Policy and Medicine

CME Programs to Reduce Opioid Abuse

Over the past several years, there has been significant attention drawn the prescription drug abuse and overuse of painkillers or opioids.  Public health experts estimate that more than 35 million Americans age 12 and older have reported non-medical use of opioid analgesics during 2010 – up from 29 million in 200.  In 2009, nearly 342,000 emergency department visits were associated with nonmedical use of opioid analgesics. In 2007, nearly 28,000 Americans died from unintended consequences of drug use, and of these, nearly 12,000 involved prescription drug pain relievers. 

In response to these concerns, many states have proposed and adopted Prescription Drug Monitoring Programs.  On the federal level, the Office of National Drug Control Policy (ONDCP) and the National Institute on Drug Abuse (NIDA) launched a new online learning tool, which will provide training for healthcare providers on proper prescribing and patient management practices for patients on opioid analgesics (painkillers).  The new tools include continuing medical education (CME) modules.  

In April of 2011, the White House unveiled a multi-agency plan aimed at reducing the “epidemic” of prescription drug abuse in the U.S.—including an FDA-backed education program that zeros-in on reducing the misuse and misprescribing of opioids.  The action plan provides a national framework for reducing prescription drug diversion and abuse by supporting education for patients and healthcare providers, recommending more convenient and environmentally responsible disposal methods to remove unused medications from the home, supporting the expansion of state-based prescription drug monitoring programs, and reducing the prevalence of pill mills and doctor shopping through enforcement efforts.  

Finally, the Food and Drug Administration (FDA) released its final Risk Evaluation and Mitigation Strategies (REMS) for extend-release (ER) and long-acting (LA) opioid medications this past summer.  Continuing its efforts to combat prescription drug and opioid abuse, FDA issued a “Prescriber Alert” in early March, calling attention to prescribers to seek physicians “help in curtailing the U.S. opioid epidemic.” 

In light of the expanding opioid epidemic in the U.S., FDA urged prescribers to take advantage of training on opioid prescribing, available as of March 1, 2013.  This voluntary training will be provided at little to no cost through accredited continuing education (CE) activities supported by independent education grants.  FDA will post all opportunities on its ER/LA Opioid Analgesics REMS site—currently there is only one activity through Boston University School of Medicine CME. 

FDA emphasized the importance of the educational component of REMS.  The first of these programs is available as of March 1 and more will become available.  Although the programs will be funded by opioid product manufacturers, the content will be objective and independent.   

Taking advantage of training opportunities on opioid therapy, now and in the future, is one of three key roles that FDA sees for prescribers in helping to curtail this pervasive problem.  The other two are:  

• knowing the content of the most current drug labels for the opioids they prescribe, and
• educating patients about the appropriate use of opioids, their potential risks, and proper disposal techniques. 

FDA-approved drug labels are frequently updated based on additional science, new benefit-risk information, or public health implications regarding the medication.  Labels of extended release and long-acting opioid drugs were changed in July, 2012.

Misuse and abuse of prescription opioids has reached epidemic proportions in America. While much of the problem is attributable to illicit use, appropriate use of medications for pain may also lead to unnecessary adverse events, addiction, and death for some patients.  No group can be more effective in reducing this trend than our nation’s front-line health care professionals, especially physicians and other prescribers.  FDA sees three key roles for prescribers in curtailing the U.S. opioid epidemic. 

1. ensuring that they have adequate training in opioid therapy,
2. knowing the content of the most current opioid drug labels (examples of the important information found in the labeling of two opioid drugs, OxyContin and Dolophine, are provided in the Key Label Examples tab), and
3. educating patients about the appropriate use of opioids, their potential risks, and proper disposal techniques. 

The programs will be offered by independent providers of continuing medical education (CME) and based on an FDA blueprint that was developed with input from a wide range of stakeholders.  Included will be information on weighing the risks and benefits of opioid therapy, the appropriate choice of therapy for each patient, and managing and monitoring patients and counseling them on the safe use of these drugs.   

The program also will include learning to recognize potential for, and evidence of, opioid misuse, abuse, and addiction, as well as general and drug-specific information about ER/LA opioid analgesics.  FDA encourages all opioid prescribers to take advantage of this valuable training to help ensure they have adequate and up-to-date training in opioid therapy.  

The July 2012, REMS for ER/LA opioids also included significant changes to the FDA-approved drug labels for these products.  The revisions focused on making the labeling consistent among ER/LA products, and on increasing the prominence of information available regarding risk and precautions, such as those for abuse and misuse, respiratory depression, and accidental exposure. 

The drug label, or package insert, that accompanies all FDA-approved medications is the most complete source of information on the drug.  Drug labels provide important safety and efficacy information and clinical data to prescribers on the benefits, risks, and appropriate use for all FDA-approved drugs.  The FDA-approved drug label is one of the most useful tools prescribers have for providing safe and effective opioid therapy to their patients. 

As with all FDA-approved drugs, each ER/LA opioid product label has information unique to its own chemical compound and formulation.  However, ER/LA opioid labels also share many important similarities.  Therefore, maintaining a thorough knowledge of the drug labels can help prescribers inform their decision-making to ensure safe, appropriate, and effective use.  Examples of important information available in the FDA-approved labeling for two ER/LA opioids with particular impact on the epidemic --OxyContin (oxycodone hydrochloride controlled-release) and Dolophine (methadone hydrochloride) -- are provided in the Key Label Examples tab. 

Labeling for all FDA-approved opioids can be found on the Drugs@FDA website, as well as at pharmacies and on many manufacturers’ websites.  Labeling is also the root source of information prescribers receive from a wide variety of commercial online reference products and other resources educating prescribers about the safe and effective use of FDA-approved drugs. 

Keep up with changes to drug labels: It is important to know that drug labels may change as new information on any FDA-approved products becomes available and that these changes occur frequently.  We encourage prescribers to regularly review these changes.  FDA’s MedWatch site provides easy access to safety labeling changes for FDA-approved drugs.  This resource clearly identifies the parts of the label that have changed.  The new alert also gives “Key Label Examples,” particularly about OxyContin and Dolophine. 

FDA also emphasized the importance of patient education.  FDA said that FDA-approved Medication Guides are key patient education tools.  Pharmacies are required to provide them to every patient who receives an ER/LA opioid.  Prescribers can also download all available Medication Guides for use in their offices.  Among other valuable information, Medication Guides for ER/LA opioids inform the patient on safe disposal of their unused medication.  FDA has also created a patient counseling document   that prescribers can use to help educate patients on the safe and effective use of opioids.

ER-LA Opioid REMS CME Critics and the ACCME’s Vigorous Response

Although many praised the Food and Drug Administration (FDA) for releasing its long-awaited Risk Evaluation and Mitigation Strategy (REMS) for extended-release (ER) and long-acting (LA) opioid analgesics, there has been some criticism about the program.   

A REMS is a risk management plan that goes beyond requirements in the drug prescribing information to manage serious risks associated with a drug.  The Food and Drug Administration Amendments Act (FDAAA) of 2007 gave FDA the authority to require companies to develop and implement a REMS when necessary to ensure that the benefits of a drug or biological product outweigh its risks.   

In a recent “Viewpoint” article published in the Journal of the American Medical Association (JAMA), Lewis S. Nelson, MD, of New York University School of Medicine and New York City Poison Control Center, and Jeanmarie Perrone, MD, of the Perelman School of Medicine in Philadelphia, Pennsylvania, asserted two problems with drug companies to provide educational materials to doctors on opioids.   

Background 

The REMS is part of a federal initiative to address the prescription drug abuse, misuse, and overdose epidemic.  The REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids, while ensuring access to needed medications for patients in pain.  FDA is requiring a REMS for ER/LA opioid analgesics because FDA has concluded that there is a disproportionate safety problem associated with these products that must be addressed. 

One cause for the opioid problem is that while they used to be prescribed for “severe pain — terrible postoperative pain, terrible preoperative pain of a surgical illness — everything that was related to being close to a hospital and needing a lot of care,” today, opioid analgesics are a “panacea for everything that hurts you.” 

A separate REMS for transmucosal immediate-release fentanyl (TIRF) products was announced in December 2011 and was implemented in March 2012.  Moreover, the latest FDA's long-acting opioid REMS plan runs contrary to the fentanyl product REMS, which mandates education for prescribers, pharmacies, distributors, and patients, they wrote. 

All ER/LA opioid analgesics will be required to have a REMS.  The new ER/LA opioid REMS will affect more than 20 companies that manufacture these opioid analgesics.  Under the new REMS, companies will be required to make education programs available to prescribers based on an FDA Blueprint.  It is expected that companies will meet this obligation by providing educational grants to accredited continuing education (CE) providers to offer training to prescribers at no or nominal cost.  These CE activities must cover the content and messages of a blueprint developed by FDA for this purpose. 

The REMS also will require companies to make available FDA-approved patient education materials on the safe use of these drugs. The companies will be required to perform periodic assessments of the implementation of the REMS and the success of the program in meeting its goals. The FDA will review these assessments and may require additional elements to achieve the goals of the program. 

Debate on Opioid REMS 

Dr. Perrone and Dr. Nelson raised concern about the REMS requirement that manufacturers of ER/LA opioids provide educational materials about the appropriate use of these drugs.  “The propriety of having the pharmaceutical industry develop unbiased education for prescribers and patients is debatable,” they asserted.  This concern is misplaced because the education will be created by independent, accredited, CME providers.  Ignoring all of the CME regulations and firewalls that prevent bias or undue influence, the authors are still concerned about the “financial motivations and creative risk/benefit messaging.” 

They also maintained that while education was a “crucial element of safety, medication guides and related warnings have generally been ineffective in educating patients about the risks associated with certain medications,” the authors add.  This point failed to understand that the central piece of the REMS is education is for doctors prescribing opioids, not patients.   

The fentanyl REMS, on the other hand, requires a patient-prescriber agreement that requires patient education. 

Karen Drexler, MD, associate professor of psychiatry at Emory University in Atlanta, Georgia, maintained that “A black box warning might have more impact.”  Another potential problem identified was the voluntary nature of the REMS for healthcare providers.  “An advisory committee expressed concern that a voluntary process would not likely provide sufficient assurance of knowledge dissemination and retention and instead recommended linking certification, through mandatory testing, to renewal of a prescriber’s Drug Enforcement Administration registration,” the authors write.  While this argument has some merit, there are several states that require opioid-related education or physicians to maintain their licenses.  This argument, however, is problematic, because it is the individual states that must mandate doctors to take pain education, and the goal of FDA’s REMS is for states and CME providers to hopefully incorporate these principles into their state laws, regulations, programs, and requirements.   

The authors cite a recent study that showed that 13.4% of 259 practicing family physicians reported that they would no longer prescribe an opioid if they were required to obtain 4 to 8 hours of training and 2 hours of continued medical education every 2 years, although they would be tolerant of lesser requirements (Slevin et al, J Opioid Manag 2011:7;109-115).  “Mandatory training is something I'm sure most physicians are not going to be happy about,” Dr. Drexler added. 

Dr. Peronne also expressed the need for short-acting opioids REMS that gives warnings about the addictive nature of the drugs even in short-term prescriptions.  “For unclear reasons, a REMS for short-acting opioids has not been publicly proposed despite data suggesting that this opioid formulation is widely associated with nonmedical use,” the authors write.  While Dr. Drexler agreed that the strength of the REMS is that it addresses a whole category of drugs rather than addressing each individual drug, one of its weaknesses is that “it singles out the [ER/LA] opioids and leaves out other members of the opioid analgesic class.”  FDA, however, maintained that it took this approach due to the disproportionate problem with the long-acting opioids. 

Response from the ACCME 

Dr. Murray Kopelow, Chief Executive of the Accreditation Council for Continuing Medical Education (ACCME), respectfully responded to this editorial by noting that the opinions on CME “should be based on the best available information.”  He asserted how accredited CME “providers are required to meet rigorous standards designed to ensure actual—not ostensible— independence.  Providers must comply with the ACCME’s Standards for Commercial Support when offering any accredited activities, including those related to the REMS for long-acting and extended-release opioid analgesics. 

He explained how these Standards “require CME providers to design activities that are independent, free from commercial bias, and based on valid content. Providers must ensure that all content- related decisions are made free of the control of commercial interests.  The ACCME believes that CME can receive commercial support from industry without receiving any advice or guidance, either nuanced or direct, on the content of the activity or on who should deliver that content.” 

Kopelow also recognized how accredited CME providers “have more than 20 years of experience managing the boundary issues created by commercial support,” and the Standards “have become a national model” for numerous other health professional groups.   

He also reiterated how FDA’s ER/LA REMS requires opioid manufacturers to offer accredited continuing education (CE) grants to produce education based on the blue print, and “explicitly state[s] that manufacturers are prohibited from having any input or influence over educational design or curriculum.”  Further, he points out how the blueprint says that “accrediting bodies and CE providers will ensure that the CE activities developed under this REMS will be in compliance with the standards for CE of the Accreditation Council for Continuing Medical Education (ACCME) or another CE accrediting body.” 

Martin Grabois, MD, and Lynn R. Webster, MD, the president and president-elect of the American Academy of Pain Medicine, respectively, also responded to the Viewpoint.  They recognized that while there is a potential for bias in industry funded CME, the current system includes only two sources for funding: government and industry.   

However, we are completely unaware of any kind of funding from the government to provide CME whatsoever.  If any such funding exists, it is likely extremely limited and probably has significant restrictions and administrative burdens.  In fact, we noted last year that the Department of Defense had to close its CME office.   

Nevertheless, Grabois and Webster are correct in recognizing that the authors “did not advocate for pragmatic solutions.”  Instead, they went for the low-hanging fruit of critizing industry support, when as Grabois and Webster correctly note, it is “the best idea to come forward because for now it is the only idea to come forward.”  Given the issues America faces funding numerous aspects of health care reform, and the complete absence of any mention of continuing education in the Affordable Care Act, it is highly likely that no funding for government for CME, or specific to opioids will ever emerge.  

Congress and FDA have negotiated for 25 years now regarding user fees to help expedite the drug approval process, and every five years included new requirements and added regulations to ensure safety.  This process of industry-funded agencies has largely succeeded, and perhaps the only true way to get more education is establishing in the next User Fee negotiations a more formal CME funding process. 

Problems for Psychiatrists  

Dr. Drexler noted that while the REMS is for all prescribers, for psychiatrists, it presents “additional challenges.”  For example, “one of the directions to prescribers is to make sure that you do a thorough history and physical examination and that you really understand the source of the pain and individualize the treatment before you prescribe any of these [ER/LA] opioids.”  But most psychiatrists don’t have an examination room in theirr office suite, and it may have been years perhaps since they have done a thorough physical examination, Drexler said.  She noted that frequently, patients ask psychiatrists to write prescriptions for opioids if they are having pain and haven't been able to see their internist or pain medicine specialist.  These are the cases where psychiatrists must be “especially cautious” to prescribe opioids without all the information they need.   

The other caution for psychiatrists, said Dr. Drexler, is to be aware of what other medications patients are taking.  “We do prescribe sedative hypnotics that can combine with opioids [and that can] lead to overdose deaths.  Adequately screening as best we can for high-risk alcohol use is also important because alcohol can combine with opioids and sedative hypnotics and lead to overdose deaths.” 

Dr. Perrone and Dr. Nelson also believe now is an ideal time to “inventory the evidence” for the efficacy and risks associated with opioid drugs for chronic non-cancer pain and moderate pain and to revise existing labeling to reflect the current clinical science and risk-benefit profile. 

It will also be important to “minimize the burden on physicians and the health care system by implementing a REMS that does not compromise patient care,” write Dr. Perrone and Dr. Nelson.  “For example, physicians may avoid prescribing a drug if they are unwilling or unsure of how to meet the REMS requirements.  This may result in increased prescribing of drugs that are not part of a REMS,” they add. 

Despite these concerns, the authors were “optimistic that the [REMS] is the first of several steps needed to enhance safe prescribing of these powerful drugs.”  

A better option, Nelson and Perrone wrote, would be to tie opioid education to certification via mandatory testing for renewal of a physician's DEA registration.

Although Nelson and Perrone assailed the FDA's recent action, they also cautioned that if the REMS is too restrictive, it may lead prescribers to choose other drugs not part of a REMS -- such as short-acting opioids like Vicodin, a hydrocodone combination product. 

The best option is to see how this first REMS works out before we go on a giant hunt to find alternatives to a program not yet tried.

FDA REMS: Mycophenolate Class Wide REMS

Over the past few months, we have seen increased activity at the Food and Drug Administration (FDA) with respect to the issuance and use of Risk Evaluation and Mitigation Strategy (REMS).  Consequently, FDA recently approved a single, shared system Risk Evaluation and Mitigation Strategy (REMS) for all mycophenolate-containing prescription medicines.  The drug mycophenolate is in a class of medications called immunosuppressive agents. It works by weakening the body's immune system so it will not attack and reject a transplanted organ. 

A REMS is a risk management plan that goes beyond requirements in the drug prescribing information to manage serious risks associated with a drug.  The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require companies to develop and implement a REMS when necessary to ensure that the benefits of a drug or biological product outweigh its risks.   

Mycophenolate-containing medicines are associated with an increased risk of first trimester pregnancy loss (miscarriage) and congenital malformation (birth defects) if taken during pregnancy.  To prevent unplanned pregnancies in patients using mycophenolate-containing medicines and to minimize fetal exposure to mycophenolate, FDA and the mycophenolate product manufacturers developed a single, shared system called the “Mycophenolate REMS.”   

The Mycophenolate REMS includes a Medication Guide, training for health care professionals, and the establishment of a pregnancy registry for women who become pregnant and agree to participate in the registry.  The training for health care professional’s component will likely require continuing medical education (CME) for physicians.   

The primary focus of the Mycophenolate REMS is women who can get pregnant. Women who can get pregnant should be aware of the risk of first trimester pregnancy loss (miscarriage) and an increased risk that the baby will be born with birth defects (congenital malformations) if mycophenolate-containing medicines are taken during pregnancy.  FDA stated that women who can get pregnant should follow these steps: 

• Talk with their prescriber about use of mycophenolate-containing medicines and the risk of pregnancy loss or birth defects.
• Use acceptable forms of birth control at all times during treatment and for six weeks after stopping mycophenolate-containing medicines. Decide with their prescriber what birth control methods are right for them.
• Have a pregnancy test immediately before starting mycophenolate-containing medicines and another pregnancy test eight to ten days later. Pregnancy tests should be repeated during routine follow-up office visits with the prescriber. 

If a woman does get pregnant while taking mycophenolate-containing medicines, she should consider participating in the Mycophenolate Pregnancy Registry.
The goals of the mycophenolate REMS are to:

1. Prevent unplanned pregnancy in patients using mycophenolate and to minimize fetal exposure by informing prescribers and females of reproductive potential about:
   • the increased risk of first trimester pregnancy loss and congenital malformation associated with exposure to mycophenolate during pregnancy; and
   • the importance of pregnancy prevention and planning
2. Minimize the risks associated with fetal exposure to mycophenolate by collecting information on pregnancy outcomes through the Mycophenolate Pregnancy Registry
3. Inform patients about the serious risks associated with mycophenolate. 

Health care professionals who prescribe mycophenolate-containing medicines will receive training materials from the Mycophenolate REMS Program and then can complete a “Training Confirmation” form (online or paper).  Mycophenolate manufacturers will maintain a list of all health care professionals who have completed the Mycophenolate REMS training.  FDA will periodically monitor participation by reviewing sponsors’ REMS assessments.  Mycophenolate manufacturers will redistribute training materials and update the Mycophenolate REMS website every two years or following substantive changes that affect the Mycophenolate REMS. 

A Medication Guide, which explains information about mycophenolate-containing medicines in consumer-friendly language, must be dispensed with each prescription.

Mycophenolate manufacturers will maintain a pregnancy registry for females who become pregnant while taking mycophenolate-containing medicines (or within six weeks of stopping treatment) and consent to participate. 

A REMS for mycophenolate-containing medicines was required by FDA due to receipt of postmarketing reports showing that exposure to mycophenolate during pregnancy is associated with increased risk of first trimester pregnancy loss (miscarriage) and birth defects (congenital malformations).  Structural malformations occur in approximately 20% of live-born infants exposed in utero to mycophenolate-containing medicines and first trimester pregnancy loss rates are increased.  While this information was included in the drug label starting in 2008, reports of pregnancy loss and birth defects continue to be reported.  The REMS was created to ensure that patients and prescribers are educated about these risks and understand what steps to take to prevent or minimize these risks. 

At this time, the Mycophenolate REMS will not require healthcare professionals to complete the training program in order to prescribe mycophenolate-containing medicines.  While the label of mycophenolate-containing products recommends pregnancy testing, the Mycophenolate REMS will not require that documentation of a negative pregnancy test be a requirement for dispensing mycophenolate-containing medicines. 

FDA reached this decision after carefully considering the risk of pregnancy loss and birth defects (teratogenicity risk), the drug’s benefits, the prescriber and patient populations who use mycophenolate-containing medicines, and the burden on patient access and the health care delivery system.

Since mycophenolate-containing products are marketed by several different sponsors, FDA requested that a single Mycophenolate REMS program be used and shared by all of these sponsors to reduce the burden on the health care system of having separate REMS programs in place for individual mycophenolate-containing medicines.  Having a single, shared system REMS for all of the products will make it easier for prescribers to participate in the REMS program because there will only be one education program for prescribers.  The manufacturers will maintain a single call center to support health care professionals and the REMS program.  The sponsors will also maintain a single pregnancy registry for females who become pregnant and consent to participate.

The Joint Commission Provides Hospitals Guidance for Better Opioid Use Management

Over the past few years, there has been a growing focus on the abuse, misuse, and overuse of opioids or painkillers.  Public health experts estimate that more than 35 million Americans age 12 and older have reported non-medical use of opioid analgesics during 2010 – up from 29 million in 200.  In 2009, nearly 342,000 emergency department visits were associated with nonmedical use of opioid analgesics.  In 2007, nearly 28,000 Americans died from unintended consequences of drug use, and of these, nearly 12,000 involved prescription drug pain relievers. 

To address these issues, the Food and Drug Administration (FDA) recently finalized its final Risk Evaluation and Mitigation Strategies (REMS) for extend-release (ER) and long-acting (LA) opioid medications.  This was the first time that FDA has mandated a class wide REMS and much of what is recommended will be looked at closely for future class REMS.  

In addition to FDA’s recent action, the Joint Commission recently warned hospitals about the dangers of using opioids on inpatients, calling for greater staff education particularly on opioid analgesics, which are most commonly associated with adverse drug events.  The warning about risks associated with opioids is part of a series of Alerts issued by The Joint Commission.  The Joint Commission sought input for the Alert from experts across the United States, including the Cancer Pain Program at Northwestern University’s Feinberg School of Medicine, the University of Wisconsin Hospital and Clinics, the Hackensack (N.J.) University Medical Center and the University Medical Center in Tucson, Arizona. 

Founded in 1951, The Joint Commission evaluates and accredits more than 19,000 health care organizations and programs in the United States, including more than 10,300 hospitals and home care organizations, and more than 6,500 other health care organizations that provide long term care, behavioral health care, laboratory and ambulatory care services. The Joint Commission currently certifies more than 2,000 disease-specific care programs, focused on the care of patients with chronic illnesses such as stroke, joint replacement, stroke rehabilitation, heart failure and many others. 

Opioid Alert

Although the Joint Commission acknowledged that opioids are generally safe for most patients, it pointed out the drugs, such as fentanyl, hydrocodone, hydromorphone, oxycodone, sufentanil, can cause side effects like sedation, dizziness, nausea, vomiting, constipation, hallucenations, falls, hypotension and aspiration pneumonia.  Reports also show that some patients, such as those who have sleep apnea, are obese or very ill, may be at higher risk for harm from opioids.  Additionally, a British study found that 16 percent of inpatient adverse drug reactions were traced back to opioids.  The reasons for such adverse events include dosing errors, improper prescribing and administering or inadequate monitoring, and interactions with other drugs, according to The Joint Commission’s Sentinel Event Database.  

Of the opioid-related adverse drug events – including deaths – that occurred in hospitals and were reported to The Joint Commission’s Sentinel Event database (2004-2011), 47 percent were wrong dose medication errors, 29 percent were related to improper monitoring of the patient, and 11 percent were related to other factors, including excessive dosing, medication interactions and adverse drug reactions. 

“Assessing and managing pain is critical to patients who otherwise would suffer, but avoiding the harm that accompanies the adverse effects of powerful opioid analgesics is equally important,” Joint Commission President Mark Chassin, M.D., said in a statement.  “Accidental opioid overuse in the hospital is absolutely preventable. Information in this Alert will help doctors and nurses keep patients safe.”   

While there are numerous problems associated with opioid use, including underprescribing, overprescribing, tolerance, dependence, and drug abuse, the Alert focused on the safe use of opioids that are prescribed and administered within the inpatient hospital setting.  The Joint Commission recognized that the emergency department presents unique challenges that should also be addressed by the hospital, but may not be directly addressed in this Alert.  Among recommendations, The Joint Commission urged the following (described in further detail below): 

• Implement effective practices, such as monitoring patients who are receiving opioids on an ongoing basis, use pain management specialists or pharmacists to review pain management plans, and track opioid incidents.
• Use available technology to improve prescribing safety of opioids such as creating alerts for dosing limits, using tall man lettering in electronic ordering systems, using a conversion support system to calculate correct dosages and using patient-controlled analgesia (PCA).
• Provide education and training for clinicians, staff and patients about the safe use of opioids.
• Use standardized tools to screen patients for risk factors such as oversedation and respiratory depression.

Actions suggested by The Joint Commission  

Hospitals can take the following evidence-based actions to help avoid adverse events associated with the use of opioids.  

1. Create and implement policies and procedures for the ongoing clinical monitoring of patients receiving opioid therapy by performing serial assessments of the quality and adequacy of respiration and the depth of sedation.  The organization will need to determine how often the assessments should take place and define the period of time that is appropriate to adequately observe trends.  Monitoring should be individualized according to the patient’s response.  The assessments are particularly important when the dose has been increased or another type of opioid is administered. In addition to monitoring respiration and sedation, pulse oximetry can be used to monitor oxygenation, and capnography can be used to monitor ventilation.  

Staff should be educated not to rely on pulse oximetry alone because pulse oximetry can suggest adequate oxygen saturation in patients who are actively experiencing respiratory depression, especially when supplemental oxygen is being used – thus the value of using capnography to monitor ventilation.6 When pulse oximetry or capnography is used, it should be used continuously rather than intermittently. 

2. Create and implement policies and procedures that allow for a second level review by a pain management specialist or pharmacist of pain management plans that include high-risk opioids, such as methadone, fentanyl, IV hydromorphone and meperidine. 

3. Create and implement policies and procedures for tracking and analyzing opioid-related incidents for quality improvement purposes.

Safe technology  

4. If available, use information technology to monitor prescribing of opioids.  

• Build red flags or alerts into e-prescribing systems for all opioids. The red flags can be either for dosing limits or alerts, or for verifications.
• Separate sound-alike and look-alike opioids, and use tall man lettering and other techniques to reduce the risk of error.
• Use conversion support systems to calculate correct doses of opioids to help prevent problems with conversions from oral, IV and transdermal routes of administration.
• Use patient-controlled analgesia (PCA) to reduce the risk of oversedation.  The use of smart infusion pump technology with dosage error reduction software can add another layer of safety.  

Appropriate education and training  

The Commission recommended that organizations assess the need for training based on the analysis of reported adverse events, near misses and staff observations. This analysis may be helpful in identifying knowledge gaps and in developing improvement strategies to reduce recurrences. 

The alert recommends that organizations advise clinicians who prescribe pain medications to use both pharmacologic and non-pharmacologic alternatives, including multi-modal adjuvant therapies (e.g., physical therapy, acupuncture, manipulation or massage, ice, music therapy).  Non-narcotic analgesics, such as acetaminophen, nonsteroidal anti-inflammatory agents, antidepressants, anticonvulsants (e.g., gabapentin and pregabalin), and muscle relaxants (e.g., baclofen, tizanidine), can be used before prescribing an opioid. In addition, when used in combination with opioids, these non-narcotics may reduce the dose of opioids required to effectively manage pain.  

The Joint Commission also recommended that organizations educate and assess the understanding of staff that care for patients receiving opioids about the potential effect of opioid therapy on sedation and respiratory depression, the continuum of consciousness, the difference between ventilation and oxygenation, and technological and clinical monitoring.  Staff training should emphasize how to assess patients for adverse drug reactions, how to recognize advancing sedation, and the importance of making timely adjustments to the plan of care based on the patient’s risk. For example, a comprehensive pain management program can help to educate clinicians, endorse best practices, and improve safety.  

The alert recommends that organizations educate and provide written instructions to patients who are on opioids (and to the patient’s family or caregiver) about:  

• The various generic and brand names, formulations, and routes of administration of opioids in order to prevent confusion and reduce the accidental duplication of opioid prescriptions;
• The principal risks and side effects of opioids, including the likelihood of constipation, and the risk of falls, nausea and vomiting;
• The impact of opioid therapy on psychomotor and cognitive function (which may affect driving and work safety);
• The potential for serious interactions with alcohol and other central nervous system depressants;
• The potential risks of tolerance, addiction, physical dependency, and withdrawal symptoms associated with opioid therapy.
• The specific dangers as a result of the potentiating effects when opioids are used in combination, such as oral and transdermal (fentanyl patches).
• The safe and secure storage of opioid analgesics in the home.  

The Joint Commission Alert also includes details about respiratory depression risk factors, which the Commission said was the “most serious [adverse] effect” of opiods, and offers information relevant to opioid risks and safety.  Specifically, when opioids are administered, the potential for opioid-induced respiratory depression should always be considered because:  

• The risk may be greater with higher opioid doses
• The occurrence may actually be higher than reported
• There is a higher incidence observed in clinical trials
• Various patients are at higher risk (see below), including patients with sleep apnea, patients who are morbidly obese, who are very young, who are elderly, who are very ill, and who concurrently receive other drugs that are central nervous system and respiratory depressants (e.g., anxiolytics, sedatives). 

Characteristics of patients who are at higher risk for oversedation and respiratory depression  

• Sleep apnea or sleep disorder diagnosis
• Morbid obesity with high risk of sleep apnea
• Snoring
• Older age; risk is
  • 2.8 times higher for individuals aged 61-70
  • 5.4 times higher for age 71-80
  • 8.7 times higher for those over age 80
  • No recent opioid use
  • Post-surgery, particularly if upper abdominal or thoracic surgery
  • Increased opioid dose requirement6 or opioid habituation
  • Longer length of time receiving general anesthesia during surgery
  • Receiving other sedating drugs, such as benzodiazepines, antihistamines, diphenhydramine, sedatives, or other central nervous system depressants
  • Preexisting pulmonary or cardiac disease or dysfunction or major organ failure
  • Thoracic or other surgical incisions that may impair breathing5,6
  • Smoker 

In addition, the Joint Commission alert recommends that organizations should make staff aware of the following factors and activities that can help avoid accidental opioid overuse:  

• Assess the patient’s previous history of analgesic use or abuse, duration and possible side effects to identify potential opioid tolerance or intolerance.
• Conduct a full body skin assessment of patients prior to administering a new opioid to rule out the possibility that the patient has an applied fentanyl patch or implanted drug delivery system or infusion pump.
• Use an individualized, multimodal treatment plan to manage pain.  A multimodal approach combines strategies such as psychosocial support, coordination of care, the promotion of healthful behaviors, nonpharmacologic approaches, and non-opioid pain medications. Upon assessment, the best approach may be to start with a non-narcotic.
• Take extra precautions with patients who are new to opioids or who are being restarted on opioids. These precautions should include starting the patient with a short-term trial15 of carefully titrated opioids at the lowest effective dose to achieve satisfactory pain control.18 Sufficient time should be allowed to assess the patient’s response to an initial dose before increasing the dosage or prescribing opioids for long-term use.
• Consult a pharmacist or pain management expert (when available) when converting from one opioid to another, or changing the route of administration (from oral to IV or transdermal). Consider that the patient may be less tolerant of the new drug (incomplete cross tolerance) or that the new drug may be more potent.
• Avoid rapid dose escalation of opioid analgesia above routine dose levels in opioid-tolerant patients.
• Take extra precautions when transferring patients between care units and facilities, and when discharging patients to their home. Consider that drug levels may reach peak concentrations during transport.
• Avoid using opioids to meet an arbitrary pain rating or a planned discharge date. Dosing should be based on the individual patient’s need and condition.

FDA Releases Final Risk Evaluation and Mitigation Strategies (REMS) for Extended Release/Long Acting Opioids Including a Prescriber Education Program

After three years of work the Food and Drug Administration (FDA) released its final Risk Evaluation and Mitigation Strategies (REMS) for extend-release (ER) and long-acting (LA) opioid medications.   This is the first time that the FDA has mandated a class wide REMS and much of what is recommended will be looked at closely for future class REMS. 

ER/LA opioids are highly potent drugs that are approved to treat moderate to severe persistent pain for serious and chronic conditions (list of ER/LA opioid products). The misuse and abuse of these drugs have resulted in a serious public health crisis of addiction, overdose, and death. 

After input from many stakeholders dating back to November 2011, the Food and Drug Administration (FDA) also released the “Blueprint for Prescriber Continuing Education Program” regarding the use of opioids.  The Blueprint contains core messages intended for use by continuing education (CE) providers to develop educational materials to train prescribers of long-acting and extended release opioids under the required risk evaluation and mitigation strategy (REMS) for these products (Opioid REMS).  

A REMS is a risk management plan that goes beyond requirements in the drug prescribing information to manage serious risks associated with a drug.  The Food and Drug Administration Amendments Act of 2007 gave FDA the authority to require companies to develop and implement a REMS when necessary to ensure that the benefits of a drug or biological product outweigh its risks.  

The CME Coalition offered its strong support for FDA’s efforts.  Andrew Rosenberg, Senior Advisor to the CME Coalition stated, “When there is a public health imperative, such as the abuse of long acting opioids, continuing education of providers is integral to improving patient outcomes and advancing the health of the country.”  Rosenberg continued, “We are pleased that the FDA views CME as a change agent and valuable resource to improve caregiver behavior in this vital area.” 

FDA’s final REMS is important because it marks a crucial step in federal health care agencies for recognizing the importance of CE and continuing medical education (CME).  The Agency’s logical and reasoned approach towards working with industry and accredited CE providers is a significant step in the right direction not only for patients and physicians but for the future of our healthcare system.  The opioid REMS represents the cross-collaboration of CE providers, industry, consumers, patients, and FDA.  Moving forward, FDA and these stakeholders should look at other opportunities to collaborate and use CE/CME to improve patient outcomes, reduce healthcare costs, and lower safety risks. 

Background 

Opioids are widely prescribed and carry a risk of abuse, misuse and death.  In 2009, there were nearly 425,000 emergency department visits involving non-medical use of opioid analgesics. According to estimates from the Centers for Disease Control and Prevention, 14,800 Americans died from overdoses involving opioid pain relievers in 2008.  In 2009, there were 15,597 deaths involving an opioid medication. 

The REMS is part of a federal initiative to address the prescription drug abuse, misuse, and overdose epidemic.  The REMS introduces new safety measures designed to reduce risks and improve the safe use of ER/LA opioids, while ensuring access to needed medications for patients in pain.  FDA is requiring a REMS for ER/LA opioid analgesics because FDA has concluded that there is a disproportionate safety problem associated with these products that must be addressed. 

“Misprescribing, misuse, and abuse of extended-release and long-acting opioids are a critical and growing public health challenge,” said FDA Commissioner Margaret A. Hamburg, M.D. “The FDA’s goal with this REMS approval is to ensure that health care professionals are educated on how to safely prescribe opioids and that patients know how to safely use these drugs.” 

All ER/LA opioid analgesics will be required to have a REMS.  The new ER/LA opioid REMS will affect more than 20 companies that manufacture these opioid analgesics.  Under the new REMS, companies will be required to make education programs available to prescribers based on an FDA Blueprint.  It is expected that companies will meet this obligation by providing educational grants to accredited continuing education (CE) providers to offer training to prescribers at no or nominal cost.  These CE activities must cover the content and messages of a blueprint developed by FDA for this purpose. 

The REMS also will require companies to make available FDA-approved patient education materials on the safe use of these drugs. The companies will be required to perform periodic assessments of the implementation of the REMS and the success of the program in meeting its goals. The FDA will review these assessments and may require additional elements to achieve the goals of the program. 

“We commend the FDA for taking action to save lives by increasing access to prescriber education,” said Gil Kerlikowske, director of the Office of National Drug Control Policy. “Since day one, the Obama Administration has been laser focused on addressing the prescription drug abuse epidemic and today’s action is an important contribution to this comprehensive effort.”  The new ER/LA opioid analgesics REMS is also part of the national prescription drug abuse plan announced by the Obama Administration in 2011 to combat prescription drug misuse and abuse. 

ER/LA opioid analgesics are widely prescribed medicines with an estimated 22.9 million prescriptions dispensed in 2011, according to IMS Health, which provides services and information to the health care and pharmaceutical industries. It is estimated that more than 320,000 prescribers registered with the Drug Enforcement Administration (DEA) wrote at least one prescription for these drugs in 2011. 

ER/LA opioid analgesics are associated with serious risks of overuse, abuse, misuse and death and the numbers continue to rise. According to the Centers for Disease Control and Prevention, 14,800 Americans died from overdoses involving opioids in 2008. In 2009, there were 15,597 deaths involving these medications – nearly four times as many deaths compared to 1999. 

"There are a limited number of options available for the treatment of pain.  Opioids are one option, but they carry a significant risk of misuse, abuse, overdose and death," says Sharon Hertz, M.D., deputy director of FDA's Division of Anesthesia, Analgesia and Addiction Products. "We're trying to help physicians manage the risks and improve the safety of using these medicines." 

“Misuse and abuse of prescription opioids is a complex problem and demands a holistic response,” said John Jenkins, M.D., director of CDER’s Office of New Drugs. “The new REMS program is one component of a multi-agency, national strategy to address this important public health issue.” 

Role of CME 

The central component of the ER/LA opioid analgesics REMS is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants).  There are approximately 320,000 prescribers of ER/LA opioid analgesics in the United States, and FDA expects companies to train 25% of these prescribers at the end of the first year following implementation of the program, 50% after two years, and 60% of them within three years of the start of training.  

It is expected that the first continuing education activities under the REMS will be offered to prescribers by March 1, 2013.  The FDA expects the training to take approximately 3 hours, but the CE providers will determine the number of CE credit hours that will be offered for the courses based on established standards for such determinations.  Key components of the ER/LA opioid analgesics REMS include: 

• Training for prescribers. Based on an FDA Blueprint, developed with input from stakeholders, educational programs for prescribers of ER/LA opioids will include information on 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. In addition, the education will include information on how to recognize evidence of, and the potential for, opioid misuse, abuse, and addiction, and general and specific drug information for ER/LA opioid analgesics. 
• Updated Medication Guide and patient counseling document. These materials contain consumer-friendly information on the safe use, storage and disposal of ER/ LA opioid analgesics. Included are instructions to consult one’s physician or other prescribing health care professional before changing doses; signs of potential overdose and emergency contact instructions; and specific advice on safe storage to prevent accidental exposure to family members and household visitors. 
• Assessment/auditing. Companies will be expected to achieve certain FDA-established goals for the percentage of prescribers of ER/ LA opioids who complete the training, as well as assess prescribers’ understanding of important risk information over time. The assessments also cover whether the REMS is adversely affecting patient access to necessary pain medications, which manufacturers must report to FDA as part of periodic required assessments. 

It is expected that the first continuing education activities under the REMS will be offered to prescribers by March 1, 2013.  

Follow-up surveys will be conducted to assess prescriber understanding of the important safety information and assess whether the REMS is adversely affecting patient access to necessary pain medications.  Companies plan to offer additional funding to CE providers as an incentive to identify and track prescribers who take the REMS-compliant training and to perform follow-up surveys to assess the amount of information retained. 

As part of the REMS, companies will report periodically on actions taken to implement the REMS, including, for training provided by CE providers, the number of grants awarded to CE providers, the number of prescribers trained, and other relevant information.  If FDA determines that the REMS is not meeting its goals, the Agency will re-evaluate the program. 

There is no mandatory requirement that prescribers take the training and no precondition to prescribing ER/LA opioids to patients.  However, the Obama Administration endorsed a mandatory training program on responsible opioid prescribing practices in April 2011 as part of its comprehensive plan to address the epidemic of prescription drug abuse. The program, which would be linked to DEA registration by providers, would require legislative changes that are being pursued by the Administration. 

The FDA continues to support this approach, but absent the needed legislation, intends to exercise its authority to require mandatory elements for companies and voluntary elements for prescribers – all of which are important and necessary steps to help curb the misuse and abuse of ER/ LA opioid analgesics, without being overly burdensome. 

For patients, the benefit is two-fold. First, Hertz notes that health care professionals who participate in the REMS program will have more knowledge and awareness and can have frank conversations with their patients about the risks and appropriate use of opioids. A new patient counseling document will be available for prescribers to use when talking to their patients about these medications. 

The REMS also includes an updated Medication Guide—a paper handout for patients that the pharmacist will provide when a patient receives an ER/LA opioid medication.  This document, Hertz says, is written in plain language to simply explain how to safely use ER/LA opioid medicines. 

The American Academy of Pain Medicine, which represents 2,600 pain physicians and treatment teams, issued a statement supporting FDA’s issuance of the REMS for opioids, calling it a “huge leap forward.” 

 “Through proper education and training, opioids can be administered safely to patients and continue to be an important option in the treatment of chronic and debilitating pain that is suffered by millions of Americans.”  AAPM will also shortly be issuing a series of best practices for both patients and prescribers that can further reduce adverse outcomes associated with opioids. 

Purdue Pharma L.P., maker of several opioids including OxyContin®, also announced its support for FDA’s REMS for opioids. 

FDA REMS to Promote Closer Ties to Healthcare Professionals

A recent article from the Food Drug Law Institute (FDLI) Update Magazine, discussed a recent session entitled “The Impact of Safety, Risk Communications, and Product Liability on Advertising and Promotion Strategies.” The session was moderated by Geoffrey M. Levitt, Senior Vice President & Associate General Counsel, Regulatory & Policy, Pfizer, Inc., and Vice Chair, FDLI Board of Director.  

During the session, James N. Czaban, Chair, FDA Practice Group, Wiley Rein LLP and Michael McCaughan, Editor, The RPM Report and Founding Member, Prevision Policy LLC, discussed risk evaluation and mitigation strategy (REMS) and other marketing issues.  

This was an important session in light of FDA’s recent focus on REMS for opioids, and the release of the agency’s new blueprint on the topic.

Background of REMS

In September 2007, the Food and Drug Administration Amendments Act (FDAAA) were signed into law providing the FDA with expanded authority.  One of the new provisions gave FDA the authority to require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that a drug or biological product’s benefits outweigh the risks.

FDA may now require REMS for any New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologic License Application (BLA) at any stage of the product lifecycle when the FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks.

If the FDA requires a REMS, the manufacturer has 120 days to submit a proposed REMS if it is for a marketed drug. For a new drug, the manufacturer must include the proposed REMS as part of its NDA submission.  Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.

REMS Requirements

To assist manufacturers in developing REMS, the FDA issued a guidance for industry in September 2009.  Additionally, FDA has outlined the specific elements that should be included in the proposed document.  FDA recommended that the proposed REMS should be concise and specific and include the goal(s) along with the explicit components that will be developed to ensure that the drug will be used safely and appropriately.  The manufacturer should also describe how it intends to evaluate whether the REMS is meeting its goal(s) and objective(s) at various time points from the time of launch and beyond.

FDA also more recently issued REMS guidance last March.

Failure to comply with FDA REMS requirements can render the company’s drug misbranded and result in substantial penalties (e.g., $250,000 to $1 million cap per violation; $1 million to $10 million cap per proceeding). Proposed REMS may contain any of the following elements:

• Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
• Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
• Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
• Implementation Plan – A description of how certain EASUs will be implemented.
• Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.

A drug’s REMS program may not require the provision of all the components above, as the specific components a REMS program employs will vary based on the severity of the risks, the population likely to be exposed, and other factors. Most common REMS only require the provision of a medication guide. While REMS components are not uniform, some do and will contain new provisions and requirements for physicians and other certified health care providers.  

REMS Discussion 

McCaughan identified the impact of a shift in the regulatory scheme, especially with the implementation of “mini-Sentinel” and the soon-to be implementation of the Sentinel system mandated under the Food and Drug Administration Amendments Act of 2007 (FDAAA).   During this explanation, McCaughan observed two models. 

The first model is REMS as mandated under section 901 of FDAAA—that is, the letter of the law—but also the “spirit” of REMS.  Both elements of this model confirm the value of marketing, according to McCaughan insomuch as they work through sponsors via the regulation. 

The second model McCaughan identified was Sentinel.  As FDLI noted, “under this model, FDA works outside the traditional biopharmaceutical sponsors via collaborations.  This model, therefore, challenges the central role of the sponsor in product communication.”  He noted that while the Sentinel model has “revolutionary implications,” it has only had a “modest impact so far.”  Levitt noted that “if Sentinel does what it is supposed to do, the program may provide more structure, but if not, some other structure or program will.” 

McCaughan also recognized that FDA’s focus on approval is not just safety and that the agency “must consider efficacy, the population needing a particular drug, and why it is needed, in a patient-centered risk/benefit analysis.” In this new model, the sponsor is not the center, but neither is FDA, McCaughan asserted.  “Safety surveillance is the focus, but comparative effectiveness research is the implication.” 

Consequently, Czaban’s presentation on drug marketing in “the Age of REMS” focused more on identifying the “silver lining” to REMS.  He suggested that “REMS could provide an incentive for further development of a drug and might not merely impose marketing restrictions that make it “impossible” to sell.”  For example, he asserted that REMS would “result in closer ties to healthcare professionals through required marketing strategies and multiple marketing tactics.”  He recognized that many positive qualities of REMS include: 

• Requirements for direct mail,
• Requirements to run print advertising in journals,
• Targeting and using key opinion leaders in speaker bureaus,
• Collaboration between marketing and medical science liaisons, and
• Targeting and tracking prescribers.  

Stepping back to look at the big picture, Czaban concluded that REMS are a burden, but also an opportunity from the marketing perspective.  The key, he identified, is how healthcare professionals view the “barrage” of REMS information, and how (or if) their behavior changes in response.

 

FDA REMS: Blue Print for Prescriber Continuing Education Program for Extended Release-Long Acting Opioids

The Food and Drug Administration (FDA) released a “Blueprint for Prescriber Continuing Education Program” regarding the use of opioids.  The draft Blueprint contains core messages intended for use by continuing education (CE) providers to develop educational materials to train prescribers of long-acting and extended release opioids under the required risk evaluation and mitigation strategy (REMS) for these products (Opioid REMS).

FDA is seeking stakeholder input on the document.  After comments are received, FDA will revise the Blueprint as appropriate, incorporate it into the Opioid REMS when it is approved, and post it on FDA’s Web site for use by CE providers.

Comments on the draft Blueprint are due by December 7, 2011.  Comments can be submitted electronically to http://www.regulations.gov, Docket No. FDA–2011–D–0771. 

Written comments can be sent to the Division of Dockets Management (HFA–305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.  For more information, contact, Michie I. Hunt, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Bldg. 51, rm. 6153, Silver Spring, MD 20993–0002, (301) 796–3504. 

Background

Health care professionals who prescribe extended-release (ER) and long-acting (LA) opioids are in a key position to balance the benefits of prescribing ER/LA opioids to treat pain against the risks of serious adverse outcomes including addiction, unintentional overdose, and death.  Opioid misuse and abuse, resulting in injury and death, has emerged as a major public health problem.

Public health experts estimate that more than 35 million Americans age 12 and older have reported non-medical use of opioid analgesics during 2010 – up from 29 million in 200.  In 2009, nearly 342,000 emergency department visits were associated with nonmedical use of opioid analgesics. In 2007, nearly 28,000 Americans died from unintended consequences of drug use, and of these, nearly 12,000 involved prescription drug pain relievers.

REMS for Long-Acting and Extended- Release Opioids 

The Food and Drug Administration Amendments Act of 2007 (FDAAA) gave FDA the authority to require manufacturers to develop and implement a REMS when necessary to ensure the benefits of a drug or biological product outweigh its risks. 

On February 6, 2009, FDA sent letters to manufacturers of certain opioid drug products indicating that these drugs will be required to have a REMS to ensure that the benefits of the drugs continue to outweigh the risks.  The affected opioid drugs include long-acting and extended-release brand name and generic products and are formulated with the active ingredients buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, oxymorphone, and tapentadol. 

After sending the letters, FDA held a series of meetings with stakeholders and convened an advisory committee to obtain input on the appropriate elements of the Opioid REMS. On April 19, 2011, in conjunction with the Office of National Drug Control Policy (ONDCP) release of the Obama Administration’s Epidemic: Responding to America’s Prescription Drug Abuse Crisis—a comprehensive action plan to address the national prescription drug abuse epidemic, FDA issued letters to application holders directing them to submit a REMS within 120 days and describing the elements that needed to be included in the REMS (REMS notification letters). 

The central component of the Opioid REMS program is an education program for prescribers (e.g., physicians, nurse practitioners, physician assistants) and patients. 

REMS Prescriber Education 

In the REMS notification letters, FDA provided an outline of the required prescriber education. The outline specified that the education must include information on 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. In addition, the education must include information on how to recognize evidence of, and the potential for, opioid misuse, abuse, and addiction. 

The REMS notification letters stated that although there is no mandatory requirement that prescribers take the course as a precondition to dispensing the medication to patients, application holders will be required to establish goals for the number of prescribers trained, collect the information about the number of prescribers who took the courses, and report the information to FDA as part of periodic required assessments. 

CE Providers Will Conduct Prescriber Education 

The REMS notification letter expressed FDA’s expectation that the training would be conducted by accredited, independent continuing education providers.  FDA later elaborated on its vision for prescriber education stating that we expect the CE training to be provided without cost to the healthcare professionals and that sponsors would offer unrestricted grants to accredited CE providers to develop CE for the appropriate prescriber groups. 

We believe having the training provided by CE organizations will be an incentive and will not create new burdens on prescribers because most healthcare professionals are routinely engaged in CE activity. 

The Blueprint Will Provide the Basic Outline and Core Messages for CE 

In response to the April REMS notification letter, application holders, through an industry working group, submitted an expanded outline of the potential topics to be covered in the CE, noting that education incorporating all of the topics in the outline could require

30 or more hours of education.  FDA’s expectation is that the initial or basic REMS related CE that should be offered to all prescribers of long-acting and extended-release opioids should consist of a ‘‘core’’ content of about 2 to 3 hours. 

FDA reviewed the industry submission and developed a basic outline and the core messages that FDA believes should be conveyed to prescribers in this basic educational module.  After it is completed and approved as part of the REMS, the Blueprint will be posted on FDA’s Web site for use by CE providers in developing CE courses.   

Although FDA recognizes that additional training modules could be helpful, FDA’s goal is to require basic education for all prescribers of long-acting and extended-release opioids, and at this time, FDA does not intend to develop or approve messages as part of the REMS beyond those approved in the basic core module. 

Blueprint for Prescriber Continuing Education Program  

Appropriate prescribing practices and patient education are important steps to help address this public health problem.  Health care professionals who prescribe ER/LA opioids have a responsibility to help ensure the safe and effective use of ER/LA opioids. Prescribers should:

• Understand how to assess patients for treatment with ER/LA opioids.
• Be familiar with how to initiate therapy, modify dose, and discontinue use of ER/LA opioids.
• Be knowledgeable about how to manage ongoing therapy with ER/LA opioids.
• Know how to counsel patients and caregivers about the safe use of ER/LA opioids, including proper storage and disposal.
• Be familiar with general and product specific drug information concerning ER/LA opioids.  

Assessing Patients for Treatment with ER/LA Opioid Therapy

Prescribers should consider risks involved with ER/LA opioids and balance these against potential benefits. Risks include: 

• Risk of overdose due to the high dosage of opioid available as an ER/LA formulation
• Intentional abuse by patient or household contacts
• Addiction
• Interactions with other medications and substances (see table below for specifics)
• Inadvertent exposure to household contacts, especially children  

Prescribers should assess each patient’s risk of abuse, including history of substance abuse and serious mental illness. Prescribers should: 

• Be knowledgeable about risk factors for opioid abuse and risk-assessment methods.
• Complete a comprehensive history and physical examination, including assessment of psychosocial factors and family history of substance abuse, as well as special considerations for the elderly, women, children, and cultural/ethnic groups. Identify appropriate referrals when the condition warrants.
• Understand and appropriately utilize screening tools for addiction or abuse, such as Prescription Drug Monitoring Programs (PDMPs), to help assess potential risks associated with chronic opioid therapy and to help manage patients using opioids products.
• Adequately document all evaluations and treatment plans.

Prescribers should be able to determine if a patient is opioid-tolerant and should know which products are safe for use only in opioid-tolerant patients. 

Initiating Therapy, Modifying Dosing, and Discontinuing Use of ER/LA Opioids

Prescribers should have awareness of federal & state regulations on opioid prescribing.  When initiating therapy with an ER/LA opioid, prescribers should be aware that: 

• Dose selection is critical, particularly when initiating therapy with an ER/LA opioid as the first opioid.
• Titration should be based on efficacy and tolerability.  

When modifying the dose of an ER/LA opioid, prescribers should understand equianalgesic dosing concepts and follow patients closely during all periods of dose adjustments.  Prescribers should also: 

• Be knowledgeable about converting patients from immediate-release to ER/LA products and from one ER/LA opioid product to another ER/LA opioid product.
• Be aware of the concept of incomplete cross-tolerance in order to safely convert patients from one opioid to another.
• Understand that tapering the opioid dose is necessary to safely discontinue treatment with ER/LA opioids when therapy is no longer needed. 

Managing Therapy with ER/LA Opioids  

Prescribers should establish goals for therapy and continuously evaluate pain as well as functioning level and quality of life.  Prescribers should also be aware of the existence of Patient Provider Agreements (PPAs), although FDA is not requiring their use. 

• PPAs are documents signed by both prescriber and patient at the time an opioid is prescribed. PPAs can help ensure patients understand the goals of treatment, the risks, and how to use the medications safely.
• PPAs can include commitments to return for follow-up visits, to comply with appropriate monitoring (such as random drug screens) and to safeguard the medication.  

Prescribers should ensure that patients adhere to a treatment plan and monitor patients for misuse and abuse by: 

• Recognizing aberrant behavior
• Utilizing PDMPs to identify potential abuse where available
• Understanding the role of drug testing and performing drug screens as indicated
• Screening and referring for substance abuse treatment when indicated
• Performing medication reconciliation at each visit  

Prescribers maintaining patients on ER/LA opioids should over time reassess whether opioids continue to be necessary for management of the patient’s pain.  Prescribers should also: 

• Understand how to manage adverse events associated with ER/LA opioid products.
• Understand the need for reevaluation of patients’ underlying medical condition if symptoms change over time.  

Counseling Patients and Caregivers About the Safe Use of ER/LA Opioids

Prescribers should: 

• Give product-specific information about the prescribed opioid.
• Explain how to take the opioid as prescribed.
• Explain adherence to dosing regimen and how to handle missed doses.
• Warn that under no circumstances should an oral ER/LA opioid be broken, chewed or crushed, and patches should not be cut or torn prior to use, as this may lead to rapid release of the ER/LA opioid causing overdose and death.
• Caution that the use of other CNS depressants, alcohol, or illegal drugs with ER/LA opioids can cause overdose and death. Patients should only use other CNS depressants under the instruction of their prescriber.
• Discuss that withdrawal symptoms can occur if an ER/LA opioid is discontinued suddenly. Patients should discuss plans to stop the ER/LA opioid with their prescriber. Patients should discuss a tapering regimen with their prescriber.
• Explain that sharing ER/LA opioids with others may cause serious side effects including death, and that selling or giving away ER/LA opioids is against the law.
• Counsel patients to store their ER/LA opioid in a safe and secure place away from children and pets and to read the product-specific disposal information included with the ER/LA opioid product.
• Caution patients that ER/LA opioids can cause serious side effects that can lead to death. Patients should call their prescriber or get emergency medical help if they have symptoms of overdose or respiratory depression; symptoms of stomach or intestinal blockage; or allergic reactions. Patients should also be counseled on the most common side effects of ER/LA opioids and be cautioned about the risk of falls, working with heavy machinery, and driving.  

Patients should call their prescriber for advice about side effects.  Prescribers or patients are encouraged to report side effects to the FDA at 1-800-FDA 1088. 

General Drug Information for ER/LA Opioid Products  

Prescribers should be knowledgeable about general characteristics, toxicities, and drug interactions for ER/LA opioid products. For example: 

• Respiratory depression is the most serious adverse effect of opioids as it can be immediately life-threatening.
• Constipation is the most common long-term side-effect but can often be managed.
• Drug-drug interaction profiles vary among the products. Knowledge of particular opioid-drug interactions, and the underlying pharmacokinetic and pharmacodynamic mechanisms, allows for the safer administration of opioid analgesics.
  • Central nervous system depressants (sedatives, hypnotics, tranquilizers, tricyclic antidepressants) and alcohol can have a potentiating effect on the sedation and respiratory depression due to opioids. Alcohol consumption should be avoided entirely with some oral products (e.g. morphine, hydromorphone, oxymorphone) because ethanol increases the plasma concentration of the drug substance.
  • Opioids may enhance the neuromuscular blocking action of skeletal relaxants (e.g. pancuronium) and produce an increased degree of respiratory depression.
  • Using opioids with monoamine oxidase inhibitors (MAOIs) may result in possible increase in confusion, anxiety, and respiratory depression.
  • Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone (ADH).
  • Some opioids (methadone, buprenorphine) can prolong the QTc interval.
  • Some opioids interact with various cytochrome P450 enzyme inhibitors and inducers and thus may result in higher or lower than expected blood levels of the drug. See detailed drug information table.
  • Tolerance to sedating and respiratory-depressant effects is critical to safe use of certain products, certain dosage unit strengths, or certain doses of some products. Opioid tolerance must be demonstrated before using any strength of ER/LA fentanyl and ER/LA hydromorphone. For other ER/LA opioids the use of certain doses of the drug requires that the patient be opioid tolerant. See detailed drug information table.
  • Tablet and capsule dosage forms must be swallowed whole. The pellets from capsule dosage forms can be sprinkled on applesauce and swallowed without chewing.
  • For transdermal products, external heat, fever, and exertion can increase absorption, leading to fatal overdose. Transdermal products with metal foil backings are not safe for use in MRIs.  

Specific Drug Information for ER/LA Opioid Products 

Prescribers should be knowledgeable about specific characteristics of the ER/LA opioid products they prescribe, including the drug substance, dosage form/strength, dosing interval, key instructions, major drug interactions, use in opioid-tolerant patients, drug-specific adverse events, and relative potency to oral morphine.  For detailed information, prescribers can refer to prescribing information available online via DailyMed at dailymed.nlm.nih.gov or Drugs@FDA at www.fda.gov/drugsatfda .

 

Physician Payment Sunshine: French Parliament Takes Up Industry Physician Payment Transparency

 
As part of a draft bill reforming the drugs approval and safety system, France may soon require that conflicts of interests between physicians/researchers and industry are publicly disclosed by directors and experts at regulatory agencies and made available publicly.  Failure to do so would now incur sanctions including fines of up to €30,000 ($43,000).

The proposal seems very similar to the Physician Payment Sunshine Act contained in the Affordable Care Act. 

If this bill is to pass, it will have significant implications for Foreign Corrupt Practices Act issues with respect to any companies that do business in France.

Etienne Caniard, president of Mutualité Française, a federation of most of France's nonprofit private health insurers, contends that the new rules will have a positive effect. “This proposal will help uncover the sectors where the state has given free rein to the pharmaceutical industry and where it should take its responsibility and regain control, such as continuous medical education,” he says.

The draft law should be presented to the French Parliament at the end of September with the objective to have it adopted by the end of the year. 

The law was developed as a response to one of the biggest French medical scandals of recent years about the Mediator,  a drug developed for treating overweight diabetics, and which side effects allegedly contributed to deaths of between 500 and 2,000 people before it was taken off the market in November 2009.

In addition, it is worth noting that the political climate is heavily affected by the up-coming presidential elections in 2012. The government therefore attempts to move this law forward through the accelerated legislative procedure.  Implementation decrees will however be required before specific items can come into force. 

Transparency requirements 

Specifically regarding the transparency requirements, in order to prevent conflicts of interest, the draft law provides on one hand a public conflict of interest declaration by all senior managers and experts working for health related public agencies, when they take office. These declarations are already an obligation for some officials. 

On the other hand, industry, drug and devices companies, will have to make public all [direct and indirect] benefits they provide to healthcare professionals, patient associations, hospitals, students, scientific societies and specialized media. 

Implementation details will be published in the follow up "implementation decree."

As far as the scope is concerned, it seems that the transparency requirements will apply to: 

• French healthcare professionals,
• French patient associations,
• French hospitals,
• French students,
• French scientific societies and
• French specialized media as well as French companies.  

Open questions at this point are the following: 

• Disclosure requirements will apply as of a certain threshold. For the moment, 100 Euros are considered for such a threshold.
• Moreover, "normal working relationships" (relations normales de travail) should fall out of the scope of the law.  Industry is lobbying in order to have a practical framework, where "normal working relationships" would be excluded.
• It is unclear at this point where the disclosed data will have to be published. The Ministry of Health informally mentioned that company’s website was a reasonable approach but following press articles seem to indicate that a central website/database is considered.  

The French are not known for such drastic measures, it is almost certain that whatever they adopt will be changed to a form that works best in the French system.  They should not throw away a medical system that has produced breaktrough medications just to placate critics.

Thanks to Marc Eigner at Polaris drawing our attention to this issue.

FDA Opioid REMS: White House Proposes Mandated Certified CME

 
This past week, the White House “unveiled a multi-agency plan aimed at reducing the “epidemic” of prescription drug abuse in the U.S.—including an FDA-backed education program that zeros-in on reducing the misuse and misprescribing of opioids.”  

Opioids are synthetic versions of opium that are used to treat moderate and severe pain. Opioids—such as morphine and oxycodone—are used to treat moderate and severe pain. Over the past few decades, drug makers have developed extended-release opioid formulas to treat people in pain over a long period. 

In concert with the White House plan, the Food and Drug Administration (FDA) is announcing a new risk reduction program—called a Risk Evaluation and Mitigation Strategy—for all extended-release and long-acting opioid medications.  According to the Food and Drug Administration’s (FDA) consumer update, key elements of the plan—called Epidemic: Responding to America’s Prescription Drug Abuse Crisis—include:

• expansion of state-based prescription drug monitoring programs
• recommending convenient and environmentally responsible ways to remove unused medications from homes
• supporting education for patients and health care providers
• reducing the number of “pill mills” and doctor-shopping through law enforcement

Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said the plan—a collaborative effort involving agencies of the departments of Justice, Health and Human Services, Veterans Affairs, Defense, and others—“provides a national framework for reducing prescription drug abuse and the diversion of prescription drugs for recreational use.” 

The consumer update notes that, “FDA experts say extended-release and long-acting opioids—including OxyContin, Avinza, Dolophine, Duragesic, and eight other brand names—are extensively misprescribed, misused, and abused, leading to overdoses, addiction, and even deaths across the United States. FDA says a 2007 survey revealed that more than half of opioid abusers got the drug from a friend or relative.”  Moreover, FDA estimates that more than 33 million Americans age 12 and older misused extended-release and long-acting opioids during 2007—up from 29 million just five years earlier. And in 2006, nearly 50,000 emergency room visits were related to opioids. 

FDA Commissioner Margaret A. Hamburg, M.D., noted that while "opioid drugs have benefit when used properly and are a necessary component of pain management for certain patients, they pose serious risks when used improperly—with serious negative consequences for individuals, families, and communities.”  Dr. Hamburg asserted that, “the prescriber education component of this opioid REMS balances the need for continued access to these medications with stronger measures to reduce their risks."  

The new REMS plan focuses primarily on: educating doctors about proper pain management, patient selection, and other requirements and improving patient awareness about how to use these drugs safely. 

As part of the plan, FDA wants companies to give patients education materials, including a medication guide that uses consumer friendly language to explain safe use and disposal. 

FDA wants drug makers to work together to develop a single system for implementing the REMS strategies. Toward that goal, FDA is now notifying opioid makers that they must propose a REMS plan within 120 days. 

Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), says this risk management strategy is designed to improve pain management, while preserving patient access to these needed medications.  Doctor training, patient counseling, and other risk reduction measures developed by opioid makers as part of the REMS are expected to become effective by early 2012.  They will be required for various brand name products known under the generic names: 

•  hydromorphone
• oxycodone
• morphine
• oxymorphone
• methadone
• transdermal fentanyl
• transdermal buprenorphine

 Although certified continuning medical education is not mandatory under the REMS plan, other federal agencies are working to get Congress to link mandatory continuing medical education to the already required Drug Enforcement Administration registration number that doctors must have to prescribe controlled substances.

FDA will also require the risk management plan to include a way to determine if the education programs are helping to reduce problems associated with long-acting and extended-release opioids, as well as allowing patients who need opioids to get them. FDA has had the power to request companies to develop REMS since 2007. The plans may also include medication guides and patient package inserts. 

In response to this announcement, an article from MedPage Today noted, that “many drug companies and pain organizations were satisfied with the new REMS, saying it balances the risk of abuse with the need to appropriately treat patients with legitimate pain.”  For example, Purdue Pharma, maker of the extended-release oxycodone product OxyContin, said in a statement that it "has supported the FDA's efforts to develop a class-wide REMS for extended-release and long-acting opioid analgesics."

“Herb Neuman, MD, chief medical officer at Covidien, maker of Exalgo, an extended-release hydromorphone product, said his company looks forward to developing the education because it will foster new partnerships with CME companies, from whom drug companies have historically had to maintain an arm's length.”  Dr. Neuman said he hopes “this will provide a pathway forward" to more efficient dialog between drugmakers and CME providers.”

Additionally, the American Pain Foundation applauded the announcement, noting that, "curbing abuse and misuse without limiting access to pain care for millions who require and deserve it is critical and necessary in any safety plan." 

As we noted last year, that FDA was heavily considering the use of continuing medical education (CME) to achieve these educational goals with regards to REMS for opioids.  Using CME to help doctors address the serious risks and side effects from opioid misuse and abuse would help close gaps in treatment and care, and could lead to safer prescribing patterns and treatment.  Accordingly, FDA and HHS, along with other health care stakeholders should continue the discussions and efforts to use CME to achieve the educational initiatives outlined in FDA and the White House’s new plan.

Risk Evaluation and Mitigation Strategies (REMS) Summary

 
According to a recent assessment by the Tufts Center for the Study of Drug Development (CSDD), “drug developers, healthcare providers, insurance companies, and others involved in the delivery of healthcare in the United States are uncertain about the benefits of a risk evaluation program introduced three years ago by the Food and Drug Administration (FDA).”

Key findings of Tufts CSDD’s assessment of the Risk Evaluation & Mitigation Strategy (REMS) program, the first systematic look at the initiative since the FDA introduced it in 2008, were reported in the January/February Tufts CSDD Impact Report, and released this week.

Christopher-Paul Milne, associate director at Tufts CSDD, who conducted the assessment, explained the findings and noted that “A majority of the organizations told us they felt the REMS program needs a major overhaul, and said that a REMS is a poor substitute for other improvements needed system-wide in drug education, communication, use monitoring, patient access, and delivery of care."

According to Milne, "Most respondents said it is virtually impossible to measure the benefits of a REMS, compared to its burdens on patient access and cost of health care delivery, for a newly approved drug, and that even for an already-approved drug, it would likely require two years or more to effectively conduct such an assessment." Among other findings developed by the survey were the following:

• Three-quarters of respondents said the REMS program needs a major overhaul.
• 68% said that REMS are a poor substitute for other improvements needed system-wide in drug education, communication, monitoring of use, patient access and delivery of care.
• 86% felt that under current guidelines, risk and benefit information was not well balanced in REMS communications.
• Only 22% of respondents thought the REMS program has been an improvement over the existing risk management system.

Milne noted that the REMS program will likely impact a growing number of healthcare stakeholders as the number of products with REMS expands in coming years.

Background of REMS

In September 2007, the Food and Drug Administration Amendments Act (FDAAA) was signed into law providing the FDA with expanded authority. One of the new provisions gave FDA the authority to require that companies submit Risk Evaluation and Mitigation Strategies (REMS) when deemed necessary to ensure that a drug or biological product’s benefits outweigh the risks.

FDA may now require REMS for any New Drug Application (NDA), Abbreviated New Drug Application (ANDA), or Biologic License Application (BLA) at any stage of the product lifecycle when the FDA determines that such a strategy is necessary to ensure that the benefits of the drug outweigh the risks.

If the FDA requires a REMS, the manufacturer has 120 days to submit a proposed REMS if it is for a marketed drug. For a new drug, the manufacturer must include the proposed REMS as part of its NDA submission.  Once approved, the REMS creates enforceable obligations for the manufacturer and the FDA.

REMS Requirements

To assist manufacturers in developing REMS, the FDA issued a guidance for industry in September 2009. The draft guidance for industry:

• Provides FDA’s current thinking on the format and content that industry should use for submissions of proposed REMS
• Describes each potential element
• Includes preliminary information on the content of assessments and proposed modifications of approved REMS
• Describes REMS policies for certain regulatory situations
• Informs industry about who to contact within FDA about a REMS
• Indicates FDA Web sites where documents about approved REMS will be posted
• Provides an example of what an approved REMS might look like for a fictitious product.

Additionally, FDA has outlined the specific elements that should be included in the proposed document. FDA recommended that the proposed REMS should be concise and specific and include the goal(s) along with the explicit components that will be developed to ensure that the drug will be used safely and appropriately. The manufacturer should also describe how it intends to evaluate whether the REMS is meeting its goal(s) and objective(s) at various time points from the time of launch and beyond.

Failure to comply with FDA REMS requirements can render the company’s drug misbranded and result in substantial penalties (e.g., $250,000 to $1 million cap per violation; $1 million to $10 million cap per proceeding). Proposed REMS may contain any of the following elements:

• Medication Guide – Document written for patients highlighting important safety information about the drug; this document must be distributed by the pharmacist to every patient receiving the drug.
• Communication Plan – Plan to educate healthcare professionals on the safe and appropriate use of the drug and consists of tools and materials that will be disseminated to the appropriate stakeholders.
• Elements to Assure Safe Use (EASU) – These are strictly controlled systems or requirements put into place to enforce the appropriate use of a drug. Examples of EASUs include physician certification requirements in order to prescribe the drug, patient enrollment in a central registry, distribution of the drug restricted to certain specialty pharmacies, etc.
• Implementation Plan – A description of how certain EASUs will be implemented.
• Timetable for Submission of Assessments – The frequency of assessment of the REMS performance with regard to meeting the goal(s) and objective(s). FDA requires that assessments be conducted at 18 months, 3 years, and 7 years post-launch, at a minimum. Results of these evaluations must be reported to the FDA and will determine whether additional actions or modifications to the REMS program are required.

A drug’s REMS program may not require the provision of all the components above, as the specific components a REMS program employs will vary based on the severity of the risks, the population likely to be exposed, and other factors. Most common REMS only require the provision of a medication guide. While REMS components are not uniform, some do and will contain new provisions and requirements for physicians and other certified health care providers.  

As of today, the FDA has approved 166  REMS since the implementation of FDAAA.

Discussion

Consequently, FDA’s Office of New Drugs Director John Jenkins discussed a draft proposal to standardize and integrate REMS into the healthcare system last month at an FDA-Industry PDUFA V Reauthorization Meeting. This proposal includes developing draft criteria for determining the need for a REMS and a series of public meetings to explore strategies to standardize REMS and better integrate them into the existing and evolving healthcare system. While further discussion of this proposal will take place in an FDA-Industry Working Group, according to the FDA Lawyers Blog, Dr. Jenkins outlined FDA's vision of "plug-and-play" REMS elements that could be standardized for specific drugs.

According to their coverage of the meeting, Dr. Jenkins explained that "Plug-and-play doesn't mean that everything's the same, it means that it's compatible . . . its interoperable." The FDA Lawyers Blog noted that 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.

According to the blog, “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.” Dr. 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.”

The blog noted that members of industry, such as Robert Clark, Pfizer Vice President of Worldwide Regulatory Strategy, “voiced support for a standardized REMS system at the summit, citing to benefits for not having to design a REMS from scratch. But Jenkins also seemed to acknowledge that while FDA has successfully negotiated some shared systems, it has been difficult to create a shared system for both innovator and generic companies.”

Analyzing Dr. Jenkins comments, the FDA Lawyers Blog noted that in the past, innovator companies, such as Celgene, “have voiced concern that they will be responsible for an increased workload once generic "share" their system, and some risk management program elements may be protected by patents listed in the Orange Book.” On the other hand, they also noted generic companies, such as Dr. Reddy's Laboratories, Inc. ("Dr. Reddy's"), who “have asked FDA to prevent innovators from using their REMS as a shield to deny reference listed drug to generic companies, which prevents generic applicants from conducting required bioequivalence studies for filing generic drug applications.”

To date however, the blog states that “both Celgene's and Dr. Reddy's petitions remain unanswered by FDA.” The blog predicted that “Even with FDA's vision for standardized REMS elements, it may prove difficult for FDA to prevent innovator companies from using REMS to block or discourage generic competition.”

Conclusion

Ultimately, with three-quarters of respondents from the Tufts CSDD assessment thinking that the REMS program needs a major overhaul, Dr. Jenkins comments about a REMS proposal to standardize the REMS process for specific drugs will be important to address industry concerns.

Since over two-thirds of respondents believed that REMS are a poor substitute for other improvements needed system-wide and because 86% felt that under current guidelines, risk and benefit information was not well balanced in REMS communications, it is clear that Dr. Jenkins proposal must create solutions to these problems. Industry’s input in this process, along with other stakeholders such as patient advocacy and consumer groups will play a significant role in the future of REMS.

Finally, those stakeholders involved in continuing medical education (CME) should also play an active role in addressing industry concerns of REMS, as they have done in the past and currently with opioids.