an analgesic marketed by Purdue Pharma L P Daytrana and Vyvanse ADHD medications marketed by Shire Pharmaceuticals Xyrem for narcolepsy mar keted by Jazz Pharmaceuticals and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc These case histories and subsequent discussions provide invaluable real world examples and illustrate both the promise of risk management programs in providing a path to market and or for keeping on the market drugs with serious potential risks They also illustrate the lim itations of such programs in actually controlling unintended consequences as well as the challenge of fi nding the right balance of reducing risks without posing undue barriers to patient access These expe riences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies REMS 2009 Elsevier Ireland Ltd All rights reserved 1 Introduction This special issue of Drug and Alcohol Dependence addresses many aspects of the management of risk for abuse and dependence of medications in the U S including the public health rationale the regulatory tools and the state of the science Food and Drug Administration FDA guidance documents for risk management FDA 2005a b c urge development of a science base and the appli This paper was conceived and developed by Drs McCormick and Henningfi eld whotakefullresponsibilityforSections1and6 Theotherauthorstakeresponsibility for only their individual case history sections within the paper Correspondingauthorat PinneyAssociates Inc 3BethesdaMetroCenter Suite 1400 Bethesda MD 20814 USA Tel 1 301 718 8440 fax 1 301 718 0034 E mail address jhenning J E Henningfi eld cationofevidencebasedtoolstomitigatedrugrisks Unfortunately the existing science base for many potential risk management approaches is in its infancy and it might be many years before key procedures are thoroughly evaluated This poses a dilemma for drugregulatorswhocoulddeferapprovalofNewDrugApplications NDAs until validated risk management procedures are developed or remove benefi cial products from the market because of uncer taintiesintheeffectivenessofproposedriskmitigationapproaches Depriving patients and health care professionals of pharmaceuti cal advances is a potential undesirable outcome The alternative of allowing marketing of drugs with serious risks that do not appear to be adequately controlled by standard regulatory approaches is also not acceptable and leads to public and political outcry e g Reinberg 2007 In the face of these pressures the FDA has worked with drug sponsors and its advisory committees to develop tools to address 0376 8716 see front matter 2009 Elsevier Ireland Ltd All rights reserved doi 10 1016 j drugalcdep 2009 08 003 C G McCormick et al Drug and Alcohol Dependence 105S 2009 S42 S55S43 specifi c risks of various medications These have included tools intended to mitigate risks as well as surveillance approaches to detect unintended consequences The core concept is to develop drug specifi c tools to reduce the risk profi le of a drug that has potential benefi t enabling approval for marketing Increasingly surveillance approaches beyond routine pharmacovigilance are required to provide assurance that if unintended consequences do emerge they will be detected in a timely manner There are now several years of experience across a variety of drugs that provide case histories in risk management illustrat ing apparent successes failures areas of need for research and a basis for future risk management development For example a transmucosal fentanyl product for treating breakthrough pain was approved contingent upon a risk management plan to address concerns about potential abuse and accidental exposure in chil dren Carreyou 2006 FDA 1998 Prescription nicotine gum and transdermal patch were approved for over the counter market ing despite concerns about potential abuse by youth which were addressed by conditions including school focused monitoring a minimumprocurementageof18years andcommitmentsbyspon sors to avoid marketing that would appeal to youth Shiffman and Sweeney 2008 Isotretinoin was approved for treatment of severe recalcitrant nodular acne despite its potential to produce birth defects with a risk management program to prevent its use at any time during pregnancy FDA 2004 Each of these regulatory deci sionsfollowedconsiderationoftheviewsofproponentsofapproval arguingthebenefi tsandopponentswhofocusedmoreontherisks the risk management approaches provided the regulatory path and rationale for product approval The approach to risk management that is increasingly used by FDA termed Risk Evaluation And Miti gation Strategies REMS gives FDA explicit authority to make the risk management approach a condition of approval as well as gives the agency the explicit power to enforce compliance with the risk managementcommitments FDA 2007 Leiderman 2009 Schuster et al 2009 The drug scheduling provisions of the Federal Controlled Sub stances Act CSA can be considered a form of risk management as discussed in the College on Problems of Drug Dependence CPDD Conference on Risk Management and post marketing surveillance of CNS Drugs Risk Management Conference Johanson et al 2009 Henningfi eld and Schuster 2009 The CSA emerged in part to enable approval of drugs for which concerns of abuse required additional controls on distribution even if safety and clinical effi cacy had been demonstrated to accepted standards Thus if FDA approves a drug with the recommendation that it should be sub ject to the provisions of the appropriate CSA schedule it cannot be marketed until the Drug Enforcement Administration DEA makes the fi nal scheduling determination with input from FDA and the National Institute on Drug Abuse NIDA Spillane and McAllister 2003 DEA 2009 The specifi c schedule dictates the nature of the controls which might be considered risk management tools that are appropriate to the abuse risk posed by the drug For example Schedule II includes the strongest controls for drugs approved for medical use and is applied to drugs such as morphine and phar maceutical cocaine Schedule III is less restrictive and is applied to lower strength dosage units and combination forms of certain opioids Schedule IV is applied to many benzodiazepines and other drugs of similar abuse risk Schedule V is applied to drugs consid ered to have signifi cant abuse risk but at the lowest level meriting CSA scheduling Spillane and McAllister 2003 DEA 2009 In cases in which the scheduling provisions themselves are not considered adequate to control the risks of the drug additional risk management tools might be required as exemplifi ed in the fore mentioned example of transmucosal fentanyl Although CSA scheduling and risk management are developed by distinct regu latory mechanisms they interrelate and at times are coordinated in a practical sense Schnoll et al 2006 posited that risk man agement might be considered a de facto supplement to the CSA with respect to controlled substances and might at times serve more appropriately to address the risks of a drug with uncertain but potential abuse concerns For example in the case of tramadol the risk management protocol supported approval without a rec ommendationforschedulingeventhoughtherewereconcernsthat tramadolmighthavesuffi cientabusepotentialtomeritscheduling It appeared that these concerns would be adequately addressed by theriskmanagementtools marketingwithoutCSAschedulingwas expectedtoprovidethebroaderaccessibilitythatappearsdesirable and consistent with the risk benefi t profi le of the drug Inciardi et al 2007 Schnoll et al 2006 The present article presents four case histories of risk manage ment for different drugs that posed differing concerns for differing populations and indications They all act on the central nervous system CNS and have abuse risks considered suffi cient by FDA to warrant its recommendation that they be scheduled in accordance with the provisions of the CSA The programs for each medication included a variety of tools intended to mitigate risks and a variety of surveillance instruments that went beyond standard pharma covigilancetodetectunintendedconsequences Thedrugsandtheir indications that are described in the following four case histories are presented in Table 1 As discussed in the case histories the factors that led to the development and implementation of the risk management pro grams varied widely across the drugs For example in the case of OxyContin the risk management program was voluntarily instated by the sponsor Purdue Pharma after the drug had been marketed for several years following calls by some that approval be withdrawn as discussed below and in an FDA advisory hear ing in 2002 FDA 2002 Risk management was not an explicit condition of approval of the opioid dependence treatment prod ucts Subutex and Suboxone but may have facilitated approval with a recommendation for placement in Schedule III of the CSA as opposed to Schedule II that had been recommended by individuals with strong concerns about the real world abuse potential of these dosage forms with an indication for opioid dependent individuals Similarly although risk management was clearly desired by FDA it wasnotanexplicitconditionofapprovalofDaytrana orVyvanse In contrast risk management was an explicit condition of approval for Xyrem For the conference and for this paper the sponsors of these medicines were invited to prepare brief overviews of their risk management approach according to a template that is provided in Table 2 Their presentations at the CPDD Risk Management Confer ence led to discussion that contributed to the observations drawn in the discussion section of this article as well as the Expert Panel Reportfromthemeeting Johansonetal 2009 Theauthorsofeach ofthefollowingsectionsmadethepresentationsattheCPDDmeet ing and also take responsibility for the content of their sections of this article They are included as authors of this article even though they were not the primary authors of this introduction or the dis Table 1 Case histories in risk management presenting the medication treatment category branded drug for which the risk management program was developed authors and sponsor 1 Opioid Analgesics OxyContin J David Haddox D D S M D Purdue Pharma L P 2 Stimulant Treatment of ADHD Daytrana Vyvanse Sajan Varughese Pharm D MBA Anders Lindholm M D Ph D Susan Rosen M D Shire Pharmaceuticals 3 GHB Treatment of Cataplexy Xyrem Janne Wissel M B A Deborah Waxman and Lawrence P Carter Ph D Jazz Pharmaceuticals 4 Opioid Dependence Treatment Subutex and Suboxone Vickie Seeger R Ph and Rolley E Johnson Pharm D Reckitt Benckiser Pharmaceuticals Inc S44C G McCormick et al Drug and Alcohol Dependence 105S 2009 S42 S55 Table 2 Template for presentation and written summaries of the risk management case histories 1 Background on company and relevant product s 2 Issues and considerations in risk management development 3 Summary of the risk management approach including key element of the risk minimization action plan tools RiskMAP tools 4 Current status including major fi ndings and development 5 Recommendations for policy regulation and research cussion althoughtheywereinvitedtomakesuggestionstocontent and offer corrections to various drafts McCormick and Henning fi eld had fi nal control over all the content of the introduction and discussion sections Conversely McCormick and Henningfi eld did notwritecasehistoriesbutwereinvolvedintheirorganizationand editing This unusual approach was taken because it was the belief of the conference planning committee and the editors of this spe cial issue of Drug and Alcohol Dependence that such an approach would provide a useful single article on real world application of risk management and what can be learned to guide further risk management development implementation and research 2 Case history of the OxyContin oxycodone HCl controlled release Tablets Risk Management Program J David Haddox D D S M D Purdue Pharma L P 2 1 Background Purdue Pharma L P a privately held pharmaceutical company develops and markets medications for the treatment of pain In 1993 Purdue established Partners Against Pain as a resource to help patients caregivers and healthcare professionals advance standards of pain care and alleviate unnecessary suffering through education and advocacy Purdue has also assumed a leading role in addressing the serious public health problem of prescription drug abuse supporting programs intended to help stem abuse A company associated with Purdue developed MS Contin morphine sulfate controlled release Tablets the fi rst modifi ed release opioid analgesic formulation MS Contin is indicated for the management of moderate to severe pain when a continuous around the clockopioidanalgesicisneededforanextendedperiod of time Purdue Pharma 2008 As it contains morphine sulfate it is scheduled as a C II i e Schedule II under the Federal CSA In part due to its modifi ed release characteristics and the fact that it is a single entity opioid analgesic with no ceiling dose imposed by a non opioid co analgesic such as aspirin or acetaminophen MS Contin proved to be a valuable asset in the treatment of pain Based on the therapeutic usefulness of MS Contin a single entity controlled release form of oxycodone was developed for patients who might fi nd an effective and tolerable profi le of relief from oxy codone This drug OxyContin was approved by the FDA in 1995 and marketed beginning in 1996 It was accepted by many health care professionals and patients alike as an effective analgesic for the management of moderate to severe pain when a continuous around the clock analgesic is needed for an extended period of time Purdue Pharma 2007b The labeled warnings included the following statement Tablets are to be swallowed whole and are not to be broken chewed or crushed Taking broken chewed or crushed OxyContin tablets leads to rapid release and absorption of a potentially fatal dose of oxycodone Purdue Pharma 2007b 2 2 Issues and considerations in risk management development By early 2000 the media began to report on OxyContin abuse and diversion particularly in the more rural areas of Appalachia e g easternKYandsouthwesternWV andMaine AsofDecember 2001 OxyContin abuse and diversion appeared to be increas ing in at least fourteen states with regionally focused pockets of apparently higher than general rates of abuse in areas such as the Appalachian mountain region Maine and elsewhere Concur rent with its strong positioning among health care professionals OxyContin appeared to have become both the most widely pre scribed and abused single entity modifi ed release prescription opioid product A challenge to Purdue and public health offi cials alike was identifying what fraction of opioid abusers was actu ally abusing OxyContin and whether it was their primary drug of abuse The limitations of the data on abuse and diversion were rec ognized in a General Accounting Offi ce report that concluded that the data on abuse and diversion are not reliable comprehensive or timely GAO 2003 see also Purdue Pharma 2004 To assess and address the nature and scope of the problem Pur due hired experts on substance abuse and sought external expert advice on the assessment and potential solutions for mitigating substance abuse These experts helped Purdue and others begin to understand actual patterns of abuse and diversion to a greater degreethanwaspossiblethroughstandardpharmacovigilanceand Federal drug abuse related surveys Simultaneously Purdue began to develop the Researched Abuse Diversion and Addiction Related Surveillance RADARS System to study the prevalence of abuse and diversion of prescription opioid analgesic medications in a geographically specifi c 3 digit ZIP Code and timely quarte