Arthur Horowitz

During the past several years, we have witnessed a dramatic change in the clinical trial landscape.These changes have included more clinical studies (more clinical investigators and sites per study); expansion and fluidity of the clinical investigator pool; new players in new parts; and new technologies. The rush to market a new drug and competition among newly acquired large multinational companies have created increased pressures on cost and time. Each year, there are more original New Drug Applications resulting in new product competition. In 1999, $5.79 billion US dollars were spent by the Pharmaceutical Research Manufacturers Association (PhRMA) member companies in Phase I—III activities. The average daily cost of delay in market introduction is estimated to be $1.3 million US dollars.1 To avoid delay and to improve efficiency in a shortage of company capacity and talent, companies are outsourcing to more contract research organisations and site management organisations as well as hiring more clinical investigators.

The number of new clinical investigators conducting one trial has increased 30% annually during the past four years (Figure 7.1). An

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Figure 7.1 Proliferation of clinical investigators. (Source: CenterWatch)

increasing number of clinical researchers are private clinicians not associated with academia, where the desire to participate in clinical research is driven by the desire for more knowledge or career advancement. The number of private doctors in research has almost tripled as illustrated in Figure 7.2. It has become a multibillion dollar industry, with drug companies working with thousands of private doctors. In this era of managed care, at any rate, in the USA, companies are urging private doctors to join the lucrative clinical research pool. The doctor-directed advertisements describing "instant cash" and "clinical research fame" become seductive. The typical, experienced, independent investigative site generated more than $1.1 million US dollars in annual net grant revenue in 1999.1

Today, the pharmaceutical industries are trying to reach peak sales faster and to extend product life cycle. The strategy of the companies is to rely on the investigators to increase the number of trials and provide future marketing input and selling initiatives. Success is not just about participating in an industry-sponsored trial: it is also about recruiting a large number of study patients. As competition has intensified, sponsors are vying for the top performing doctors by offering incentive monetary bonuses and gifts. Despite these incentives, most investigative sites believe that patient recruitment is much more difficult today than it was several years ago. On an average, only one patient for every 20 patients solicited, will complete a clinical trial.1 This results in more pressure on the clinical investigator to perform.

Patients have become more knowledgeable about their disease and new therapies. This knowledge is obtained from direct to consumer advertisements of marketed product, Internet web sites, and lay press

□ Private doctors

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Figure 7.2 Number of new drug trials by location, 1989-97. (Source: NYTimes) 106

describing new investigational trials. Patients are more motivated, more independent, and less trusting of a single medical opinion. These changes have resulted in patients who are increasingly receptive to clinical trials. In 1999 alone, 3.8 million study subjects participated (defined as screened and/or enrolled) in industry-sponsored clinical trials. Confidence among trial participants familiar with clinical research remains high, despite increasing numbers of complaints received by the FDA (Figure 7.3). Of the 13 clinical investigator complaints received by the FDA from sponsors in the fiscal year 1999, seven cases were related to potential data falsification.

In contrast, new patients and the general public have developed adverse views through the exposure to articles related to the misconduct of a few highly visible investigators and US Congressional Oversight hearings. Among the more recent examples of adverse clinical findings include the fraud perpetuated by Doctors Fiddes, Diamond and Borrison and the death of Jessie Gelsinger enrolled in a gene transfer trial at the University of Pennsylvania (see p. 109).

Each new case of scientific misconduct and fraud that makes its way into the public consciousness erodes away public trust in clinical research. Nevertheless the number of cases of scientific misconduct is small (average 3.4% of the total FDA audited cases, 1994-99) compared with the total number of academic and industry-sponsored research studies. When it does occur, it affects public confidence in the clinical trial process and raises questions about the effectiveness of trial monitoring and its follow up by sponsors. This is particularly valid with fraud because the clinical results have a direct impact on the treatment of patients. Media attention and US Congressional Oversight hearings devoted to fraud ultimately affect the careers of clinicians and their institutions as well as the overall management of research.

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Figure 7.3 Complaints received by the FDA, 1993-2000.

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