A STRATEGIC APPROACH TO CLINICAL DRUG DEVELOPMENT

If FDA says nothing to the contrary, thirty days after the IND is filed the company may initiate the submitted Phase I study. Though this is the culmination of years of research and planning, it is merely the beginning of the long and arduous process of turning a chemical into a marketed medicine. Because human testing is by far the most expensive and time-consuming part of drug development, the clinical development program must be designed to be as efficient as possible.

PLANNING AHEAD BY WORKING BACKWARDS

It is common for pharmaceutical companies, and particularly newly emerging ones, to take the development

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The connections that a company forms with key opinion leaders (KOL) in the clinical community during development can dramatically impact how quickly the drug will penetrate the market once it is launched and how well it sells. If the KOLs follow the progress of the drug and are convinced of its utility, they will be instrumental in educating the rest of the medical community in how and when to prescribe the drug. Pharmaceutical companies make a concerted effort to recruit the right people to serve as clinical trial investigators or advisors, usually starting at Phase II.

of their compounds one step at a time. The assumption is that you need to see the results of one study before designing the next. Although true to some extent, it is a poor argument for not planning ahead. The best way to plan ahead in drug development is to think backwards. Even before the first Phase I study is initiated, the company should begin to consider how the drug's package insert will read. That is, as soon as enough information is available about the molecule to make a reasonable guess as to its ultimate clinical utility, the company should begin to construct a model of how they would like to see it used in patient care. If the compound is being developed as an anti-depressant, does its pharmacology make it most suitable for bipolar disease, general depression, or another indication? If it has antineoplastic properties, which malignancy would be the most appropriate first clinical target? Or perhaps the compound is so promising that it deserves simultaneous development in multiple indications. Such decisions depend not only on the underlying pharmacology but on the unmet medical need, the size of the potential market, and the nature of current and pending competition.

THE PRODUCT PROFILE

The company should formalize its vision for the compound by constructing a target product profile, which describes its key potentially achievable features. The typical target product profile specifies an indication, route and frequency of dosing, and some sense of efficacy and safety compared to any currently marketed products with which it will compete. Depending on the therapeutic area and the competition, additional attributes such as pricing, cost of goods, and launch date may be relevant. A companion minimally acceptable profile should be drafted as well. If the accumulating clinical data begin to show that the compound's attributes are clearly falling below the minimally acceptable profile, the company should maintain discipline and cut its losses by halting the drug's development. Only very rarely should the minimally acceptable profile be adjusted to accommodate unfavorable data.

PLAN ALL THE WAY TO AN NDA

Many emerging biotechnology companies have no intention of taking their compound through a complete clinical development. This process, culminating in the filing of an NDA, requires considerable capital and expertise to which a young company may not have access. A typical exit strategy is to license the development rights to a large multinational pharmaceutical company after a successful Phase I study or after proof of concept (usually in Phase II) is established. Even if this is the intent, the company should draft a complete clinical development plan. This is important for two reasons:

  • It is not possible to optimally design the early clinical studies unless the entire clinical development trajectory is articulated. This is because earlier studies must be carefully designed to lay the groundwork for subsequent ones.
  • Investors and potential partners want assurance that the company has a clear vision for the development and commercialization of the product.

THE CLINICAL DEVELOPMENT PLAN

The clinical development plan should summarize the proposed design, timing, and logic behind the clinical trials that will be included in the NDA filing. Having a robust clinical development plan in place early on offers numerous benefits:

  • The plan serves as a reality check on timeframes. Biotech startups often substantially underestimate the time to NDA filing. Unlike most laboratory experiments, a large clinical trial may take two years or more from protocol design to initial data analysis. The frequency with which eligible patients are referred to trial sites is an under-appreciated factor. Even a trial that only involves treating and evaluating a patient for a month may still require a year or longer to enroll all the necessary patients.
  • The plan helps to ensure that the proposed studies will satisfy regulatory requirements. The ICH general guidance to clinical trials (see http://www.fda.gov/cder/guidance/959fnl.pdf), which is endorsed by the FDA, discusses the numbers of patients and duration of exposures expected for marketing approval.
  • The plan defines the magnitude of the clinical development effort. Projecting the full gamut of anticipated studies, particularly their length and patient numbers, allows an estimate of the resources and cost that will be required to complete the clinical component of the NDA.
  • Having a plan facilitates discussions with various inhouse experts as well as consultants. For example, even before the start of Phase II, if the company toxicologist sees that the plan calls for a six-month Phase III study, he or she knows that it is not too soon to begin scheduling (and requesting a budget for!) the toxicology studies required to support such extended human drug exposure. Meanwhile, commercially-oriented staff can consider whether the proposed studies will allow them to make desired commercial claims. If not, they can negotiate with the clinical team regarding modification of trial design, or even the inclusion of additional studies to generate data relevant to marketing.

The clinical development plan should be referred to frequently in the course of the compound's development to maintain the discipline and rigor of the clinical program. Of course, information from recently completed clinical studies, new competitive intelligence, advances in science, and approvals of other products may lead to modifications of the plan. Such modifications may affect both the development timeline and the ultimate product profile.