FDA Lawyers Blog

On July 11, FLH Partner Brian J. Malkin will speak at Q1 Productions' Global Clinical Risk Management & Regulatory Policy Conference in Alexandria, VA on the topic "Developing a Single, Shared REMS in a Collaborative Setting". Joining Mr. Malkin will be Mark A. Collings, Ph.D., M.B.A., Director, REMS Programs, Pharmacovigilance and Risk Management, Endo Pharmaceuticals, Inc. The session description reads:

The FDA approves single, shared REMS for product categories with similar risk management programs to help relieve some of the burden on healthcare providers and pharmacies. The development of shared REMS requires that multiple companies and the FDA work in tandem to unify data and risk minimization systems, a model which some companies have also used to help organize risk management plans internationally. By ensuring a strong cross-corporate collaboration, internal regulatory policies, data analysis and communication systems can be synchronized internationally for advanced risk management programs.

• Structuring lines of communication within shared REMS network

• Establishing similar regulatory policies

• Utilizing data from all companies for international RMP development.

The Conference will be held on July 11-12, 2013. Throughout this two-day program, executive from industry will have an opportunity to discuss and debate the many challenges associated with profiling the risk of products as well as minimizing these risks and meeting regulatory expectations. As with all Q1 programs, the focus of the event will not only lie upon the educational content, but also providing attendees with an opportunity to network and build relationships across this highly dynamic and evolving market.

On December 12, FDA held a meeting of its Drug Safety and Risk Management ("DSaRM") Advisory Committee regarding development of a framework for addressing what risk evaluation and mitigation strategies ("REMS") are appropriate for teratogenic drugs. Teratogenic drugs are drugs that may cause birth defects for developing fetuses. The Food and Drug Administration Amendments Act ("FDAAA") requires FDA to bring to the DSaRM Advisory Committee for review at least one drug with Elements to Assure Safe Use ("ETASU"), and this was the topic chosen for 2012.

According to the opening remarks, FDA has recognized that over the years, its approach regarding the development of risk management programs for teratogenic drugs "appears to be inconsistent." The DSaRM Advisory Committee began with FDA presentations, continued with stakeholder presentations from industry, prescribers, patients, and then ended with the full committee's discussion of the questions to address:

Written by Brian Malkin

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FDA's proposed framework would take as intrinsic factors: (1) scientific evidence of teratogenicity (biological plausibility, non-clinical data, and human data) and (2) drug-product related factors (characteristic of the drug product, efficacy, and safety profile). The proposed extrinsic factors to consider in the framework are (1) drug product-related factors (actual drug use), (2) clinical-use related factors (characteristics of medical condition, patient population profile, and context of care), (3) regulatory factors (regulatory precedent, previous REMS experience, availability of new REMS tools), and (4) anticipated consequences of REMS.

Written by Brian Malkin

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On July 26, FLH Partner Brian J. Malkin was interviewed and quoted in FDAnews' article: "Jazz Petitions FDA, Alleges Agency Wrongly Accepted Xyrem ANDA" available here (subscription required for full story). Malkin and another FDA attorney, David Rosen, were both quoted in the article to provide some color surrounding Jazz's latest Citizen Petition regarding generic Xyrem® (sodium oxybate):

Despite Jazz's arguments, David Rosen, an attorney at Foley & Lardner, questions whether the FDA actually accepted an incomplete application. The FDA, including the Office of Generic Drugs, is well aware of REMS requirements and wouldn't accept an ANDA application if it was deficient on its face, Rosen told DID, noting there is more than one way to put appropriate controls in place for drugs. "The FDA has been taking [ANDA] filings seriously," he said, adding he is confident the FDA is good at judging completed applications.

And Brian Malkin, an attorney at Frommer Lawrence & Haug, explained that because Jazz's Xyrem REMS is still pending and not yet accepted by the agency, generic filers would typically only be required to include the "same essential elements" of a risk management plan in their ANDA application, a flexible approach that could have been satisfied by Roxane. ANDA filers for companies with approved REMS are held to a different standard, Malkin explained.

Jazz's Xyrem Citizen Petition

While Xyrem® has been designated by FDA as a product that has been deemed to have a Risk Evaluation and Mitigation Strategy ("REMS"), FDA does not list Xyrem® as a product with an approved REMS. To some extent, Xyrem® 's risk management program called the Xyrem® Success Program has been described on its website and in FDA's review package and public documents for Xyrem®.

Written by Christopher Gosselin

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Earlier this month, Jazz Pharmaceuticals ("Jazz") submitted a Citizen Petition requesting that the FDA rescind its acceptance of Roxane's abbreviated new drug application ("ANDA") referencing Xyrem®, an oral solution indicated for the treatment of patients with narcolepsy. In its petition, Jazz argues that Roxane's ANDA did not have the same labeling and conditions of use as Xyrem®, because it did not contain a risk management system when it was submitted. Jazz asks that the FDA require Roxane to file a new ANDA, which would result in a new thirty-month stay of the associated New Jersey Hatch-Waxman litigation.

Jazz's Xyrem Citizen Petition

Xyrem® is the sodium salt of gamma-hydoxybutyric acid ("GHB"), a notorious "date-rape" drug. In 2000, Congress passed the Hillory J. Farias and Samantha Reid Date-Rape Drug Prohibition Act, defining GHB as a Schedule I controlled substance but creating an exception for FDA-approved drugs containing GHB. FDA approved Xyrem® in 2002, requiring extraordinary restrictions on the drug product's use under 21 C.F.R. § 314, Subpart H, including a restricted distribution program, an education program, restrictions on the distribution of prescriptions, and a registry system. To meet these demands, Jazz implemented and patented the "Xyrem® Success Program," and listed the patents claiming methods of using its program in FDA's Orange Book.

Jazz claims that Roxane's ANDA did not include a proposed risk management system when it was submitted. Instead, Jazz explains that Roxane submitted a six-page document describing a partial proposed risk management program for generic Xyrem® ten months after its initial ANDA submission and did not submit a full proposal until more than a year after the initial ANDA submission.

by Richard F. Kurz

On March 9, the Drug Enforcement Administration ("DEA") filed its opposition to Cardinal Health, Inc.'s ("Cardinal's") appeal of a recent United States District Court ruling. At issue is the DEA's Immediate Suspension Order ("ISO") revoking Cardinal's Lakeland, Florida facility's registration to ship controlled substances, which has been previously reported here and here. The DEA alleges that Cardinal did not adequately stop diversion of oxycodone, an often-abused pain medication (diversion exists when controlled substances are distributed to an entity that does not have a valid DEA registration). Cardinal is not accused of diversion itself, but instead is accused of not adequately preventing diversion at four pharmacies. Because the ISO was issued prior to an administrative hearing, Cardinal requested that the suspension be halted pending the resolution of this upcoming hearing. The district court denied this request.

Typically, the DEA revokes a distributor's registration after providing the registrant notice of the intent to revoke and a hearing. The DEA may issue an ISO without a hearing, however, when there is an "imminent danger to the public health or safety." Cardinal's appeal argues that the DEA was "arbitrary and capricious" when it issued the ISO because the DEA never met the "heightened standard" Cardinal argues is required to find that the Lakeland facility posed an imminent danger to public health or safety. Additionally, Cardinal argues that it already took remedial measures that obviated any imminent danger, including suspending or sharply curtailing shipments to the four pharmacies specified in the ISO. Consequently, Cardinal argues, issuing the ISO was contrary to law and denied Cardinal its due process right to be heard before the DEA suspended its registration.

The District Court, however, stated that "the DEA's issuance of the ISO easily passes the arbitrary and capricious standard of review." The court noted that the DEA considered the following factors: "(1) the rampant pharmaceutical drug problem in Florida, (2) Cardinal Lakeland's history of inadequate anti-diversion controls, (3) the large and increasing amounts of oxycodone distributed by Cardinal Lakeland to the four pharmacies from 2009 to 2011, (4) the sizeable amounts of oxycodone distributed to 25 other pharmacies in 2011 that exceeded state and national averages, and (5) the evidence of Cardinal Lakeland's failure to monitor its chain pharmacy customers, despite clear warning signs of inadequate anti-diversion controls at those pharmacies . . . ." Based on these factors, the court found that the DEA had a reasonable basis to conclude that the Lakeland facility's continued registration posed an imminent danger to public health or safety. This, combined with the DEA's explanation for the action and consideration of Cardinal's remedial efforts, led the court to conclude Cardinal was unlikely to succeed in proving that the ISO was arbitrary and capricious.

by Richard F. Kurz

On March 2, the United States Court of Appeals for the District of Columbia ordered an administrative stay on the Immediate Suspension Order ("ISO") issued by the Drug Enforcement Administration ("DEA") against Cardinal Health, Inc.'s ("Cardinal") distribution facility in Lakeland, Florida. This stay postpones the ISO while the court considers Cardinal's emergency injunction motion, which would halt the ISO pending Cardinal's separate appeal of the ISO. When granting the stay, the court stated that it had not yet considered the injunction motion on its merits. A decision on the merits will likely come soon, however, because the court ordered an expedited briefing schedule, requiring the DEA's response to the motion by Friday, March 9, followed by Cardinal's reply on Monday, March 12.

The ISO, previously reported here, suspended Cardinal's registration to distribute controlled substances (such as the pain medication oxycodone) from its Lakeland facility to approximately 2,700 customers, including hospitals and pharmacies. Typically, the DEA revokes a registration after providing the registrant notice of the intent to revoke and a hearing. The DEA may issue an ISO without a hearing, however, when there is an "imminent danger to the public health or safety." Here, according to Cardinal, the DEA alleged imminent danger and issued the ISO without notice and a hearing.

Cardinal argues that there was no imminent danger to justify the DEA's action. The ISO did not allege that Cardinal distributed controlled substances to anyone that the DEA had not authorized to receive them. Instead, the ISO alleged that Cardinal sold high aggregate volumes of oxycodone to four pharmacies between 2008 and 2011. But by the time the ISO was issued, Cardinal had already suspended shipments to two of the pharmacies. Cardinal also noted that its shipments to the other two pharmacies had decreased by 80% prior to the ISO, which Cardinal then suspended after receiving the ISO. Consequently, Cardinal argues that its own remedial measures already negated any danger to the public and the ISO is unnecessary pending Cardinal's appeal.

by Richard F. Kurz

On February 29, a federal district court judge issued an Order requiring that Cardinal Health, Inc. comply with an Immediate Suspension Order ("ISO") issued by the Drug Enforcement Administration ("DEA"). The court previously granted a temporary restraining order delaying Cardinal's compliance with the ISO, pending a decision on a preliminary injunction requested by Cardinal. However, the Court denied this preliminary injunction in its Order. Cardinal appealed this decision on the same day as the court's Order.

Partially at issue in this dispute is the question of who is responsible for stopping diversion, a form of illegal sales of controlled drug substances. Diversion is distributing controlled drug substances to an entity without a valid DEA registration. In this case, diversion of the prescription pain killer oxycodone allegedly took place at pharmacies supplied by Cardinal's Lakeland, Florida distribution facility. Cardinal states that it has a system in place to stop diversion and that it is ready and willing to suspend shipments to any pharmacy that the DEA identifies as likely to be engaged in diversion. The DEA, however, states that the Lakeland facility has a continuing, affirmative obligation to police its retail customers to ensure that the controlled drug substances it provides are not being unlawfully diverted--and the Lakeland facility fell short of its legal and contractual obligations.

According to a Complaint filed by Cardinal, the ISO requires the Lakeland facility to immediately halt shipments of all controlled drug substances to about 2,700 pharmacies, hospitals, and other customers to prevent alleged imminent danger to the public health or safety. Notably, only Cardinal's Lakeland facility is subject to the ISO. The DEA, however, does not allege that Cardinal itself distributed controlled drug substances to any entity not permitted to purchase them. Instead, the ISO was issued because four pharmacies that were supplied by the Lakeland facility have allegedly distributed oxycodone for illegitimate uses.

by Brian Malkin

On December 29, FDA announced that immediate -release transmucosal fentanyl products would have a shared Risk Evaluation and Mitigation Strategy ("REMS") that would replace the individual REMS presently in place for approved products in this category. In addition to other benefits, the single shared system would permit prescribers and pharmacies to enroll in one system rather than multiple, similar REMS programs. The shared REMS is called the Transmucosal Immediate-Release Fentanyl ("TIRF") REMS Access Program and will become effective in March 2012.

Presently, the list of affected brand-name drugs includes Abstral®, Actiq®. Fentora®, Lazanda®, and Onsolis®. which are all opioid drugs indicated to manage pain in cancer patients, who routinely take other opioid pain medications on a continual basis. Breakthrough pain is pain that comes on suddenly for short periods of time and cannot be reduced by a patient's normal pain management program. For TIRFs to be used safely, they must be used by patients who are already opioid tolerant based on their concurrent regular use of another opioid pain medication.

Janet Woodcock, M.D., Director of the Center for Drug Evaluation and Research ("CDER") said, "This TIRF REMS will ensure safe use and access to these drugs for patients who need them. We have worked with the sponsors of both the innovator and generic drugs to develop this single, shared system that will streamline the process and decrease the burden of the REMS on the health care system."

by Brian Malkin

Less than a week after the Centers for Disease Control and Prevention ("CDC") reported on the growing epidemic of opioid pain reliever ("OPR") overdoses, which we reported on here and asked for FDA to take action, FDA announced in a Federal Register Notice that FDA had developed a draft blueprint entitled "Blueprint for Prescriber Education for the Long-Acting/Extended-Release Opioid Class-Wide REMS" ("Blueprint") . FDA has obviously been thinking about ways that its class-wide opioid Risk Evaluation and Mitigation Strategies ("REMS") can have an impact on the growing prescription drug abuse crisis. FDA's latest Blueprint appears triggered, at least in part, by a report released by the Obama Administration on April 19, 2011 entitled, "Epidemic: Responding to America's Prescription Drug Abuse Crisis", which we reported on here.

As indicated in FDA's Notice, FDA issued letters to application holders for long-acting and extended-release innovator and generic opioid drug products requiring them to submit a REMS within 120 days and providing certain elements that had to be included in each of the REMS. FDA's "central component" was the requirement for a cost-free, drug education program for prescribers, yet there is no prerequirement for training for prescribing. Instead, FDA requested that application holders set goals for numbers of prescribers trained, collect information about the number of prescribers who took the courses, and report the information to FDA as part of the required periodic assessments for REMS.

FDA's Blueprint is meant to provide the basic outline and core messages for continuing education that should be offered to all prescribers of long-acting and extended-release opioids, suggesting that the message be delivered in 2-3 hours. According to the Notice, the outline requires information weighing the risks and benefits of opioid therapy, choosing patients appropriately, managing and monitoring patients, and counseling patients on the safe use of these drugs. The education must also include information how to recognize evidence of, and the potential for opioid misuse, abuse, and addiction.

While the Blueprint goes a long way to provide valuable information to the prescribers who choose to be educated, it remains unclear why FDA is not mandating the prescriber education for all prescribers as a precondition to dispensing the medication to patients or more effectively targeting the perceived source of the problem. At least suggested by CDC's report, the majority of OPR overdoses seem to be attributed to a relatively small percentage of OPR prescribers with more loose prescribing practices. How could FDA's mandated REMS reach the prescribers who would most benefit from the training? One might think then it would make sense to either mandate the education for all prescribers (i.e., an even-playing-field approach) or at least mandate the training for prescribers who have had documented instances of OPR misuse or abuse (i.e., a more targeted approach to save resources). How, for example, will FDA's requirement lead the prescribers who need the training to take it rather than provide more information to the majority of prescribers who are already being cautions about prescribing OPRs? Also, why should the training exclude immediate-release OPRs? CDC's report did not single out extended-release and long-acting opioids as the only source of the problem with OPRs.

FDA's mandated REMS and Blueprint also does not seem to go far enough in its recommendations. For example, while the Blueprint describes the possibility for patient prescriber agreements ("PPAs") (i.e., agreements signed at the time of prescribing providing mutual commitments and goals in the treatment between prescriber and physician) and suggests a treatment plan, why are these PPAs only something prescribers should be "aware of"? Without making PPAs a requirement, it would seem most prescribers may choose to operate without them. Similarly, it would seem that other voluntary elements such as patient treatment plans, reassessments whether OPRs are still necessary, and plans to withdraw patients from OPRs including tapering doses, as well as the risks associated with diversion should be reconsidered as elements of the mandated class-wide REMS.

State legislators should consider passing complementary regulations to help provide pharmacists with the appropriate tools to be "gatekeepers" to prevent addictive OPRs from getting in the wrong hands. In Delaware, for example, new laws have been passed to require special "tamper-proof" prescription pads and prescribers will soon be able to electronically prescribe controlled drugs directly to a patient's pharmacy--measures designed to help prevent counterfeit prescriptions and to collect more detailed information about every prescription for controlled drugs written by Delaware doctors.

FDA has asked for comments on their draft education Blueprint by December 7, 2011.

by Brian Malkin

On November 1, the Centers for Disease Control and Prevention ("CDC") published in its publication, Morbidity and Mortality Weekly Report ("MMWR"), the results of a study that confirmed the epidemic of overdoses of opioid pain relievers ("OPRs") has continued to worsen particularly from 1999-2008. OPR deaths now account for more drug overdose deaths than heroin or cocaine combined and represent nearly 75% of all prescription drug overdose deaths. Drug overdose deaths (36,450) are now almost as high as the number of deaths from motor vehicles (39,973), which is the leading cause of injury death in the United States.

What is also alarming is that the OPR overdose rates have continued to rise despite increased warnings and recommendations over the past decade for voluntary education of health-care providers about more cautious use of OPRs. According to the MMWR, the death rate of drug overdoses of 11.8 per 100,000 population (nearly 100 people per day) is about three times the rate in 1991. Since 1999, most of the drug overdose increases have been attributed to prescription drug overdoses. In 2009 alone there were 1.2 million emergency department visits related to misuse of pharmaceuticals, which represented a 98.4% increase from 2004, compared to 1.0 million for use of the illegal drugs heroin and cocaine.

According to the MMWR, sales of OPRs quadrupled between 1999 and 2010 so that by 2010 enough OPRs were sold to mediate every American adult with a typical dose of hydrocodone every 4 hours for 1 month. Increased use of OPRs has contributed to overall increases in overdose death and nonmedical use. Yet the total number of prescribers responsible for the increase appears to be small: one study found only 3% of physicians accounted for 62% of the OPRs prescribed. Once prescribed, OPRs may be diverted for nonmedical uses (i.e., to patients for whom the drug was not prescribed or for other uses not attributed to pain for whom the drug was prescribed) or sold on the street. In 2010, 4.8% of the U.S. population 12 and older reportedly used OPRs nonmedically. This, in turn, cost insurance companies up to $72.5 billion in health-care costs.

by Brian Malkin

On April 19, President Barack Obama announced a new action plan: Epidemic: Responding to America's Prescription Drug Abuse Crisis. The plan combines efforts from the White House Office of National Drug Control Policy ("ONDCP"), FDA, and the U.S. Drug Enforcement Agency ("DEA") to help educate the medical community about proper prescribing practices. The overall plan supports expanding state-based prescription drug monitoring programs, environmentally-responsible disposal methods to remove unused medications from the home, education for patients and healthcare providers, and reducing the number of "pill mills" and doctor shopping through greater enforcement.

FDA's component involved updates to FDA's website Opioid Drugs and Risk Evaluation and Mitigation Strategies (REMS) including a new list of long-acting and extended-release opioid drug products required to have a REMS, a Post-Approval REMS Notification Letter to holders of applications for innovator or generic drug products in the new list, a Questions and Answers document about the new requirements, and a consumer-friendly Consumer Health Information article describing how this fits into the new initiative. According to FDA Commissioner Margaret A. Hamburg, M.D., "Opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients, but we know that they pose serious risks when used improperly--with serious negative consequences for individuals, families, and communities. The prescriber education component of this Opioid REMS balances the need for continued access to these medications with stronger measures to reduce their risks."

FDA's Letter states that FDA has determined that a REMS is necessary for certain long-acting and extended-release opioid drugs, and "[i]n the interest of public health and to minimize the burden on the healthcare delivery system of having multiple unique REMS programs," a single, shared system should be used by all members in the class to implement the REMS. Within 120 days of the date of the letter, each application holder must submit a proposed REMS including a "REMS supporting document" that must include: (1) training for prescribers to include successfully completing a knowledge assessment and proof of successful program, (2) educational materials for prescribers to use to educate patients in the safe use, storage, and disposal of opioids, (3) information to prescribers of the REMS and need to successfully complete the training, and (4) a timetable for submitting assessments that are no less frequent than 6 months, 12 months, an then annually after an initial REMS is approved.

by Brian Malkin

On February 25, FDA released a draft guidance entitled Medication Guides--Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS). FDA stated that the guidance addresses when FDA intends to exercise enforcement discretion for distribution of certain Medication Guides and when Medication Guides will be required as part of a risk evaluation and mitigation strategy ("REMS"). Medication Guides are a form of enhanced labeling that provides additional risk- or safety-related information about a drug or special directions of use that are deemed critical to the safe and effective use of a drug. REMS is the new term for risk management programs required by the Food and Drug Administration Amendments Act of 2007 ("FDAAA"), when necessary to ensure that the benefits of a drug outweigh the risks. "Drug" in this context also includes biologics.

Medication Guides--Distribution Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS)

FDA said that questions have arisen whether a Medication Guide needs to be distributed every time the drug is dispensed and whether every time a drug has a Medication Guide, distribution of the Medication Guide needs to be included in a REMS, when there are no elements to assure safe use of a drug as part of a REMS. In the Guidance, FDA states that between March 25, 2008, when the REMS provisions of FDAAA took effect, and January 1, 2011, FDA has approved over 150 Medication Guides as part of a REMS, of which 108 were Medication Guide-only REMS.

FDA determined that FDA will continue to have Medication Guide-only REMS, if FDA determines that having a Medication Guide without a REMS will not be sufficient to ensure the benefits of the drug outweigh the risks. FDA will exercise enforcement discretion of a Medication Guide in certain circumstances--primarily when a drug is dispensed in an inpatient setting, such as a hospital under the supervision of a healthcare professional, or when dispensed to a healthcare professional for administration to a patient in an outpatient setting, such as a clinic. FDA, however, believes distribution of a Medication Guide is still mandatory whenever: (1) the Medication Guide has been materially changed, (2) it is requested by a healthcare professional or patient, (3) the drug is dispensed in an outpatient setting without direct supervision of a healthcare professional, e.g., retail pharmacy, and (4) the first time the drug is dispensed to a healthcare professional for administration to a patient in an outpatient setting.

The Guidance further provides that applicants with a REMS that does not include elements to assure safe use of a drug may submit a prior approval supplement to eliminate the Medication Guide from the REMS--but still to remain as part of the approved labeling--consistent with the Guidance, which must be accompanied by a REMS assessment in certain circumstances. Based on FDA's new Guidance, it appears that FDA is trying to trim its Medication Guide-only REMS to drugs that truly require such a program and to reduce its workload to police distribution of Medication Guides in general.

by Brian Malkin

On December 9, FDA's Office of New Drugs Director John Jenkins, spoke out about FDA's view of the future of risk evaluation and mitigation strategies ("REMS") at an FDA-CMS Summit for Biopharma Executives sponsored by the publisher of The Pink Sheet (The Pink Sheet, December 9 and 20). Jenkins outlined FDA's vision of "plug-and-play" REMS elements that could be standardized for specific drugs. Jenkins reportedly said, "Plug-and-play doesn't mean that everything's the same, it means that it's compatible . . . its interoperable."

Based on these reports, Jenkins appears to believe that FDA currently does not have much control over what risk management elements are selected by new drug application ("NDA") holders, when a product is first approved. Following approval, moreover, FDA can ask a company to impose certain risk management elements but can only withdraw a product from the market, if an NDA holder does not want to comply with FDA's wishes.

Jenkins further said that FDA wants to be able to mandate a single, shared risk management program across a class of drugs, such as what FDA has been working towards for the opioid drug class, which is preferable to the other option of about 20-30 different REMS for the current opioid products on the market. Speaking to the audience, Jenkins indicated that there are pharmacy payment computer systems that may be helpful in the REMS standardization effort to facilitate payments and REMS program information for specific products. FDA also plans to reduce the number of Medication Guide-only REMS to reduce some of the REMS workload for pharmacists, who have a spotty record for distributing the mandated information.

by Brian Malkin

On September 23, FDA announced and published in the New England Journal of Medicine that Avandia® (rosiglitazone) would remain on the market with a special restricted access program called a risk evaluation and mitigation strategy (REMS). On the same day, the European Medicines Agency (EMA) recommended suspending products containing the same active ingredient because the risks outweighed the benefits. Both actions will take several months to implement. Avandia® is prescribed to help control blood glucose levels in patients with type 2 diabetes mellitus as an adjunct to diet and exercise.

Avandia® has been associated with increased risk of ischemic cardiovascular events relative to other products in the same therapeutic class, including its direct competitor in the same drug family, pioglitizone (Actos®). FDA described the data associated with this association as "not robust or consistent," leading to its decision to severely limit rather than eliminate the use of rosiglitazone in the U.S.

Under the REMS, current Avandia® users may continue taking Avandia® if they have been benefitting from it and attest that they understand the risks. New users, however, may only take Avandia® if they are unable to achieve glucose control with other products. FDA also placed also placed a post-marketing study, TIDE (Thiazoldinedione Intervention with vitamin D Evaluation), on a full clinical hold. According to FDA, TIDE no longer would be ethical to conduct as a postmarketing study. TIDE was designed to establish the comparative cardiovascular safety of rosiglitazone an pioglitazone. FDA also created an Internet page for patients and providers to learn more about FDA's decision.

In contrast, the EMA suspension provides that the suspension will remain effective until the drug's manufacture, GlaxoSmithKline provides convincing data to identify a group of patients for whom the benefits of the drug would outweigh the risks. Given the differences of the regulatory approval processes between FDA and the EMA, it will be interesting to see whether rosiglitazone will be able to overcome its new stigma and whether the two regulatory agencies will harmonize their decisions. For more on how the EMA regulates drug products, please see our new European Drug Law Resource page.

by Fitz Beckwith Collings

In light of the increasing prevalence of opioid abuse, FDA proposed the creation of a Risk Evaluation and Management Strategy (REMS) for extended-release (ER) and long-acting (LA) opioids in February 2009. On July 22-23, 2010, an FDA advisory panel consisting of both the Anesthetic and Life Support Drugs and Drug Safety Committee and the Risk Management Advisory Committee convened to consider four major REMS questions and conduct a simple up-down vote on FDA's proposed REMS. The advisory panel heard presentations regarding the nature of opioid abuse and misuse; efforts to address the abuse/misuse problem; the content of FDA's REMS proposal; metrics for REMS evaluation; the safe use initiative; and patient and prescriber training programs designed to prevent abuse and misuse.

FDA presented data from the National Survey on Drug Use and Health showing that the proportion of patients using ER/LA opioid pain killers for non-medical use has doubled in the last ten years. The data also indicated that a vast majority of non-medical ER/LA opioid users obtained the product either directly from their doctor or from friends and relatives who obtained the product directly from their doctor. Despite the apparent disconnect between prescribers and patients, the training component of FDA's proposed REMS mandated only sponsor-developed patient education materials for voluntary use by prescribers.

The proposed REMS did not include features like enrollment of individual prescribers into a REMS program or real-time electronic verification of prescriber training at the pharmacy level. FDA noted the potential high cost of such programs, but acknowledged the possibility of piggy-backing such features onto the DEA registration system, a step which would require legislation. Presenters from the industry working group (IWG) agreed that FDA's voluntary prescriber and patient educational programs were necessary REMS components. IWG also highlighted educational problem areas, such as the lack of time prescribers spend discussing the possibility of a fatal overdose with patients and the lack of patient awareness about what to do in the event of an overdose. Like FDA, however, IWG did not express support for mandatory prescriber training.

Twenty-five members of the 35-member advisory panel voted to reject FDA's proposed REMS. (The Pink Sheet, July 23, 2010). The panel specifically cited concerns over the lack of mandatory prescriber training. (The Pink Sheet, July 23, 2010). Going forward, the extent of patient and prescriber educational programs on the use and abuse of opioids remains a key unresolved issue that FDA will need to address. Legislation may be required in order to reconcile the potentially prohibitive cost of such programs with the need to close the prescriber-patient communication gap.