Regulatory Alchemy: The Transformative Power of the Opioid REMS

The three-year long process towards a class-wide Risk Evaluation & Mitigation Strategy has been anything but straightforward. Still, the final twist may be the most surprising: FDA is now espousing the most industry-friendly approach on the table. The details of the opioid REMS will take months to work out and years to judge, but understanding the choices made in crafting this policy are a critical starting point.

By Michael McCaughan

Who says you can't have your cake and eat it too?

When the Food & Drug Administration unveiled its class-wide Risk Evaluation & Mitigation Strategy for the long-acting opioids on April 19, Center for Drug Evaluation & Research Director Janet Woodcock noted that the agency needed to balance two potentially competing goals: "reduce the risk" of abuse of opioids and "ensure access for patients" in need of pain relief.

"In fact, I personally think the REMS as you'll hear about it that it might actually improve access for patients who are in pain and actually need these medications," Woodcock said. "It's not always clear to doctors who should get these drugs and how to best help patients manage their pain," Woodcock noted, so "sometimes physicians are reluctant to prescribe these drugs and patients suffer as a result."

The idea that a new, mandatory educational program imposed on drug manufacturers could increase use of medicines may seem like a stretch, but it underscores how dramatically the opioid REMS process has shifted since FDA first began talking about the need to apply the new post-marketing tools to the OxyContin class three years ago.

FDA has emphasized the dual message of reducing abuse while assuring access to pain therapy since the opioid REMS process began. But three years ago, the emphasis was inevitably on the control side of the ledger: the agency was applying new, largely untested regulatory tools to a very large, rapidly growing drug class. FDA, in effect, was in the position of trying to find a way to ratchet back the use of those medicines.

Now, however, FDA is playing the role of protector of patient access—and is even suggesting that the new program will actually expand the market.

Whether the opioid REMS can, in fact, pull off that almost too-perfect outcome will take years to determine. (The REMS itself will not be implemented until 2012.) But the mere idea that FDA can plausibly present a regulatory action of unprecedented scope and scale as an attempt to increase use of a controversial prescription class is remarkable in itself.

The opioid REMS may or may not transform the treatment of pain in the US. But the process to craft the final proposal has unequivocally demonstrated the transformative power of REMS when it comes to reshaping regulatory models, business practices and stakeholder relationships.

Finding the Right Balance

So much of the drug regulatory process is a balancing act. When FDA reviews a new drug application, the decision comes down to weighing the benefits of the therapy against the risk. In the world of REMS, that balancing act has expanded to include so many more elements that factor into finding the right approach to managing real-world use of medicines in the commercial setting.

Now the balancing act is even more challenging, involving weighing the interests of many different stakeholders, trying to find the right balance between cutting off inappropriate use of a medicine and disrupting medical practice.

In moving ahead with the opioid REMS, FDA made a number of critical choices about which side of the scale to come down on. On the biggest issue, finding the right balance between access and risk reduction, FDA tilted decidedly toward the side of access. But there are at least half-a-dozen different choices that make up that final balance.

In finalizing the REMS, FDA came down on the side of:

FDA's internal REMS development team rather than the agency's external advisory committee;

Pharmacists, who have no new burdens under the program, rather than physicians and other prescribers who will feel the impact most;

Sharing authority with other agencies—and in particular with the Drug Enforcement Administration—rather than adopting a go-it-alone approach;

Administrative simplicity in the form of a shared REMS system and joint assessments, rather than product differentiation;

Encouraging abuse resistant formulation development rather than focusing exclusively on non-technological approaches to controlling abuse;

The CME establishment, which will play a critical role in making the opioid REMS work, despite the strident critics who question the integrity of the entire industry-funded educational model.

As that list suggests, it is possible to divide up the opioid REMS (or any other regulatory action) into winners and losers. That isn't so different from any other time FDA makes tough choices in pushing ahead with a regulatory action.

In this case, it is relatively easy to conclude that manufacturers of long-acting products belong in the "winner" category—at least in comparison to the other options on the table.

Simply put, the agency and its REMS proposal now look like the best hope for manufacturers seeking to stave off much more draconian restrictions on use of the pain therapies. For sponsors of products affected by the REMS, that means it shouldn't be hard to support the final plan. The only viable alternative would be to fight worse proposals—a fight that at best will be a public relations disaster and at worst would lead to an immediate, dramatic cut in the size of the market. ( See "Controlling Opioids.")

But that in itself is a remarkable turn of events. After all, manufacturers are, in effect, the targets of the REMS. The idea that they could be among the strongest advocates for a system that imposes significant costs and potential liabilities on themselves is, to put it mildly, counterintuitive.

Such is the transformative power of the new world of REMS. The development of the class REMS has had a profound impact on business development models, commercial strategies and stakeholder relationships. Whatever else the REMS accomplishes, that is a powerful lesson in itself.

Sticking With the "Soft Touch"

The immediate headline from the April 19 announcement is that FDA is pushing ahead with a "soft-touch" approach to the opioid control problem, even though that approach was overwhelmingly rejected by its own advisory committee last July. ( See "Opioid REMS: Committee Rejects FDA Proposal, But Sponsors Should Embrace It," The RPM Report, September 2010.)

The final REMS is essentially unchanged from the proposal presented by the agency to an advisory committee in July.

The key elements of the REMS are a requirement for sponsors to provide training for prescribers of opioids, with an expectation that the training will follow a curriculum outlined by FDA and be administered by independent CME providers "to the extent practicable." The REMS also requires manufacturers to distribute patient education information on safe use, storage and disposal of opioids. ( See "The Opioid REMS Template.")

However, the REMS stops far short of a "closed-loop" model of the type urged by advisory committee members, who wanted requirements like physician and/or patient registries, formal prescriber certification, etc.

Rather than pursue a tougher and/or more burdensome REMS, FDA has instead released the proposal as part of a broader set of policies to address prescription drug abuse. That broader plan includes one element in particular that would clearly address concerns raised at the advisory committee meeting: a legislative change to the Drug Enforcement Agency certification process to require opioid training as a condition for DEA licensing. ( See "The Bigger Picture.")

The advisory committee overwhelmingly rejected the proposed REMS as too weak; however, FDA officials made clear following the committee vote that they viewed many of the panel's recommendations as exceeding the agency's authority. So it is not surprising that FDA is sticking with the plan it outlined last year.

Still, the overwhelming public rejection of the opioid REMS by the agency's own advisors will affect public reaction to FDA's final plan and likely strengthen calls for more direct intervention by Congress. That highlights the artfulness of the plan to seek extra authority for DEA as part of the current opioid package of improvements: it gives Congress something to sink its teeth into. Of course, one of problems with that is whenever Congress takes up a topic, it is hard to control exactly where it will end up.

Enticing Congress further into the opioid issue means FDA will have to navigate between an unusual set of allies who are urging tougher restrictions on opioids. Calls for tougher steps are coming from staunch industry critics (Public Citizen's Sid Wolfe) and law-enforcement first advocates like Kentucky Republican Rep. Hal Rogers.

In defending the "soft touch" model, FDA is striking some themes that may resonate well in a climate where government regulation is itself a careful balancing exercise.

CDER's Woodcock explained the agency's approach as finding the least burdensome method possible to achieve the desired end.

When asked by reporters about calls for relabeling, she responded: "The government can't be in everybody's office when they're prescribing. That system is not going to work. We need to make sure that prescribers, who are highly trained professionals, have the tools that they need to choose the appropriate pain medication just like when they choose other medications, that's right for their patient. The way we do that, we think at least to start, is training."

And then Woodcock noted a key feature of the REMS as a regulatory tool: unlikely the decision to approve or withdraw a drug, a REMS can be adjusted incrementally to change the balance between access and control.

If the focus on physician training "doesn't work," Woodcock noted, "the FDA has other tools that can impose, but the more restrictive the tools we impose the more likely it is that there are people in pain who will suffer by not having access to appropriate pain medication. So we have to balance those two things."

The adjustability of REMS—including the built-in assessment process that triggers opportunities to reconsider the balancing act inherent in the regulatory process—is one of its most powerful features, transforming FDA regulatory decisions from binary (you are on the market or you are off) into more tiered, nuanced controls. ( See "Pyramid Schemes and Pipeline Dreams," The RPM Report, November 2007.)

Making it Stick Politically

The opioid REMS suggests that the new regulatory tools do much more than transform the regulatory model for dealing with post-approval safety issues; they also have the ability to transform the dynamics of FDA's relationship to regulated industry and other stakeholder groups. While the regulatory process is often seen as inherently adversarial, the need to craft a workable REMS so far seems to be herding the diverse affected groups towards a sense of shared mission.

The transformation is most obvious for manufacturers. Sponsors of long-acting opioids began as, in effect, the target of the FDA action. Their initial efforts by a broad industry group to develop a collective response drew an embarrassing public rebuke from the agency. ( See "The Opioid REMS: Health Care Reform, One Class at a Time," The RPM Report, February 2010.)

As the REMS reaches the final stages, however, manufacturers are now more clearly in the role of advocates for the program—given the alternatives.

That sense of shared purpose may be especially crucial in the years that follow the implementation. The critics of the soft-touch approach will be ready to pounce on any evidence that the program is failing to have a sufficient impact on abuse.

And the one thing the program is essentially guaranteed to deliver is exactly that evidence.

One of the most important aspects of the REMS from FDA's perspective is that it should provide much better tools to track physician and patient awareness of opioid issues and use/abuse patterns —and also to measure the impact of specific risk management activities. That is an exciting development for the agency, offering a sort of quality improvement system for REMS in general—but it is a significant challenge for sponsors.

Indeed, it is almost a certainty that the REMS will prove disappointing in at least some aspects—after all, if it were easy to find a solution to opioid abuse, the REMS process would have been unnecessary in the first place. Moreover, even a largely successful program is certain to fail in some particulars—and manufacturers will be obliged to develop and report robust data on exactly where those failings are. ( See "Market Research With a Twist.")

So not only will the new REMS be costly to implement and maintain, it could expose manufacturers to significant new liability if the programs fail to make an impact on opioid abuse.

That may not feel like a positive change for the industry, but there is no question that the ground has shifted. The REMS began as something imposed on industry by FDA; now the political landscape puts FDA and industry in very much the same position of trying to make the physician training approach work as well as possible to change prescribing habits.

The Transformative Power of REMS

Thankfully for pharmaceutical sponsors the opioid REMS isn't just bringing together unlikely opponents like Sid Wolf and Hal Rogers—it is also building its own coalition of advocates and allies, very much including FDA itself.

One group offering enthusiastic support for the REMS model are retail pharmacists. They were the first stakeholder group to recognize the potential impact of the new risk management tools in general—and the opioid REMS in particular—on their work flow, and the agency's final approach to REMS underscores how successfully they communicated their concerns.

FDA's Woodcock noted during a media briefing on the new REMS that there are no requirements directed at pharmacies in the program, because "pharmacists have enough to do." Instead, the emphasis is on physician education.

The American Pharmacists Association greeted the Administration's prescription drug abuse plan with an enthusiastic statement of support, and noted that it is continuing to work with FDA on improving the REMS process overall.

Physicians organizations are less enthusiastic about the overall plan—but the Administration's focus on changing DEA licensing requirements keeps FDA out of the hot seat for now. Provider groups are not complaining about the REMS per se, and are instead focusing on how to respond to the proposed changes in the Controlled Substances Act.

And FDA's decision to stop well short of some of the toughest possible controls—like patient registries—assures that most of the key patient organizations are also offering support for the REMS.

FDA-Approved CME

Arguably the biggest winner among outside stakeholders in the final FDA REMS plan will be continuing medical education providers. At a time when manufacturers have been pulling back on sponsoring CME in response to ramped-up conflict-of-interest scrutiny and onerous disclosure mandates, FDA is essentially ordering manufacturers to fund CME programs on appropriate opioid prescribing. So the opioid REMS serves as an important government imprimatur on the value of the CME enterprise—and likely will trigger a welcome flow of funding to providers ( See "FDA Turns Back to CME as Opioid Control Tool," The RPM Report, September 2010.)

Again, there is no denying the transformative power of the REMS in this area—even if there is plenty of room to wonder about exactly how things will turn out in the long run.

The relationship between FDA and CME providers has been up-and-down at best for the past two decades, with CME providers generally viewing FDA regulation as a threat: the agency at times has listened to the viewpoint that there is an inherent conflict-of-interest in industry-funded CME. The pattern has been for FDA to make noises about a crackdown, and then for CME accrediting organizations to toughen standards, with FDA backing off.

The opioid REMS involves a completely different model: FDA-mandated CME, with content reviewed and approved by the agency. Now the regulator is no longer the threat to CME providers, but rather their champion.

The final REMS includes a lengthy outline for the content of the physician-education program, with sponsors directed to flesh the program out into a full curriculum. In keeping with FDA's overall approach to the REMS, sponsors are expected to develop a single, shared backbone for the educational program, with some limited room for drug specific information.

"We would expect that there be a single content for the general content about recognizing the right patients and many other aspects of the program," Woodcock told stakeholders. "Then there will be drug-specific information that will be contributed by each sponsor."

"After this is developed, FDA will review and approve the factual content." Woodcock stressed the point: "This will be FDA approved and regulated and it will not be promotional or anything like that. It will be factual information."

FDA has some models for the CME curriculum in mind. "There's some very good examples of information like this that have been developed by say the federation of state medical boards and others that have much of the factual information in there already. So we think much effort and thought has already gone into what do prescribers need to know before they prescribe these?"

So why involve the manufacturers? First off, they have an incentive to keep the curriculum up to date.

"The current existing drug information on all of the existing drugs will be added and also if there's any new drugs approved that fit into this category, that information would be added as well," Woodcock said. "So the training can be kept up to date on what people need to know about these products."

But manufacturers also have the resources to support the training, well beyond anything state medical boards would be likely to do on their own.

"After we approve the content, then we expect that unrestricted grants would be offered to accredited CME providers and other continuing education providers for the appropriate medical and prescriber groups," Woodcock said.

The beauty of the CME model is that there is a built in incentive for physicians to take the training, even if it isn't mandated. "We think having the training provided by CME organizations will be an incentive and will not create new burdens on prescribers since…most healthcare professionals are engaged routinely in continuing education activity. And we would expect this training to be provided without cost to the healthcare professional."

Talk about having your cake and eating it too: FDA is focusing a REMS on provider education, but working to ensure that the providers see it as a benefit—free CME that helps them meet professional requirements. And the REMS assessment/enforcement components essentially require sponsors to make sure the CME is as attractive as possible, since sponsors are directed to report on the percentage of prescribers who complete the training.

Sponsors Secure New Business Model

So providers get free CME, paid for by industry and regulated by FDA. For sponsors, that is hardly an ideal situation—but, like the REMS itself it has the silver lining of leaving the sponsor with a measure of control in shaping the educational content, with some wiggle room to tailor it for a specific therapy.

Still, if the only "benefit" of the REMS is that it could be worse, that isn't much to get excited about. But there is much more going on than just swallowing tough regulation in order to avoid even tougher steps.

That's because the opioid REMS effort is helping to drive a transformation in the pain category. While manufacturers continue to invest in novel, non-opioid pain therapies, the opioid category has entered a new and very different period of innovation, one that offers the potential for continuous formulation improvement to extend product life-cycles indefinitely. ( See "Redefining Innovation in Pain Therapy," The RPM Report, February 2010).

The REMS and attending commercial burdens related to post-marketing studies and prescription tracking are very expensive—but also significant barriers to entry for generic or smaller branded competitors. The potential to play in that market long term has already attracted one large investment, from Pfizer Inc. when it acquired King Pharmaceuticals last year. ( See "King of Pain," The RPM Report, November 2010.)

And Pfizer CEO Ian Read offered one of the early endorsements of FDA's REMS policy during Pfizer's first quarter conference call. "I am very encouraged by the opportunities given the REMS that has just come out" and "by the government's recognition of how important this area is in abuse deterrence." The King acquisition "will work out very well for us" in the "medium- to long-term."

That vote of confidence comes despite Pfizer's problems with its first entries in the "abuse deterrent" class: Embeda is approved but off the market due to what the company describes as stability problems, while Remoxy is likely to be delayed by some manufacturing issues as well as by the need to adapt to the REMS.

In that light, FDA's overall policy on abuse resistance would seek to encourage a new field of drug development: abuse deterrent products. As part of the broader Administration plan to address prescription abuse, the agency is promising to deliver guidance on standards in the space, and to work with the National Institutes of Health to encourage novel work in the space.

It is not a given that innovation in delivery technology will be a part of the public policy response to opioid abuse. During a recent Congressional hearing on prescription abuse, Kentucky Governor Steve Beshear noted that the recent launch of a modified formulation of OxyContin may have worked insofar as it is difficult to abuse, but not in reducing the problem of abuse.

"Since the recent reformulation of oxycodone ( OxyContin), Kentucky has seen a shift in diversion to oxymorphone ( Opana), a powerful narcotic with a significant risk of overdose death," Beshear testified. Endo Pharmaceuticals does have an application pending with FDA for a reformulated version of Opana ER; the application received a "complete response" temporary rejection from FDA in early January.

During the same Capitol Hill hearing, Representative Adam Kinzinger (R-IL) asked DEA Administrator Michele Leonhart whether new formulations have had an effect in preventing abuse. Leonhart said DEA is concerned because workarounds are quickly publicized, but "we don't want to discourage industry from continuing to develop these drugs." Other members of the committee chimed in to assert how quickly information about defeating abuse deterrent formulations spreads on the Internet.

FDA and the Administration policy, however, come down firmly on the side of supporting continued innovation in formulation work, rather than throwing in the towel and concentrating on law enforcement or other tools to restrict distribution of the current formulations.

Which offers a final, critical piece of regulatory alchemy FDA hopes to pull off in regulating opioids: implementing new controls on the products while simultaneously helping to shepherd more to market.