Experts call for improved FDA Risk Evaluation and Mitigation Strategy program

In November, the FDA announced the removal of restrictions on prescribing and use of the diabetes drug rosiglitazone, based on updated cardiovascular data, allowing health care providers to prescribe the drug without enrollment in a Risk Evaluation and Mitigation Strategy, or REMS, program.

Now the agency is seeking to review the program to improve risk communication and management between clinicians and their patients. However, there has been discussion as to the precise definition of a REMS and how much assessment is actually necessary.

Elaine H. Morrato, DrPH, MPH, CPH, former member of the FDA Drug Safety and Risk Management Advisory Committee, told Endocrine Today that the purpose of a REMS can include raising awareness of what that risk is and ensuring patients and doctors are making informed choices and following appropriate safe use practices.

“Sometimes you hope you can take steps to mitigate those risks, but you can never eliminate risk,” said Morrato, associate professor in the department of health systems, management and policy at the Colorado School of Public Health, University of Colorado Anschutz Medical Campus.

Existing REMS program

The Federal Food, Drug, and Cosmetic Act was amended by the FDA Amendments Act of 2007 and the FDA Safety and Innovation Act of 2012, allowing the FDA to require REMS for certain drugs and biological products to ensure their benefits outweigh their risks, according to FDA documents. REMS are required in the minority of cases when labeling and routine reporting requirements are not sufficient to mitigate risks and preserve benefits.

These REMS are developed to manage specific risks such as injury or death; when the FDA requires this, the drug manufacturer is ordered to develop, implement and assess the REMS. Subsequently, the agency may require one or more of the following components in addition to the timetable for assessments: medication guide or patient package insert, a communication plan, or elements to assure safe use (ETASU).

Morrato was on the advisory committee that originally reviewed the safety and efficacy of rosiglitazone (Avandia, GlaxoSmithKline) in 2010.

“In the case of rosiglitazone, part of the discussion was looking at the safety evidence from the available clinical trials and observational data; looking at the fact that there was an alternative on the market,” Morrato said.

She said she ultimately voted to keep rosiglitazone on the market with restrictions because some patients who benefited from rosiglitazone might not find pioglitazone an effective agent and concerns were raised at that time about potential cancer risks associated with pioglitazone.

“The committee wrestled with contradictions in the available safety data and didn’t take its decision lightly,” Morrato said. “With imperfect information, these are hard choices.”

In 2013, the advisory committee reviewed new information from a comprehensive, outside, expert re-evaluation of the safety data from a large, long-term clinical trial. These data did not show an increased risk of heart attack compared to metformin and sulfonylurea. This evidence ultimately led to FDA’s decision to remove some prescribing and dispensing restrictions for rosiglitazone.

Morrato also was on the committee that considered the approval for the obesity drug phentermine/topiramate (Qsymia, Vivus) in February 2012. It was ultimately approved on July 17, 2012, as an addition to a reduced-calorie diet and exercise for long-term weight management with a REMS consisting of a patient medication guide and elements (prescriber training and pharmacy certification) to ensure safe use. The purpose of the Qsymia REMS is to inform prescribers and females of reproductive potential about the increased risk of congenital malformation, specifically orofacial clefts, in infants exposed to Qsymia during the first trimester of pregnancy.

“It came down to the question: Do you take a clinical view on the risk for an individual patient or do you take a population-based view in which you ask how many millions of women of reproductive potential might want to take this drug?” Morrato said. “Even if you have a small fraction that had exposed pregnancies, this could represent a significant number of affected babies and families. We know that many of FDA’s REMS have been required for drugs that are teratogenic.”

Missing data raise concern

In February 2013, Daniel R. Levinson, head of the Office of Inspector General at the US Department of Health and Human Services, released a report arguing whether the FDA lacked comprehensive data to determine whether REMS actually improve drug safety.

The office reviewed the REMS approved since the program began through 2011, and conducted interviews with FDA officials on the efforts to evaluate the program’s components. They also looked at 49 sponsors’ REMS and FDA’s reviews of the assessments to examine their integrity, according to the report. Further investigation was conducted to understand whether the FDA evaluated the ETASU of one drug in each year of the program — a requirement by federal law.

Ultimately, the office found that the FDA approved 199 REMS between 2008 and 2011, 99 of which were still required in 2012. However, nearly half of sponsor assessments for the 49 REMS reviewed did not include comprehensive information requested by FDA assessment plans, according to the report. Moreover, 10 were not submitted to the FDA within the required time frames.

It also was reported that seven of the 49 REMS reviewed met FDA goals; however, 21 did not. A point of contention is that the FDA did not identify reliable methods to assess the effectiveness of REMS. FDA’s assessment review times exceeded its goal of 60 days for all but one sponsor assessment; reducing the sponsor’s time to make the recommended changes prior to submitting such assessments, according to the report.

“In conclusion, our findings raise concerns about the overall effectiveness of the REMS program,” Levinson wrote.

To address these concerns, Levinson recommended that the FDA:

Develop and implement a plan to identify, develop, validate and assess REMS components;

Identify REMS that are not meeting their goals and take appropriate actions to protect the public health;

Evaluate the ETASUs of one REMS each year as required by federal law;

Identify incomplete sponsor assessments and work with sponsors to obtain missing information;

Clarify expectations for sponsors’ assessments in FDA assessment plans; and

Seek legislative authority to enforce FDA assessment plans; and ensure that assessment reviews are timely.

In response to these recommendations, the FDA issued a letter stating that the agency agrees with the need to improve future REMS assessments.

“There will always be challenges in attempting to measure the impact of a REMS program (or individual REMS tools) on outcomes, since multiple concurrent REMS and non-REMS variables may contribute to an outcome. Although we can track and measure ‘system inputs’ (such as how many prescribers are trained or how many medication guides are distributed), attempting to associate particular interventions with specific outcomes (for example, fewer emergency room visits) will continue to be difficult,” the FDA wrote.

Mixed clinical perceptions

Morrato said one benefit of REMS is that patients and clinicians have access to medication they would not otherwise have.

“Without a risk management plan, these drugs would likely have been taken off the market or not approved. The goal is to try and get to some standardization. The challenge right now is that health care professionals and patients view them as burdensome,” Morrato said.

For instance, the restrictions may create financial burden for patients by increasing office visits or laboratory tests, depending on their insurance carriers.

The burdensome paperwork associated with a restricted drug is nothing new to pharmacists. Although he is not an ardent opponent to the REMS program, James Bennett, RPh, CDE, founder of a community pharmacy in Corinth, Miss., said he admits that the paperwork required to be attached on each prescription bag becomes excessive at times.

“In a perfect world, you would give that patient medication guides; they’d read it; and you would be able to talk them through the information,” Bennett told Endocrine Today. “But, the world is certainly not that way right now. What you do now is hand them the guide and hope they read and understand it.”

Sometimes, he said, the patient throws away the medication guide without giving it a quick read. In these cases, the training on the REMS programs tends to be helpful.

“The REMS educational tool I took online for Qsymia was helpful for me. From my angle, I felt it was valuable information because I don’t think I’ve dispensed it or spoken to anybody about it yet,” Bennett said. “My philosophy has always been to never dispense a drug if you don’t know how it works or what is in it.”

Other barriers remain, according to Randy C. Hatton, BPharm, PharmD, FCCP, BCPS, clinical professor in the department of pharmaceutical outcomes and policy in the College of Pharmacy at the University of Florida. Hatton said he worked as a pharmacist in a hospital setting for more than 30 years, and one barrier that is less recognized is that the REMS program is often created for chronic use issues.

“There are a few notable exceptions when they’re designed for acute use or inpatient use. But when they become problematic, the majority of REMS are for chronic, longer-term use for rare disease or dangerous treatments that require extra monitoring,” Hatton said.

Oftentimes, it is an afterthought on how these patients should be handled, he said. For example, if a patient is involved in a serious motor vehicle accident and transported to a local hospital, the first thing the physician will do is continue medications the patient is currently taking daily. However, if one of the drugs falls under the REMS program, it becomes more difficult to monitor the distribution.

“One solution would be to allow the patient to use their own supply if they had it. Some manufacturers or distribution programs would allow the hospital to acquire it and there would be some way to keep track of it. Others would just say it will be shipped to the hospital,” Hatton said. “It’s inconsistent because patients do not plan for this type of scenario.”

Jane M. Orient, MD, executive director of the Association of American Physicians and Surgeons and private practitioner, said she does not believe that the REMS program holds any true benefit to clinical practice.

“A lot of us have a strong preference to using old tried-and-true drugs because so many of the new drugs that have come out have great expectations and promises, and then they get withdrawn from the market because once you try them on enough patients, you find out there are side effects too uncommon to show up in the initial trials, which is just how it is,” Orient told Endocrine Today.

She suggests a new, widespread postmarketing surveillance program.

“We would need a national database to which people could report information voluntarily and confidentially. It would be good to have a secure report of the clinical details so each of these reports could be followed up,” Orient said. “We have these for vaccine adverse events. Anybody can report theirs if there is a vaccine reaction. The weakness is that it only picks up 10%, at most, of the reactions.”

FDA weighs in on REMS

Clinicians have said there is little guidance as to what constitutes significant harm. In response to an email request sent by Endocrine Today, Lisa Kubaska, PharmD, an FDA spokeswoman, wrote that the FDA will require a REMS when the agency determines that such a strategy is necessary to ensure the benefits of the drug outweigh the risk.

“FDA can require a REMS upon initial approval of a drug or as a post-approval requirement. Decisions about REMS are made on a case-by-case basis, taking into account the benefits of treatment and the risks of the drug. This benefit–risk assessment is a complex analysis that takes into account numerous factors related to a given drug,” Kubaska wrote.

Factors include size of a population likely to use a drug, seriousness of the disease or condition, expected benefit of the drug, expected or actual duration of treatment, the seriousness of known or potential adverse events, and whether the drug is a new molecular entity, she wrote.

As electronic health records become more widespread, it is uncertain whether REMS will move to a 100% digital platform to eliminate paper burden.

“Our goal is to design REMS that can be better integrated into, and minimize the burden on, the existing and evolving health care delivery system,” Kubaska wrote. “Currently, certain REMS requirements are implemented using electronic-based systems. For example, in certain REMS, training and other certification requirements such as enrollment by prescribers or pharmacies are available online via the REMS program secure website.”

When asked what clinicians should keep in mind when met with challenging requirements issued by the REMS program, Kubaska wrote, “For the majority of approved products, the FDA has determined that labeling and routine reporting requirements are sufficient to help mitigate risk, therefore the FDA has not required a REMS for most drugs. The REMS authority enables the FDA to approve, and patients to continue to have access to, certain drugs whose risks would otherwise exceed their benefits.”

She added that the FDA continues to learn more about designing REMS programs that can be readily implemented and integrated into the existing health care system.

“We welcome input from stakeholders about their experiences with REMS,” Kubaska wrote.

Proposed project work plan

On Dec. 17, 2013, members of the FDA Risk Communication Advisory Committee met to identify and discuss new methods for communicating risk information to health care providers as part of REMS. Their discussion also addressed how the sponsors and FDA can evaluate whether a REMS communication is reaching targeted populations, increasing awareness and understanding the key risk messages; and whether the communications are adequately affecting the knowledge, behaviors and/or outcomes.

Gary Slatko, MD, director of the Office of Medication Error and Prevention and Risk Management at FDA/CDER/OSE, presented a possible pilot project plan that could improve tools for health care providers to use when counseling patients about medications with a REMS. Project steps will include a review of the existing REMS patient counseling tools; identification of improvement opportunities; and report on the findings.

The committee also made best practice recommendations for communicating information about a drug’s risk to health care providers; designated dissemination of REMS information; conducted an assessment of REMS communication; reviewed REMS patient counseling tools; and proposed how a work plan could improve the existing REMS program.

Slatko said the FDA’s communication of benefits in product labeling is often limited to stating the indication. In addition, the FDA has traditionally limited REMS tool content to only serious safety risk information.

“Stakeholders have given us a lot of feedback that patients need a benefit context to help them understand and balance what they’re hearing about the risks when they start and while they maintain therapy,” Slatko said during the meeting. “We believe that health care providers are uniquely capable of communicating this benefit-and-risk information tailored to each individual patient profile.”– by Samantha Costa

Do the existing REMS tools adequately prepare clinicians for patient counseling?

Yes.

The REMS program has served to be a stop-and-think reminder for the primary care physician. They’re very busy seeing patients every 10 to 15 minutes. Some of the things that can be helpful to doctors to facilitate reminders are things like a REMS program where there’s information given to the doctor, including an online training program [doctors need to take] before they are able to prescribe the medication, or materials on how to counsel patients about warnings and adverse events in a less onerous manner. We don’t want to tell a doctor what they can and cannot do because they’ve studied quite a long time to be where they are, but on the other hand they are very busy. The REMS program provides helpful situations for the doctor and not just additional barriers in order to prescribe medications to their patients.

For example, the REMS program relating to Qysmia was a very good practice. It served as a reminder for me because I am very busy and I tend to see many patients. It reminded me to make sure that I discuss the potential for side effects and teratogenicity.

The REMS program for Qsymia initially required doctors to prescribe the drug at a central pharmacy [after] the doctor had participated in an online training program. The online training program educates clinicians about the potential warnings and the biggest one was the teratogenicity of topiramate portion of Qsymia. Therefore, the suggestion to the doctor was that any female of child bearing age should be counseled on birth control but also have a pregnancy test. Some felt that was maybe too onerous, but it has since been relaxed and I think it’s much better now. My suggestion is that we only alert the doctor about the teratogenicity of topiramate and leave it up to them to decide what to do prior to prescribing.

No.

The goal of the FDA’s REMS program is to ensure clinicians like myself are adequately informed of the potential risks associated with the administration of a specific medication. We can use REMS tools to determine on an individual patient basis if the medication is suitable and then counsel our patient appropriately. REMS tools are still rare in my clinic setting, with only three main examples that come to mind: rosiglitazone, liraglutide and exenatide extended-release. I have reviewed these REMS thoroughly, yet still find them non-specific with regard to the data supporting their claims. The lack of specificity on those data limits my ability to appropriately counsel patients on the noted risks.

The case with rosiglitazone and its “risk” for myocardial infarction is certainly one worth mentioning, as the prescribing restrictions have just recently been relaxed. The initial 2007 New England Journal of Medicine meta-analysis of CVD events in patients who had used rosiglitazone alerted us to a potential significant risk, and further retrospective data analysis led to restrictions. This presented us with a prescribing quandary — does the identified CVD risk with rosiglitazone outweigh the benefit? The information conveyed in the REMS is available to our patients and they naturally have questions on those highlighted risks. My suggestion is that the FDA-mandated REMS tools highlight the specific data on the emphasized risk. We practice evidence-based medicine, so show us the evidence in a concise format that will allow us to interpret the conclusions and appropriately counsel our patients.