Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary (2010)

Depression is a chronic disease characterized by recurrent episodes that interfere with daily life and normal functioning, exacting large costs for both individuals and society. James McNulty, Vice President of Peer Support at the Depression and Bipolar Support Alliance, presented data from the World Health Organization (WHO) revealing that depression is the primary cause of disability in the United States and Canada for individuals aged 15–44 (WHO, 2002). Indeed, depression and other mental illnesses result in a greater loss of healthy life years to disability and death than cardiovascular disease, cancer, or diabetes (WHO, 2004). The onset of mental illness occurs primarily at a young age—by age 24 in 75 percent of cases (Kessler et al., 2005)—but can strike at any age. Regardless of age at onset, a study by the Council of Medical Directors of the National Association of State Mental Health Program Directors showed that individuals who receive treatment for a serious mental illness still die 25 years earlier than the normal population (NASMHPD, 2006). Disconcertingly, similar statistics are not available for those who do not receive care for a mental illness.

The neuroscience knowledge base underlying the study of depression has been growing since the emergence of biochemical pharmacology and molecular technologies in the 1970s and 1980s. Over this same period of time, pharmaceutical companies, the National Institutes of Health’s (NIH’s) National Institute of Mental Health (NIMH), and patient advocacy groups have aggressively pursued new treatments for the disease. The success of selective serotonin reuptake inhibitors (SSRIs) and the many structurally similar drugs that followed improved the lives of many patients. However, William Potter, most recently Vice President of Translational Neuroscience

at Merck Research Labs, Merck & Co., Inc., explained that a truly novel antidepressant has not been introduced in the last 40 years. According to Potter, the period of SSRI development established a level of comfort in the mental health community that may have temporarily hindered the development of new and better antidepressants. Today, significant effort is focused on understanding the challenges to developing novel antidepressant therapies and designing the informative clinical trials necessary to test the effectiveness of new discoveries.

This chapter begins with a patient’s perspective on clinical trials in depression. Next, the commercial contract research organization (CRO) model for conducting clinical trials in depression is described. A discussion of the unique issues in conducting clinical trials in depression is then presented. Finally, the chapter summarizes workshop participants’ discussion of specific ways to develop informative clinical trials to accelerate depression research.

As a patient advocate living with the psychiatric diagnosis of bipolar disorder, McNulty shared his perspective on mental health research and the role of patients in clinical trials. Having participated as a subject in both industry- and NIH-sponsored studies, he received SSRIs in the clinical trial setting and experienced life-changing improvements in his condition due to these breakthrough drugs. McNulty described depression as a protean disease—extremely variable and readily assuming different shapes and forms. In his own life, depression had devastating effects, including the loss of his family and business, as well as a period of homelessness. Noting that there is a significant human dimension to the disease, he explained that his success in battling depression has been due only partially to medications. This is an important point to note because, in McNulty’s experience, scientists can become excessively focused on data and lose sight of the real-life manifestation of depression and its effects on individuals and families.

At the age of 20, McNulty experienced his first major depressive episode. In 1985, he received his first diagnosis of mental illness. At one point, he lied about which medication he had previously used so as to become eligible for a clinical trial. Then, after being diagnosed with bipolar disorder type II, he began a period of years during which he searched for stability with medications. His involvement in an NIH-sponsored trial and eventually an Institutional Review Board (IRB) led him to a career focused on national mental health policy and clinical research as the vehicle for answering questions of great importance to the field of mental health.

Referencing the policy debate that surrounds funding for mental health services and the allocation of scarce resources, McNulty noted that it is very expensive not to treat mental illness. Although the true cost of mental

illness involves societal and personal costs that are not easily captured in financial terms, the sum of the societal and personal costs of failing to provide care to those who suffer from mental illness is probably greater than the cost of providing the care.

According to McNulty, patient advocates should be involved in developing and conducting clinical trials. Bringing this expertise into the clinical trial process at an early stage could help avoid some of the pitfalls that hinder trials today. An example is the informed consent process. McNulty serves on the board of directors of the Association for Accreditation of Human Research Protection Programs—an organization that resulted from recommendations in the IOM study Preserving Public Trust: Accreditation and Human Research Participant Protection Programs (IOM, 2001b). As a member of the IOM study committee for that report, McNulty joined in recommending that the informed consent process for clinical trial participants be simplified and streamlined. According to McNulty, however, the consent process has been hijacked by lawyers who have rendered consent documents unintelligible to both patients and researchers. The need to simplify the informed consent process was echoed by a number of participants throughout the workshop.

Aligning industry efforts more closely with the real-world needs of patients is another area that could benefit from more patient input. McNulty described his experience in which a pharmaceutical company asked a patient group what the ideal antidepressant would be like. He said that for most patients, the ideal antidepressant would be one that restored their life to a presickness state. When doctors were given the opportunity to answer the same question, some responded that sexual functioning was not important to their patients taking antidepressants. McNulty and the patient group clarified that, of course, sexual functioning recedes in importance when other major symptoms are considered, but it is not unimportant. Such divergences of opinion need to be illuminated early in the process of drug development.

As an executive with the largest global contract research organization (CRO) in the world, Amir Kalali shared his perspective on the role of CROs today. Drawing on his experience in randomizing thousands of patients into global clinical trials, he discussed why, in his view, trials are increasingly conducted outside the United States (see also the discussion of this issue in Chapters 3 and 4).

Clinical trials conducted according to the CRO model are not specifically designed to produce results that can be translated into useful information for clinical practice. Rather, most CRO-run preapproval clinical trials

are conducted with the goal of regulatory approval, and complex protocols that involve a number of study questions are often a recipe for failure.

In the area of psychiatry, Kalali stressed the importance of conducting scientifically robust and efficient clinical trials, a theme repeated frequently throughout the workshop. More than any other area, psychiatry has been scrutinized with respect to the drug development process and the role of pharmaceutical companies in the marketing of drugs. High-profile attention has surrounded a number of issues, including antidepressants and suicide, the safety of newly marketed drugs, the dissemination of negative clinical trial data, the lack of evidence-based drug development in psychiatry, and the globalization of clinical trials in this area. These issues have contributed to a decline in the public’s trust of the pharmaceutical industry and the clinical research enterprise. Kalali cited the high-profile withdrawal of pharmaceutical products from the market, as well as scientific misconduct, primarily at academic institutions. For these reasons, clinical research, especially in psychiatry, is under increasing scrutiny.

In addressing the issue of globalization, Kalali spoke to the concern about the applicability of global trial results to the U.S. population by noting that for decades medicines were tested only in America and Western Europe yet used around the world. He highlighted the benefits he perceives in conducting global clinical trials:

• wider, early patient and physician access to novel therapies;

• shortened drug development times due to more rapid patient recruitment;

• reduced drug development costs (i.e., the ability to develop more drugs);

• the generation of data to address ethnic diversity;

• study personnel with higher qualifications;

• accelerated local product approval;

• the availability of drug-naïve patients;

• improved patient retention rates;

• better medication compliance rates; and

• stability of the patient population, facilitating long-term follow-up.

According to Kalali, the quality of clinical trials conducted globally is very high. The average level of education and expertise of study personnel abroad is higher than that in the United States, and this greater expertise also comes at a lower cost in the global market. Kalali also pointed to notable differences between U.S. and global study populations. For example, given the large number of chemically similar antipsychotics on the market today, most individuals with schizophrenia in the United States have tried a number of medications to treat the disease. If the seventh in a string of

antipsychotics with a similar mechanism of action is developed, there is little reason to believe it will be effective for individuals with schizophrenia who have not responded to previous drugs. In contrast, a patient population of individuals with schizophrenia in Ukraine has likely been exposed to various drugs with different mechanisms of action (e.g., haldol, chlorpromazine). As a result, the Ukrainian population might be responsive to the new antipsychotic drug.

Kalali explained that there is no inherent interest in conducting research outside the United States. The United States is the largest pharmaceutical market in the world, and companies are unlikely to abandon U.S.-based clinical trials. The U.S. Food and Drug Administration (FDA) requires that, to gain access to the U.S. market, global clinical trials include a separate U.S. population. This requirement is aimed at the development of U.S.-based data on the safety and efficacy of a drug for the population in which it will be marketed. In selecting the best clinical trial sites, however, it no longer makes sense to choose 50 U.S. sites, 20 of which could be inadequate and fail to enroll patients, when there are significant advantages to choosing sites globally.

Califf responded by questioning whether it is appropriate to market a new drug in the United States that has been tested on a very different patient population, for example, in Ukraine. In addition, he suggested that the solution to improving clinical research in the United States is not to move clinical trials abroad. Rather, U.S.-based global companies, such as Quintiles and many other CROs, should help fix problems with the current U.S.-based clinical trial system.

According to Madhukar Trivedi, Professor and Chief of the Division of Mood Disorders in the Department of Psychiatry at the University of Texas Southwestern Medical Center at Dallas, two of the greatest challenges in depression research are (1) the lack of a definitive marker for diagnosing depression—a pathophysiologic “smoking gun,” as he described it; and (2) the fact that a significant number of trials in depression are not focused on answering the most important clinical questions—that is, there are many uninformative trials in the field.

As was discussed in Chapter 4, the successful classification of acute coronary syndromes allows clinical investigators to identify the appropriate patient population for a study quickly and easily. Similar to the difficulties seen with the diagnosis of heart failure, depression currently lacks a robust mechanism for diagnosis. The current standard for measuring depression in clinical trials is the Hamilton Depression Rating Scale (HAM-D), a rating system based on the subjective determination of the diagnosing physician or

other qualified personnel. The result, according to a number of workshop participants, is the identification of patient populations inadequate for distinguishing treatments for depression.

Trivedi further explained that there is very little scientific evidence regarding which patients will respond to which of 25 to 30 treatments for depression. Treatments are similar but may be different in important ways. The result is substantial variation in clinical practice patterns for depression. It is unclear in many cases which antidepressant a clinician should choose for a patient, as well as how long to treat the patient with a given drug.

Presenters discussed the issues involved in identifying the correct study population for a successful clinical trial in a heterogeneous disease such as depression. First, as suggested above, the diagnosis of depression is less technical and more subjective than that of other diseases. Moreover, changes in the way depression has been diagnosed over time call into question the use of large, historical databases. There is significant uncertainty as to whether a population diagnosed with depression in 1990 would be comparable to a population diagnosed with depression in 2000. Potter further explained how two patients diagnosed with depression at the same time might have very little in common. The criteria for diagnosing depression require that the patient have a depressed mood or a markedly diminished interest in pleasure (anhedonia). Hypothetically, one depressed patient could have a depressed mood as well as weight gain, hypersomnia, and recurrent thoughts of death, while another could have anhedonia, weight loss, and insomnia. Both of these patients would be diagnosed with depression and yet have no symptoms in common, and both could be enrolled in a clinical trial for depression. This treatment of a heterogeneous disease as if it were homogeneous is one reason clinical research in depression struggles to distinguish among antidepressants.

Potter described the difficulty of using entry criteria for clinical trial participants based on the severity of their disease. The standard minimum criterion for enrolling an individual in a clinical trial for depression is a total HAM-D score greater than 18. Conventional wisdom in the psychiatry field is that increasing the severity criterion creates a study population with more severe cases of depression, which in turn reduces the placebo response rate. Potter described his research to better understand the effects of the severity-based entry criterion on trial outcomes. He and his colleagues studied the relationship between patients’ and physicians’ ratings according to the HAM-D over the course of a 6-week trial. Potter said it was not surprising to find in the first week of the trial that physicians rating patients for admittance to

the trial gave them at least the minimum score to get them into the study. When patients were asked to rate themselves (via telephone) during the first week of the trial, the HAM-D scores ranged from high to low and were of a normal distribution. As the trial continued, the patient and physician ratings increasingly converged. Kalali explained that after their high initial ratings designed to get patients into the trial, physicians began rating the condition of patients accurately. The result was a large drop in the HAM-D scores, which made the placebo appear effective.

Potter’s research highlights the difficulties inherent in setting a severity criterion for entry into a clinical trial in which the measure of disease is subjective and easily manipulated. The result can be to introduce bias into a study and create significant statistical problems due to the skewed distribution of the patient population. Kalali added that HAM-D is an incomplete measure in that it does not include anhedonia, cognition, or the painful physical symptoms that are important in depression. Potter noted that while research is being conducted to understand the issues surrounding the use of severity criteria for trials in depression, solutions to the problem have yet to be developed.

Trivedi estimated that in the last 3 to 5 years, more than 300 randomized controlled trials (RCTs) for antidepressants have been conducted. He described the patient populations studied in these trials as “symptomatic” volunteers. His example of a symptomatic volunteer is an individual who responds to an advertisement for a clinical trial in depression and who would otherwise not seek treatment for depression outside the trial setting—that is, the clinical trial is the patient’s only interaction with the treatment setting. This unique, symptomatic patient population in which antidepressants are tested is different from the depressed population that will eventually be treated with the drug in the real-world clinical setting. Patients in clinical trials for depression often are not chronically ill and rarely have comorbidities, whereas it is well known in psychiatry that patients with major depressive disorder frequently have a number of comorbidities. In addition, there is overwhelming evidence that a patient with depression is at increased risk for cardiovascular disease, diabetes, and a number of other conditions. Thus, excluding patients with comorbidities from depression trials, as is most often the case, diminishes the applicability of the trial results to the real-world population.

Kalali also addressed the existence of “professional patients” in psychiatry. These patients seek to enroll themselves in multiple trials or study sites at once as a source of money and medicines. Kalali said active efforts to screen out these professional patients have been necessary. In one trial involving 300 patients, for example, 30 were found to be randomized to the same study by separate study sites.