Understanding Post-Marketing Surveillance Trials Challenges: Honoring Guidelines and Promoting Safer Medicines

By Nicole Gray

When pharmaceutical companies announce FDA approval of new agents developed to save, prolong, or improve life, their intensive research and development efforts are recognized by the media. Often, agents are added to the treatment armamentarium to address chronic conditions that are debilitating and potentially life-threatening and to provide physicians with options for treating a biologically diverse population. Sometimes the reactions from the media are positive and sometimes not so positive. Nonetheless, these efforts are costly---$30 billion in 2001. In fact, according to data from the Pharmaceutical Research and Manufacturers of America, 17% of sales are reinvested in research efforts, the highest R&D-to-sales ratio of any industry in the United States. Yet, despite this investment, as well as the average 15-year approval cycle, the process of assessing the effectiveness and safety of drugs needs to continue beyond phase 3 registration trials in order to increase data on various populations in real-world settings.

Registration trials are thorough and data-intensive, but an important part of testing is monitoring what happens during an agent's widespread use. Therefore, phase 4 trials and post-marketing surveillance have become a vital part of the medical testing continuum and a proven means of attaining additional safety and efficacy information about the impact of drugs in different populations. Yet, although phase 4 trials and post-marketing surveillance are necessary, actual use trials are sometimes criticized because they may be supported by large educational initiatives and involve many physicians.

Criticism of the pharmaceutical industry often focuses on post-marketing surveillance and is grounded in misconceptions about actual use trials. Critics are concerned about off-label usage of drugs in trials, reimbursements to participating physicians, and the role of investigators' meetings as part of post-marketing surveillance. What is viewed as unnecessary additional investigation has actually led to improvements in the standard of care---because physicians gain experience with drugs in a real-world setting. The value of this cannot be underestimated. It is important to note that these trials are conducted within label, and if there are problems with indicated dosages in specific populations, this is likely to show up during post-marketing surveillance.

The challenge in drug discovery is to bring safe, effective agents to market as quickly as possible, and now with the advent of genomics and informatics, the pressure to develop increasingly sophisticated agents has increased. The expedited FDA approval process underscored by the Prescription Drug User Fee Act allows patients access to drugs used to treat chronic and life-threatening illnesses more quickly. The downside is that data in various populations and settings are not always available prior to large-scale patient exposure. Therefore, post-marketing studies are a critical component of providing physicians with additional data. Within this realm, physicians can gauge patient responses to drugs in a real-world clinical setting looking at a variety of end-points, including quality-of-life (QOL) measures. In the phase 4 setting, physicians test drugs used to treat numerous chronic and debilitating conditions, including depression and other psychiatric disorders, acid reflux disease, headache, diabetes, arthritis and other illnesses. Morbidity related to these chronic conditions is strongly correlated with diminished QOL. By looking at a variety of QOL outcomes, investigating physicians are better able to discern the nuances of treatment using a specific agent.

The need for continued education drives post-marketing activity. Data from phase 4 trials are important components of continuing medical education, and in many cases, these data help physicians to make better prescribing decisions for their patients who may not have been represented in phase 3 registration trials. Moreover, phase 4 trials allow physicians to determine if a drug is usable under various real-world conditions, especially considering that pre-marketing trials are conducted in highly controlled environments. At the same time, participating physicians/investigators can learn to use the drug correctly, develop comfort and evaluate unexpected adverse events. In reality, failure to identify all potential side effects of drugs during the drug-development process is simply a function of the vast biological biodiversity of human beings. [1] Moreover, despite the fact that these trials represent the beginning of post-marketing surveillance, if there is a definitive pattern, pharmaceutical companies can be apprised of what could become potentially problematic and re-consider dosing guidelines or drug-drug interactions.

A structure has evolved that allows pharmaceutical companies to support post-marketing surveillance. Pharmaceutical companies realize that not all physicians are clinical investigators and these physicians need to gain access to the drug and gain experience in a real-world setting. This not only facilitates making complex prescribing decisions, but also allows them to use the drug in their own particular clinical setting. During the initial post-marketing trials, nonacademic local clinicians have the opportunity to participate in clinical study. This is beneficial for several reasons. First, these physicians are on the front line of treating patients. By getting local practitioners to record their experiences treating patients with recently approved agents, pharmaceutical companies gain valuable information that may not be apparent during the pre-marketing phase. Analysis of data from these trials can yield a wide variety of practical information. It is important to consider that many of the patients who are treated in these local settings most likely would be excluded from earlier trials if they did not meet specific criteria. Also, it is during this time that physicians frequently look at QOL-related end-points, and the implications of these results should not be underestimated. [2] By understanding how a particular agent affects a patient's QOL, clinicians have clues about compliance and related issues. Noncompliance compromises treatment. Frequently, if there are problems that arise demonstrating that patient compliance may be a problem, dosing guidelines can be reassessed. Conversely, trials that show improved QOL for patients help treating practitioners understand how patients benefit from specific agents as opposed to other agents. Established QOL parameters provide a basis for comparison. Additionally, participation in these trials is an important learning experience for physicians. Finally, phase 4 trials provide additional information about how drugs function in very diverse populations that reflect differences in age, gender, race, health status, and individual biochemistry.

Like any industry, there is an economic incentive for pharmaceutical companies and physicians to excel and be productive. As it stands, productivity in this industry is directly correlated with QOL for millions of patients. However, like any other industry, there are ethical guidelines that act as parameters for the inevitable tension between economic incentives, productivity, and conduct. FDA guidelines are stringent. It is this stringency that makes the drug development and approval process so complex. Though the approval process can be expedited, the pre-marketing phase is still time-intensive. Most potential drug candidates fail during the preclinical phase or during phase 1 as a result of poor absorption, distribution, metabolism, excretion and toxicity (ADME/T) results. Preclinical study that evaluates safety in animals in the laboratory setting takes a full 4 to 5 years, followed by phase 1 trials, which generally involve 20 to 80 patients for a 1- to 2-year period. By the time a drug has made it to phase 2 testing, 100 to 300 patients with the target disease are enrolled in the trials for 2 years, and finally 750 to 2000 patients with the target disease are studied during phase 3 registration trials for 3 to 4 years. After phase 3 registration trials, the FDA evaluates the drug for 1 to 2 years, and post-marketing surveillance begins after approval.

There are various types of educational programs and initiatives to communicate data. In addition to clinical investigation, the educational elements of these programs, which include meetings and other events, play a critical role in post-marketing surveillance. Each of these meetings regardless of venue is designed to educate physicians thoroughly and carefully about drugs and their indications, with the ultimate goal of seeing how a dug works in a real-world setting and thereby facilitating compliance and accurate dosing. Investigators' meetings represent an opportunity for physician education on the local level. In addition to dinner meetings where physicians listen to results and watch presentations of data, there are frequently teleconferences or cybersessions during which interim data from ongoing trials are shared. While these meetings and other continuing education events have come under scrutiny, there are few options for physicians seeking continuing education besides the efforts supported by the pharmaceutical industry.

Physicians who attend these meetings are qualified healthcare providers who are using an opportunity to gain a better understanding of how a new medication works. They also have the experience and good judgment to differentiate between scientific trial results and inappropriate attempts to influence them. With respect to participating physicians, they receive a great deal of assistance and support from the pharmaceutical companies' scientific teams and the availability of CROs. These resources in combination with educational support help physicians perform the trials properly and attain substantive test results in real-world settings. Continual dissemination of clinical findings that can impact daily practice helps practicing physicians in their day-to-day decision-making. In exchange for their administrative time, physicians receive nominal reimbursement from pharmaceutical companies.

Physicians who support post-marketing surveillance and the educational efforts that surround it rely on post-marketing data and assert that phase 4 clinical trials are necessary. On January 7, 2002, Rachelle Doody, MD, PhD, an associate professor at Baylor College of Medicine in Houston, Texas discussed post-marketing studies with a journalist reporting for the Wall Street Journal. According to Dr. Doody, "More needs to be learned about how drugs work. That's what post-marketing studies are for. It's fascistic to try to control information and say, 'Because this local doctor might overstate the case, let's not tell him about this.'" When asked about pharmaceutical companies that support post-marketing studies, Dr. Doody, who is widely recognized for her work in Alzheimer's disease and neurodegenerative dementia, concluded, "If it improves their sales and marketing so be it." [3]

Recognizing that the investigation that follows registration trials , including phase 4 trials and post-marketing surveillance, is vital for the health care industry, physicians and pharmaceutical companies are committed to maintaining the integrity of this process. Most importantly, they are real trials that honor FDA regulations and guidelines. Moreover, they monitor any off-label claims and usage of the drugs being tested. As it turns out, these trials are a vital part of the drug development continuum. Despite this reality, the media often does not understand the role that post-marketing surveillance plays in making medical practice more effective. It is incumbent upon the medical and pharmaceutical industries to educate the media and ensure a balanced perspective on the individual roles of phase 4 trials, participating physicians, pharmaceutical companies, medical education companies and CME events. The media needs to gain a better understanding of post-marketing surveillance as part of the process that continues to bring life-enhancing drugs to the general public. By gaining a better understanding of the overall process, the media can convey a more accurate picture of the role of the pharmaceutical companies and the participating physicians. An accurate depiction will demonstrate that pharmaceutical companies and medical education partners understand the guidelines for post-marketing surveillance and phase 4 trials, that all trials that fall under the umbrellas of phase 4 trials are governed by regulations that are recognized by all involved parties, that pharmaceutical companies are providing a service that is not provided by others in either the public or private sector, and most importantly, that without phase 4 post-marketing surveillance trials and adequately trained physicians to participate in these trials, the general public would lose an important and potentially lifesaving safeguard in the drug approval process.