Pharmacy & Therapeutics Journal...January 2012
Battles Loom as Congress Aims to Pass a Major Bill by September 2012
Congress's return to Washington in January starts the clock ticking on a 10-month deadline for updating the Food and Drug Administration's (FDA) new drug approval and post marketing authorities. Those were last tweaked in 2007, when Congress passed the FDA Amendments Act (FDAAA), a mélange of reforms wrapped around the fourth iteration of the Prescription Drug User Fee Act (PDUFA), the law first passed in 1992. The PDUFA specifies the fees drug companies must pay when submitting applications to the FDA for approval of a new drug or biologic. The fees supplement--in fact the user fees exceed--annual congressional appropriations and help underwrite the salaries for staff the FDA needs to comb through those applications, and help both speed up FDA approval times and prevent backlogs.
Back in 2007, Democratic titans Rep. Henry Waxman (D-Calif.) and former Sen. Edward Kennedy (D-MA) were ascendant, and pushed a wheelbarrow of post-marketing safety reforms through Congress. Drug companies agreed to pay higher user fees for faster FDA approval times, and agreed, for the first time, that user fees--to the tune of $225 million over five years--could be used for the new safety programs.
What a difference half a decade makes. Republicans now essentially dictate congressional action. The FDA, well aware of the GOP's anti-regulatory bent, has produced a PDUFA V proposal heavily weighted toward "process" improvements in assessing new drug applications and cautious commitments to consider taming some of the unruly aspects of some of the 2007 safety measures, such as Risk Evaluation and Mitigation Strategies (REMS) which the 2007 law allowed the FDA to require for drugs whose risks are higher than what the FDA might otherwise like to see in a new drug. A REMS might require just distribution of a MedGuide or can be much more complicated forcing physicians and pharmacists to follow numerous "elements to assure safe use (ETASU)."
The REMS that drug companies have produced--the FDA has not established a standard format--have come in different sizes and colors, making life difficult for pharmacists. The drug companies haven't been much happier with the FDA's unfocused administration of its REMS authority, which the agency, in its PDUFA V proposal, admits needs to be clarified.
That will be the big issue for the pharmacy community as Congress begins to fashion the 2012 version of FDAAA, which will be wrapped around PDUFA V, which will specify higher fees for drug companies. But revamping REMS won't be the only issue. Pharmacists are concerned about another FDAAA provision: the FDA creation of an active Sentinel adverse reaction alert system, meant to supplement its existing passive MedWatch system, which has been roundly criticized for its shortcomings. In fact, expect both Democrats and Republicans, often at the behest of interest groups, to toss all sorts of proposals in what will a stew pot of FDA reform, simmering all year on the congressional front burner.
The FDA got the reform process started in late August when it published a draft commitment letter which outlined the kinds of process changes it wants to make to improve the current drug approval and post-marketing programs. The agency aired those proposals at a public meeting at FDA headquarters on October 24. The guts of that initial effort are an increase in drug company user fees to $712 million in fiscal 2013, which starts October 1, 2012. The fees amounted to $672 million in fiscal 2012. In exchange, the FDA essentially retains the PDUFA IV timeframes of approving 90 percent of priority applications for new drugs and biologics within six months and 90 percent of standard applications within 10 months. There is no proposed change here, which isn't all that surprising, given the fact that the FDA, once it digested some of the FDAAA required reforms, has done a good job of approving new drug applications.
The guts of this program is additional meetings the FDA promises to hold with an applicant prior to submission of a new drug application, and during the application process. In addition, with an eye to helping drug companies speed up clinical trials, the FDA will develop a dedicated drug development communication and training staff focused on "enhancing communication" between FDA and sponsors during drug development. Other improvements are development of staff capacity to review submissions that contain complex issues involving pharmacogenomics and biomarkers and advancing development of patient-reported outcomes (PROs) and other endpoint assessment tools.
With regard to REMS and Sentinel, the FDA made some vague commitments to hold workshops and listen to complaints.
The FDA put together its PDUFA proposal after hearing ideas from all interested parties starting in early 2010. The agency winnowed that "wish list" down, dropping numerous proposals, and then submitted the ideas to the pharmaceutical industry, seeking its buy-in since the drug companies pay the user fees.
At the October 24 meeting, representatives of consumer and patient groups gave the PDUFA V proposals mostly lukewarm praise, but highlighted ideas that had not been included, criticized the fuzziness of the REMS and Sentinel enhancements and generally complained that the issue of drug "safety" was being made a handmaiden to the issue of easing the path to approval of new drugs. Celia Wexler, Washington Representative for the Union of Concerned Scientists, says she was surprised by the "tone" of the FDA's PDUFA V proposals. "I don't have any problems with improving the FDA's new drug review process, but this proposal is so wedded to timelines that it sends the message that promptness trumps all."
Janet Woodcock, M.D., Director of the FDA Center for Drug Evaluation and Research (CDER), says she hopes that "PDUFA can go through Congress cleanly." By that she means she hopes there are no policy initiatives tacked on to the process improvements the FDA proposed in the draft commitment letter. The FDA will deliver a formal PDUFA V proposal to Congress in January, and may make some changes to reflect some of the criticisms heard on October 24. Whatever its final shape, expect members of Congress to attempt to graft on policy initiatives in the areas of drug advertising, off-label use, conflicts of interest at FDA advisory committees, drug recall authority, inspection of foreign facilities and much more.
There is a good reason why the FDA's PDUFA V "process improvement" proposals are so unambitious. Jeff Allen, PhD, Executive Director, Friends of Cancer Research, says the FDA approval process is working fine as is. The FDA is approving new cancer drugs twice as fast as the European Union does. Of the 27 new cancer drugs that came on the market since 2003, all have been available in the U.S. before they were available in Europe. Allen says the "unsustainable crisis we are nearing" is the 15 years and $1 billion it takes to bring a new drug to market. "The FDA part of this is such a small component of the problem," he adds.
"My hope is that as this discussion moves ahead that all stakeholders will acknowledge that there are challenges to new drug development that are much bigger than just FDA review," says Allen of the Friends of Cancer Research. "As other components of a resulting bill are mulled by Congress and others perhaps some attention can be given to elements that could go after addressing the 15year/$1B challenge drug development challenge."
But the key objective for pharmacy groups is a revision of the REMS provisions of the 2007 FDAAA. "That is our key priority," says Marcie Bough, Senior Director, American Pharmacists Association (APhA).
The good news here is that almost all stakeholders, including the drug companies, think that the 2007 REMS provisions have been troublesome. The pharmaceutical companies complain that the FDA has no black-and-white criteria for determining when a REMS is necessary, that the FDA requires them willy nilly. Pharmacy groups complain that the REMS the FDA has approved have been all over the place, in terms of their provisions, complicating life for pharmacists, both in retail, hospital and nursing home settings. Not only have the REMS had workflow implications for pharmacists, they have, at least in the hospital setting, added to confusion and opened the door to potential medical mistakes.
Kasey Thompson, Vice President, Office of Policy, Planning and Communications, American Society of Health-Systems Pharmacists, says, "It is not clear that REMS are being created for patient safety." He said some drug companies are creating REMS as marketing tools. REMS which include ETASU requirements have in some instances led to a problem the ASHP calls "brown bagging." That describes a situation where a patient has to obtain an injectable product from a specialty supplier and then bring that product with them for administration in the hospital.
The FDAAA essentially substituted REMSs for the Risk Minimization Action Plans (RiskMAPs) the FDA had been requiring of some new drugs since PDUFA III. After 2007, those RiskMAPs were automatically converted into REMSs, and new first- time REMSs were issued. Many of these essentially required only that pharmacists provide a patient with a MedGuide when he or she picked up his or her prescription. In some other instances, REMSs include ETASU which the FDA, in a Federal Register notice previewing the October 24 public meeting, admitted "can be challenging to implement and evaluate." The agency acknowledged: "Our experience with REMS to date suggests that the development of multiple individual programs has the potential to create burdens on the health care system and, in some cases, could limit appropriate patient access to important therapies." REMS are designed from scratch by the pharmaceutical manufacturer and then subject to negotiations with the FDA during the new drug approval process. They can require such tools as prescriber training or certification, pharmacy training or certification, dispensing only in certain health care settings, documentation of safe use conditions, patient monitoring, and patient registries. Through March 2011, according to the APhA, the FDA had approved 177 drugs which included REMS, some of them converted from RiskMAPs. The majority of these, 123, were MedGuide-only. Of the remaining 54, 37 included a communications plan and 17 included ETASU (12 approved since passage of FDAAA, five being RiskMAPs converted to a REMS).
In terms of impact on a pharmacy, a REMS can involved a number of administrative, training/education, registration, monitoring or other restricted distribution elements. that can strain workloads, and thus may encourage prescribers and dispensers to do such things as seek alternative drug products that may not be as effective or require a REMS, or limit patient access by not prescribing, distributing or dispensing the drug.
FDAAA authorized the FDA to require a REMS when one was necessary to "ensure that the benefits of the drug outweigh the risks of the drug.” In making that decision, the FDA has to consider several factors, including: (1) the estimated size of the population likely to use the drug involved;” (2) the seriousness of the disease or condition that is to be treated with the drug; (3) the expected benefit of the drug with respect to such disease or condition; (4) the expected or actual duration of treatment with the drug; (5) the seriousness of any known or potential adverse events that may be related to the drug and the background incidence of such events in the population likely to use the drug; and (6) whether the drug is a new molecular entity.”
On the issue of standardizing REMS, the FDA has already taken a step in that direction by seeking to develop an industry-wide REMS with all brand-name and generic manufacturers of long-acting and extended-release opioids. An Industry Working Group submitted a proposed opioids REMS to the FDA in August. The agency has not approved it yet. The agency originally proposed an opioids REMS in 2009, but the industry balked, arguing it was too detailed, prescriptive and onerous, and would incent physicians to avoid prescribing the drugs. The FDA then loosened its terms, which formed the skeleton on which the industry put the meat in its August 2011 submission.
The PDUFA V proposal does not mention all that spadework done on the opioids REMS as a basis for standardizing REMS going forward. The draft commitment letter simply includes a commitment to develop and issue guidance by the end of fiscal 2013 on how to apply the statutory criteria (i.e. in the FDAAA) to determine whether a REMS is necessary to ensure that the benefits of a drug outweigh the risks. The FDA also promises to explore strategies to standardize REMS, where appropriate, with the goal of reducing the burden of implementing REMS on practitioners, patients, and others in various healthcare settings. Wexler of the Union of Concerned Scientists says, "There is almost nothing there on how the FDA plans to accomplish its goals."
Moreover, the intentions don't go nearly far enough, given various criticisms, such as those voiced by the American Society of Health System Pharmacists (ASHP). ASHP and the APhA, the latter of whom held a workshop on REMS in July 2010 and has produced two detailed White Papers, the latest in May of 2011. The APhA would like to see, for example, an improved FDA website on REMS and, perhaps more importantly, some mechanism for reimbursing pharmacists for the time they spend implementing their part of a REMS. The APhA's Bough suggests, for example, some part of the user fee pool could be used to reimburse pharmacists.
Other than unspecified changes to REMS, the only other post-marketing safety change the FDA has talked about deals with its Sentinel system. That is the "supplement" adverse reaction system to MedWatch, which has, up until now, been the data repository for admittedly incomplete and sometimes unclear reports from physicians, pharmacists, patients and others on adverse reactions caused by drugs already on the market. The idea behind the Sentinel system is that the FDA, after getting some inkling of problems with a new drug just on the market, perhaps from initial results of a post-marketing survey, could "query" a data bank containing health records of millions of Americans to see whether that adverse reaction was frequent enough for the FDA to take remedial action. "It is very important to our membership," explains Marissa Schlaifer, Director, Pharmacy Affairs, Academy of Managed Care Pharmacy.
The FDA's PDUFA V proposal on changes to Sentinel, as is the case with its approach to REMS improvements, sticks to vague process clarifications which would come out of public meetings in the fiscal 2013-2017 time period. Here is what the draft commitment letter published in September says: "FDA will use user fee funds to conduct a series of activities to determine the feasibility of using Sentinel to evaluate drug safety issues that may require regulatory action..."
The FDA is now using a pilot "mini-Sentinel" system with data from 17 "data partners" who control health information for 25 million-plus individuals. The first real test was done last July when over a period of two days the FDA queried mini-Sentinel on myocardial infarctions suffered by individuals who were taking the smoking cessation drugs varenicline and bupropion. Varenicline is a new drug, and the FDA wanted to see whether it was causing more myocardial infarctions than the long-time drug used for that indication, bupropion. The answer was "no," there was no difference between the two. However, one academic who works on mini-Sentinel noted the query on varenicline was "quick and dirty" and "not a full epidemiological study." Asked what the FDA was going to do next, he said he did not know.
Amy Allina, Program Director, National Women's Health Network, complains the FDA has no specific plans for pushing Sentinel forward. "The agency has only vague statements in its PDUFA V plan," she states. "Sentinel has been tested, and it is working in a limited way. It is time to move forward. At some point, the rubber has to meet the road. If the FDA only uses Sentinel to find risks it expects to see, instead of broader data on unexpected adverse reactions, it will have missed a huge opportunity."
Talking about missed opportunities, every representative from every consumer and pharmacy group who spoke at the October 24 meeting advocated broader authority for the FDA so it could review drug ads on TV, in print and on the Internet more thoroughly than it does now, which is to say not thoroughly at all. The FDA draft commitment letter says nothing about drug advertising. Additional authority provided by Congress in 2012 would be the kind of "policy initiative" Janet Woodcock opposes. Sally Greenberg, Executive Director of the National Consumers League, says, "It is imperative that the FDA review ads for accuracy before they reach the consumer." Companies can now voluntarily submit their ads to the FDA for review. In some instances they wait to get a green light, in some instances they air the ads before hearing from the FDA. Greenberg and others think all ads should be reviewed before they are disseminated. She advocates a moratorium on ads for all new drugs where there are unanswered questions about the drug's safety, questions that could be answered via post-marketing surveys. "User fees should be allocated for advertising reviews so that the FDA can hire additional staff," she states.
The FDA's failure to include any proposed drug advertising changes and the general timidity of its PDUFA V proposal probably are no accident. No federal agency in its right mind would have the temerity, in this anti-regulatory political climate, to suggest expansion of its regulatory reach. Janet Woodcock and her FDA colleagues are not blind. They can read the tea party leaves.