Not quite two years ago, we posted about how, under Wyeth v. Levine, 555 U.S. 555 (2009), and subsequent Supreme Court cases, private plaintiffs can’t make claims that so-and-so should have warned about such-and-such with respect to the off-label use of a prescription medical product.  That’s because the FDA zealously guards its authority over warnings concerning off-label uses and does not allow such warnings unless the Agency specifically says so.  That’s crystal clear for drugs.  21 C.F.R. §§201.57(c)(6)(i), 21 C.F.R. §201.80(e).  It’s a little more roundabout for devices (which we explained in that post), but for now, we’re talking about drugs.  Bottom line − since off-label warnings aren’t something a manufacturer can do unilaterally under the CBE regulation, a la Levine, any tort claim demanding such warnings is preempted.

The remedy is to file a citizen’s petition asking the FDA to impose such a warning.

A former colleague recently passed along an example of how such a petition can crash and burn, making preemption even more likely in any civil litigation.  Earlier in the same year (2013) we wrote our post, one James P. Reichmann filed a citizen’s petition concerning the drug ondansetron asserting that it was used off-label for relief of morning sickness (“nausea and vomiting during pregnancy,” or “NVP”) and that the FDA should require warnings (and some other stuff) about birth defects.  The FDA therefore opened up Docket No. 2013-P-0048.  The FDA took its time because the petition “raise[d] complex issues requiring extensive review and analysis by Agency officials.”

Late last month the Agency acted.  It said “no.”  So now the issue is double preempted – with the FDA’s rejection as “clear evidence.”  First, the FDA stated, “[w]e are aware of the unapproved [what the FDA calls off-label] use of oral and injectable ondansetron for treatment of nausea and vomiting in pregnancy.”  FDA denial letter at 3.  The FDA looked at a bunch of scientific evidence (which goes on for pages and pages), and concluded, “[w]hen reviewed together, the totality of the available data does not support a determination that there is an increased risk of adverse fetal outcomes” for the off-label use in question.  Id. at 13.  Therefore:

[W]e find that the available data are not sufficient to conclude that there is a safety concern with regard to the use of ondansetron during pregnancy that would warrant changes at this time to the pregnancy risk category . . ., or to the [relevant] sections in labeling. . . .

Id. at 14.

The FDA went on (after more science-intensive discussion) to reject, as well, asserted risks to the pregnant women themselves who take the drug.  Id. at 17 (“our review of your Petition did not find evidence to support your concerns regarding treatment of pregnant women”).

Because nothing warranted a label change to address the risks of what was, after all, an off-label use, the FDA rejected the request to order “Dear Doctor” letters about the purported “risk”:

[W]e do not agree with the Petition that the available data reviewed by FDA . . . warrant a conclusion that ondansetron use during pregnancy poses an increased risk of fetal or maternal adverse outcomes.  Thus a notification to OB/GYNs that ondansetron may lead to adverse maternal or fetal outcomes is not necessary and could be misleading.

Id. at 19.

In what we find the most interesting part of the FDA’s discussion, the Agency reiterates that it is not in the business of evaluating the safety or efficiency of off-label uses:

[T]he Petition states that there are only a small number of studies regarding the efficacy of ondansetron in treating NVP or its relative efficacy . . . compared with other NVP treatments.  While this may be true, ondansetron is not approved for use to treat NVP.  Absent a compelling legal or public health concern, FDA generally does not comment on the number or quality of studies regarding the efficacy of a drug product for an unapproved use or provide notification to health care providers regarding its relative efficacy as compared to other drug products for such unapproved use.

Id. (emphasis added).  Nor, because of the lack of any “safety concern,” did the FDA require issuance of a “Dear Doctor” letter that pain pumps for ondansetron “may not be marketed or promoted in any way in the absence of FDA approval for [that] indication . . . and that such promotion is a violation of FDA regulations.”  Id. at 20.

The result of the FDA’s action is twofold – (1) because the FDA’s “compelling concern” standard for off-label warnings is not met, any warning-based tort claim about this particular off-label use should be preempted as “impossible,” since the manufacturer(s) of this drug have to get the FDA’s prior OK for such warnings, and (2) for these particular risks, there is “clear evidence” under Levine that the FDA would not permit any warnings.  So preemption should doubly bar any tort claims on the subject matter of the unsuccessful petition.

This is somewhat ironic.  Some of us are veterans of the Bendectin wars, in which scientifically bogus − Daubert v. Merrell Dow Pharmaceuticals, 509 U.S. 579 (1993), was a Bendectin case − but widespread, teratogenicity allegations forced off the market what was then the only drug FDA approved for the treatment of morning sickness.  Even now, there are very few (we think, only one) approved products intended for this use.  Not too many companies would want to run the risk of a similar avalanche of meritless, but expensive, litigation.

So off-label may well be better, from a liability standpoint, for products with therapeutic value for morning sickness.  If that use were on-label, then under Levine, the fact that label changes could be made unilaterally via “changes being effected” could let the litigation floodgates open.  With off-label use, however, FDA pre-approval (under the strict “compelling” need standard) is required.  Therefore, preemption applies because manufacturers cannot make warning changes about off-label uses independently of the FDA.  On-label:  no preemption; off-label:  preemption.  How would you prefer to defend that case?

From the moment we first read Levine, we’ve been convinced that it was wrongly decided.  The example of drugs used (mostly off-label) to treat morning sickness, and how Levine acts to discourage submission of this use to the FDA, is yet another reason why this is so.