BOX 35 Continued

competition from the "same drug" for the same approved indication. The regulations describe how to assess two products on a physical-chemical basis to determine if they should be regarded as the "same drug." The regulations further provide that even if the physical-chemical criteria for "same drug" are met, a demonstration of clinical superiority of the subsequent product compared to the original product will enable a determination that the two products are in fact not the "same drug." In such circumstances, the subsequent product may be given immediate marketing approval. The regulations also describe the circumstances for determining clinical superiority. A new product can be considered clinically superior if greater effectiveness has been shown or on the basis of greater safety in a substantial portion of the target population. An important aspect of this determination is that demonstration of greater effectiveness will in most cases entail direct comparative clinical trials, whereas direct comparative trials for a demonstration of superior safety are expected to be necessary in only some cases. The regulations do not state that clinical superiority must be based on overall risk-benefit being deemed superior for the subsequent product compared to the prior product. In fact, the regulations indicate that only a selected aspect may constitute a sufficient basis to reach a conclusion of clinical superiority. That is, the aspect not selected by the sponsor for focus (e.g., safety when efficacy is selected; efficacy when safety is selected) does not require a comparative assessment. Consequently, knowledge of the comparison of efficacy could be entirely lacking (and somewhat inferior efficacy a real potential), yet a clinical superiority determination, based on safety, can be reached.

Study Design of Rebif, Another Variant of Interferon-Beta 1a, That Eventually Gained FDA Approval for Marketing

The second Serono trial was a multicenter randomized study of Rebif at 44mg sub-cutaneously three times per week compared to Avonex at 30 mg intramuscularly weekly. The primary efficacy outcome was the incidence of exacerbations through week 24. Avonex was administered according the recommended regimen in the FDA-approved labeling, and Rebif according to the recommended regimen in Serono's proposed labeling. Serono elected to conduct the study open label, but with a blinded clinical evaluator.

The Center for Biologics Evaluation Research (CBER) reviewed the results of the study and consulted extensively with the FDA's Office of Orphan Product Development. Regulatory officials determined that the comparative clinical study demonstrated that Rebif is more effective than Avonex in that it provides a significant therapeutic advantage over Avonex: 74.9% of study subjects taking Rebif were exacerbation-free versus 63.3% of Avonex subjects. According to the FDA, this is a meaningful difference because it signifies that a patient on Rebif is 32% less likely to experience an MS exacerbation, which can substantially lower his or her quality of life for weeks or months. MS exacerbations can be manifested by paralysis, loss of vision, loss of control of bladder and bowel function, as well as other impairments. Although Rebif caused injection site reactions more frequently than Avonex, the FDA determined that the severity and frequency of such adverse events do not render Rebif unli-censable, and therefore, the agency approved Rebif for marketing in March 2002.

*Data source: BLA document published by CBER for Rebif (2002).

antibodies than any other biotechnology product.

The first monoclonal antibody—OKT3 or Orthoclone—was designed to be immunosuppressive and to reduce the likelihood of transplant rejection. Now monoclonal antibodies are used to treat a wide range of diseases, including arthritis, certain kind of cancers, and microbial and viral infections.

In principal, gene-based biopharmaceu-ticals, such as DNA plasmids and viral vectors that carry the message for expressing specific proteins, can also be used to influence disease. Biotechnology companies are pursuing gene therapy strategies for cancer and other diseases. There is on the market a product called Vitravene (fomivirsen) that uses an antisense strategy to block cytomegalovirus (CMV) replication and treat CMV retinitis. Fomivirsen is an oligonucleotide that mimics gene sequences and is designed to bind directly to CMV DNA, thereby inactivating viral replication. It can be considered a form of gene therapy. The mechanism(s) by which it inhibits viral replication, however, may or may not involve direct binding of the antisense DNA to the viral DNA. Neverthe-

less, it provides an effective and safe means to modulate CMV retinitis.

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