Opinion ID: 203426
Heading Depth: 3
Heading Rank: 2

Heading: Combination Therapy Claims

Text: In a related but distinct set of claims, plaintiffs allege that defendants affirmatively stated that TYSABRI was safe when used in combination with other drugs when in fact they had no reasonable basis to believe so. This is different from the allegations that defendants knew of the risk of opportunistic infections but did not disclose the risk. Plaintiffs point out the two PML diagnoses which led to withdrawal of the drug occurred during the clinical trials of TYSABRI in combination with AVONEX, Biogen's other MS drug. And when the FDA approved the reentry of TYSABRI into the market, the package insert contained the following warning about the use of TYSABRI with other MS therapies: Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of TYSABRI alone. The plaintiffs allege that the use of TYSABRI in combination therapy was highly material to TYSABRI's future market share because approximately 180,000 patients or slightly over half of the potential MS market was on other MS drugs. CAC ¶ 180.
Before addressing the merits of the argument, we look to whether it has been waived. The defendants argue that this combination therapy theory has been waived because plaintiffs did not brief it in their opposition to the motion to dismiss. Further, the district court did not comment on the theory at all. The theory is, however, plainly stated in the amended complaint. See CAC ¶¶ 402-404. It was the defendants' motion to dismiss which failed to mention or brief the theory, thus failing to call the court's attention to it. Plaintiffs may have been unwise not to brief the theory in their opposition and thus be sure the district court was aware of it. However, plaintiffs did refer to the theory, albeit briefly, at oral argument in the district court. Defendants' failure to brief in their motion to dismiss a theory raised by the complaint should not be rewarded by finding waiver by plaintiffs. Cf. Peterson v. Highland Music, Inc., 140 F.3d 1313, 1318 (9th Cir. 1998) (finding that defendants did not waive on appeal its defense of lack of personal jurisdiction when, in the absence of any allegations of deliberate, strategic behavior, defendants contested jurisdiction only in their initial pleading and did not raise the issue again until appeal). Neither side advances the cause by hiding the ball from the district court. Cf. Adden v. Middlebrooks, 688 F.2d 1147, 1156-57 (7th Cir.1982) (finding no waiver by defendants even though defendants never raised issue after initial pleading until supplemental briefing was ordered by the appellate court, but warning that [defendants] are well advised to brief fully all grounds ... in their favor).
On the merits, the plaintiffs' theory  that defendants had no reasonable basis to say at the time they made their statements that TYSABRI was safe in combination with AVONEX  is not nearly as compelling as opposing inferences from the undisputed facts in the record. First, and most importantly, at the time these statements were made, the FDA had approved TYSABRI for use with AVONEX after contemplating any safety risks. In the FDA's medical review of the drug before approval, the FDA analyzed data from the first year of the SENTINEL trial, which tested TYSABRI in combination with AVONEX. In the Safety section of the review, the FDA noted that [n]atalizumab's overall safety profile was similar in Studies 1801 [TYSABRI as a monotherapy] and 1802 [TYSABRI in combination with AVONEX], suggesting that co-administration of [AVONEX] does not necessitate a change in that natalizumab dose to maintain safety. Biogen included similar language as part of the original package insert label accompanying TYSABRI. Addendum to Defs.' Br. at 5. Plaintiffs point to this language in the original label as evidence that defendants falsely implied that TYSABRI was safe when used in combination with AVONEX. When viewed along with the FDA review described above and the new package insert label after TYSABRI's re-introduction, the inference of scienter is less than compelling. The original label's Indications and Usage section, which described the FDA-approved uses of the drug, noted that: TYSABRI ® is indicated for the treatment of patients with relapsing forms of multiple sclerosis. Addendum to Defs.' Br at 4. The new package insert label specifically states that TYSABRI should be used on its own: TYSABRI ® is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis.... Joint App'x at 538 (emphasis added). Also, as discussed above, the label comes with a warning of the risk of TYSABRI when used in combination with other MS therapies. Based on these undisputed facts, we find the defendants' inference more compelling: up until the first diagnosis of PML, no significant safety risk had been associated with use of TYSABRI as a combination therapy. To the contrary, one of the clinical trials (SENTINEL) was focused on the safety and efficacy of TYSABRI in combination with AVONEX. Once the diagnoses of PML occurred and the drug was withdrawn, Biogen recognized that a safety risk may exist when TYSABRI is used as a combination therapy because the two instances of PML had occurred in the SENTINEL trial. This was reported to the FDA and discussed in the Advisory Committee hearings. When the FDA re-approved the drug for use in June 2006, it was only as a monotherapy, and Biogen disclosed this in the label accordingly. Defendants may have based their optimistic financial projections on a broader market that includes TYSABRI being used with AVONEX. But plaintiffs have not raised a plausible inference that defendants knew at the time these projections were made that TYSABRI used with AVONEX was unsafe. As a result, we cannot say that either defendants' representations about TYSABRI as a combination therapy or the ensuing forecasts about market share were misleading at the time they were made. There is no strong inference of scienter.