Full article reprinted from The RPM Report July 14, 2009
FDA’s top management can’t be accused of overstating the importance of the agency’s new drug safety tools. But sponsors need to wake up to the reality: the REMS are a critical fact of drug development and marketing. Read on...
Maybe it’s the acronym. When Congress settled on the term Risk Evaluation & Mitigation Strategies as the catch-all term for new authorities granted to the Food & Drug Administration to dictate terms for access to prescription drugs in the marketplace, they presumably weren’t trying to put people to sleep by invoking the shorthand for deep, dream-state slumber.
REMS may not be the most dynamic acronym, but there are a lot of reasons sponsors may have been slow to wake up to the implications of FDA’s new drug safety authority.
The provisions of the FDA Amendment Act creating the REMS were terse, and in almost all particulars crafted to tone down any sense of a bold new regulatory mission for FDA.
Sponsors rightly felt that, because risk management plans had already become a routine part of the new drug review process, there was nothing really new in the authorities themselves. For that matter, REMS are not, by law, required for all drugs. Nor are any specific restrictions required as part of a REMS. The agency is directed to select the “least burdensome” option that allows safe marketing when it does impose restrictions. And any language that might have caused some nightmares in industry—like provisions that would have explicitly authorized restrictions on television advertising, or giving FDA the authority to review marketing plans—was stricken from the final bill.
FDA’s leadership also contributed to the quiet reaction. The agency’s management certainly didn’t seem eager to launch a new regulatory era; if anything, the tone was one of apprehension or even exhaustion at the thought of applying the new tools too broadly.
So, sponsors can be forgiven if they filed the REMS away as an issue important for regulatory affairs but not a fundamental change in the regulation of medicine.
Well, the biopharma industry has gotten a wake-up call.
When 500 people packed a two-day public workshop on issues to consider in designing a new REMS for the opioid class, it was more than an important regulatory topic for an important class of medicines. It was a coming out party for REMS: an indication that everyone is now waking up to the idea that these new drug safety tools are a very big deal indeed. (See “Planning Ahead.”).
That wake up call, of course, came much sooner for some companies. From one perspective, the pioneers in the new REMS authority were unlucky—facing an extra challenge at the last step of the regulatory process. But they also gained something invaluable in the process: first hand knowledge of the importance of the new authorities and—just maybe—a head start in navigating the new realities of the US regulatory system that could pay off for months and years to come.
The RPM Report has been tracking the impact of the new law since enactment, and in this article and a series to follow we will be taking a deeper look at some of the ways FDAAA is changing the rules of drug development and marketing.
In Part One, we tackle a deceptively simple question: how often are REMS being used in the first place?
FDA Sees Little Change
To hear Janet Woodcock, head of FDA’s Center for Drug Evaluation & Research tell it, the new post-marketing tools are not that big of a deal.
The agency isn’t imposing the formal REMS any more often than it used to negotiate voluntary risk management agreements before it received legal authority to impose the program via the FDA Amendments Act of 2007, she said during a keynote address at the recent Post Approval Summit hosted by Harvard Medical School.
By her count, FDA imposed a REMS a total of 34 times during the first year after FDAAA took effect, out of approximately 200 applications where a REMS could have been required.
In other words, FDA uses the central authority of FDAAA only about 17% of the time. That is “not a huge number,” Woodcock says. When FDA has imposed a REMS, it is almost always because the agency has decided that a consumer medication guide is required for the medicine; that was the case in 28 of the 34 first-year REMS. Two more products required some enhanced communication plan, and just four of the REMS involved the most onerous provisions (“elements to assure safe use”) that amount to a restricted distribution program.
“I would say this is about the proportion that we were running before” the new law, she said.
That is a very different way of looking at the first year of FDAAA than The RPM Report’s analysis of the impact of the law.
Our top line conclusion: only about one-quarter of new molecules approved by the agency in the last 12 months were unaffected by the new drug safety authorities. Those differences come from two very different ways of slicing the data. But it also underscores the desire to downplay the intrusiveness of the new law on the part of FDA’s senior management.
It is perfectly possible that Woodcock will be proven right, and the new law will ultimately do no more than formalize what had already become the status quo in drug approvals before 2007. But sponsors would be wise to take that perspective carefully——especially as a new Administration that is more likely to embrace the REMS model takes over the implementation process.
Lies, Damned Lies and Statistics
The REMS authority only took effect a year ago, so it shouldn’t be surprising that there are very different perspectives on what exactly the implications of the new authorities are.
But the difference between Woodcock’s assessment that the tools are used less than 20% of the time and The RPM Report’s figure of almost 75% is not as mysterious as it looks: the two estimates rely on very different slices of the data.
First: the numerator. Woodcock focuses exclusively on REMS, while The RPM Report focuses on two different sections of FDAAA—the REMS authority and a separate section that allows the agency to mandate post-marketing clinical studies. Both authorities are new in FDAAA, and both share the basic principle of putting added burdens on the sponsor in the post-marketing setting to help assure safe use of medicines. (Indeed, early drafts of FDAAA included mandatory trials as one element of a REMS.)
So for sponsors interested in the impact of the new law overall, The RPM Report takes a broader view.
Then there is the denominator: Woodcock cites 200 applications for which a REMS could have been imposed. That total, she says, includes new molecules, new dosage forms, new combinations, efficacy supplements, etc. The agency acknowledges that there is no simple definition to determine which applications could be REMS-eligible. The 200 estimate is, in that sense, a ballpark figure. However, it is the most accurate baseline available, since no one outside the agency could know for sure how many applications it receives that could theoretically trigger a REMS.
The RPM Report focuses on two different cohorts that can be tracked by outsiders. The 75% figure is based on new molecules (including biologics and vaccines that are not regulated by CDER) on the principle that the new molecules are the most important applications for sponsors. Without them, there would be no secondary filings which make up the vast majority of the 200 applications cited by Woodcock.
The second cohort analyzed is all “original approvals” as reported by CDER. That sample was chosen primary for convenience, since it is reported monthly by FDA; it includes new molecular entity approvals, but also other kinds of new products (new salts, new dosage forms, new combinations, etc. etc.). It does not, however, include all efficacy supplements or other applications that Woodcock is tracking.
Concern About Burden on Health Care System
Clearly, Woodcock’s statistics are a perfectly valid way to track the impact of the new REMS authority.
But it is also important to understand the context in which FDA thinks about the new tools.
During the debate over FDAAA, the agency was distinctly unenthusiastic about REMS. Some of that can be attributed to the political dynamics of a Republican Administration interacting with a Democratic Congress, but it is also a reflection of the deeply held misgivings of the agency’s top career managers about the burden risk management plans impose on the health care system—and the agency’s review staff—without unequivocal evidence of public health benefit in many cases.
In addition, the agency is eager to show that it is complying with both the letter and the spirit of the new law, which explicitly directs FDA to apply the least burdensome regulatory approach it can.
During the Harvard conference, Woodcock noted that “there was a great concern that there would be a huge number of REMS put into place and there would be a tremendous burden both for sponsors and for the health care system” in the wake of the law.
“The burden for the health care system continues to remain a concern,” Woodcock stressed. She said, in fact, that was a factor in the agency’s decision to mandate a class-wide REMS for high-potency opioids. While FDA itself sees the opioids program as the most intrusive REMS yet, imposing a single class-wide program is an attempt to keep the impact as small as possible, Woodcock said.
“If we had to put in place multiple wide spread REMS and there were multiple versions of it, we could bring the health care system to a standstill.”
With that introduction, Woodcock noted that the agency has done 34 REMS out of 200 applications. “This is probably not a huge number of them,” she said.
Looking solely at new molecules, however, the agency has imposed REMS on 10 of the 27 approved so far, which is more than one-third of the total. In addition, while post-marketing studies are more obviously a burden on sponsors than on the health care system, in some cases the requirement involves a registry or observational trial that could become burdensome for providers.
Mostly MedGuides
Woodcock’s other point about the relatively limited impact of the REMS authority is that by far the majority of REMS (28 out of 34) require only a consumer medication guide. “These are not considered that burdensome” since many pharmacies routinely deliver a consumer leaflet with every prescription, and FDA was already requiring MedGuides for many drugs under existing regulations.
Sponsors, however, should recognize that even MedGuide-only REMS have built in re-assessment deadlines, with no clear guidelines on how success or failure will be judged. Those first assessments will begin this fall.
There is no reason to anticipate that the first batch of assessments will be difficult for sponsors—but there are plenty of reasons to wonder how long it will take before the questions start to get tougher.
Knowledgeable observers like former Deputy Commissioner Scott Gottlieb wonder how long Congress will be satisfied with that level of intervention. After all, FDAAA was supposed to improve drug safety, and it may be difficult for the agency to show Congress that it is using the law effectively if it is only relying on MedGuides.
“I can envision an oversight hearing two or three years down the road, where everyone is going to be on the hook to answer what they did to help ensure that the practice was complying with the restrictions that were put in place,” Gottlieb said during The RPM Report’s FDA/CMS Summit at the end of 2008. “I think that question, if put to a lot of sponsors today and put to the agency, looking at some of the newer risk management plans, I don’t think the answer back would pass muster in a political arena.”
Woodcock noted that FDA itself doesn’t think MedGuides are working as intended. “It isn’t at all clear that people are getting the information they need,” she says. Indeed, FDA is “rethinking the entire consumer-directed medical information arena,” she said—noting that the agency was petitioned by pharmacies to do so, in part because (in the pharmacy trade’s view) MedGuides may be more burdensome than they appear.
And that is the Catch 22 for FDA as it completes implementation of FDAAA. On the one hand, the agency wants to reassure the medical community (and hence sponsors) that its intrusion on the practice of medicine will be minimal.
On the other hand, Congress gave the agency new authorities to fix a perceived problem with the regulation of pharmaceuticals. If FDA doesn’t do anything differently, how can anything be fixed?
Projecting for the Future
Woodcock, interestingly, doesn’t think there is any reason to predict an increase in the first-year pattern of REMS. “We really hope that most of the new products aren’t going to need overt interventions,” she says.
So far, there have only been “a small residual of things that need restricted distribution or other major interventions, and we expect that to continue to be a small fraction.”
That, to put it mildly, is not a consensus opinion.
FDA’s first year under REMS came primarily under guidance of an Administration in opposition to the authors of FDAAA—and then under caretaker leadership during the transition.
The agency now has a newly confirmed Commissioner (Margaret Hamburg) and a deputy (Josh Sharfstein) who are certain to work more closely in alignment with the Democratic congressional leadership that helped shape FDAAA.
There has already been an uptick in the use of REMS: FDA approved 16 in April and May—almost 50% of the amount it did in the first year after enactment. Virtually all of those have been of the “MedGuide-only” variety, and so may reinforce Woodcock’s point. On the other hand, the agency has not yet acted upon the 14 products with “deemed” REMS under the law—all of which will entail more than a simple MedGuide.
The biggest danger for industry in the debate over the first year statistics, however, may be the possibility of missing the forest for the trees. The new authorities given to FDA don’t matter—unless they affect your product.
And the burden on the health care system can change quickly. Consider the opioid REMS: that program will cover dozens of products, and, in theory at least, affect 375,000 prescribers and approximately 26 million prescriptions annually.
How Big A Deal Are MedGuides?
Everyone recognizes the potential for the opioid REMS to reshape a huge commercial market.
But, for sponsors with REMS in other classes—even those simple sounding “MedGuide-only” REMS—reality has already changed. Yes, there is nothing new about the requirement for a MedGuide to accompany a prescription. But the assessment of the success of the distribution effort is new—and FDA acknowledges that places a new burden on sponsors.
The burden takes two very different forms. The first is essentially logistical. Sponsors must design and conduct surveys to determine whether the MedGuide is being distributed as intended. That takes time and money.
But it is the second burden that probably weighs heavier: the uncertainty about what exactly will be viewed as success.
The challenge isn’t made any easier by Woodcock’s discussion of the agency’s own concerns about the overall value of MedGuides and other consumer directed medical information—prompted in part by a petition from pharmacy trade groups concerned about the proliferation of MedGuides. (See “FDA Poised to Overhaul Distribution of Consumer Medical Information,” The Pink Sheet, March 9, 2009.)
FDA currently has several different regulations and formats for consumer information. “It is confusing and it isn’t at all clear that people are getting the information they need,” Woodcock said.
“I don’t think it is good that people get prescription meds, and yet they aren’t getting reliable uniform information about that medicine that they can access,” she said.
In other words, the MedGuide of 2009 may not be the MedGuide of the future—but sponsors with mandatory REMS will have no choice but to keep up.
Flying Blind
And that is the biggest reason why the growing number of sponsors covered by REMS are waking up to the idea that this new safety program is not business as usual. MedGuides may be nothing new—but formal assessments of their effectiveness certainly are.
FDA officials agree with the observation that, while MedGuide-only REMS may not be overly burdensome on health care providers, they are more onerous on sponsors.
The simple truth is that there are no clear guidelines for those sponsors as they enter the assessment phase. FDA is going to develop guidance, but not until after it has some experience with those assessments. For the most part, those assessments don’t begin until this fall: 18 months after the first were approved. (FDA has conducted some assessments already, the agency notes, involving REMS with more frequent checkpoints.)
FDA will be issuing guidance on the conditions for imposing a REMS much sooner—because the agency has a lot of experience there already. And that experience is growing, one case at a time.
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