Thursday, October 08, 2009

Off-Label Use - The Times They Are A Changin'

We’ve decided to get a couple of off-label use-related items off of our to-do-eventually list today. The first we’ve alluded to already. It's the First Amendment litigation that Allergan recently commenced against the FDA involving the truthful "promotion" of off-label use (specifically use of Botox to treat muscle spasticity). The second is a new law review article on off-label use: R. Dresser & J. Frader, “Off-Label Prescribing: A Call For Heightened Professional & Government Oversight,” 37 J.L. Med. & Ethics 476 (Fall 2009).



The first gives us some hope that, just as Conley gave way to Twombly, the FDA’s 50-year-old meat-axe approach to off-label promotion may not be long for this world. The second gives us some ideas or our own as to what an off-label promotion regime that complies with the First Amendment might look like – although our ideas aren't necessarily the ones that the article’s authors had in mind.


That a major pharmaceutical company has affirmatively stepped forward to challenge the FDA’s blanket off-label promotion prohibition is a big deal. Previously, the First Amendment issue had come up almost entirely in three contexts: (1) as a defense raised to criminal prosecutions for off-label promotion, (United States v. Caputo, 517 F.3d 935 (7th Cir. 2008); United States v. Caronia, 576 F. Supp.2d 385 (E.D.N.Y. 2008)); (2) in litigation brought by non-profit advocacy groups (Washington Legal Foundation v. Henney, 202 F.3d 331 (D.C. Cir. 2000); Washington Legal Foundation v. Friedman, 13 F. Supp.2d 51 (D.D.C. 1998)); or (3) in analogous litigation involving FDA regulation in other areas (Thompson v. Western States Medical Center, 535 U.S. 357 (2002) (pharmacy compounding); Pearson v. Shalala, 164 F.3d 650 (D.C. Cir. 1999) (dietary supplements).


Each of these prior contexts has significant drawbacks. The criminal cases are burdened with bad facts. Let's face it, the FDA doesn’t prosecute everybody; it picks its spots. We haven’t seen a prosecution yet that involved only truthful promotion of off-label use – and untruthful speech isn’t entitled to free speech protection. Thus, in the criminal prosecutions, the party raising the First Amendment won’t be very sympathetic, and the First Amendment issues (when reached at all) tend to wind up as dictum in opinions that uphold convictions on other grounds. There's a very real risk in these cases of bad facts making bad law.


Advocacy group litigation suffers from lack of a concrete dispute. The plaintiff doesn’t face prosecution or other administrative sanctions from the FDA. Such litigation skirts the edge of the case or controversy requirement, and as a result tends only to go as far as the Agency is willing to take it. That’s what happened with the WLF litigation. The WLF won most of the preliminary rounds, but when the FDA finally faced a significant risk that it might actually lose on appeal, it chose to withdraw the challenged position. That mooted the case, and years of litigation ended with only some good language in trial court opinions – and (more importantly) with the FDA emerging free to fight another day.


Finally, the analogous litigation is just that – analogous. Even though the FDA has lost significant First Amendment battles over truthful speech prohibitions in other areas, those opinions don’t, and can’t, require the Agency to change its position on off-label promotion of drugs or medical devices. And the FDA hasn’t chosen to do so. It professed willingness to look at the First Amendment issue generally in the aftermath of Western States Medical – but that initiative quickly disappeared into an administrative black hole, never to emerge again. See 67 Fed. Reg. 34942 (FDA May 16, 2002) (requesting comment on “First Amendment issues”). There hasn’t been a peep in the Federal Register responsive to the comments that the Agency sought in 2002.


One area where the First Amendment issue hasn't come up is in the various civil prosecutions of drug companies that state the DoJ, AGs (either “attorneys general” or “aspiring governors” – take your pick) or qui tam plaintiffs have brought concerning alleged off-label promotion in recent years. Why? One obvious reason is that big cases tend to settle because defendants generally are risk averse (this is the same reasons that certifying class actions leads to heavy settlement pressure). Another reason, more relevant to what we're discussing is that the First Amendment is something of a doomday defense, and regulated companies are reluctant to take on their regulator that directly. Regulated entities, rightly or wrongly, fear agency retaliation if they raise a defense with the potential of upsetting the entire regulatory applecart.


Nor does the Allergan suit suffer from the “bad facts” problem of the criminal cases. Initiating the suit allowed the company as plaintiff to choose the facts against which to pitch its legal arguments: limiting it solely to truthful distribution of accurate scientific information about a use that, according to the motion for preliminary injunction, is approved in just about every First World country in the world. The off-label use in question is also “medically accepted” so that it's reimbursed by federal government programs such as Medicare. Motion at 13. Not only that, just about all of the information sought to be distributed is safety related – advice to physicians about proper patient selection, how often the medicine should be dispensed, and where injections should be given. Id. at 14-15. Plaintiffs get to pick their battlegrounds; defendants don’t. That's also true when drug companies are plaintiffs.


Basically, in seeking a preliminary injunction, the motion accuses the FDA of taking an “innocuous” section of the FDCA and turning it into a blanket ban enforced by threat of criminal prosecution. This ban is created through the following steps:


  • The Food, Drug & Cosmetic Act (“FDCA” or “Act”) prohibits a manufacturer from “suggest[ing]” an off-label use of a drug in “labeling,” which the FDA has defined to include any tangible materials about that use that are disseminated by the manufacturer, whether or not they accompany the drug. 21 U.S.C. §§355(a), 321(p); 21 C.F.R. §202.1(l)(2).

  • The Government takes the position that it is unlawful to make even bona fide scientific claims about an off-label use in tangible materials about that use that are disseminated by the manufacturer, on the rationale that all speech about an off-label use is by definition “false or misleading.” See U.S. Sentencing Memo., United States v. Warner-Lambert Co. at 8–9, No. 04-10150 (D. Mass. 2004) (“Warner-Lambert Sentencing Memo”); 21 U.S.C. § 352(a).

  • The FDA has imposed a per se ban on “advertisement[s]” for an off-label use of a prescription drug, 21 C.F.R. §202.1(e)(4)(i)(a), including advertisements directed to health care professionals.

  • And FDA regulations prohibit a manufacturer from “express[ing]” an “intent” or merely “know[ing]” or having “notice” that its product “is to be used” off-label. 21 C.F.R. §§201.100, 201.128; see 21 U.S.C. §352(f)(1).

Preliminary Injunction Motion at 2-3. Each step, the motion charges, is unconstitutional because there is no clear intent of Congress to prohibit truthful scientific speech. The FDA has used a strained reading of the statute, to “hide elephants in mouseholes.” Id. at 3.


Thus the FDA’s regulatory regime: (1) prohibits communication of information about off-label uses through any form of printed material or media advertising – even though such uses are themselves perfectly legal; (2) imposes a “per se” ban without regard to truth or the amount of scientific support a statement might have; (3) absolutely prohibits not just communication but mere knowledge of off-label uses; and (4) is without meaningful safe harbors for truthful scientific speech protected by the First Amendment. Motion at 8-12 (we’ve simply adapted the headings here – the motion itself discusses each of these features in depth).


This regime, variously described as a “Catch 22” (id. at 11) and as “Kafkaesque” (id. at 17), prohibits even the distribution of scientifically accurate, safety-related information by a manufacturer if it involves off-label use:



The inconsistency that lies at the heart of the FDA’s regulatory regime places [plaintiff] in an untenable position. While on the one hand the FDA encourages off-label uses as an integral part of quality medical care, on the other hand its regulations forbid a manufacturer from selling an approved drug with constructive knowledge that it is to be used off-label. [Plaintiff] can hardly avoid violating this Kafkaesque rule. Off-label use accounts for a substantial percentage of [the drug’s] and this is likely to continue even if the FDA approves [additional uses under consideration]. [Plaintiff’s] only choice is to speak as little as possible so that prosecutors, in the exercise of their discretion, hopefully will not decide to prosecute it.


Motion at 17.


The basic four-pronged First Amendment/commercial speech argument itself is familiar to any regular reader of this blog. See here, here, here, and especially here. Thus, we’re not going to go and repeat the entire First Amendment argument made in the motion.


We simply note the following points in the Allergan motion, which we find new or otherwise interesting in the off-label use/First Amendment context:


  • Scientific speech is not just somewhat protected commercial speech, but fully protected core speech. And commercial speech intertwined with fully-protected scientific speech receives full protection. Motion at 19-20.

  • If pushed, plaintiff will argue that Central Hudson should be overturned and commercial speech afforded full First Amendment protection. Motion at 20 n.7.

  • A government interest in protecting the FDA’s authority cannot justify censoring truthful scientific/commercial speech that itself has public health implications. Motion at 23.

  • Government paternalism, bad to start with, is even worse in the prescription drug situation, considering that physicians are highly skilled professionals. Motion at 23-24.

  • The FDA’s regime doesn’t distinguish between blatant hucksterism and truthful scientific information, thus rendering the prohibition wildly overbroad. Motion at 24-25.

  • The entire prohibition rests upon the FDA’s invalidly broad interpretation of the language of the FDCA. The Act must be interpreted narrowly to ensure its constitutionality. Motion at 25, 30-31.

  • The FDA’s regulations prohibit off-label promotion even once the supposed government interest – submission of the use for FDA approval – has been accomplished. Motion at 26.

  • The “objective intent” regulation (§201.128) criminalizing mere knowledge of off-label use is inconsistent with the supposed governmental interest in that submission of a new use to the FDA could be evidence of illegal knowledge. Motion at 26-27.

  • New (limited to ones, ones we haven’t briefed ourselves) less burdensome alternatives: allowing more promotion as a use advanced through the stages of the approval process; higher taxes on medications sold for off-label use. Motion at 27-28.

  • A prescription drug is a prescription drug, and does not become less so due to off-label use. Therefore, the requirement of “adequate directions for use” does not apply to off-label use and the entire regulatory house of cards upon which the FDA’s prohibition is based falls. Motion at 31-33 (not being regulatory lawyers, we hadn’t thought of that).

  • The FDA’s expansive definition of labeling should be trimmed. The supposed support for that, the Kordel case, was decided before the development of modern First Amendment law, and in any event has been greatly overread by the FDA. Motion at 35-37.

  • Government pre-approval is not a precondition for the dissemination of truthful scientific information. Motion at 37-40.

  • The FDA cannot indiscriminately ban advertising of off-label use, not only to the public, but to physicians as well. Motion at 41-42.

  • Prohibitions relating to off-label uses that are already prevalent and accepted in the medical community – so much so that Medicare reimburses them – cannot be banned. Motion at 43-44.

  • At the very least, where the FDA has ordered a manufacturer to warn about the risks of an off-label use, it cannot ban truthful information that assists physicians in avoiding or managing that risk. Motion at 44.

Remember, these highlights are just the things that strike us – who have briefed this issue ourselves – as particularly new or useful. Anyone interested in the intersection of off-label use and First Amendment should certainly read the motion in its entirety.


One more thing – don’t forget that the Supreme Court has a big First Amendment case before it right now. Citizens United v. FEC (08-205). Some knowledgeable commentators think that that case could wind up being a ringing endorsement of the First Amendment rights of corporations generally. See here (at analysis and oral argument recap). If that happens, it would likely strengthen the case for an injunction against the FDA even further.


In an interesting juxtaposition, this new litigation against the FDA comes shortly after the release of the Dresser (a lawyer) and Frader (a doctor) article on off-label use. Their article deals mostly with responsible off-label prescribing, rather than FDA regulatory issues (although those are certainly mentioned as well). Their thesis is:



Responsible off-label prescribing requires physicians to: (1) evaluate whether there is sufficient evidence to justify an off-label use; (2) press for additional information and research when adequate evidence is lacking; and (3) inform patients about the uncertainties and potential costs associated with off-label prescribing.


37 J.L. Med. & Ethics at 476. That sounds reasonable to us. Our informed consent position has always been that uncertainty is a medical risk that, when it impacts upon the likely success of medical treatment, should be part of the informed consent discussion. That makes much more sense than the blunderbuss proposition that all off-label use, simply because it’s off-label, should be disclosed to patients. After all, as the article recognizes, “[a]n off-label use may provide the best available intervention for a patient, as well as the standard of care for a particular health problem.” Id.


As for the fate of the FDA’s off-label use prohibitions, the article seems to be of the view that a lot of those prohibitions will eventually be struck down, but that “disclosure requirements and prohibitions on consumer advertising” will remain. Id. at 478. In addition to whatever restrictions the FDA places on promotion, the article identifies “ethical considerations” for doctors engaging in off-label prescribing:



(1) evaluating the existing evidence for off-label prescribing; and (2) collecting information and conducting research when there is inadequate evidence about an off-label use. A third consideration addresses disclosure to patients: what should physicians tell patients about off-label interventions?


Id. at 479.


With respect to the first of these, the article provides a useful compendium of sources that make it their business to evaluate off-label uses, listing the American Hospital Formulary Service Drug Information, DrugDex, the Agency for Healthcare Research and Quality, and the Medical letter. Id. There are cites for all of these in the article, so if you want them, go read it.



Following the obligatory jab at the fact of industry-supported research, id., the authors go beyond simply bemoaning the fact that drug companies are for-profit entities and actually propose something else, at least for off-label use:




Professional organizations and the academic community should actively identify emerging off-label uses and gather information about such uses. As physicians learn about patient responses to off-label uses, they should share information about side effects and outcomes with colleagues through publications, presentations, and other methods of communication. They should also alert manufacturers and the FDA to any adverse events associated with an off-label use. Medical journals and websites should promote communication by setting aside space for reports about emerging off-label applications. Health care institutions should develop policies on off-label prescribing and exchange information about positive and negative experiences with off-label applications.

Id. at 480. We don’t really disagree with any of this either.


The article would also like to promote “research about off-label uses.” Id. Frankly, so would we. “If members of the profession think that an off-label use is developing without adequate evidentiary support or examination of potential harms, they should urge manufacturers to sponsor the needed research.” Id. Agreed, but the companies are, after all, profit making entities. If there actually were a profit of some sort in doing this, there’d be no need to ask them.


Then there’s the issue of warning patients. The authors note that “[s]ome commentators (that would be Bexis) argue that information about off-label status is less important than information about the evidence that supports a product's use in an individual patient’s case,” and that this has been the answer courts have given. Id. The article then goes on to discuss what “professional groups” propose regarding patient disclosure of off-label use. Interestingly, these medically-related guidelines seem entirely consistent with the legal consensus:


  • “to use professional judgment in deciding when to discuss with patients and parents a drug’s off-label status and its acceptance in the medical community" (AAP Committee on Drugs);

  • “discuss potential benefits and harms of off-label applications with patients” (various European sources);

  • “informing patients when a proposed off-label use is unusual or offered as a ‘last resort’” (Australia).

Like the law has done, the medical societies focus on medical risks and benefits, or else the existence of actual uncertainty, and call for exercise of medical judgment. Interestingly, only “legal commentators,” not any medical ones, support the kind of FDA-status-based requirements that the courts have rejected. Id. The article’s conclusion:




We think that reasonable patients would want to know when an off-label application lacks strong support in the scientific or medical literature, when experience suggests the use involves substantial risk, or when there is a possibility that insurers will refuse to cover a costly off-label application.

Id. at 481 (footnote omitted). We pretty much agree, although whether one’s insurer is likely to be obnoxious isn’t really a basis for imposing any legal duty on a third person. As a practical matter, divorced from legal duty, such disclosure doesn’t bother us. In fact, it gives us food for thought.


In discussing “specific” off-label situations, the article distinguishes between off-label use of “newly approved” as opposed to “older products.” Novelty, the article argues, goes hand in hand with risk. “Physicians prescribing products for innovative off-label uses should tell patients about the unknowns, monitor them closely, and begin collecting formal study data.” Id. Older off-label uses are more likely to be safe, but come with their own issues:




One problem in this area is that product manufacturers often lack financial incentives to sponsor research on older products, because the products are no longer protected by patent or are widely prescribed without formal supplemental approval. As a result, it may be necessary to seek government or other noncommercial support for research.

Id. We agree with the recognition of the problem, but we’re wondering whether there might be a different solution.


After reviewing the FDA’s recent “good reprint practices” guidance (more about that here), the article offers the following proposals for “policy reforms”:


  • a mechanism that “recommend[s] or require[s] that manufacturers work toward FDA approval of the uses discussed.”

  • a “requirement for manufacturers to give the FDA an opportunity to review the materials before they are given to physicians”

  • “A more direct approach to promoting patients’ interests would be to require manufacturers to submit more off-label uses for FDA review.”

  • “The FDA could simplify the requirements for adding new uses to the approved product label or allow labels to include more information about off-label uses.”

  • “The agency could. . .analyze and distribute reports about the evidence on selected off-label uses and require manufacturers seeking initial product approval to present information about potential off-label uses.”

  • “Congress could create financial incentives, such as an additional period of market exclusivity, for manufacturers sponsoring research on wide-spread or promising off-label uses.”

  • “Federal officials could adopt more rigorous policies on reimbursement for off-label uses, limiting Medicare and Medicaid payments.”

Id. at 482-83.


In making these proposals, the article acknowledges the First Amendment as a constraint on governmental restrictions of speech:




The critics, however, under-estimate the First Amendment problems with imposing severe restrictions on distribution of scientific and medical publications about off-label uses. They also assume that physicians will make better prescribing decisions if manufacturers are prohibited from distributing enduring materials about off-label uses. Such a ban might reduce the incidence of off-label prescribing, for it could reduce the number of physicians aware of potential off-label applications.

Id. at 483. Keeping doctors ignorant isn't a recipe for better healthcare for patients.


This one-two punch of a thoughtful article on off-label use followed up quickly by litigation that presents the First Amendment issues squarely for the first time in the context of legitimate scientific information has gotten us thinking – always a dangerous proposition.


We think that if the FDA wants to salvage legitimate restrictions upon promotion of off-label uses, as well as to move to a regime that respects constitutional rights, it needs to ditch its archaic one-size-fits-all prohibition and recognize as the article does that there is a hierarchy of off-label uses.


Both the Allergan litigation and the article recognize that the government is required to keep lists of “medically accepted” off-label uses, and that Medicare reimburses those uses. See 42 U.S.C. §§1396b(i)(10), 1396r-8(k)(2, 6). We think that promotion (within reasonable time, place, and manner limits) should be allowed for all these off-label uses that even the government recognizes are “medically accepted.” The FDA’s prohibition in this context affirmatively injures the public health by depriving doctors of truthful, scientifically valid information about uses that are either the medical standard of care, or at least a “medically accepted” treatment option.


Once ditching its prohibition based upon speech, the FDA could be given power to condition approval of off-label promotion with a “mandat[e] that manufacturers apply for FDA approval of certain off-label uses, such as uses that pass a threshold of prevalence or sales.” Motion at 27. Such a mandate would have to include generic manufacturers as well, since in a lot of these situations the drug may already be off-patent, or be so close to going off-patent that it’s only fair for generics to bear part of the burden.


As to off-label uses that have not achieved “medical acceptance,” we think that more restrictive limits upon promotion are appropriate – but we don’t think that, even there, the FDA can get away with an outright prohibition. We wonder if, with respect to less proven uses, the system through which physicians report adverse drug reactions to the FDA shouldn’t be made mandatory. There’s also a more persuasive argument to be made that all off-label “promotion” of such uses that don't have medical acceptance should be restricted to purely scientific information presented in a scientific format, either along the lines of the current “enduring materials” guidance or through continuing medical education programs. We also agree that more information is better than less, and thus the results of every medical study of such uses, regardless of who conducts it, should be made available to doctors on some centralized site.


We’re not regulatory experts and we don’t claim to have all the answers. There may be reasons we aren’t aware of why some of these proposals might not work – and we won’t mind if you tell us. There are undoubtedly other elements that could be added.


But given current state of constitutional law concerning freedom of scientific and commercial speech, we’d be surprised if the current FDA prohibition upon truthful manufacturers’ speech about off-label uses survives in anything close to its current form. That’s especially so if the Allergan suit prompts similar litigation by other companies that targets other factual situations where the current ban doesn’t make any sense. We think change is coming, and it will soon shake the FDA’s windows and rattle its walls. The FDA needs, for once, to get out in front of the curve – for he that gets hurt will be he who has stalled.

4 comments:

Soronel Haetir said...

If you guys had won on preemption I would be far less sympathetic in this area. But with losing that battle manufacturers should be free to speak about what they truthfully know, if for no other reason than to reduce their own liability.

Anonymous said...

How do you achieve truthful disclosure without clinical trials? The Solutions are far simpler than you portray.

Solution 1 Require Pharma to fully disclose in writing to every doctor wishing to use the drug or device off label every possible complication or side effect. Step 2Require the Doctors to pass the same information in writing to each prospective patient. If patient still wants to use the off label drug or device have them sign an agreement indemnifying the Doctor and manufacturer. Solution 2 Create a small group of patients comprised of Pharma Execs and their Families plus Pharma Defense council and their families to ingest the drug on a trial off label basis for 2 years. If it works market away if harm occurs at least they will not have wasted a lot of money.Full truthful disclosure is the only ethical answer. Often he who gets hurt is he who trusted.

Anonymous said...

Pharma companies are free to provide truthful scientific information related to the off-label use of their products IF the request is unsolicited. This is the role that Scientific and Medical Affairs Liasons and Clinical Communications play. Allergan is seeking to communicate this information proactively and presumably by sales representatives whose primary goal is increasing sales.

Furthermore, 'truthful information' can also reflect cherry-picked information, misleading information and information lacking fair balance.

Anonymous said...

I don't understand the purpose of the suit. FDA published a guidance document earlier this year regarding the circumsntances under which pharma companies can proactively distribute truthful, non-misleading scientific information to physicians. http://www.fda.gov/RegulatoryInformation/Guidances/ucm125126.htm I read Allergan's suit, and they seem to be asking for a right that they already have (as recognized by the previous WLF cases and, more recently, in the FDA Guidance). What's the distinction? Everything that Allergan is asking to be allowed to do seems to me to be allowed by the Guidance. (Is it that the Guidance isn't binding, and they want a Court to essentially validate the Guidance into law?)