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FDA’s requirements for risk evaluation and mitigation challenge both new and existing commercialization processes
A key element of the 2007 FDA Amendments Act (FDAA)—the change from “requested” post-marketing compliance plans to mandated Risk Evaluation and Mitigation Strategies (REMS)—has now come to the forefront for both newly approved and commercial biopharmaceuticals. While some REMS are little more than a beefed-up patient medication guide, others can involve complicated patient registries and certifications of physicians, pharmacists and even distributors. Moreover, the unexpected announcement of a “class-wide” REMS requirement for long-acting opioid drugs last spring (Pharmaceutical Commerce, March p. 24) raises the possibility of programs that potentially will alter the fundamental process of delivering medications to patients.
There are the preliminary signs of an industry backlash, as evidenced by the lawsuit filed by Allergan over how a version of its Botox muscle relaxant is marketed (see box). But for the most part, brand managers are marshaling their resources and developing and executing plans per FDA guidance. For service providers to the industry, a minor land rush is on to gain recognition as contractors that can handle the new requirements effectively.
“In a healthcare environment where access is already an issue for many patients on multiple other levels, REMS is adding a layer of complexity whose impact will need to be evaluated,” observes Uwe Tigör, MD, SVP of medical strategy for the InVentiv REMS team, InVentiv Health (Saratoga Springs, NY).
By design, REMS programs are meant to implement a variety of measures to control prescribing practices, drug handling and utilization in order to safeguard patients and others from adverse events or unintended exposure to the drug. However, industry is increasingly recognizing that these programs have the potential to erect logistical and administrative barriers. These barriers could lead prescribers to select alternative therapies for reasons that have nothing to do with clinical appropriateness and in doing so, restrict a product’s market. “Especially when other, more-easily prescribed products are available for the particular medical condition, the product with the REMS restrictions might suffer a competitive disadvantage,” says Kelly Davis, MD, VP safety, epidemiology and risk management for United BioSource Corp. (UBC; Blue Bell, PA).
As biopharma manufacturers consider the future REMS requirements for their products, experts agree that the power is in their hands to shape the program specifics. The process of designing and implementing individual REMS programs — and negotiating with FDA to hammer out the specific terms — gives affected drug makers an opportunity to re-imagine all aspects of their post-marketing activities, and to work with payors, pharmacies and distributors to streamline seemingly duplicative aspects of the drug’s REMS, reimbursement and distribution requirements.
The long arm of the law
Under the broad mandate of the FDAAA, FDA can now require a REMS program to manage known or potential side effects that may be associated with any drug, to ensure that the clinical benefits of the product outweigh its potential risks in the marketplace. While individual program specifics will vary considerably depending on the perceived risks of the product, therapeutic area of interest, and even the target population who will use the product.
REMS requirements fall into three general categories that range in complexity (Figure)— those that will require only a medication guide to communicate risks to patients, those that will also require a communication plan with educational materials directed to healthcare providers, and those that will require additional, varied “elements to assure safe use” (ETASU).
“FDAAA extends FDA’s reach, as the new drug-safety mandates are no longer limited to assuring that a drug is proven safe and effective in clinical trials. Now the agency can also seek to ensure that the products can be safely and effectively used by patients in the real world,” says Tigör of InVentiv Health. “The mandate is broad, the tools FDA is developing for this purpose are still evolving, and the Agency’s response can require a spectrum of measures for biopharma producers.”
“FDA has the power to require a REMS program for any biologic or drug product based on the real or perceived risks associated with the product,” adds Heather Morel, VP and GM of reimbursement and access services for McKesson Specialty Care Solutions (Scottsdale, AZ).
As of mid-November, FDA lists 89 REMS programs on its website. Of the 24 new molecular entity approvals in 2008, eight (33%) received a REMS request from FDA. Roughly half of the REMS programs approved in 2008 were for new drug launches; the rest for drugs already on the market.
Assessing the cost impact of REMS
The complexity and expansive requirements associated with most REMS programs will have far-reaching cost implications for drug makers and these will ripple throughout the entire healthcare arena. For instance, there are costs associated with developing and distributing educational materials (such as medication guides, published articles and direct mailings) to patients, prescribers and pharmacists. There are additional costs to develop certification and registry processes for physicians, patients and pharmacies (which usually require continuing education or training administered by third-party providers), establish and maintain call centers and Web-based support, and to develop data-management systems to capture information about adverse events.
“It is conceivable that more-elaborate programs could cost in excess of $1 million to launch, plus monthly operational fees approaching $100,000,” adds Edgar Adams, ScD, executive director, epidemiology, for the Periapproval Services unit of Covance (Conshohocken, PA).
One perhaps ironic twist is that the high premium that REMS places on aggressive communication outreach from drug companies (for instance, to educate prescribers about proper use and drug safety issues) will likely help to validate the importance of pharma sales reps, compensated speaker bureaus and such — which have been under fire for years — and help to “rebrand” this aspect of pharma marketing as a regulatory obligation rather than a direct attempt to drive sales.
REMS-related costs will also carry forward into the future, not just in terms of ongoing program administration but in terms of compliance demonstration over time, as well, since REMS programs are subject not only to validated reporting at designated intervals (nominally at 18 months, 3 years and 7 years post-launch), but to severe fines for noncompliance. The penalties for noncompliance start at $250,000 per violation, with penalties doubling for each subsequent 30-day period following FDA notification.
“How do we adequately compensate the distributor to deal with these complex prescriber, patient and pharmacy registries?” asks Dan Steiber, RPh, principal of D2 Pharma Consulting LLC. “REMS is in a very real way adding to the cost of these products because at the end of the day, someone has to pay for all of these requirements to be carried out and these programs all have recurring transactional costs.”
Similarly, “pharmacies are also likely to look to pharmaceutical manufacturers to share in the financial burden of developing these systems, and it is safe to assume that some of the costs will be passed on to the end user and thus will have an effect on the overall price tag of the nation’s drug bill,” adds Tigör of InVentiv Health.
“In the early days of REMS, the process was largely reactive, and manufacturers often called us as they were preparing to implement their programs. This was costly, since the requirements were not always developed in a way that could be operationalized efficiently,” says Jay Jackson, senior director of medical services for Xcenda, a business unit of AmerisourceBergen Specialty Group. “Today, we tend to work with manufacturers one to two years prior to FDA approval, in order to develop a comprehensive strategy to maximize patient access with REMS considerations being just one component.”
The goal is to not only streamline the actual costs associated with program development and execution but to avoid the hidden costs associated with a less-than-optimal REMS program — namely the potential forfeiture of market share that may inadvertently result from physicians consciously or subconsciously shunning specific medications for which the certification, patient-registry, lab-work requirements might be burdensome.
“It’s not just important to look at what’s required to achieve clinical approvals — the program has to be implementable,’ says Steiber. “When envisioning your potential REMS strategy, you’ve got to ask ‘Will it work in the real world?’”
Many industry observers agree that partnering with a third-party service provider that already has a broad base of other clients who are also developing REMS-related programs can help to speed the process, as such providers have their finger on the pulse of parallel efforts that are underway elsewhere in the space. “The right partner can help biopharma companies to analyze potential risk scenarios, outline the scope of the requirements, and develop properly-scaled, well-targeted tools to support the specific requirements, and this can help to drive efficiency and reduce costs,” says Tigör.
When considering external partners to assist in REMS development and implementation, companies should conduct an analysis of their distribution partner’s capabilities, to identify any services and capabilities that already exist within their partner’s offerings, to maximize the efficiencies and minimize costs, says Maryann Dowd, R.Ph., VP, regulatory and supply chain integrity for D2 Pharma Consulting. For instance a given specialty pharmacy or distributor may have access to certain fulfillment and distribution data, all of which may be required for REMS compliance and auditing. “In these cases, it may not be necessary to duplicate efforts with a third-party REMS solution provider to capture this information,” she adds.
While pharma and biologic applicants and the consultants working with them have a responsibility to construct a program that ensures that the benefits of the drug outweigh its potential risks in the marketplace, the process definitely allows for a negotiation with FDA. “We in the pharma industry are absolutely in control of this, since we know our products and the workflow of physicians, pharmacies and other healthcare settings intimately — better than FDA,” says Morel of McKesson. “We should absolutely be in the driver’s seat, to identify the specific tools and strategic aspects and build a workable program that is best suited to address the risk profile of a given product.”
“Through dialogue with FDA, companies need to provide the rationale for the strategy they are proposing — to consider what the risks of the product are and what mechanisms might work best to minimize those particular risks — and to explain how the proposed approach will be effective in minimizing the product’s risks in the marketplace,” adds Davis of UBC. “Especially if the REMS-development efforts begin early in the drug-approval process, companies may be able to influence the outcome.”
None of the tools FDA is implementing in this early phase of REMS introduction has an established history of proven effectiveness, although some have already been used as part of the older RiskMAP program, adds Tigör of InVentiv Health. “This allows for discussions and differences of opinion, and proactive negotiations with the FDA will help clarify scope of requirements early in the process to prevent unnecessary spends.”
When pondering their potential REMS schemes, biopharma companies should also benchmark their proposals against the REMS programs of similar products, and use their findings to provide evidence to support REMS recommendations to the agency, says Jackson of Xcenda. “Think of it as conducting a ‘landscape assessment’ of similar products or product classes. Drug companies might perform a comparison assessment of its product’s risk profile versus the risk profile of other products with REMS programs.”
REMS’ impact on distribution
Numerous specialty pharmaceuticals are already going the route of specialty distribution/specialty pharmacy (Pharmaceutical Commerce, September, p. 1), and REMS may push some drugs into the more hands-on processes of specialty distribution. “Managing distribution and the complex flow of information and transactions between doctor registries, patient registries and certified pharmacies — that’s where the rubber meets the road,” says Steiber of D2 Pharma Consulting. “This is an area that’s still very much in flux and could very much benefit from the development of standards.”
Steiber notes that within the 2015-2016 timeframe, all pharma products are expected to require track-and-trace serialization (to follow the journey of products to reduce counterfeiting and product diversion). “These track-and-trace methodologies offer great promise to be leveraged in a REMS setting, to enable better efficiencies around physician credentialing and patient registries,” he says. “I envision REMS and pedigree requirements, and the technology-based tools developed to support them, intersecting at some point to really help stakeholders manage safety and risk more efficiently.”
To meet REMS restrictions, the selection of the right distribution partner and dispending model is critical. “If the REMS program will place rigorous requirements on pharmacies, a classical distribution model may be more difficult to manage compared to the use of a more-restricted model that is characterized by limited distribution or the use of single-source specialty pharmacy model,” says Heather Raschtschenia, MSEL, principal, market access services, for Covance (San Diego).
For instance, Raschtschenia notes that a REMS program that will require pharmacies to verify prescriber and patient enrollment may impose too much complexity on a typical retail setting, and would also require significant outreach to educate and train retail pharmacies to carry out follow-up and monitoring to ensure program compliance. “However, should a retail model be the right methodology for distribution, there are new technologies, such as Web-based systems that we have employed and tested to reduce the burden,” she says.
“Choosing a distribution partner with a good record of having already passed prior FDA distribution channel audits is a critical factor,” says Tigör of InVentiv Health. “Since approval of a new compound can be held up until the REMS is in place, operational efficiency and speed is important.”
In fact, while the REMS process is still evolving, a recent report from Datamonitor estimates that the development a REMS plan may add between three and nine months to the New Drug Application (NDA) or Biological License Application (BLA) approval process, with significant cost implications (“Future Pharmaceutical Industry Trends,” Datamonitor, DMHC2497, March 2009).
ETASU refer to any number of special restrictions that may be imposed with the explicit goal of controlling (and hence restricting) the prescribing or dispensing processes of a given product, and are at “the most-severe end of the REMS spectrum, providing the greatest operational challenges for drug companies,” says InVentiv’s Tigör.
For instance, the types of tools that may be considered under ETASU include:
Healthcare providers who prescribe the drug must have particular training or experience, or be specially certified and enrolled in a validated registry
Pharmacies, practitioners, or healthcare settings that dispense the drug must be specially certified and registered
The drug can be dispensed only in certain specified healthcare settings, such as hospitals
The drug can be dispensed only to patients with evidence or other documentation of safe-use conditions, such as laboratory test results
Each patient using the drug must be subject to certain monitoring
Each patient using the drug must be enrolled in a registry.
“ETASU are tools that drug companies and FDA can use to reach out into the marketplace to control how specific pharma products are used in the marketplace,” says Morel of McKesson. “The ability to limit the distribution footprint — by ensuring, for instance, that only certain doctors can prescribe the product, only registered patients can get it, and only certain pharmacies can distribute it (or can only distribute it in limited quantities) — are some of the most restrictive controls that FDA can require drug companies to use.”
As the most-stringent tools in the REMS toolbox, ETASU must be considered “when a drug has an inherent toxicity or potential harm, which, if not properly controlled, might result in the product either not being approved, or actually being withdrawn from the market,” says Adams of Covance. He notes that drugs whose REMS already have ETASU requirements include those that are teratogenic (isotretinoin), hepatotoxic (letairis), and certain potent opioid analgesics that should not be given to opioid-naïve patients (Onsolis).
Today, such severe restrictions should no longer be considered the exception to the rule. “There were twice as many REMS approved in 2009 compared to the first year following enactment, and today, more than half of the REMS that are currently under development include complex ETASU components,” says Morel of McKesson.
Upside with payors
Because complex REMS programs also aim to manage many of the same key objectives as restrictive payor coverage policies — aiming to drive judicious prescribing by physicians and appropriate use by patients in order to reduce risk and adverse events and control off-label use — there is considerable overlap between reimbursement requirements and REMS. These overlaps create redundancies for program managers and prescribers, but could also be a source of improved productivity.
“We have found that appropriately developed REMS programs provide a range of support services, such as reimbursement coordination, for both prescribers and patients, and ensure the most appropriate patient access for the product,” says Jackson of Xcenda. “Strategic investment in REMS programs, such as through the development of Web-based support resources, can provide a marketing advantage for products, especially when these efforts are approached in a way that aims to maximize patient access and convenience for all participants.”
To weed out the inherent inefficiencies associated with such redundancy of effort, Morel of McKesson advises drugmakers to work with payors and to strive for synergies that may arise from eliminating overlaps between the various reimbursement requirements and REMS requirements of individual drugs. “Companies should work with payors to eliminate prior authorization when a REMS with ETASU is in place. Along those same lines, we should seek to eliminate restrictive national coverage policy when the REMS already restricts use within strict guidelines,” she says. “Since payors today are not yet generally well-educated about REMS, you should articulate the benefits of REMS and to encourage payors to potentially reconsider their prior authorization approaches, pointing out the wisdom of lifting some of the redundant restrictions once the mandated REMS systems are in place.”
Similarly, for drug makers, “the ability to develop a centralized ‘one-stop-shopping’ hub — to manage both the REMS requirements and provide reimbursement support for physicians and patients (in terms of coordinating prior authorization, benefits approval and reimbursement assistance) — will also help to minimize duplication of the effort required to collect and manage the needed information,” adds Davis of UBC. “Prescribers want to talk to one person about the product and related programs, not two or three.”
A class-wide REMS for certain opioid painkillers
Because the long-acting, extended-release opioid painkillers — such as fentanyl, methadone, oxycodone, hydromorphone, and others that that are indicated for the treatment of moderate to severe pain associated with cancer and other serious chronic conditions — are so prone to abuse and misuse, the case for greater REMS-related protections is undisputed.
In recent years, the number of poisoning deaths resulting from opioid analgesics has more than tripled, from 4,000 deaths per year in 1996 to 13,000 in 2006 (National Household Survey on Drug Use). These narcotics accounted for 40% of all poisoning deaths in the US in 2006, according to the Centers for Disease Control (CDC). “Nearly 14,000 deaths per year attributed to any class of drugs is unacceptable. We talk about ‘planes falling from the skies’ — we as an industry should not be willing to stand for this,” says Morel.
Covance’s Adams notes that opiod risks can arise from physicians’ inexperience in prescribing drugs such as methadone, as well as the existence of “opioid naïve” patients. “Such factors support a REMS approach geared toward proper patient selection and education regarding risks,” he says.
FDA is in the process of developing a common REMS mandate for the entire class of long-acting opioids, which will include more than 24 branded and generic drugs from 26 different manufacturers. To date, FDA has collected comments from the public, and recently extended the comment period into 2010. (This class-wide REMS program does not apply to short-acting opioids, which will likely eventually have their own unique class-wide REMS.)
“This sort of class-wide strategy can make sense when the goals and objectives of the risk-minimization program are the same for multiple products,” says Davis of UBC. “It seems that FDA is not only intending to make the REMS requirements uniform across the entire class, they are aiming to develop a shared system — including ETASU — that would include all the products.”
“What’s unique is the scale of this REMS,” says Morel of McKesson, who notes that roughly 21 million prescriptions for long-acting opioids are written by more than 350,000 prescribers each year in the US. “The implications of such an expansive program will be challenging and far-reaching, and it’s clear that the existing paper-based workflow processes won’t work for a program of this magnitude,” she says. “Implementing restrictive requirements at this scale will require a technology solution powered by the existing networks linking pharmacies, providers and other points of care.”
There is some precedent for this type of unorthodox cooperation. The FDA-mandated iPledge system was initiated in the pre-REMS era (and is still in use today) to ensure appropriate risk management for branded and generic isotretinoin (branded by Roche Laboratories as Accutane), which is used to treat severe acne but can cause severe birth defects. It is now an interactive, computer-based registry that monitors pregnancy in women on isotretinoin therapy, to minimize the risk of birth defects among patients. Since it was put in place in 2006, this complex risk-management system has registered more than 40,000 pharmacies, 16,000 prescribers and 300,000 patients. The online iPledge registry is administered by Covance.
Some have argued for the need to extend the class-wide REMS safety net even further to include all Class 2 opioids. If this were to occur, the number of prescriptions covered by such a class-wide REMS would jump from 21 million to 200 million. “The iPledge registry system designed to support isotretinoin is part of the most extensive REMS to date, and it currently covers about a million prescriptions per year,” says Adams of Covance. “Clearly, any opioid-class REMS has the potential to create a dramatic increase in patient burden, as well as a significant burden on the overall healthcare system.”
Two recent opioid approvals illustrate the breadth of potential REMS requirements: BioDelivery International’s Onsolis (buccal fentanyl), and King Pharmaceuticals’ Embeda (a combination of morphine and naltrexone). Onsolis will require a medication guide, communication plan, ETASU, and a restricted network of distributors and pharmacies (Pharmaceutical Commerce, July/August, p. 9). Delivery will be made by a courier and the patient must sign a receipt. Embeda requires only a medication guide and communications plan.
“If you’ve ever seen a patient with chronic and debilitating pain, it is unethical to be standing in the way of them and the relief they’re seeking,” adds Morel. “If the program becomes too restrictive (either preventing products from getting to market, or preventing or delaying patients from accessing products they need), we’ll end up with a solution that works against the clinical utility of the products and the efficiencies we’ve already established in our healthcare system.”
It seems that the opioids are not the only drug class for which FDA is contemplating a class-wide REMS mandate. Tigör of InVentiv Health notes that certain antidepressants, anti-epileptics and fluoroquinolone antibiotics are also being considered for a class risk-management requirement.
“REMS represents perhaps the most significant change in U.S. drug regulation in many years and drug manufacturers will have to live with their final REMS program for a long time as the restrictions become part of the drug labeling and the drug identity, and it’s not easy to make changes later,” says Morel of McKesson. “This is not lost upon companies that have already come through the REMS ring of fire, but it’s probably not fully appreciated by those who are just starting to develop their own programs.” PC