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FDA's risk-reduction requirements could be the bridge to a bright new future for the pharma industry.
Drug safety has emerged as a make-or-break issue for pharma over the past decade. In the wake of media fire storms and congressional investigations into withholding of safety data and deaths and disability linked to the marketing of Wyeth's Fen-phen and Merck's Vioxx, public trust in not only the drug industry but FDA hit bottom—and has remained there. In 2007, Congress took action, instituting a new program at FDA called Risk Evaluation and Mitigation Strategies (REMS) to, as the agency's Web site says, "ensure that the benefit of a drug or biological product outweigh its risks."
The primary objective of the REMS program is to reduce the danger drugs pose to patients by leveraging the existing communication and marketing capabilities of the pharmaceutical industry in one or more of the following ways: providing adequate information to patients, healthcare providers, and others; confirming that stakeholders are fully aware of the drug's risks; improving the appropriateness of drug use ("the right drug to the right patient"); and monitoring and measuring drug-safety outcomes.
FDA has created four REMS categories according to the degree and kind of risk a drug is perceived to pose. The minimal requirement is a medication guide (and package insert) to alert patients to the drug's serious adverse events, such as increased risk of suicidal thoughts or behavior. In addition, a communication plan—generally a letter—for healthcare providers to reinforce the warning may be mandated. In some cases, patients may be asked to sign a form confirming that they understand the risks; companies may also be asked to conduct follow-up surveys with patients.
10 Tips to REMSember
But often FDA has more serious concerns about a product's toxicity. Drugs deemed approvable only if specific risk-mitigation strategies are assured require an ETASU (Elements to Assure Safe Use) and an implementation plan. An ETASU can require the training and certification of the doctor (and sometimes the pharmacist, while drug's distribution sites may be registered; regular audits of both prescribers and distributors can be mandated. At its strictest level, REMS require screening and registry of patients along with regular monitoring of patient records to create an ongoing database to pick up further safety issues. The patient trades confidentiality of his or her record for access to drug, as in the case of Acutane to prevent its use by women who are pregnant.
To determine if a REMS is needed, FDA looks for safety signals in clinical data, with risks to heart or liver health high on its list of concerns. The potential for abuse, as in the case of a controlled substance, is a certain trigger, as is the need to minimize off-label usage. A new compound in a class that already falls into any of these categories is likely to require REMS. To make a final determination on a REMS requirement, the agency will consider, during its drug review process, the amount of information known about the product or drug class in relation to the size of the target population, treatment length, number of reported adverse events, and severity of the indication to be treated. REMS may also be requested of drugs that are already on the market due to reports of adverse events via post-marketing surveillance or due to safety concerns arising from new data from phase 4 studies or literature reviews.
Since the inception of the REMS program in March 2008, a total of 125 drug products have had risk-reduction strategies developed to enhance their safety. In its first 12 months there were 40 REMS; by March 2010 that number had tripled (see figure 1). Yet the proportion of REMS that have required only the minimal category of medication guide has remained constant at 60 percent. A breakdown of the remaining 40 percent that consist of the more complex categories—communication plans, ETASUs, and implementation plans—shows a similar consistency. Still, it is safe to assume that the number of REMS will continue to rise, depending on the rate at which new drugs are approved.
Certain therapeutic areas are red-flagged for REMS. A new drug developed to treat any of the following eight diseases has a high probability—between 5.5 and 8 percent—of requiring REMS as a condition of approval: diabetes; asthma/allergy/COPD; antibiotics for infections; epilepsy; depression; HIV; arthritis; and opioids for pain (see figure 2). Yet no drug or disease is automatically exempt, and the 125 products with approved REMS span the entire spectrum of medical conditions. Complex REMS programs involving ETASUs and implementation plans are typically sparked by risks related to tetrogenicity, cardiac problems, hematological risks, liver dysfunction, and new or worsened malignancies.
It's common for drugmakers to rue REMS because they add extra work and cost. In addition, certain REMS can circumscribe a drug's potential market by specifying an appropriate patient profile, with the result that the large-scale prescribing that can turn an arthritis painkiller like Vioxx into a megablockbuster will be far less common.
Yet REMS can also play a beneficial role in the marketing of a new drug. In that sense, REMS are not just a regulatory requirement. They can also be a strategic driver of change for the commercialization of a drug. While much grumbling has already been heard about the challenges in developing and managing REMS programs, it's worth noting how REMS can not only maximize brand value but help meet the drug development needs of the future. Gradually, the industry is recognizing that in the long run the REMS system can burnish its own value in terms of public trust.
Physicians, however, are not looking forward to the additional load of paperwork that REMS will entail. Pharma will have to labor to educate doctors about not only the implementation but the potential upside of REMS. The best possible risk-mitigation strategy for a pharma to develop will be one that is the least onerous for physicians, so involving doctors early in the process pays dividends. If successfully executed by the drugmaker and the physician, REMS are likely to ultimately reduce legal liabilities—less harm to patients means fewer lawsuits.
The most aggravating irritation posed by REMS is predictably that of cost. Maintaining registries as well as data tracking and analysis demand a substantial investment. Failure to plan ahead for the early signal detection of a drug's potential adverse event—and the appropriate follow-up in a detailed submission to FDA for REMS—is likely to result in a delay of approval and a loss of revenue. It also may force the drugmaker to rack up costs as it hurries to ramp up its complex REMS program.
A post-marketing REMS commitment runs what many may consider an excessive length of time. All REMS programs must include a timetable for submission of assessment at 18 months, at three years, and at seven years. (The timetable to ensure that the REMS is working for drugs granted fast-track approval is still a work in progress.) With the first set of REMS assessments currently coming back to FDA, it behooves pharma to closely watch how the agency handles its reviews. Whether officials will determine that the system is over- or underperforming remains to be seen.
The length of time of some REMS may rival a drug's patent life. For example, the Novo Nordisk's Victoza, the first once-daily GLP-1 for type-2 diabetes, was approved based on the Danish firm's maintaining a post-marketing registry for 15 years—not an especially promising sign for makers of diabetes drugs. Faced with such burdens, companies will have to weigh the expense involved in the commercialization of a new drug before making the go/no-go decision. The ultimate effect may be to stifle innovation.
The complexity of REMS will definitely place new burdens on doctors, patients, and payers. For example, Amgen's Nplate for chronic adult ITP and GSK's Promacta for low platelet count—two orphan drugs—require the physician to conduct an elaborate procedure of paperwork before prescribing it. This may result in decreased use of the product (and even suboptimal treatment of the patient) in favor of competitor drugs that are easier to prescribe.
The distribution of specialty products through a hospital or physician practice can be easily controlled by means of a REMS. Still, REMS are almost certain to reduce a drug's market size—or at least slow its take-up. Nowhere will this be more evident than in the category of controlled substances and other drugs that have a history of abuse—especially when distributed through retail channels with multiple manufacturers involved. Serious safety issues can also limit access. Adolor's Entereg, which was initially developed for opioid-induced constipation, was believed to have blockbuster potential, but its REMS program has restricted use to short-term inpatient settings. And Adolor has already been slapped with a warning letter from FDA for overstating its drug's efficacy in its promotional material as the company struggles to increase sales.
Payers have expressed concern that REMS may be used by drugmakers to control or close distribution of their products, restricting outreach by limiting access to certain "qualified" outlets. Pharma can use this control as a bargaining chip in financial negotiations with payers, too. Recently Kaiser Permanente, California's huge integrated healthcare system, filed a citizen petition requesting that the FDA take steps to ensure that the REMS process is transparent and that payers are involved in the pre-approval process. FDA has yet to respond to the petition, but its deployment has implications for how FDA handles REMS in the future. (The result in this case, not unsurprisingly, was that the drugmaker and Kaiser negotiated a confidential deal.)
With the REMS process only two years old, much of its implication remains fluid and unpredictable. It is important that drugmakers work closely with the agency early in the development of a drug to assemble an appropriate REMS program. Equally critical is to watch how the agency's enforcement unfolds.
Yet enhanced regulation of a drug's use by the drugmaker comes with a definite upside. Above all, the effort to evaluate and minimize a product's risk should result, over time, in a significant increase in the safety of all prescription drugs. This, in turn, can only increase public trust in the drug industry. REMS also provides a unique opportunity for a company to enhance the brand value of a product (see figure 3). Designing, implementing, managing, and monitoring an appropriate REMS program can be leveraged by the firm to communicate that "patients comes first when it comes to drug safety."
REMS may improve the probability that FDA will approve a drug, especially an innovative one in an untreated area. To this end, close communication with FDA during the development process about the detection of safety signals and other data should increase the agency's comfort level once the REMS program is in place. As a result, pharmacovigilance and other data-mining techniques that detect safety signals are increasingly critical.
In the post-marketing phase, REMS also improve data collection. Drugs that require registries, distribution tracking, or survey insights on market dynamics provide rich sources of supply-chain information. As the sharing of prescribing data becomes increasingly restricted, a REMS program can lead to superior market intelligence.
REMS can improve access to and interactivity with healthcare providers and patients. Several REMS programs have already been implemented with specific communication plans to assure safe use—doctors and patients need to be registered, trained, and certified first. The drugmaker's deepening involvement in the doctor-patient relationship may increase positive feelings all around. Patient adherence may increase as well.
In their capacity to both monitor safety and personalize usage, REMS programs can produce an overall improvement in the value proposition of a brand. Celgene's STEPs program for Thalomid and Revlimid for multiple myeloma and other hematological syndromes and Biogen Idec/Elan's MS drug Tysabri are prime examples. Payers can see the value of a product and opt to cover it if its REMS restricts use for certain diagnosis and patient characteristics.
An effective REMS programs requires the participation of virtually every division in a company, from clinical to regulatory to marketing. This exercise can help to strengthen pharma's new emphasis on building cross-functional teams. Marketing a new drug with a REMS program will transform the launch, as the drug's safety alert and monitoring become a kind of service that differentiates the product from competitors. REMS programs also provide benefits to marketing efforts, such as better prescriber segmentation and preferred prescriber programs and an improved promotional mix with well-defined roles for sales reps, medical science liaisons, speaker's bureaus, and journal ads.
The REMS system, in significant albeit select ways, grants the industry some favors that even the most expensive lobbying could not buy. For one, REMS can offer a drug a kind of market exclusivity. Botox's REMS include a provision that no Botox-like product can be substituted for the cosmetic enhancement. Lilly's blood thinner Effient has a REM ensuring that sales reps get face time with docs to explain the drug's special use. And if a company patents its REMS, generic competition could be shut out of the market unless REMS are waived or they develop their own. Distribution restrictions can also make it difficult for generics to acquire branded products for comparative evaluations, leading to entry barriers.
The primary objective of the REMS program is to improve the safety of, and trust in, pharmaceutical products. REMS programs can protect patients, educate providers, and improve the reputation of the FDA and the industry alike. Because the system presents drugmakers with additional regulatory responsibilities, some heavy lifting will be required and new capabilities developed. In the evolving REMS landscape, FDA and pharma are learning simultaneously; in order to minimize uncertainty companies is advised to constantly assess the challenges and find ways to manage them. Yet it should be clear that more than a few gains will also come pharma's way. In addition, REMS can provide significant opportunities to enhance the value of the brand, including improved probability of approval. If successful, then, REMS will finally lay to rest the notion that safety comes at the expense of innovation, speed, and cost. And that will be good news for everyone.
Thani Jambulingam is the chair of, and an associate professor at, the department of pharmaceutical marketing at St. Joseph's University. He can be reached at firstname.lastname@example.org