Access and Utilization of New Antidepressant and Antipsychotic Medications. B. Clinical Development and Marketing

The clinical trials submitted for review to the FDA by the manufacturer determine the indications for which a drug may be marketed. Although trials used to obtain approval may be sufficient to convince regulatory authorities that a new drug is safe and effective, their design may or may not be adequate to convince health care payers that a new drug represents a therapeutic advance over existing therapies. Therefore, trial design from first toxicology testing to pivotal trials and post-marketing studies is of paramount importance in affecting future drug utilization.

Numerous factors influence which drugs manufacturers choose to develop, and for which particular indications:

• Market competition or saturation;
• In-house clinical expertise and infrastructure;
• Potential market size and patient recruitment potential; and
• Reimbursement status of target population.

In general, manufacturers express no bias against developing a new drug for mental health indications in comparison with physical health indications. One manufacturer did mention that because most behavioral health users have public health insurance, patient recruitment and retention could be a greater challenge for behavioral health than for physical health drugs. This could be especially true in non-institutionalized schizophrenia patients, for example. Similarly, if a product demonstrates potential for both mental health and physical health indications, a lack of clinical expertise in mental health may lead the manufacturer to pursue the physical health indication. In general, manufacturers do not design trials for specific racial/ethnic groups or special populations (e.g., children) unless requested to do so by the FDA.

The MCOs and PBMs interviewed reported that traditional clinical trials are of relatively short duration and measure outcomes using instruments not readily translatable into regular clinical practice, such as standardized psychiatric rating scales. As a result, many manufacturers conduct outcomes studies that measure clinical, quality of life and/or economic endpoints. The respondents interviewed in this study indicated that in order to speed formulary acceptance, manufacturers should:

• Complete head-to-head comparisons with competing agents;
• Conduct long-term trials;
• Conduct real world effectiveness trials in naturalistic settings; and
• Include measures of "big picture" issues such as employee productivity.

Some health care payers are beginning to standardize their operating procedures for the review of new agents. For example, Regence BlueShield (Seattle, WA)³⁹ and Blue Cross/Blue Shield of Colorado and Nevada⁴⁰ have published guidelines for the submission of clinical and economic data supporting formulary consideration.

Manufacturers are responding to the request for such studies. We are aware of numerous outcomes studies of this type for both antidepressants and antipsychotics. Eli Lilly has conducted two direct comparisons of olanzapine and risperidone.⁴¹ Janssen is conducting a comparison of outcomes in patients treated with risperidone to those achieved in patients treated with one of 13 different conventional antipsychotics (this trial is named the ROSE trial). Often, payers are conducting this work themselves. For example, Group Health of Puget Sound conducted a comparison of the efficacy and cost-effectiveness of SSRIs to TCAs in a naturalistic, primary care setting.⁴²

Manufacturers devote considerable effort to marketing psychotherapeutics to physicians, although tactics vary. For example, both Janssen and Eli Lilly maintain a specialized detail force for mental health, whereas SmithKline Beecham promotes paroxetine largely through a non-specialty force. AstraZeneca promotes quetiapine through a generalized sales force dedicated to central nervous system products.¹⁴

The experience of a company in marketing through certain channels may affect the success of a particular drug. Eli Lilly and Janssen are recognized as experts in mental health marketing. The synergy of fluoxetine and olanzapine doubtless provide Lilly with a certain advantage in promotion. On the other hand, the relative inexperience of AstraZeneca in the mental health market may account in part for the slow diffusion of quetiapine in the treatment of schizophrenia.

It is generally assumed that manufacturer contracts and rebates may affect drug utilization. However, no data exists to support this idea, largely because such data are considered trade secrets. Indeed, none of the manufacturers or health care payers interviewed would discuss any such arrangements. For example, Medi-Cal requires manufacturers to enter into supplemental rebate arrangements with the State prior to including a drug on the formulary, although the exclusion of a drug from the formulary does not necessarily represent the failure of the manufacturer to offer Medi-Cal an acceptable rebate. However, Medi-Cal would not disclose the terms of any such arrangements. Our research does not support the assertion that rebate arrangements are more or less common for physical health medications than they are for psychotherapeutics. Although several MCOs and PBMs participate in volume-based or market share-based rebates or contracts for psychotherapeutics, the significant price differential between the branded and generic therapies prevents contracts or rebates from demonstrating considerable cost-effectiveness to providers.

To increase consumer demand and awareness for particular drugs, manufacturers often use direct-to-consumer advertising. There is a strong belief among consumer and provider associations that direct-to-consumer (DTC) marketing affects drug utilization. However, there are currently no data to support this. This issue may represent another area where follow up research may be useful.

The NMHA believes that direct-to-consumer advertising disseminates valuable information to patients that they may not otherwise receive. However, other respondents feel that marketing efforts may be merely a form of physician or consumer "brainwashing." That is to say, physicians are convinced to prescribe drugs manufactured by the company whose representative visits most frequently, even as consumers grow to demand the drugs with the most appealing promotional materials. The APA reported that DTC marketing probably increases drug utilization, but has not collected data to support this.

Several manufacturers maintain websites that describe their drugs or the diseases they are intended to treat. Sites generally have areas for consumers and for providers. Manufacturers believe these methods of promotion to be effective, but did not provide data on their direct effect on product sales. Sites are often named for the drug on which they provide information. Examples include citalopram (www.Celexa.com), fluoxetine (www.Prozac.com), paroxetine (www.Paxil.com), olanzapine (www.Zyprexa.com), and quetiapine (www.Seroquel.com). Solvay maintains a comprehensive site of information on the treatment of obsessive compulsive disorder (www.ocdresource.com). The paroxetine site now focuses heavily on the use of paroxetine in the treatment of social anxiety disorder, the newest indication for paroxetine. The launch of paroxetine for social anxiety disorder also represents one of the most visible uses of DTC in the mental health area.

Providers express some frustration at the potential for misinformation and the increase in consumer demand for particular products that may or may not be the best therapy for a patient who demands it.