Center for Health & Pharmaceutical Law & Policy Introduces First Edition of Pharmaceutical and Medical Device Compliance Manual
The Seton Hall Law Center for Health & Pharmaceutical Law & Policy, American Health Lawyers Association (AHLA) and the Food and Drug Law Institute (FDLI) have released the first edition of the Pharmaceutical and Medical Device Compliance Manual. The Manual is a guide to deciphering the intricate web of federal and state laws and the practices of regulatory and enforcement authorities within the healthcare and life sciences arena, while also providing the practical skills needed to implement an effective compliance program.
Designed to aid health law attorneys, compliance professionals and others in the pharmaceutical and medical device field, the Manual explains the law in layman’s terms in addition to providing advice and guidelines on creating, managing, monitoring and auditing an effective compliance program, in essence, marrying legal expectations with the operational demands of business units.
The book was co-edited by Seton Hall Law Associate Dean Kathleen M. Boozang, J.D., LL.M., who founded the school’s Health Law program in 1990, ranked among the top 10 by U.S. News & World Report for the past 16 years; and by Simone Handler-Hutchinson, J.D. ’93, Executive Director of the Center for Health & Pharmaceutical Law & Policy.
Dean Boozang notes: “Over the last two decades the trend in government oversight has resulted in a regulatory environment of increased accountability among organizations across a number of sectors, with the health and life sciences industries being the subject of particular attention – a trend that shows no sign of waning. We produced this manual for compliance officers, health and life sciences lawyers and their clients to enable them to build a framework for creating and sustaining an effective compliance function.”
As co-editor, Ms. Handler-Hutchinson said, “Each chapter was written by a leading regulatory official, practicing attorney, or healthcare consultant who has either shaped the policies as an official and/or counsel in the nation’s regulatory agencies, served as counsel to or built compliance functions within life science corporations. They offer first hand, in-depth compliance insight and actionable advice.”
The Pharmaceutical and Medical Device Compliance Manual is available as a softbound book and a variety of eBook formats; it may be ordered by visiting http://law.shu.edu/compliancemanual.
The Seton Hall Law Center for Health & Pharmaceutical Law & Policy advances scholarship and recommendations for policy on the varied and complex issues that emerge within pharmaceutical and health law. Additionally, the Center is a leader in providing compliance training on the wide-ranging state, national and international mandates that apply to the safety, promotion and sale of drugs and devices. Seton Hall University School of Law, New Jersey’s only private law school and a leading law school in the New York metropolitan area, is dedicated to preparing students for the practice of law through excellence in scholarship and teaching with a strong focus on experiential learning. Founded in 1951, Seton Hall Law School is located in Newark and offers both day and evening degree programs. For more information visit law.shu.edu.
The American Health Lawyers Association (AHLA) is the nation’s largest nonpartisan educational organization devoted to legal issues in the healthcare field. The Association’s 11,000 members practice in a variety of settings in the healthcare community. For information about our resources, publications, and educational offerings, visit www.healthlawyers.org.
Research Fellow & Lecturer in Law Kate Greenwood in a Featured Op-ed in Pharmalot on the U.S. Supreme Court and Liability for Defects in Generic Drugs
Research Fellow & Lecturer in Law Kate Greenwood published a Featured Op-ed in Pharmalot on the U.S. Supreme Court and the prospect of liability for personal injury from defects in generic drugs. In “Betting on Liability for Generic Defects,” Ms. Greenwood writes:
As reported on Pharmalot, the US Supreme Court has agreed to review the First Circuit Court of Appeals’ decision in Mutual Pharmaceutical Company v. Bartlett that federal law did not preempt a New Hampshire jury’s determination that the generic drug sulindac had a “design defect” and so should have been recalled (back story with briefs).
It is highly likely that the Supreme Court will reverse the First Circuit’s decision, and, in so doing, confirm that manufacturers cannot be held liable for failing to re-design or recall unsafe generic drugs, just as they cannot be held liable for failing to update the labeling of such drugs. The ball will then be in Congress’ court to fill the resulting postmarketing safety gap.
As the First Circuit explained in the Bartlett decision, New Hampshire law provides that a drug has a design defect “‘if the magnitude of the danger outweighs the utility of the product.’” At trial, plaintiff Karen Bartlett’s expert testified that sulindac met this standard and the jury agreed, finding Mutual Pharmaceutical liable for selling a product with a defective design and awarding Bartlett over $21 million for the horrific SJS/TEN-related injuries she suffered after taking sulindac.
Read more in the feature Op-ed, “Betting on Liability for Generic Defects.”
United States v. Caronia: Some Preliminary Thoughts on the Second Circuit’s Decision Invalidating the Ban on Off-Label Promotion
Earlier this week, the Second Circuit Court of Appeals at last issued its decision in United States v. Caronia and it is momentous (and predicted to be heading to the Supreme Court). A two-judge majority of the Circuit Court held that Alfred Caronia, a pharmaceutical sales representative, “was convicted for his speech – for promoting [the central nervous system depressant Xyrem] for an off-label use – in violation of his right of free speech under the First Amendment.”
The majority’s decision begins with a threshold question. Was Caronia convicted for conspiracy to misbrand Xyrem because he engaged in off-label promotion qua off-label promotion, that is, for his speech? Or, was his speech simply “evidence that the ‘off-label uses were intended ones for which Xyrem’s labeling failed to provide [the required] directions[,]” as the government argued on appeal? The former would implicate the First Amendment, but the latter would not. The Supreme Court has held that “[t]he First Amendment … does not prohibit the evidentiary use of speech to establish the elements of a crime or to prove motive or intent.” As the Caronia dissent (colorfully) explained, “Abby and Martha [do not have] a First Amendent right to offer arsenic-laced wine to lonely old bachelors with the intent that they drink it. … And any statements Abby or Martha made suggesting their intent—even if all of the statements were truthful and not misleading—would not be barred from evidence by the First Amendment…”
The majority found that Caronia was convicted for his speech alone, pointing to the lower court’s instructions to the jury and to a number of statements that the government made at trial including “[Caronia] conspired through some act of misbranding, and that act of misbranding … was the promotion on October 26th and November 2nd[,] marketing [a] drug for unapproved uses.” Caronia’s conviction must therefore be vacated, the majority concluded. The Food Drug and Cosmetic Act does not “criminaliz[e] the simple promotion of a drug’s off-label use because such a construction would raise First Amendment concerns.” The majority did not disagree with the general proposition that speech may be used as evidence of intent, and it expressly declined to decide the specific question whether the FDCA violates the First Amendment by “defin[ing] misbranding in terms of whether a drug’s labeling is adequate for its intended use, and permit[ting] the government to prove intended use by reference to promotional statements made by drug manufacturers or their representatives.” Even if the Second Circuit’s decision stands, then, the government may be able to argue that Caronia is a case about an erroneous jury instruction with limited practical effect
The majority went on to hold that a ban on off-label promotion qua off-label promotion—like the Vermont law barring drug companies from using physician-specific prescribing data to craft physician-specific sales pitches at issue in the Supreme Court’s 2011 decision in Sorrell v. IMS Health (which I discussed on this blog here)—is unconstitutional regardless of whether strict or intermediate scrutiny applies. The majority gave short shrift (no shrift, really) to the argument that the ban on off-label promotion is necessary to preserve the integrity of the FDA’s drug approval process, suggesting that the government could “minimize … manufacturer evasion of the approval process” by imposing “ceilings or caps on off-label prescriptions.”
The majority did not elaborate on how ceilings or caps on off-label prescriptions would work, on the grounds that the First Amendment puts the burden on the government to demonstrate that they would not. Here, too, there may be an opening for the government, to make a stronger case to the Supreme Court than it did before the Second Circuit (in its briefs or at oral argument) that ceilings or caps would not be “administrable, feasible, or otherwise effective” and that the ban on off-label promotion therefore provides a direct, narrowly-tailored, and crucial incentive to clinical research into already-approved drugs. As the dissent suggested, “[a] ceiling on off-label prescriptions would require collecting data from countless numbers of doctors and patients and, given the medical uncertainties involved, could needlessly (and simultaneously) result in the denial of some effective treatments and the overprescription of ineffective and even dangerous ones.”
Filed under: Drugs & Devices, Food and Drug Administration (FDA)
Recently, the Food and Drug Administration announced that the manufacturer Impax Laboratories has asked the agency to withdraw its approval of a generic version of the antidepressant Wellbutrin XL 300 mg that is manufactured by Impax and marketed by Teva Pharmaceuticals. A bioequivalence study sponsored by the FDA compared the Impax/Teva 300 mg generic to Wellbutrin XL 300 mg and found that the generic tablets failed to release the medication’s active ingredient into the blood “at the same rate and to the same extent” as the name brand. While the results of the study only recently became available, the FDA acknowledges that it has been aware of concerns about the Impax/Teva 300 mg generic for over five years.
The Impax/Teva 300 mg generic was approved in 2006 on the basis of a study establishing that Impax’s 150 mg generic was bioequivalent to Wellbutrin XL 150 mg. The FDA did not require that a bioequivalence study of the 300 mg generic be done, because the 300 mg dose of the drug poses a risk of seizures. Soon after the Impax/Teva 300 mg generic was approved, the FDA began to receive “reports describing either adverse events or lack of an effect.” As ABC News reports here, Joe Graedon of the consumer advocacy group the People’s Pharmacy was hearing the same things, and, in 2007, he asked Consumer Lab –according to its website, “the leading provider of independent test results and information to help consumers and healthcare professionals identify the best quality health and nutrition products”–to compare the Impax/Teva generic to its name brand counterpart.
Consumer Lab published an analysis demonstrating that “[i]n the first two hours of a dissolution test, we found [the generic] released 34 percent of the drug, while Wellbutrin released 8 percent” and that “[a]t four hours, the [Impax/]Teva product released nearly half of its ingredients, while original Wellbutrin released 25 percent.” Consumer Lab’s president explained to ABC that the patent on the extended release technology used in Wellbutrin XL was still in effect when the Impax/Teva generic was approved. As a result, the generic contained the same medication as the original but used a different (or perhaps no) extended release technology.
The FDA was made aware of Consumer Lab’s results, but declined to act on them. The agency believed that differences in rate of release were unlikely to be clinically significant because “[t]he antidepressant effect of this drug does not appear for several weeks after initiation of treatment, and the effect is, in large part, related to long-acting metabolites.” The FDA concluded that “[t]he recurrent nature of [major depressive disorder] offers a scientifically reasonable explanation for the reports of lack of efficacy following a switch to a generic product.”
As the FDA explains in a Questions and Answers document posted to its website, despite its conclusion that the Impax/Teva generic was clinically equivalent to the name brand, in November 2007 the agency “asked Impax/Teva to conduct a study directly on its 300 mg extended-release product to compare its bioequivalence to Wellbutrin XL 300 mg … [in]patients who had reported lack of efficacy after switching from Wellbutrin XL 300 mg to [the Impax/Teva product].” That study was terminated in late 2011 because “Impax/Teva was unable to recruit a significant number of affected patients to generate the necessary data.” It was not until 2010 that the FDA decided to sponsor its own bioequivalence study. That study, of 24 healthy adult volunteers, was not completed until August of this year, because the agency had to “get funding for the study, design the study, obtain approval from the Institutional Review Board for Protection of Human Subjects, recruit and enroll healthy volunteers, conduct the study, develop an analytical method of analyzing the data, and complete its analysis of the study data.”
As a result of its experience with the Impax/Teva 300 mg generic, the FDA reports that it “is revising its guidance to industry for how to conduct premarket bioequivalence studies in generic [Wellbutrin] products.” It will no longer be possible for a company to extrapolate the results of bioequivalence studies done on 150 mg tablets to 300 mg tablets.
One wonders whether there might be other lessons to be learned from the Impax/Teva 300 mg generic experience. For one, I wonder if the FDA could have–and, if so, if it should have–acted more quickly. The agency does seem to have taken patients’ complaints about the Impax/Teva tablets seriously. At the same time, it took six years to withdraw a generic drug that patients complained about immediately upon its approval. Delays of this sort have the potential to undermine trust in generics generally.
Another potential lesson to be learned from the Impax/Teva 300 mg generic experience is specific to antidepressants. As Michelle Hottinger and Bryan A. Liang note in their article Deficiencies of the FDA in Evaluating Generic Formulations: Addressing Narrow Therapeutic Index Drugs, which is forthcoming in the American Journal of Law and Medicine, much about antidepressants’ mechanism of action is still not understood, which “may leave some uncertainty as to [their] pharmacokinetics.” Even where an antidepressant meets the FDA’s bioequivalence standards, Hottinger and Liang write, “therapeutic equivalence is not guaranteed.” Given this, the FDA might be well-advised to pay heightened attention to adverse event reports about generic antidepressants.