With a Few Stumbles, REMS Begins to Hit Its Stride

Pharmaceutical CommercePharmaceutical Commerce - March/April 2011

Nearly 200 drugs now carry requirements for a risk management program, as FDA evaluates the initial follow-up reporting from manufacturers

The Risk Evaluation and Mitigation Strategies (REMS) program of FDA, brought into being by a 2007 law, is now approaching its fourth birthday. As of mid-March, 179 newly introduced or already commercial drugs, branded or generic, have a REMS attached to them (one drug, Sucraid [sacrosidase], had a REMS requirement lifted last December after field reporting showed minimal allergic risk). The original logic of REMS was to allow drugs that had significant risks—primarily of side effects—associated with them to enter or remain on the market, while more rigorous post-marketing education, data collection and monitoring would be performed to minimize these risks.

REMS hasn’t enabled a spurt of new drugs to be approved, although numerous product launches have arguably occurred sooner than they would have without the program. Conversely, the burden on many drug sponsors has turned out to be less than initial expectations—even while members of the healthcare provider community, who have to take extra steps in many cases when REMS drugs have been prescribed, complain of an added burden that complicates patient treatment. Meanwhile, FDA has an open docket on proposed changes to how the REMS program operates, including separating out the most common type of REMS action, a medication guide for patients.


Overall, since the start of the program, one out of every three new molecular entities has required a REMS, and among specialty or biologic products, the ratio climbs to one out of every two new products, says Jeff Fetterman, president of ParagonRx International LLC (Wilmington, DE), a division of inVentiv Health. However, he notes that while the prevalence of REMS “has probably been higher than a lot of people expected, the severity of most REMS requirements has been somewhat less than what most people expected early on.”

“When REMS first came out, it really was a ‘four-letter word’ and many feared that the majority would require more-strict Elements to Assure Safe Use (ETASU) provisions but this has not been borne out by the data,” says Terri Madison, PhD, MPH, VP, Epidemiology and Risk Management, for Xcenda (Palm Harbor, FL), a part of AmerisourceBergen Consulting Services.

Communications, safe use

REMS originates in the FDA Amendments Act of 2007, and supersedes FDA’s earlier actions requiring Risk Management Action Plans (RiskMAPS) and several other post-marketing requirements. (Existing RiskMAPS became “deemed REMS” after the REMS program went into effect.) As individual REMS plans became formalized, the drug-specific requirements have a rising level of complexity:

• medication guide, building upon an expanded patient insert

• healthcare-provider communications plan, providing additional guidance to prescribers

• elements to assure safe use (ETASU), a variety of steps, such as diagnostic tests or additional training of healthcare providers

• implementation plan, which can require various complicated steps, usually association with ETASU, such as certifying the prescriber, the pharmacist or even the distributor of a drug, or developing a patient registry.

Drug sponsors not only have to execute the REMS program when it is imposed; they have to also survey patients or prescribers to confirm that required activities (such as patient education) have occurred. All this gets rolled up and reported back to FDA, beginning 18 months after the imposition of the REMS program, and potentially continuing for the next seven years.

To date, the percentage of new drug approvals requiring some form of a REMS program has increased each year, from 17% in 2008 to 30% in 2009 to 35% in 2010, says Heather Morel, VP and GM, Reimbursement and Access Services for McKesson Specialty Care Solutions (Scottsdale, AZ). In 2010, 48% of all new molecular entities, and 60% of all new specialty drug approvals, required a REMS program.

ETASU require such risk-reduction mechanisms as physician or pharmacist training or certification prior to dispensing, dispensing with specified parameters (such as required lab values and other patient-eligibility criteria), patient registries or use of specialized distribution partners.

The relative proportion of products requiring REMS with ETASU is growing. For instance, while the historic overall proportion has been 12% since 2008, in the 2009—2010 time frame, roughly 20% of the approved REMS programs required ETASU, notes Morel. (Fig. 1)

Because ETASU requirements are far more complex than a communications-based compliance plan, experts agree that they have greater potential to create unintended consequences in the marketplace. Prescribers might choose a path of least resistance and avoid specific therapies because of the complexity or burden of their REMS requirements.

“If a patient could benefit from a product but does not receive it due to the associated burden, then both the patient and the REMS product will be disadvantaged, and we have already seen this happening to a number of new products that are currently on the market,” says Morel.

Mixed success

As the first wave of approved REMS has started to hit the 18-month deadline, “The top-line feedback to date has been that the REMS focusing on risk communication (both to patients and healthcare providers) are falling a little short on goals related to knowledge (both for patients and HCPs) and many of the assessments are not yet measuring if these risk communications are actually influencing prescribing behavior in a way that reduces risk,” says Xcenda’s Madison.


“FDA has been steadily advancing the requirements associated with those assessments, yet the agency doesn’t make the submitted assessments available to the public, so there’s no opportunity to learn from them,” says one industry observer, who notes that this lack of transparency thwarts the development of any natural learning curve that could move the entire industry forward, and requires sponsors to “re-invent the wheel” with each post-implementation assessment.

While REMS plans that require only some form of communications-based outreach are certainly simpler to design and execute than those requiring ETASU, “FDA seems to be raising the bar on its expectations for risk-based communications,” says Madison of Xcenda. The proportion of plans that required both medication guides and HCP communication plans has more than doubled, to 28% of current REMS, from 2008 to 2010.

One problem that exists, however, is that “we’re in a real-world laboratory right when it comes to physician-targeted communications,” says Madison. “Drug companies are responsible for developing the knowledge piece, and of course the expectation is that all of this information will change prescribing behavior. However, while we know from studies that such outreach does affect physician knowledge, we do not know if it necessarily impacts prescribing behavior in a way that reduces risk for the patient.”

Lately, there has been a trend toward REMS-related HCP communications being designed for a more-targeted distribution (for instance, in the form of articles distributed through professional societies and published in peer-reviewed journals, rather than mass mailings sent to HCPs). Another pathway opening up—and, surprisingly, getting support from medical practice insurers—is through the Health Care Notification Network (HCNN) operated by PDR Network (Montvale, NJ). In October, PDR Network announced that it had partnered with The Doctors Company (Napa, CA), the nation’s largest provider of medical liability insurance, to provide CME credit to doctors who complete testing of REMS communications as they are issued. Pharma manufacturers can confirm that training has been received; doctors have an incentive to do the training; and presumably liability risks for medication errors goes down, a benefit to the insurer.


“As we expand our REMS offering to manufacturers, we keep the need to engage prescribers in their workflow, and in a manner that offers real value — front and center,” said Christine Côté, MD, PDR Network’s Chief Medical Officer. “Our independent analysis of clinical information in REMS programs and creation of related CME questions offer tangible value to busy clinicians.” PDR Network claims to have delivered over six million REMS and FDA Drug Alerts over the past three years (not all with a CME component).

The picture is more muddled for patient-focused education. Medication Guides that are poorly conceived can bring their own unintended consequences. “We have seen an example where a patient participating in a Knowledge, Attitudes and Behavior (KAB) survey related to a specific product became concerned about the risk messages being tested, appeared not to have been told about the risks, and wanted to change physicians as a result,” says Gretchen Dieck, PhD, VP, Safety, Epidemiology & Risk Management, United BioSource Corp. (Blue Bell, PA).

And since Medication Guides are required for so many approved REMS, care must be taken to make sure the technical language is written at a level that most patients can understand, and anticipate and rectify any language and cultural barriers that could limit the document’s utility among the target audience.


Another ongoing challenge for many companies is how to assess whether or not people understood the Medication Guide. “Ultimately, it’s about educating the patients to minimize the risks associated with the drug, so of course it’s logical to ask ‘Did you understand the information provided?’” says Craig Kephart, president of Centric Health Resources (Chesterfield, MO), a specialty distributor managing orphan drugs. “Otherwise it’s an exercise in futility.”

Interestingly, there is a movement afoot now to essentially decouple the Medication Guide from the REMS program. “FDA has, as a matter of policy, considered any products that are required to have a Medication Guide to automatically be part of the REMS program, but this may be changing,” says Fetterman of ParagonRx.

On February 28, FDA issued a new Draft Guidance for Industry on Medication Guides in the Federal Register (Volume 76, Number 39), which proposes that not every drug requiring a Medication Guide would automatically be subject to a REMS; rather, a REMS would most often be required in conjunction with ETASU requirements to assure the benefits of the drug outweigh its risks. “The implication of this publication is that not all drugs that require a Medication Guide to communicate potential risks to patients will be part of the larger overall REMS program by default,” says Fetterman.

FDA’s draft guidance seeks to articulate “the circumstances under which FDA intends to exercise enforcement discretion regarding Medication Guide distribution.” Comments are due by May 31.

Negative influence on prescribing

ParagonRx recently conducted a study of 475 primary care physicians and cardiologists. The company asked participants about their willingness to prescribe certain hypothetical products across three therapeutic categories that had varying degrees of risk-management requirements associated with them. The results showed that the impact of certain elements of a REMS program “could cut the market potential for a given drug by 50%,” says ParagonRx’s Fetterman. The study also indicated that 58% of prescribers said they would avoid products whose safety-related controls created too burdensome a prescribing process.

However, Fetterman notes that one surprising finding was that the opposite was equally true — that is, when prescribers considered the tailored combination of safety elements to be appropriate to reduce the risk of the particular product among patients, their intention to prescribe was increased by 42%. “This shows that with the right combination of properly designed safety elements, the prescribers would feel more confident prescribing the product.”


“REMS isn’t always a bad thing for drug makers — in some cases it may be gladly accepted as a means of access to products that otherwise wouldn’t be approved for use because of safety concerns,” says Jonothan Tierce, C.Phil., Senior Scientific Consultant to IMS Health (Arlington, VA).

Similarly, Dieck of United BioSource says: “I would argue that in some circumstances, what is good for the patient is also good for the product — that is, that the drug or biological that is prescribed incorrectly, taken incorrectly or can cause unnecessary risk if patients aren’t adequately informed may result in increased serious adverse events, and that is not good for the product concerned.”

Disenchanted stakeholders

Many stakeholders agree that the existing REMS framework — whereby drug makers routinely develop and administer their product-specific programs in a silo — is fraught with inefficiency and confusion. Three-quarters of the respondents to a survey published in January by the Boston-based Tufts University Center for the Study of Drug Development (CSDD) said the existing REMS program needs a major overhaul. In addition:

• 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 the current guidelines, risk and benefit information was not well-balanced in REMS communications

• Only 22% of respondents thought that the REMS program has been an improvement over the existing risk-management system.

Respondents included a mix of drug sponsors, payers, providers and patient advocates.

“Most respondents said it is virtually impossible to measure the benefits of a REMS, compared to its burdens on patient access and cost of healthcare 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,” said Christopher-Paul Milne, associate director at Tufts CSDD, who conducted the assessment.

Redundancy of effort is especially apparent for drugmakers when they develop essentially parallel REMS for products with similar risk profiles in the same therapeutic class. Experts agree that attempts to standardize certain REMS requirements, where possible, will help to assuage some of the industry’s concerns, and there have been calls from industry and other healthcare stakeholders for FDA to come up a suitable approach.

Such a shared-risk approach would not only streamline the time and effort required to develop parallel REMS for similar products, but also help level the playing field among competing drugs by reducing the disparities in REMS requirements that can sway decisionmaking in drug therapies.

At the FDA-Industry PDUFA V Reauthorization Meeting held last December in Silver Spring, MD, John Jenkins, FDA’s Office of New Drugs Director, discussed FDA’s strategies to standardize REMS and certain aspects of the program, outlining a vision of eventually developing “plug-and-play” REMS elements that could be standardized for specific drugs, where specific REMS elements would be more “compatible” and “interoperable.”

FDA’s ongoing efforts to develop a class-wide REMS to ensure the safe use of on extended-release and long-acting opioid analgesics — a broad class of drugs that is prescribed by nearly every medical specialty and used by millions of patients each year, according to Jenkins — is based on this desire to create a single, standardized REMS program for these drugs, rather than forcing unique programs to be developed and administered for each of the two dozen or more current opioids on the market. To date, FDA has received more than 2,000 comments from pain specialists and other healthcare professionals on the proposed opioid REMS, but the agency has yet to issue a final ruling.

“The majority of REMS programs to date (more than half) are products that have similar class-wide side effects and potential hazards, such as all bisphosphonates, all long-acting beta-agonists, anti-depressants, anti-epileptics,” says Madison of Xcenda. “FDA would really like the legislative authority to stipulate class-wide REMS and hold all affected companies accountable for developing and implementing similar REMS requirements at the class level. However, with the current wording of the FDAAA, FDA does not have the authority to enforce REMS at this level. In order for FDA to gain that authority, the FDAAA legislation would need to be revised.”

In the absence of an FDA mandate, the industry has already seen some precedents for class-wide REMS collaboration among manufacturers. Amgen and Johnson & Johnson worked together to develop their REMS for similar erythropoiesis-stimulating agents (ESAs) products Aranesp, Epogen and Procrit, which work by stimulating bone marrow to produce red blood cells. “The manufacturers took the lead and sat down at the table to harmonize their efforts and coordinate the REMS program design,” says Madison of Xcenda. “We haven’t seen that level of competitor collaboration in other classes yet, but it certainly brings certain efficiencies and cost savings to the process.”

Similarly, at the time that FDA was approving the REMS plan for Amgen’s Nplate (romiplostim), a product designed to stimulate the production of blood platelets, the agency was also reviewing the proposed REMS for ProMacta (eltrombopag), a similar drug from GlaxoSmithKline. “Despite the fact that these were separate products from two different companies, if you look at the individual REMS for both products, it’s fairly clear that the degree of similarity between the two programs goes beyond simple coincidence,” says Fetterman of ParagonRx. “We’ve interpreted this to mean that FDA worked with both manufacturers to achieve some level of harmonization.” PC

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