Envisage Magazine - New Directions

New Directions

by Roxanne Nelson

January 2007

As post–marketing studies become more commonplace—and more frequently mandated—pharmaceutical companies and investigators are learning how best to conduct them.

Clinical trials have evolved considerably since the first properly randomized, controlled trial was conducted in 1948. Regulatory agencies now require the three–phase system for the initial registration of a product before it is permitted to enter the market.

In 1970, the U.S. Food and Drug Administration (FDA) approved levodopa for the treatment of Parkinson’s disease on the condition that the manufacturer perform long–term safety research. This was the first FDA product approval to carry a stipulation that the sponsor conduct a study of the long–term effects of chronic use. Since that time, regulatory agencies around the world have increasingly required Phase IV studies as a condition for marketing approval. This increase is prompting pharmaceutical companies to reassess how these trials are designed, what questions they should answer and, more importantly, how to motivate investigators to conduct them.

Marketing Tool

Historically, post–marketing trials were performed primarily as a vehicle to find alternate—and commercially viable—indications for a drug. “This type of trial was driven by the need to expand the market for a particular drug,” says Dr. Hugo Stephenson, president of Strategic Research & Safety at Quintiles Transnational, in Parsippany, N.J., USA, and author of Strategic Research: A Practical Handbook for Phase IIIB and Phase IV Clinical Studies. “A lot of these trials were actually being done, but the manufacturer was doing them for marketing, not for safety.”

As a result, post–marketing studies were associated negatively with the so–called “seeding studies” that gave physicians incentives to prescribe a specific drug, Stephenson says. The primary result of these seeding studies was that thousands of new patients received prescriptions for the study drug, Stephenson says. But with the passage of the Medicare and Medicaid Protection Act of 1987, the regulatory environment in the United States became “increasingly hostile to this type of trial, and most reputable organizations have ceased to conduct them,” Stephenson says. The act resulted in a greater recognition of the scientific importance of post–approval studies and a greater emphasis on product safety.

Getting Proactive

The industry is responding to the changing regulatory landscape by placing a greater emphasis on conducting Phase IV studies that advance scientific knowledge. In many cases, there already is a proactive development of post–marketing studies before a sponsor files an initial new drug application, says Peter A. DiBiaso, director of worldwide development operations at Pfizer Global Research & Development, New London, Conn., USA. “Sometimes the Phase IV studies are done to support new indications post–approval, and in some cases there are additional requirements that come as a mandate of the FDA approval process to support long–term safety research,” DiBiaso says.

“There are now maturing Asian markets, for example, which are becoming very active so there are newly emerging regulatory guidelines for their markets,” DiBiaso says. “The European Union has adopted their own standards over the past three to five years. In the United States, we have had some of the same regulatory harmonization challenges within the FDA.” With varying regulatory requirements from country to country, close cooperation between industry and agencies is necessary to identify the scope and structure of a post–approval study. The FDA, for example, is willing to work with sponsors to help focus the development of a post–marketing study, according to Crystal Rice, spokesperson for the office of new drugs at the FDA’s Center for Drug Evaluation and Research (CDER), in Rockville, Md., USA. “Doing this avoids unnecessary resource investments.”

The industry’s increased attention to scientifically based Phase IV trials is due to a combination of factors, says Dr. Michael Lincoff, vice chairman for research and professor of cardiovascular medicine at the Cleveland Clinic, Cleveland, Ohio, USA. “Instead of trying to design the entire lifecycle of the drugs, companies are now intelligently designing trials so that the first goal is to get it approved as quickly as possible, even if it’s for a fairly limited indication,” he says. “Physicians are also becoming increasingly careful about using drugs beyond what their indications are. They are requiring evidence of efficacy beyond the preliminary endpoints of the initial trials, so there is a lot of [sponsor] motivation to expand the label later with Phase IV trials.”

Opportunity Knocks

Increasingly motivated to sponsor post–approval trials, the industry nonetheless faces the challenge of finding ways to conduct large prospective studies efficiently and with the utmost scientific integrity. The median cost of post–marketing studies between 1998 and 2003 was $3.7 million, according to a 2004 Impact Report of post–marketing commitments by the Tufts Center for the Study of Drug Development, Boston, Mass., USA. Although this cost is significant, the potential of increasing revenue by obtaining a new indication for an existing drug could considerably offset the initial expense.

“Initial trials explore the product in a very narrow population and for a short period of time,” Stephenson says. “Once the drug is approved, we actually have very limited experience with it. We don’t know a lot about how it should best be used, what population it may work best in, and we don’t know much about the safety profile in a broader population.” A properly designed Phase IV trial can address these safety concerns and also can provide long–term efficacy data that would not have been collected in earlier studies.

There usually isn’t sufficient data to evaluate how a drug works over the long term, Stephenson says. “For example, if we have a drug that lowers cholesterol, we still may not know if it reduces the rate of heart attacks,” he says. “So in order to really give some depth and color to a product, and to give the population more information about how to use it, Phase IV trials have become important as a means to gather more information.” But the process of actually gathering this information is typically in the hands of investigators, and the level of motivation they bring to the study is a critical factor in the ultimate success of a Phase IV trial.

Science and Progress

Once a product receives approval, motivation on the part of both the investigator and the patient may decrease, Stephenson says. “Ideally, a Phase IV trial should be designed to minimize the workload of the investigators, while providing a significant benefit to patients,” he says. It’s also important to note that protocols for post–approval studies are quite different from those used in earlier phase trials and are rarely conducted in the same centers.

The primary motivation of investigators should be the opportunity to participate in ongoing research in novel therapies or new indications, DiBiaso says. By doing so, investigators are directly involved in assessing the safety and long–term impact of certain drugs and are able to provide close medical attention and screening for their patients. “It is almost a sense of altruism, and they want to be part of that,” DiBiaso says.

Lincoff agrees that the science is a strong motivator to participate in late–phase studies. “A drug that is approved for a rather limited indication may not have much impact on medical practice,” he says. “And if the drugs are approved on the basis of trials designed for rapid approval to get them quickly onto the market, they aren’t going to be answering a big medical question.”

The key for sponsors is to design a trial protocol rooted in science—as opposed to marketing—to get quality investigators on board. “Often, Phase IV trials are the more important trials in terms of finding wider uses for drugs,” Lincoff says. “From a scientific standpoint, investigators are motivated to participate for the scientific merit.”

The Growth of Post–Marketing Commitments

Post–approval studies have been growing in number over the past three decades. According to a 2004 Impact Report of post–marketing commitments (PMCs) by the Tufts Center for the Study of Drug Development (CSDD), in Boston, Mass., USA, between 1970 and 1984, less than 30 percent of new approvals faced a post–marketing commitment. That number rose to 73 percent during 1998–2003, according to the same report. And although PMCs have existed for several decades, PMC documentation and monitoring have been slow to evolve.

Before the mid 1990s, PMCs often were verbal commitments made by a sponsor at the time of a drug’s approval, according to Crystal Rice, spokesperson for the office of new drugs at the FDA’s Center for Drug Evaluation and Research (CDER), in Rockville, Md., USA. “We did not track them formally, and many, if not most, were never fully documented in a product’s approval letter or the [new drug application] file at FDA,” Rice says.

The CDER’s increased focus on PMCs and their documentation and tracking began in the late 1980s and early 1990s, with the sudden increase in drugs to treat serious and life–threatening diseases, particularly HIV and its complications and cancers. “The FDA was working on approving drugs for such conditions based on surrogate markers that would require follow–up studies after marketing to confirm the drug’s benefits,” Rice says. “Having those commitments in writing as part of a product’s approval letter began to take hold as a standard aspect of documenting PMCs.”

The increase in documented PMCs also may be due to the shortened review timelines mandated by the Prescription Drug User Fee Act legislation enacted during the early 1990s. As a result of this legislation, some of the data that fit submission requirements prior to a drug’s approval may have shifted into Phase IV studies. However, the “information requested in PMCs is not considered necessary to support the safe and effective use of the product, but rather provides additional information about the product,” Rice says.

In November 2004, the FDA began a program aimed at increasing the safety of marketed drugs. This initiative included the sponsorship of an Institute of Medicine study of the U.S. drug safety system and the appointment of a director for the Office of Drug Safety within the FDA. Risk management guidelines designed to help pharmaceutical sponsors identify and assess the potential safety risks of their drugs were first published in March 2005 by the CDER. According to Rice, the implementation of this program does not necessarily mean that more PMCs will be required, but rather that they will be requested and agreed upon when a need for a specific type or quantity of data is identified by the CDER.

Overall, the number of PMCs for any specific product primarily depends on the product itself, the regulations by which it received approval and the data supporting its safety and efficacy, Rice says. The requirements for PMCs also vary widely by class and indications. For example, 100 percent of all new anti–infectives approved between 1998 and 2003 required post–marketing commitments, compared to only 36 percent for analgesia, anti–inflammatory and ophthalmic drugs, according to the Tufts CSDD report.

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