Efficient drug development takes a potential medicine from "bench to bedside," from research and discovery through the phases of testing and in a timely, cost-effective, manner. Efficiency often parallels advances in science and technology. Witness the emergence of pharmacogenomics, the science of "mining" the genome for potential new drug targets.

While still in its infancy, this rapidly growing field promises to improve our ability to identify patients most likely to respond to a treatment and/or less likely to experience its toxicities.

An example is trastuzumab (Herceptin), a monoclonal antibody engineered to bind to HER2, a protein expressed on approximately 25 per cent of all breast cancers. Approved in 1998, this biotechnology product prolongs the time to tumour progression in women whose cells over-express this protein.

The FDA recognizes the tremendous potential for pharmacogenomic data to optimize drug development, and recently issued guidance on this subject.

The agency, industry, and lawmakers continuously assess, develop, and implement, through regulation and guidance, procedures and processes to improve drug development times and/or enhance the availability of safer and more effective medicines. For example, in 1992, the agency set forth regulations describing the conditions under which a drug could be marketed on the basis of studies showing an effect on a surrogate endpoint reasonably likely to predict clinical benefit.

Generally, surrogates are easier to measure than clinical endpoints and occur earlier in the course of the disease; thus, they allow for shorter, smaller, and thus, less expensive studies. Since 1992, many new therapies for HIV/AIDS, cancer, and other serious diseases have come to market on the basis of this approval mechanism.

The Prescription Drug User Fee Act (PDUFA) plays a major role in efficiency in drug development, as does the 1997 FDA Modernization Act (FDAMA) In 1992, under PDUFA I, a mechanism was established for regulated industry to pay a fee for marketing applications. In return, the agency committed to meet specific review goals.

This programme has been very successful. In the five years following implementation of PDUFA I, the number of new marketing applications, efficacy supplements, and manufacturing supplements increased and approval times were reduced PDUFA was reauthorized in 1997 and again in 2002. FDAMA led to implementation of Fast Track and the rolling review, a process by which companies with Fast Track designation could submit portions of their marketing application in advance.

However, FDA was not obligated to review the portions until submission of a complete marketing application, and it is uncertain what types of efficiencies came about through the rolling review. Novel features of PDUFA III are two pilot programs, referred to as the Continuous Marketing Application (CMA) I and CMA II. The focus of CMA I is the reviewable unit. If accepted into this programme, the applicant can submit portions of their marketing applications (reviewable units) in advance of the complete marketing application. In contrast to the rolling review, the FDA will fully assess each reviewable unit within a specified timeframe and provide early feedback.

The pilot includes "an analysis of the benefits and costs of this type of early review feedback and its impact on the efficiency of the review process." Under the second CMA pilot programme, Pilot 2, the FDA and applicants with eligible Fast Track drug and biological products can enter into an agreement to engage in frequent scientific feedback and interactions during the IND (investigational new drug application) phase of product development. Pilot 2 will also "evaluate the cost of such enhanced interaction between the FDA and applicants and whether it improves the efficiency and effectiveness of development programmes."

It is hoped that these two programs will enhance the quality of the submissions to FDA and shorten the drug development time.

Greater efficiency does not always need to wait for new technologies or new laws and guidance. Efficiency also occurs through careful planning and execution of a sound development programme.

In designing the major trials to support efficacy, the choice of the endpoints, or efficacy outcomes, the number of efficacy trials, trial design(s), and size of the safety database necessary to determine net clinical benefit depend on a number of factors, including but not limited to the class of product under development, the condition or disease being studied, and the availability of other therapies. The standard for effectiveness is substantial evidence defined in the FD&C Act. Trials intended to provide substantial evidence of efficacy must be "adequate" and "well-controlled".

An "adequate and well controlled" investigation is one whose design and execution produces valid scientific data. Clinical investigations intended to show efficacy must be controlled so that the effect(s) of the intervention can be distinguished from other influences, such as spontaneous change, placebo effect, or biased observation. However, the appropriate control, or comparator group (e.g., historical, active, placebo, etc.), depends on the clinical setting. An invalid, or inappropriate, comparator may make it impossible to draw conclusions regarding the drug's efficacy.

Each type of control has its advantages and limitations. Existing guidance under the auspices of the International Conference on Harmonization (ICH) provides extensive discussion on this topic. Safety data must be evaluated in the context of the nature and extent of the observed efficacy to formulate a benefit/risk analysis.

Concerns about late adverse sequelae, such as new malignancies occurring years or decades following administration of replication competent, integrating viruses, resulted in FDA guidance regarding testing for replication competent retrovirus (RCR) in product and patient's serum and clinical monitoring for certain classes of gene therapy products.

- The author is M.D., Director, Office of Drug Evaluation VI, Office of New Drugs, CDER, FDA