New Draft FDA Guidance On Off-label Uses Raises Concerns

On March 3, 2014, FDA made available for comment a revised draft of its "Guidance for Industry: Distributing Scientific and Medical Publications on Unapproved New Uses--Recommended Practices".  The revised guidance seeks to clarify and expand upon FDA's 2009 draft guidance that generated significant controversy. Although the recently released draft guidance addresses some industry concerns, does it address the concerns of those who believed the earlier guidance took a position at variance with the First Amendment?    

An excellent discussion of the revised draft guidance is provided in the Client Alert recently issued by Epstein Becker Green attorneys Amy K. Dow, Ryan R. Benz and Daniel G. Gottlieb.  In summary, the draft guidance expands upon the types of materials that may be distributed (subject to FDA's enforcement discretion) and, for the first time, includes clinical practice guidelines.  In particular, industry had been pushing for more clarity from FDA on this issue. The draft guidance requires that a manufacturer, before disseminating a clinical practice guideline, establish that the clinical practice guideline is "trustworthy" and, as detailed in the Client Alert, meets six tests based on standards developed by the Institute of Medicine.   

Of particular interest, however, is the extent to which FDA may be modifying its position on restrictions on truthful, non-misleading, off-label speech in light of the Second Circuit's important  2012 decision in U.S. v. Caronia.

FDA  has long held the position that, although off-label promotion by pharmaceutical manufacturers and/or their agents is not expressly prohibited by the FDCA or its attendant regulations, such commercial activities are impliedly prohibited as "misbranding."   Thus, when a drug is placed in interstate commerce without adequate directions for use and adequate warnings It is the FDA's view that, by definition, a drug fails to bear adequate directions for an off-label use. Therefore, promotion beyond the scope of the product label may be construed as "misbranding" in violation of the FDCA.

In Caronia, the Second Circuit vacated the conviction of Alfred Caronia, a former pharmaceutical sales representative for Jazz Pharmaceuticals whom a federal district court jury found guilty of conspiring to introduce a "misbranded" drug into interstate commerce in violation of the FDCA.  

The majority held that the FDCA's misbranding provisions cannot be interpreted as a blanket ban on off-label promotion by pharmaceutical manufacturers. However, the court was clear that its holding did not prevent the FDA from regulating the marketing or promotion of prescription drugs and limited its decision to the truthful off-label promotion of prescription drugs for which an off-label use is not prohibited.  The court also stated that more narrowly tailored regulation of speech by the FDA as it concerns off-label use might survive judicial scrutiny.

In analyzing Caronia, it is important to keep in mind that courts, in general, are hesitant to criminalize speech without an articulable public good (such as harm or safety) to be gained from doing so. That is, a desire merely to stop speech is not a sufficient interest (without another countervailing public need) in order to permit the government to regulate or prohibit speech.

In earlier cases, the Supreme Court has disfavored categorical bans on truthful, non-misleading speech because it arises from the "paternalistic assumption" that the public will use truthful, non-misleading commercial information unwisely,  Such paternalism is all the more misguided when the speech is being directed to the medical community over whom  FDA can assert no regulatory authority.  A medical clinician, who has presumably more knowledge than FDA staffers about the diseases and conditions she treats, should not be unnecessarily hamstrung in seeking to become more knowledgeable about a particular drug.

Although Caronia represented a setback for the Agency, it is inaccurate to conclude from this decision that FDA does not retain broad regulatory authority  to regulate promotional speech. The likely battleground in the future will be when the First Amendment is raised as a defense to civil fraud cases, particularly qui tam actions, brought under the federal civil False Claims Act.

The revised draft guidance does not include the same blanket prohibitions included in the earlier pre-Caronia guidance. Under the revised draft guidance, some highlighting and summarizing is permitted as long as it does not promote an off-label use or is misleading. Although FDA clearly still believes that it can regulate non-misleading speech, it has backed off somewhat (perhaps in light of Caronia), and sought to bolster its position by adhering closely to the statutory prohibitions in the FDCA.

A thorough discussion of Caronia and its possible ramifications was the subject of a Client Alert authored by Epstein Becker Green's Stuart M. Gerson, Wendy C. Goldstein, Benjamin S. Martin, Daniel G. Gottlieb, David C. Gibbons, and Natasha F. Thoren issued on the heels of the Second Circuit's publication of its decision.

In the absence of further modification of the draft guidance, to what extent will the risk of noncompliance outweigh the benefit to industry of being able to distribute scientific or medical publications on unapproved new uses?  How will the new guidance affect, if at all, the ability of the medical community to obtain reliable information on off-label uses from drug manufacturers?  It will be interesting to see how the various stakeholders' positions evolve during discussions over the coming months.

Pharmaceutical Failure to Warn.... On Facebook?

The Facebook page of Switzerland-based drug maker, IBSA Institut Biochimique S.A. (“IBSA”), appeared innocent enough: 

If you have just been diagnosed with hypothyroidism or are having difficulty controlling your levothyroxine blood levels, talk to your doctor about prescription Tirosint, a unique liquid gel cap form of levothyroxine.

In an untitled letter to the drug maker on February 28, 2014, FDA advised IBSA that its Facebook webpage was false or misleading because it made representations about the efficacy of Tirosint, but failed to communicate any risk information associated with its use and omitted material facts regarding Tirosint's FDA-approved indications. 

FDA advised IBSA that the webpage misbranded Tirosint within the meaning of the Federal Food, Drug and Cosmetic Act (“FDCA”) and made its distribution violative of federal regulation. Specifically, FDA referenced 21 U.S.C. 352(a), (n); 321(n); 331(a); and 21 CFR 202.1(e)(5). Further, FDA reminded the company that Tirosint is associated with a number of serious risks and includes a Boxed Warning indicating that Tirosint should not be used for the treatment of obesity or for weight loss, among other potential risks associated with the use of this medication.  FDA also alleged that IBSA had failed to disclose important limitations on the approved indications of the product, increasing the risk that the product would be used in patients with conditions that were expressly excluded from the approved indications for use.

FDA and the regulated community has been grappling for some time over what might constitute the improvident use of social media. Unquestionably, a pharmaceutical company will run afoul of FDA if product risks are not disclosed. In this instance, FDA noted that IBSA had failed to disclose any (emphasis FDA’s) of the risks associated with the product’s use. 

FDA directed IBSA to immediately cease activity violative of the Act and to submit a plan for discontinuing the use of all non-compliant promotional materials.

Despite the public attention given to IBSA’s ill-advised social media posting, the pharmaceutical industry and the medical community have made significant strides in recent years to ensure that physicians are receiving full and complete information concerning the medications they are prescribing for their patients. 

One enormous step in the right direction is Sermo, an online community for physicians founded in 2006. Sermo was originally founded by doctors, for doctors. Originally imagined as an adverse effect reporting system without industry influence, Sermo is now a vibrant place where physicians can post observations and questions about clinical issues and hear other doctors’ opinions. 

In just a few short years, Sermo has grown to include 200,000 licensed physicians. Some of the heaviest users of Sermo are older physicians, which is somewhat surprising in that the youngest members of a professional group typically adopt technologies first. 

Increasingly, the major pharmaceutical companies take the view that social media and other on-line resources can provide an important tool in ensuring that its products are used safely, effectively and appropriately. 

At a public hearing conducted by FDA in 2009, Dr. Freda Lewis-Hall, the Chief Medical Officer for Pfizer, reported that the average physician spends about eight hours a week using the internet for professional purposes; that 87% of physicians are interacting with drug and device companies online; and that 60% of physicians are interested in participating in online communities. She opined that the majority of physicians want to engage with health care companies in the social media space to obtain drug information.  These physician participation statistics are probably even more striking today.

Pfizer and other companies now communicate with physicians through social media, particularly through collaboration with Sermo. Dr. Lewis-Hall describes Sermo as the online physician’s lounge where informal but highly valuable consults take place.

On January 13, 2014, FDA issued a portion of its long-awaited social media guidance titled "Fulfilling Regulatory Requirements for Postmarketing Submissions of Interactive Promotional Media for Prescription Human and Animal Drugs and Biologics".  Although industry is likely to seek clarification and revision on certain of the rules-of-the-road discussed in the draft, some of the basic concepts expressed are:

1. a company will not be deemed responsible for visitor posts on company-run social media (blogs, chat rooms, message boards, etc) so long as the visitor has no affiliation with the company and the company has no influence over the user-generated content;

2. a company is responsible for content generated by an agent or employee.

3. every advertisement on social media must contain a "fair balance" of the risks and benefits of a drug product and complete disclosure of the product's approved indications for use.  Query. Could a Twitter entry with its 140-character limit ever meet this standard?  FDA is supposed to provide further guidance on this concern down the line.

4. marketing material postmarketing submission requirements must be complied with for any site where the company "exerts influence.......even if the influence is limited in scope. For example, if the firm collaborates on or has editorial, preview, or review privilege over the content provided, then it is responsible for that content."  However, if the company only provides financial support to the site, and its influence is otherwise limited, there is not a reporting requirement. 

The issue of "exerting influence" is problematic and, despite some helpful hypotheticals in the guidance, ambiguous.  Big Pharma has an interest, perhaps even a responsibility, to be involved in e-media forums where the scientific and medical community is seeking interactive information on pharmaceutical products.  However, the draft guidance arguably produces a push-pull reaction.  Do we engage or, by engaging, do we run the risk of having an added regulatory burden by having to file FDA reports concerning participation on the site?  Some clarity for the industry is warranted to avoid over and under-reporting.  

As reflected in this discussion, as all of us – consumers and companies – continue to move forward in a world increasingly dominated by social media, challenges and opportunities abound. On the one hand, there are the missteps, as we see in the case of IBSA. On the other hand, the pharmaceutical industry is moving ahead of the curve to use social media to ensure that its prescribing physicians are well-educated and their patients provided the best possible care. We hope that the final social media guidance facilitates, rather than impedes, this process.

The author acknowledges the important contributions made to this article by Amy K. Dow, a partner at Epstein Becker Green, and Natasha F. Thoren, an associate

FDA Reports 12% of U.S. Spice Imports Contaminated With Insect Parts And Rodent Hairs...What's In Your Salad?

New York Times reporter Gardiner Harris reported on October 30, 2013 that an FDA study found that about 12 percent of spices brought to the United States are contaminated with insect parts, whole insects, rodent hairs and other things, based upon an analysis of spice imports.

According to FDA officials, it is unclear what share of the nearly 1.2 million annual salmonella illnesses in the United States result from consuming contaminated spices.  Less  than 2,000 people had their illnesses definitively tied to contaminated spices from 1973 to 2010, and most people eat spices in small quantities.   But because people often fail to remember eating spices when asked what foods might have sickened them, FDA officials speculated that problems related to spices may be under-reported.  The Scientific literature has associated foodborne illness outbreaks from microbial contaminants in spices.

According to the FDA, spice imports from Mexico and India have been found to have the highest rate of contamination. Nearly one-quarter of the spices, oils and food colorings used in the United States comes from India. However, reports have associated salmonella outbreaks with spices associated with other spice exporters as well, including Italy. The spices under scrutiny include widely sold, everyday spices, including oregano and basil, among many others. 

"The American Spice Trade Association, which is dedicated to ensuring the supply of clean, safe spice to the American public, had not yet seen the FDA report and therefore could not comment.  However, spice manufacturers have argued in the past that food manufacturers often treat imported spices before marketing them. Therefore,  findings of contamination levels in FDA's import screening program do not necessarily mean that spices sold to consumers are dangerous.

The adverse publicity facing the spice industry is endemic of much greater litigation risks to the food industry as a whole.  “The New Lawsuit Ecosystem” (10/13), a report issued by the U.S. Chamber Institute for Legal Reform, identifies food class action litigation as an emerging liability threat to American business.

The Executive Summary states that the report describes the "lawsuit 'ecosystem'  for the areas of litigation abuse of most concern to the business community....Defending these lawsuits drains millions of dollars from businesses that could be spent spurring business expansion and creating new jobs with few countervailing benefits.”  Although the emphasis of the discussion concerns class action litigation alleging trivial violations of federal regulations, there is no question that food poisoning claims have riveted media and public attention as well.  Some plaintiff lawyers have devoted their entire practice to the prosecution of food poisoning claims.  

Food poisoning litigation has also become big business for companies that host legal conferences.  An upcoming conference in San Francisco, sponsored by the American Conference Institute, is titled "Food Borne Illness Litigation: Advanced strategies for Defending and Managing High Profile Food Contamination Claims".  An advertisement for the conference leads with the following:

Each year roughly 1 in 6 Americans (or 48 million people) get sick, 128,000 are hospitalized, and 3,000 die of foodborne diseases.”

- 2011 Estimates from the Center for Disease Control and Prevention

There is no question – as the food supply becomes more global, the chance of contamination increases. The latest food outbreaks come from non-traditional pathogens and foods that came from overseas - the number of affected people is still unknown. In addition, the increasing reliance on international suppliers has led to a host of supply chain food safety issues that are increasingly difficult to monitor and combat.

The defense bar is also mobilizing considerable resources and effort to assist companies targeted by plaintiff lawyers. One prominent defense firm is urging its clients to be prepared by assembling a litigation response team to develop a "thorough traceback program through which food items can be traced back to their origins".  This firm cautions that defending these cases is not for amateurs, but requires the "coordination of expedited investigation and documentation, evidence location and preservation, supplier agreements and indemnification commitments, selection of and consultation with (often) a constellation of experts...."  

Any litigation arising from Mr. Harris' story in the New York Times about contaminated imported spices should be recognized for what it really is.....the tip of an enormous iceberg that has been heading toward the food industry for some time. 

 

Fungal Meningitis Outbreak Spurs FDA Oversight Of Drug Compounders

In 2012, a major outbreak of fungal meningitis was traced to drugs compounded by New England Compounding Centers. The outbreak included approximately 750 confirmed cases and has resulted in 64 deaths to date. Tragedies of this scale have often been the impetus for major changes to federal food and drug laws in the past; the FDCA itself was enacted in 1938 in response to a tragedy in which the use of an improperly manufactured drug (elixir sulfanilamide) led to over 100 patient deaths.

Drug compounding is a process of combining different ingredients to create customized pharmaceutical products for patients.  The practice predates the rise of mass-produced drugs in the United States, and was essentially unregulated by FDA for 50-plus years after passage of the FDCA.

In a Client Alert titled, "Major Changes in Drug Compounding and Drug Distribution Requirements (Part 1 of 2)", Epstein Becker & Green health care practice partners, James A. Boiani (D.C.) and Kim Tyrell-Knott (San Diego), provide an insightful analysis of the Drug Quality and Security Act (H.R. 3204). 

According to Jim and Kim, the bill is compromise legislation crafted by the Senate Health, Education, Labor, and Pension (“HELP”) and House Energy and Commerce Committees, and is expected to pass the Senate soon after it reconvenes today. Once signed into law, H.R. 3204 will fundamentally change the regulation of drug compounding and drug distribution in the United States.

We look forward to the publication of Part 2 of their Alert concerning this important piece of legislation.

Adding Primary Jurisdiction To The Defense Lawyer's Toolbox

When the preemption defense is not available, it may still be possible to effectively dismiss a plaintiff's claim by arguing that the court should consider primary jurisdiction. Primary jurisdiction is a judicially created doctrine that addresses the proper relationship between court and administrative agencies. 

Raising primary jurisdiction may be particularly helpful to food and cosmetics manufacturers where a plaintiff's particular deceptive trade practice allegations may not be specifically addressed by FDA (or Nutrition Labeling and Education Act , "NLEA" ) regulation. A case in point is Astiana v. Hain Celestial Group, Inc., a putative class action in which plaintiffs alleged that the defendant's claims of "all natural" and "pure, natural & organic" were false and misleading under California law.  In dismissing the case, the California court agreed that the FDA, rather than the court, should evaluate plaintiffs' claims in an administrative setting in light of the complexity of the issues presented and the agency's expertise in the subject matter. 

An excellent explanation of primary jurisdiction is found in a decision by U.S. District Court Judge Susan R. Nelson in Taradejna v. General Mills, Inc., 909 F.Supp.2d 1128 (D.Minn. 2012):

Primary jurisdiction is a common-law doctrine that is utilized to coordinate judicial and administrative decision making. Although there is no fixed formula for deciding whether to apply the doctrine, the doctrine applies where a claim is originally cognizable in the courts, and comes into play whenever enforcement of the claim requires the resolution of issues which, under a regulatory scheme, have been placed within the special competence of an administrative body. Agency expertise is the most common reason that courts apply the doctrine of primary jurisdiction. In addition, courts apply the doctrine to promote uniformity and consistency within the particular field of regulation. . . . When the primary jurisdiction doctrine applies, the district court has discretion either to stay the case and retain jurisdiction or, if the parties would not be unfairly disadvantaged, to dismiss the case without prejudice. Id. at 1134

In Taradejna, the Minnesota court applied primary jurisdiction to dismiss a plaintiff's case relating to the advertising and selling of "Yoplait Greek" yogurt.  As discussed in the Product Liability Monitor, Lisa Sokolowski of Weil, Gotshal & Manges LLP concludes her thoughtful discussion of the decision commenting that "Judge Nelson ultimately found that the ambiguity and murky regulatory history surrounding the FDA’s “standard of identity” for yogurt meant that the U.S. Food and Drug Administration (“FDA”) should decide whether defendants’ actions violated the law."

In addition to Ms. Sokolowski, some astute commentators have weighed in on the preemption/primary jurisdiction distinction in recent months.  James A. Becker of Reed Smith authored a well-written discussion in Drug and Device Law (11/28/12) titled "Primary Jurisdiction: A Natural Alternative to Preemption".  Glenn Pogust and Michael Gruver at Kaye Scholer authored an article titled "Preemption and Jurisdiction Defenses in Caffeine Litigation", which appeared in the New York Law Journal on July 11, 2013.  Reading these authors should provide defense counsel with a road map concerning the kinds of cases in which primary jurisdiction arguments may succeed.

Supreme Court's Bartlett Decision Could Strengthen FIFRA Preemption

The U.S. Supreme Court’s decision in Mutual Pharmaceutical Co., Inc. v. Bartlett, No. 12-142, decided June 24, 2013, may assist defense counsel in defending product liability cases involving FIFRA-regulated products such as herbicides and pesticides. Although Bartlett involved design defect claims against manufacturers of generic drugs, which are regulated by FDA, the principles enunciated in Bartlett potentially have much greater application.

In Bartlett, the court held that the Federal Food, Drug and Cosmetic Act preempts state-law design defect claims against manufacturers of generic drugs. The court rejected outright plaintiff’s contention that under the so-called “stop-selling” theory, a generic manufacturer could comply with both federal and state law merely by removing its drug from the market.

In rejecting that argument, Justice Samuel Alito, writing for the majority, held that “the incoherence of the stop-selling theory becomes plain when viewed through the lens of our previous cases. In every instance in which the court has found impossibility pre-emption, the ‘direct conflict’ between federal and state law duties could easily have been avoided if the regulated actor had simply ceased acting.”

Thus, in reversing the First Circuit decision, the court slammed the door on plaintiffs hoping to circumvent the preemption defense by contending that a manufacturer might merely stop selling the product.

In an article in Law360 titled, “Bartlett’s Benefits Will Extend Beyond Generic Drug Makers,” 6/28/13, commentators offer the view that pesticide manufacturers may now be protected from plaintiff alleging a stop-selling theory of liability.  If the case’s holding is so extended, plaintiffs should no longer be able to allege that an herbicide manufacturer should not have placed a pesticide into commerce in the first instance. In essence, this is a variation of the often espoused argument that a product should not be marketed because its risks outweigh any potential benefits.  After all, the whole point of federal regulation is the underlying assumption you are going to market the product.