A New Phase for Phase IV: Post-marketing Studies Won't Be the Same After Drug Safety Bill

The world of post-approval research is going to get more public, more crowded, and more dangerous to pharma. Post-marketing surveillance, transparent clinical trial results and mandated post-approval studies mean the traditional world of marketing-oriented Phase IV is about to change dramatically.

Cole Werble

The Food & Drug Administration Amendments Act is famously the "drug safety law"—a once-in-forty-years overhaul of FDA authority to bring the agency’s drug safety activities back up to par with the agency’s focus on drug efficacy.

But don’t overlook the fundamental changes that the new law will impose on the drug development process, especially on the nature of follow-up research on products once they have achieved initial FDA approval.

The law that was signed by President Bush on Sept. 27 contains an interlocking array of provisions that will shift Phase IV work from the exclusive province of drug sponsors to an activity where sponsors will share control with new, independent active surveillance groups and where they will have to share the results of all trials more openly with the public. (See "Rethinking Phase IV," The RPM Report, May 2007 (Also see "Rethinking Phase IV: Congress Wants to Get Tough on Post-Marketing Requirements, but FDA May Soften the Blow" - Pink Sheet, 1 May, 2007.).)

Former FDA commissioner Mark McClellan sees the new legislation as a milestone to Phase IV, strategic research. The "post-marketing period will move out of the control of the pharmaceutical industry," McClellan told a September 12 briefing on drug safety hosted by American University.

McClellan was the first FDA commissioner in the George W. Bush Administration (2002-2004). He currently heads the Engelberg Center for Health Care Reform at the Brookings Institution, which is the early front-runner for coordinating the government’s public-private partnership to handle active surveillance of drugs after FDA approval. (See "McClellan Leads the Way to New Post-marketing World," The RPM Report, June 2007 (Also see "McClellan Leads the Way to New Postmarketing World" - Pink Sheet, 1 Jun, 2007.).)

The impact of the new amendments on Phase IV cannot be over-estimated. For over two decades, pharma has lavished resources onto Phase IV to support extended indications, improving ties to medical thought leaders, generating cost data and justifications and gaining access to large user groups.

The strong commercial bent of post-market research has become a weak point in the industry’s public image. Some advocates from academia even urged the Institute of Medicine to push for taking post-market research out of the hands commercial sponsors. (See "Drug Safety Reform: Did FDA Buy Time or Trouble?" The RPM Report, April 2006 (Also see "Drug Safety Reform: Did FDA Buy Time or Trouble?" - Pink Sheet, 1 Apr, 2006.).)

Pharma allies like patient advocacy groups for rare diseases also have soured on the goals of post-market research. As Robert Beall, the president of the Cystic Fibrosis Foundation told an Institute of Medicine meeting on September 14, Genentech Inc.’s Phase IV studies for Pulmozyme in the late 1990’s were done for "one reason: they used it as a marketing tool." He professed a fondness for the company and its research on cystic fibrosis treatments, but the nature of the post approval trials clearly left an unpleasant taste.

Post-market Surveillance is the Keystone

From one perspective, the FDA amendments are an important victory for pharma: at least the industry did not cede the right to conduct post-marketing studies completely. That means the changes to Phase IV will not be as drastic as some of the industry’s critics wanted. Beyond that basic victory, however, the new law promises a dramatic shift in balance of power in the post-marketing world. Four separate authorities in the law will create the changes in Phase IV.

Post-marketing surveillance: The biggest change will be the establishment of a private-public partnership to conduct post-marketing surveillance with funding of $25 million per year for the five years through 2012.

The public-private partnership creates an opening for an outside group to act as an intermediary or surrogate for FDA to help the agency choose the methods for surveillance and forge the links to existing data centers. The ultimate goal is to create a large, ongoing active surveillance effort that can collect data on 100 million people by 2012.

Transparency of data: The amendments enlarge the role for the National Institutes of Health in collecting and disseminating information on clinical trials conducted for the regulatory approval of drugs and medical devices.

The publicly available information will extend eventually to post-marketing clinical trials conducted for new indications. It will take FDA and NIH a long time to enlarge the current clinicaltrials.gov effort; but Congress will watch this effort closely. It is easy to monitor and close the hearts of some Democratic leaders.

FDA-mandated Phase IV trials: FDA gets, for the first time, the explicit authority to mandate Phase IV trials. The agency has been making follow-up studies part of NDA approval agreements but has not had an easy way to enforce its requirements short of a long process of trying to withdraw an NDA. The FDAAA amendments shorten the route to withdrawal by saying specifically that a drug sponsor "may not introduce or deliver for introduction into interstate commerce" if the sponsor is in violation of a post-market study requirement.

The new law also grants FDA the authority to impose civil monetary penalties ($250,000 per incident) for failure to live up post-marketing study or clinical trial commitments.

Registries: This tool is often overlooked in summaries of the effect of FDAAA on the post-approval work. Under the risk management provisions of the law (the Risk Evaluation and Mitigation Strategies section), FDA can continue to require firms to establish registries of patients for products with known serious risks that could not be made available commercially without close post-market monitoring.

The information collected by companies from these registries is likely to become more widely available to the public. Sponsors already report on the registries that exist under Risk Minimization Action Plans (RiskMAPs) to FDA advisory committees. In the future, FDA will be obliged to put public information about RiskMAPs and REMS up on the internet and make the product experience information from close monitoring of patients much more widely available.

Inviting New Stakeholders into Phase IV

McClellan believes this full array of new post-market requirements will attract a large group of new players in post-marketing research. The former FDA commissioner expects other stakeholders in drug use to enter the field of post-marketing research on the heels of the public-private partnership called for by the new law.

Health insurers, benefit managers, academic centers and employers will find it easier and more practical to fund post-marketing research on drugs using the network and infrastructure established by the bill, McClellan predicts. That will change the purpose and objective of post-marketing surveillance dramatically. The new participants in Phase IV and active surveillance will have different economic interests and quality goals from pharma.

McClellan is not alone in recognizing the importance of adapting to a new post-marketing world and on focusing on post-marketing surveillance as the keystone of the new system.

Following the White House signing of the bill on Sept. 27, FDA’s chief medical officer Janet Woodcock said the post-marketing surveillance provisions in the law will give the agency a way "to really get a handle on which products are providing major benefits and perhaps discover performance problems more quickly." Woodcock cited the estimate that the agency now learns of only about 1 out of 10 actual drug adverse events and that working with existing private systems will help get the complete data.

"We’re very excited about this," Woodcock declared. "We are really preparing to begin implementing this; this is the future for medical product surveillance."

GSK Sees Surveillance as One of Top Strategic Issues

Pharma is preparing for in the new post-marketing surveillance model as a major structural change in the industry. According to a report in the Wall Street Journal, GlaxoSmithKline PLC chose post-marketing surveillance as one of the key strategic issues for testing the next generation of the company’s top management.

As part of the selection process for the successor to GSK CEO Jean-Pierre Garnier, the company has assigned a special strategic planning exercise to each of the three leading candidates. Chris Viehbacher, currently the president of US pharmaceuticals, drew the challenge of mapping a way for GSK to respond to changes in post-marketing surveillance.

GSK has been among the most active pharma firms in the policy debates preceding the new law’s treatment of post-marketing surveillance. The company’s chief medical officer Ronald Krall has publicly argued for the need for a strong organization to take leadership over the large number of groups and researchers beginning to raise safety questions about marketed drugs based on analyses of disparate databases.

GSK is not alone in thinking about that challenge.

Former Wyeth EVP Bruce Burlington told a Food & Drug Law Institute conference September 17 that preparing for active surveillance is an immedicate priority in response to the new law.

Companies need to ask, "How are we going to know what this active surveillance is going to discover about our products before the whole world knows?" Sponsors need to "have the information so we can put it in the appropriate perspective and not just put it in the hands of the fear mongers who raise the story in a newspaper first and leave us solely in a reactive mode."

Pray for McClellan

McClellan’s role in establishing that system is widely anticipated–and hoped for--by many in industry. McClellan is generally credited for starting the serious legislative discussion of a private-public partnership in discussions with Senate staff earlier this year.

Wayne Rosenkrans, AstraZeneca PLC ’s business strategy director of external scientific affairs in the US, reflects the focus within industry on McClellan’s leadership role. Speaking briefly after an address by McClellan to the Personalized Medicine Coalition’s annual meeting on September 18, Rosenkrans told the meeting that he has occasionally answered questions at AstraZeneca on how to prepare for the future with the simple advice: "Pray for Mark McClellan’s good health."

In fact, one of the risks for pharma in the post-FDAAA era may be that some parts of the new authorities do not get implemented fast enough. If FDA does not get a fast start setting up some of the procedures and rules for implementing its new authorities, pharma may face the prospect of having the system established in a much more hostile environment after the 2008 elections.

The phase-in plan for the post-marketing surveillance program, for example, anticipates that it will take until the spring of 2011 before FDA will be in a position to contract with outside entities to conduct routine surveillance activities . (See Exhibit 1.)

At that point, FDA should be ready to establish a system for routinely contracting with "one or more qualified entities" to make use of a variety of data sources to handle priority drug safety issues. There are milestone stages on the way to a 2011 start-up for surveillance. The most quantifiable targets are two deadlines for collecting the datasets for surveillance: FDA is supposed to have access to 25 million lives by July 1, 2010 and 100 million lives by July 1, 2012.

The law anticipates that the surveillance will be aimed to address unresolved safety issues for marketed drugs or classes of marketed drugs; to investigate safety signals raised during clinical trials for newly approved products and to search for serious rare events or study populations which may not have been examined during clinical trials (such as the elderly, children or pregnant women).

The surveillance network will also help FDA perform advanced research and analysis on identified safety risks and to determine whether further post-approval studies or trials are necessary.

Congress implicitly recognized the complexity of the future world of post-marketing by including specific provisions for FDA to contract with subsidiaries of larger firms. The drafters of the law addressed the fact that much of the drug safety data may be in the hands of commercial organizations that already use the data for other purposes: presumably health plans that use the data for product choice decisions or who have subsidiaries like UnitedHealth Group Inc. (Ingenix) which use the data in studies for other clients.

If the FDA contractor is a component of "another organization," the law says, "the qualified entity shall establish appropriate security measures to maintain the confidentiality and privacy of such data; and the entity shall not make an unauthorized disclosure of such data to the other components of the organization."

FDA Foresees Long Road to Transparency

The transparency provisions also have a long phase-in period. FDA’s Woodcock, in fact, describes the process for putting them in place "quite complicated" and beyond an easy explanation.

FDA and the National Institutes of Health have a long lead time to upgrade the transparency of clinical trials data and safety data, both of which are set to become much easier for the general public to access. The ultimate goal would be to include adverse event information and "even trials of unapproved products," Woodcock notes. She points out that there would be public meetings and a public rulemaking process before the agency begins requiring that type of information to be made public.

But the transparency provisions are important to the current health leadership on Capitol Hill and are likely to be one of the barometers Capitol Hill uses to track the effective implementation of the new law.

House Energy & Commerce Heath Subcommittee Chairman Frank Pallone (D-NJ) highlighted the transparency provisions in his statement on the bill. "Patients will be happy to know that the bill before us also requires greater transparency of drug makers by calling for clinical trials to be registered in a database monitored by the National Institutes of Health, along with basic results data."

Pallone focused on the broader access to data on products as a new form of checks and balances on post-approval safety. "As we saw with the case of Avandia," Pallone said, "making this information available to patients, providers and researchers is critical to uncovering potential harmful effects of a drug."

That statement by the chair of the key House health committee represents a form of warning that FDA, NIH and the drug industry will not be permitted to let new the clinical trial registry rules slide as they did following the first call for a registry by Congress in a previous user fee act in 1997.

The world of post-approval research is going to get more public, more crowded, and more dangerous to pharma. There are some obvious large risks for the industry. If FDA gets access to information to support the estimate that only 10% of adverse effects are showing up currently, that could worsen the public perception of the benefits of drug treatments. But the new law sets up a procedure for collecting the post-marketing data that offers an opportunity to add some order to the new world of post-marketing approval. The industry crossed the starting line to make that happen on Sept. 27. The next three years will be an important test.