Opinion ID: 203426
Heading Depth: 2
Heading Rank: 2

Heading: TYSABRI's Path to Market and the FDA Approval Process

Text: The Food and Drug Administration (FDA) requires any drug to go through a series of clinical trials before it can be approved for marketing and sales in the United States. See generally L. Sukhatme, Note, Deterring Fraud: Mandatory Disclosure and the FDA Drug Approval Process, 82 N.Y.U.L. Rev. 1210, 1219-20 (2007) (describing the FDA's drug approval process). After a drug is initially tested on animals, the developer of the drug submits an application to the FDA for approval to test the drug on humans. Id.; see also 21 C.F.R. § 312.20. If this request is approved, human testing begins, and typically follows three phases, commonly known as clinical trials. See 21 C.F.R. § 312.21. Each phase requires the company to test the drug on a broader population and results in more stringent monitoring and evaluation. Id. Phase I studies generally involve twenty to eighty subjects, and are designed to determine how the drug works in humans and the side effects associated with increasing doses. Id. § 312.21(a)(1). Phase II studies usually involve no more than several hundred subjects, and are designed to evaluate the effectiveness of the drug, as well as common short-term side effects and risks. Id. § 312.21(b). Phase III studies are large-scale trials, usually involving several hundred to several thousand subjects, and are intended to gather the information necessary to provide an adequate basis for labeling the drug. Id. § 312.21(c). Throughout the clinical trials, the drug company must report to the FDA and to all participating physicians any serious and unexpected adverse drug experiences that occur. Id. § 312.32(c)(1)(i)(A). After Phase III, the FDA considers the results of all of the clinical trials in determining whether to approve a drug for market. See id. §§ 314.125(b), 314.126(a). If a proposed drug address[es][an] unmet medical need for a serious or life-threatening condition, like TYSABRI does, the FDA provides an expedited approval process. 21 U.S.C. § 356(a)(1); see also Consolidated Am. Compl. (CAC) ¶¶ 83-85. Through this process, which has a target for FDA action of six months, the drug maker interacts with the FDA during drug development and the FDA can begin reviewing portions of the drug application before the full application is completed. See U.S. Food and Drug Administration, Center for Drug Evaluation and Research, FDA's Drug Review and Approval Times, available at http://www.fda.gov/cder/reports/reviewtimes/default.htm. The FDA can approve drugs treating life-threatening illnesses that are significant advancements over existing treatments on the basis of preliminary evidence prior to formal demonstration of patient benefit. [4] See 21 C.F.R. §§ 314.500, 314.510. In August 2000, Biogen and another company, Elan Pharma International Limited (Elan), announced that they had entered into a joint collaboration agreement to bring TYSABRI to market. The agreement required the two companies to share equally in the revenues and costs and set up a number of joint teams, so that both companies played a role in both the development of TYSABRI, including clinical trials, and the marketing of TYSABRI. The agreement also required that any information, including adverse events, discovered by one company be reported to the other in a timely manner. Both the pre-clinical animal trials and the first phase of clinical trials of TYSABRI as a treatment for MS had been completed in the 1990s by Elan's corporate predecessor. After the collaboration agreement, it was decided that Biogen would lead the clinical trials for MS and Elan would lead the clinical trials for Crohn's disease. By September 2001, preliminary Phase II MS results had begun yielding promising data. Biogen then began Phase III of MS testing in December 2001 with two trials. The first trial, named AFFIRM, sought to test whether TYSABRI was effective in slowing the rate of disability in MS patients. The second, SENTINEL, sought to evaluate the safety and efficacy of TYSABRI in combination with another MS drug produced by Biogen, AVONEX. The Phase III clinical trials for Crohn's disease began in December 2001 and consisted of two trials: ENACT-1 (designed to evaluate clinical responses to TYSABRI and its ability to induce remission of Crohn's disease) and ENACT-2 (designed to evaluate the duration and effects of TYSABRI). In July 2003, Biogen announced that it could not act on the results of ENACT-1 because of a larger than expected placebo response rate. On January 29, 2004, Biogen announced that the ENACT-2 trial had met its primary endpoint, and that because the ENACT-1 trial had been unsuccessful, Biogen was beginning an additional Phase III trial, ENCORE, which was designed to evaluate the safety and efficacy of TYSABRI in patients with moderate to severe Crohn's disease. Altogether, approximately 3,900 patients received TYSABRI in the three phases of the MS and Crohn's disease clinical trials. On February 18, 2004, Biogen announced its intention to apply to the FDA for expedited approval for TYSABRI as a treatment for MS, based on data from one year of its two Phase III MS trials, AFFIRM and SENTINEL. Over the next two days, the price of Biogen stock increased from $44.26 to $58.98, an increase of 33.3%, and was traded at a daily volume of between six-and-a-half and nine times greater than the average daily trading volume during the class period. On May 25, 2004, Biogen announced that it had submitted its application to the FDA. The FDA then conducted a detailed analysis of the safety and efficacy data available for TYSABRI, focusing on the data for the MS clinical trials but also considering any serious safety events that occurred in the Crohn's trials. For the ongoing Phase III trials, which provided the primary evidence of safety and efficacy, the FDA's review considered data through cut-off dates ranging from March 1st to April 30th, 2004. On November 23, 2004, Biogen announced that the FDA had granted accelerated approval of TYSABRI and the drug was available for sale. The following day, the stock price rose from $57.43 to $58.59, an increase of 2.0%. The FDA placed no limitations on TYSABRI's use in combination with other drugs. The package insert label included with the drug noted only that TYSABRI® is indicated for the treatment of patients with relapsing forms of multiple sclerosis. However, the package insert label did contain the following statement relevant to the plaintiffs' claim: The safety and efficacy of TYSABRI in combination with other immunosuppressive agents have not been evaluated.