Recommended Reading: New Legal Scholarship from Ryan Abbott and Jennifer Herbst on Pharmacovigilance Topics

In his article Big Data and Pharmacovigilance: Using Health Information Exchanges to Revolutionize Drug Safety, which is forthcoming in the Iowa Law Review, Ryan Abbott argues that third parties, including academics, insurance companies, and rival drug companies, should be incentivized via an “administrative bounty proceeding” to analyze the large and rich datasets that will be generated by health information exchanges.  Should a third party’s original statistical analysis reveal safety or efficacy concerns about a drug, Abbott suggests, it could submit the results to the Food and Drug Administration and be paid a taxpayer-funded bounty, the amount of which would be based on the value of the new information to the government in terms of health care dollars saved.  If a drug’s manufacturer knew or should have known about the concerns brought to light by the third party, Abbott proposes that the manufacturer fund the bounty, the amount of which would be based on the drug’s sales; depending on its degree of culpability, a manufacturer could even be liable to both the third party and the government for damages.

Abbott believes that the bounty system he proposes would level the pharmacovigilance playing field in a way that would redound to the benefit of consumers.  In his words: “The public deserves an advocate as equally committed to challenging the safety and efficacy of approved drugs as product sponsors are to maintaining these drugs on the market.”  Writing about Abbott’s proposal at the Bill of Health blog, Dov Fox distills it down to the following provocative question: Are we “better off evaluating medicines under an inquisitorial system or an adversarial system”?

I also recommend Jennifer Herbst’s article How Medicare Part D, Medicaid, Electronic Prescribing and ICD-10 Could Improve Public Health (but Only if CMS Lets Them), which is forthcoming in Health Matrix: Journal of Law-Medicine.  While the title might seem daunting, the article itself brings clarity to a murky, highly-technical area of the law with enormous significance for public policy.  As Herbst explains, although both Medicare Part D and Medicaid limit reimbursement to drugs prescribed for “medically accepted indications,” this limitation is not enforced, at least not at the time of payment.  And, while the government’s attempts to enforce it retroactively have led to headline-making settlements with pharmaceutical companies, they have not resulted in a significant dent in the rate of unscientifically-supported prescribing.

Herbst recommends that the government take advantage of the inroads made by electronic prescribing and require that patient diagnosis codes be made a condition of payment for outpatient prescription drugs.  Linking drugs to diagnoses in this way would allow pharmacists to do a more thorough safety review of the prescriptions they fill and it would give the government a powerful pharmacovigilance tool.  Of course, it would also allow the government to decline to provide reimbursement for drugs prescribed for indications that are not “medically accepted.”  Herbst argues that this would be a mistake because it could lead to widespread miscoding – there’s a disconnect between what the government deems medically accepted and what providers consider sound medical practice – which would undermine the value of the data being collected.  I wonder, however, whether it would be politically feasible for the Centers for Medicare & Medicaid Services “to continue its current policy of paying for all outpatient prescriptions not subject to prior authorization (contrary to the letter of the Medicare Part D and Medicaid statutes)” in the face of the data Herbst’s proposal would generate.

Recommended Reading: Recent Legal Scholarship on Workplace Wellness Programs

Since its release last month, Sheryl Sandberg’s bestseller Lean In has attracted seemingly continuous attention and controversy.  Critics charge that the book encourages women to “lean in” to their outside-of-the-home work without fully addressing the barriers that might be impeding women’s advancement.  They express concern that too intense a focus on what individual women can do to address the persistent achievement gap between women and men will only result in women blaming themselves for structural, societal problems.  Similar concerns underlie the controversy over workplace wellness programs.  While almost no one is against “wellness,” there is concern that emphasizing what individuals should do to achieve it, potentially on pain of losing their jobs, could be ineffective and even counterproductive.

Workplace wellness programs run the gamut from providing more nutritious food in the office cafeteria, to building an on-site gym, to providing counseling and other supportive services, to positive financial incentives keyed to achieving goals such as blood pressure control or smoking cessation, to negative incentives including hiring bans, health insurance surcharges, and, ultimately, termination.  With regard to variations in the price of health insurance, Tara Ragone has explained that “[a]lthough the [Patient Protection and Affordable Care Act] prohibits issuers in the individual and small group markets from basing premium variations on health status or claims experience, Federal law permits insurers to offer premium discounts to enrollees in the small and large group markets based on participation in certain wellness programs.”  The statute provides for wellness rewards of up to 30 percent of the cost of coverage, and the Secretaries of Labor, Health and Human Services, and the Treasury have discretion to increase the rewards to up to 50 percent.

In Jessica Roberts’ latest article, Healthism and The Law of Employment Discrimination, which is available on SSRN, she explains that while “issues of income, insurance, and health” seem discrete, in fact they are “intimately intertwined.”  Wellness programs could exacerbate existing health disparities by restricting relatively unhealthy individuals’ access to wages, wellness programs, and employer-provided health insurance.  Moreover, while “using tobacco and being overweight are conduct-based statuses”—and thus not fully protected under the federal statutes that outlaw trait-based employment discrimination—“the underlying choices are not simple ones.”  As Roberts notes, “[t]he lack of access to healthy foods and time to work out or a longstanding addiction to tobacco may be difficult obstacles to overcome without some help.”  Roberts recommends that Congress, or the substantial number of state legislatures that have not already done so, pass legislation shielding employees from discrimination not just on the basis of their health-related traits, but also on the basis of their health-related conduct.  She recommends that such legislation permit employers “to promote the healthy lifestyle choices of their employees through rewards programs that do not relate directly to employment status or compensation.”  I recommend Roberts’ article for its helpful (and thought-provoking) overview of the intersection between employment discrimination law, insurance regulation, and workplace wellness programs and for its nuanced legislative proposal.

I also recommend Wendy Mariner’s article, The Affordable Care Act and Health Promotion: The Role of Insurance in Defining Responsibility for Health Risks and Costs, published last year in the Duquesne Law Review.  In it, Mariner argues, pithily, that “wellness program incentive systems range from minor and marginally effective, to major and possibly coercive.”  She believes that the wellness rewards that PPACA permits “are likely to be too crude to significantly improve the population’s health or save money, and they pose an unnecessary threat to the [statute’s] underlying goals[.]”  By fostering the idea that the unhealthy are at fault for their condition, such rewards may increase resistance to the “public programs to provide preventive services, safer social and built environments, research and education” for which Mariner advocates.  She calls for the elimination of PPACA’s wellness program exception to the ban on basing the price of health insurance on health status or claims experience.  With the projected cost of premiums in the new health insurance exchanges widely-reported and much decried, elimination of the wellness program exception is unlikely.  Mariner’s article nonetheless offers a valuable note of caution as 2014 approaches.

Giving Patients a Piece of the Action: Appealing Proposals from Richard Frank and Christopher Robertson

In a recent edition of the New England Journal of Medicine, Richard Frank discussed recent efforts on the part of federal and state governments to enroll so-called “dual eligibles,” that is, individuals who qualify for both Medicare and Medicaid, into health plans that use “a strong care-management system under a unified budget.”  Many believe that such plans have the potential to both save the government money and provide better coordinated, higher quality health care.  (I discussed the need to better coordinate care for dually-eligible people here.)  Individual beneficiaries are not necessarily convinced, however.  Frank reports that it has been “very difficult to lure” them into “state-designed care coordination entities.”  Beneficiaries may be hesitant to leave their fee-for-service doctors and other providers; they may also be afraid of the incentive to restrict services that a capitated global payment creates.

To get beneficiaries to make the switch from fee-for-service to coordinated care, states are taking a page from Nudge and making enrollment in a coordinated care plan automatic.  The burden is then placed on the beneficiary to opt out if he or she so chooses.  The use of “passive enrollment” will no doubt “work” to increase the rolls of coordinated care plans, but Frank wants states to aim higher, to strive to “promote self-determination for vulnerable populations and offer them a reason to engage with a new care delivery system with coordinated-care arrangements[.]”

As Frank explains, “[c]oordinated care for dually eligible people is built on a financial structure known as shared savings, in which three of the parties involved –- the federal government and state governments and the [coordinated care plan] –- share any financial gains from coordinating care.”  Frank proposes that beneficiaries, too, be given a share of the expected savings– a share that they would be permitted to use to pay for “supplemental services and supports such as transportation, home modifications, and personal assistance with activities of daily living.”  The prospect of (limited) control over a share of the expected savings would serve as an incentive to beneficiaries to engage in care coordination, while also “promot[ing] self-determination and the exercise of real options.”

Frank’s very appealing idea brought to mind the proposal Christopher Robertson makes in The Split Benefit: The Painless Way to put Skin Back in the Healthcare Game, which is forthcoming in the Cornell Law Review.  While Frank would give beneficiaries an incentive to opt in to coordinated care, Robertson would give them an incentive to opt out of inefficient, high-cost care.  Specifically, Robertson proposes that when a physician “prescribes a high-cost treatment that the insurer reasonably believes is inefficient[,]” the insurer would “[p]ay a small but substantial part of the insurance benefit”—-what he terms the “split benefit”—-in cash directly to the patient beneficiary.  Then, “[i]f the patient chooses to proceed with the treatment, the patient takes the cash payment to the provider (along with any required cost share obligation), and the insurer matches it with the balance of the insurance benefit[.]”  Patients who choose not to proceed with treatment, however, could spend the cash differently, on a “treatment that is not covered by the insurer (whether it is acupuncture, an alternative diet regimen, a concierge doctor, or visiting nursing services), paying money to a member of the family to stay home and provide care to the dying patient, or purchasing disability insurance to help cope with the symptoms of the illness.”  They could even use the money to pay for non-health-related expenses.  As Robertson explains, the split benefit would save insurers (and, down the line, purchasers of insurance) money by giving beneficiaries a financial incentive to turn down high-cost, low-value treatments.  In Robertson’s words, the patient autonomy movement has been “cramped” by the fact that patients have been offered only “a walled garden of medical choices.”  His split benefit, by contrast, “embraces a value-pluralism, respecting the patient’s weighing of medical and non-medical values.”

I highly recommend both Frank’s and Robertson’s pieces to anyone who—-like me—-is interested in ways to give patients a piece of the action when it comes to the multiplicity of current efforts to coordinate and rationalize their care.

Recommended Reading: ‘Patients’ Racial Preferences and the Medical Culture of Accommodation’

I highly recommend Kimani Paul-Emile’s provocative article in the latest issue of the UCLA Law Review, Patients’ Racial Preferences and the Medical Culture of Accommodation, in which she “makes the counterintuitive claim … that the law does and should permit” physicians and hospitals to accommodate “patients’ racial preferences with respect to their choice of physician … in the hospital setting.”  Such accommodation is, Professor Paul-Emile reports, a quiet, but routine, occurrence, one that recent studies suggest “may not only alleviate race-based health disparities but also constitute a life-saving measure for many racial-minority patients.”

Professor Paul-Emile’s article begins with a concise and helpful summary of the relevant default legal rules, in particular the right of patients to refuse medical treatment and the obligation of hospitals to provide care in an emergency.  As Professor Paul-Emile explains, “[i]f a patient who desires treatment will not yield in his preference for a provider of a particular race and will not agree to a transfer, then the hospital is faced with the dilemma of choosing between (1) having a physician unwanted by the patient forcibly perform the [Emergency Medical Treatment and Active Labor Act]-mandated medical screening, thereby violating informed consent and battery laws, and (2) rejecting the patient in violation of EMTALA, thereby risking liability and the chance that this decision will cause the patient to suffer, experience grievous harm, or die.”

The article goes on to analyze hospitals’ decisions to accommodate a patient’s race-based request for a new doctor under Titles II, VI, and VII of the 1964 Civil Rights Act, and concludes that although “it is difficult to imagine preferences of this sort indulged in any other sector,” in the hospital setting such accommodation does not violate anti-discrimination laws.  Professor Paul-Emile goes further, arguing that accommodation “may be one of the best available means of enforcing Title VI’s mandate to enable individuals to enjoy the benefits of a covered entity or program, regardless of race, color, or national origin” to the extent that it “counter[s] the effects of implicit bias, discrimination, and stereotyping by physicians[.]”

Professor Paul-Emile concedes that “the notion of white patients rejecting minority physicians for bigoted reasons in emergency departments and other hospital settings is deeply troubling and uncomfortably reminiscent of the type of discrimination that the civil rights statutes were designed to eliminate[,]” but she counters with empirical evidence (1) that “requests for treatment by a physician of a particular race are more often accommodated when made by racial minority patients” and (2) that the benefits of racial concordance are many, including longer visits characterized by patient-centered participatory decision-making.

Reading Professor Paul-Emile’s article, it struck me that for every patient who insists on a change of doctor, there are likely many more who assume, rightly or wrongly, that they have no choice and so endure discriminatory treatment in the hospital setting.  Accommodating the demands of the few who speak up is at best a partial solution.  Professor Paul-Emile does not deny this.  She concludes her article with a call for an increase in the diversity of doctors and for an expansion of “cultural awareness at all levels of practice and training to enable providers to interact more effectively with various patient populations”—worthy, if daunting, goals.

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 26^th and November 2^nd[,] 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.”

 

Stillbirth: An Interdisciplinary Approach to ‘Closing the Knowledge and Solution Gaps’*

In an article out in the American Journal of Obstetrics and Gynecology, the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS)—a Gates Foundation-funded initiative of Seattle Children’s Hospital and the University of Washington School of Medicine’s Departments of Global Health and of Obstetrics and Gynecology—reports on its efforts to develop “a research agenda related to pregnancy, childbirth, and early life[.]”  In addition to interviewing scientific thought leaders and convening a “technical team of 13 prominent researchers from multiple disciplines in the developed and developing world,” the GAPPS spoke to “18 representatives of funding organizations—including government agencies, global foundations, and other financial partners—to gain a deeper understanding of the current perspectives, attitudes, and commitments of funders toward research on pregnancy, childbirth, and early life.”

The GAPPS’ conversations with funders surfaced a number of challenges to increasing funding, including 1) “a range of understanding of the issues[,]” 2) “varying degrees of interest in the topic[,]” and 3) concern about “the challenges of progress with such a long-term and complex problem.”  The authors, to their credit, do not deny that the question (questions, really) of what causes prematurity, stillbirth, and other pregnancy and early life problems are among the “most difficult … in biomedical research today.”  The authors note that “[d]ifferent biological pathways are involved in the adverse outcomes of pregnancy, and these can be characterized at different biological levels from the genome to the exposome (the combined effects of environmental influences).”

At the level of the exposome, recently-published research by investigators from New Jersey’s own UMDNJ-Robert Wood Johnson Medical School, brings us incrementally closer to understanding the effects of ambient air pollution on stillbirth, while exemplifying the complexity of the science involved.  Ambarina Faiz and colleagues compiled data contained in “New Jersey electronic birth certificate records for live births and fetal death certificates for stillbirths linked to their corresponding hospital delivery discharge records from 1998 to 2004[,]” along with data on air pollutants from 25 New Jersey Department of Environmental Protection monitoring stations.  Their analysis of the data revealed that “[i]ncreased concentrations of ambient air pollutants during pregnancy were associated with increased relative odds of stillbirth after adjustment for known risk factors for stillbirth, mean temperature, and a neighborhood level measure of socioeconomic status.”  Numerous questions remain, though.  The authors call for “molecular studies with specific biomarkers … to define more clearly the roles of specific pollutants and to investigate possible biologic mechanisms that lead to stillbirth.”

Drawing on what it learned from funders, as well as from scientific thought leaders and from the technical team it convened, the GAPPS developed eight recommendations aimed at encouraging such research, with the ultimate goal of “making every pregnancy a healthy pregnancy[.]”  The GAPPS calls for 1) determining and publicizing the true cost of prematurity, stillbirth, and other pregnancy and early life problems, 2) establishing alliances among funders, researchers, and other stakeholders, 3) agreeing on research priorities, and 4) promoting research opportunities, particularly opportunities for “new investigators from multiple disciplines.”  While these are clearly daunting tasks, the authors report that “[s]everal interviewees observed that the Bill and Melinda Gates Foundation has an unparalleled ability to persuade, convene, and organize important players, both nationally and internationally.  In particular, they pointed to the potential for the foundation to move the concept of coordinated funding forward.”  The prospect of a new clarity about research priorities, combined with a coordinated approach to funding, is a hopeful one for all of us since “healthy outcomes in pregnancy benefit everyone, directly and indirectly.”

*I thank Catherine Finizio, the Administrator of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, for keeping me focused on this important issue.  (My prior posts are here, here, and here).  Cathy’s grandson, Colin Joseph Mahoney, was stillborn at 39 weeks gestation on November 10, 2008.

Canaries in a Coal Mine: Patient Complaints (Finally) Lead to Withdrawal of Generic Wellbutrin XL

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.

Childhood Cancer: Pushing and Pulling Against a Powerful Foe

Since September is National Childhood Cancer Awareness Month –a calendar of events can be found here– a review of relevant recent and pending federal legislation seemed appropriate.  The Food and Drug Administration Safety and Innovation Act (FDASIA), which the President signed into law on July 9, 2012, included a number of provisions that it is hoped will speed development of drugs to treat childhood cancers and other rare diseases.  As Peter L. Saltonstall, who heads up the National Organization for Rare Disorders (NORD), explains here, the central purpose of the FDASIA was to reauthorize the Prescription Drug User Fee Act, but several separately-introduced bills “of particular importance to rare disease patients and supported by NORD” were incorporated into it.  These included the Creating Hope Act, which was powerfully advocated for by Kids v Cancer and the bi-partisan Congressional Childhood Cancer Caucus.

The Creating Hope Act expands the FDA’s priority review voucher (PRV) program– which was passed to incentivize the development of treatments for neglected tropical diseases, malaria, and tuberculosis– to cover rare pediatric diseases, including childhood cancers.  Under the program, “[t]he [FDA] shall award a priority review voucher to the sponsor of a rare pediatric disease product application upon approval by the [FDA] of such rare pediatric disease application.”  The fully-transferable voucher can be redeemed for review of–and action on–another new drug application within just six months.  In an influential 2006 article in Health Affairs, David Ridley and colleagues estimated that if a “voucher speeds FDA approval by a year, it could increase the present value of sales of a blockbuster drug by more than $300 million.”

While a voucher worth as much as $300 million would seem to add up to an attractive “pull” mechanism, the PRV program for neglected tropical diseases has, unfortunately, not lived up to expectations.  Only one company, Novartis, has received a PRV, for an anti-malaria drug which was already approved and marketed outside the United States.  Writing at The Incidental Economist earlier this year, Kevin Outterson characterized the PRV program as “unsuccessful” and its extension to rare pediatric diseases as “disappointing.”  More promising, Professor Outterson suggests, are “push” mechanisms like the Innovative Medicines Initiative (IMI) in Europe, described here, which will, among other things, funnel $738 million to antibiotics researchers between now and 2020, with the initial goals of “building and training networks of researchers, facilitating and increasing the exchange of research data, and improving the efficiency of clinical trials on new antibiotics through better laboratory tests and better trial design” and the long-term goal of “speed[ing] up the development of much-needed antimicrobial drugs.”  Notably, the IMI was established with $1.23 billion of European Union funds and an impressive $1.23 billion of “mainly in kind contributions (consisting mostly of research activities)” from the European Federation of Pharmaceutical Industries.

The National Pediatric Research Network Act of 2012, which is currently pending in the House and Senate, bears some similarities to the IMI’s antimicrobial drug development effort.  The Act would appropriate government funds to support the establishment and operation of a network of pediatric research consortia that would conduct “basic, clinical, behavioral, or translational research to meet unmet needs for pediatric research” and “train[] researchers in pediatric research techniques.”  The Act provides that “an appropriate number of such awards” must be awarded to consortia that, among other things, agree to “conduct or coordinate one or more multisite clinical trials of therapies for, or approaches to, the prevention, diagnosis, or treatment of one or more pediatric rare diseases or conditions[.]”

Childhood cancers are not specifically mentioned in the text of the National Pediatric Research Network Act, however, and, should it pass, the Network it establishes is likely to focus on other rare pediatric diseases.  An existing network, the Children’s Oncology Group (COG), which is principally supported by the National Cancer Institute, “unites more than 8,000 experts in childhood cancer at more than 200 leading children’s hospitals, universities, and cancer centers across North America, Australia, New Zealand, and Europe in the fight against childhood cancer.”  COG “has nearly 100 active clinical trials open at any given time … include[ing] front-line treatment for many types of childhood cancers, studies aimed at determining the underlying biology of these diseases, and trials involving new and emerging treatments, supportive care, and survivorship.”  The existence and success of COG — it’s “research has turned children’s cancer from a virtually incurable disease 50 years ago to one with a combined 5-year survival rate of 80% today,” although it has suffered from budget cuts in recent years–likely explains why advocates have turned their attention to pull mechanisms like the Creating Hope Act that build on existing incentives aimed at increasing industry investment in drug research.

Another model for increasing industry involvement is to require it.  This could perhaps be described as a strong pull mechanism.  The Pediatric Research Equity Act (PREA) takes this approach, requiring, with some exceptions, that a sponsor of a new drug application study that drug in children.  FDASIA, as the FDA summarizes here, makes PREA “permanent — no longer subject to reauthorization every five years[,] … requires earlier pediatric study plan submission by drug manufacturers subject to PREA and gives FDA new authority to help ensure PREA requirements are addressed in a more timely fashion.”  PREA, though, has not worked to generate research into pediatric cancer treatments, and the FDASIA reforms will not change that.  In remarks delivered at the 2^nd Annual Childhood Cancer Summit in September 2011, Dr. Peter Adamson, the Chair of the Children’s Oncology Group, explained that an exception to PREA’s requirements “can be granted for most new cancer drugs, as the common cancers observed in adults essentially do not occur in children.”

Of course, industry involvement could increase though profit-driven activity without additional pushes or pulls from government.  Childhood cancers have not, thus far, been an industry focus.  In the past twenty years, the FDA has approved just two drugs, clofarabine and erwinaze, to treat pediatric-specific cancers.  It was not until this past August that the agency approved the first “pediatric-specific dosage form” of a cancer-fighting drug, everolimus.  A story reported in Fortune’s September 3, 2012 issue entitled Rare Diseases Mean Big Profits (an online version is available here), suggests that there may be hope that the pace of development will accelerate.  According to Fortune:

Wall Street skews bullish on Alexion[, a specialty pharmaceutical company that developed and sells the drug Soliris which is used to treat two rare disorders,] and its peers in the ultra-rare-disease market.  With Pfizer and other big pharma companies facing devastating revenue drops as blockbuster drugs like Lipitor go off patent, niche players like Alexion look good because of their monopoly pricing power.

Soliris, Fortune reports, costs “around $400,000 per patient per year.”  There may be, then, cause for hope that in the coming years the private sector will increase its investment in the surpassingly important search for treatments for childhood cancers and other rare pediatric diseases.  I welcome your thoughts.

Recommended Reading: Recent Scholarship on Suits Brought by Plaintiffs Who Have Not (Yet) Been Harmed

In Not Sick Yet: Food-Safety-Impact Litigation and Barriers to Justiciability (forthcoming in the Brooklyn Law Review), Diana R.H. Winters focuses on a number of hurdles that must be cleared by plaintiffs challenging the “behemoth” that is America’s food safety regulatory apparatus.  Among these hurdles, “[p]laintiffs in food-safety-impact suits must find a way to show that they have suffered concrete and particularized injury from the challenged regulation although they have not contracted a foodborne illness.”

At least in certain circuits, plaintiffs can show the requisite concrete and particularized injury by “alleging an increased risk of contracting foodborne illness because of an established governmental policy.”  The Second Circuit, for example, held in Baur v. Veneman that “[a]lthough this type of injury has been most commonly recognized in environmental cases, the reasons for treating enhanced risk as sufficient injury-in-fact in the environmental context extend by analogy to consumer food and drug safety suits.  Like threatened environmental harm, the potential harm from exposure to dangerous food products or drugs ‘is by nature probabilistic,’ yet an unreasonable exposure to risk may itself cause cognizable injury.”

I recommend Professor Winters’ article for her cogent analysis of the litigation challenges that arise when a food-safety-impact plaintiff’s only harm is exposure to allegedly unreasonable risk (which, as the Second Circuit points out, has obvious implications for drug safety litigation).  However, her article is also well-worth reading for its overview of the “inefficiencies, inconsistencies, and even some absurdities” that characterize federal agency oversight of food safety and for its very interesting discussion of the significance of the lack of a well-organized food-safety-impact plaintiff movement.

I also recommend Against Liability for Private Risk-Exposure (forthcoming in the Harvard Journal of Law and Public Policy), in which Sheila B. Scheuerman focuses, like Professor Winters, on suits brought by plaintiffs whose only harm is exposure to allegedly unreasonable risk.  While Professor Winters’ article addresses Administrative Procedure Act suits brought against government agencies, Professor Scheuerman discusses tort and warranty suits brought against private companies.  Establishing a concrete and particularized injury is a hurdle confronting “no injury” plaintiffs in cases brought against corporations as it is in cases brought against the government.  Plaintiffs in tort and warranty cases do not typically allege that they suffered emotional harm as a result of their risk of exposure, or that they suffered economic harm because they sold the product at issue at a reduced value, because allegations such as these would raise “individual issues, thereby precluding class certification.”

In Cole v. General Motors, a Fifth Circuit case, the class representatives “brought claims for breach of the implied warranty of merchantability and breach of the express warranty against a car manufacturer based on alleged defects in the car’s air bag system.”  The Cole court allowed the case to proceed, on the grounds that while the plaintiffs had not sustained physical harm as a result of the air bag issue, they had sustained “‘actual economic harm … emanating from the loss of their benefit of the bargain.”  As one could guess from the title of her article, Professor Scheuerman believes that Cole and the other similar cases she discusses were wrongly decided and that “[a]llowing liability for private-risk exposure is not justified by any of the dominant rationales for the tort or warranty law.”  She quotes with approval a court that held that allowing such liability only benefits “‘the lawyers handling the case and perhaps the few consumers directly involved in the litigation,’” and notes that the class representatives in Cole consisted of a paralegal who worked for plaintiffs’ counsel, the paralegal’s cousin, and the mother of one of plaintiffs’ counsel.  Professor Scheuerman concludes that “the solution to encouraging risk reduction by manufacturers, without exposing companies to bankrupting litigation, lies with government regulation.”  Coming full circle, it is worth noting that none of the arguments Professor Scheuerman makes against no-injury tort and warranty suits would apply to preclude no-injury suits of the sort that Professor Winters discusses, brought to challenge-or enforce-such regulation.

Recommended Reading: Recent Legal Scholarship on the Affordable Care Act’s Medicaid Expansion

As Frank Pasquale noted recently at the Health Law Prof Blog and here at HRW, law review scholarship is starting to emerge on the Supreme Court’s holding in National Federation of Independent Business v. Sebelius that the Patient Protection and Affordable Care Act’s expansion of the Medicaid program was an unconstitutionally coercive exercise of Congress’ Spending Clause authority.  Professor Pasquale recommends Plunging into Endless Difficulties: Medicaid and Coercion in the Healthcare Cases, an article co-authored by Nicole Huberfeld, Elizabeth Weeks Leonard & Kevin Outterson, writing that it is “sure to make an impact.”

Also well worth reading is Samuel R. Bagenstos’ article, The Anti-Leveraging Principle and the Spending Clause after NFIB, which is forthcoming in the Georgetown Law Journal.  Professor Bagenstos contends that Chief Justice Roberts’ opinion in NFIB is best read narrowly as setting forth a three-part test–which Professor Bagenstos terms the “anti-leveraging principle”–for determining whether a condition Congress places on participation in a joint federal-state program unconstitutionally coerces the states to participate.  To apply the anti-leveraging principle, one must first ask whether a condition on federal spending “change[s] the terms of participation in [an] entrenched cooperative program[.]”  The second question is whether the condition leaves a state without a real choice to decline the funds at issue because, for example, there is a “very large amount of money at stake[,]” as there was with the Medicaid expansion.  The third and final question is whether “Congress was using a state’s desire to continue to participate in a lucrative program as leverage to force the states also to participate in a separate and independent program.”  Only if the answer to all three questions is yes, Professor Bagenstos contends, should a court find that a spending condition is unconstitutionally coercive.

The final section of Professor Bagenstos’ article, in which he applies the anti-leveraging principle, is particularly interesting.  Professor Bagenstos analyzes, among other things, the Affordable Care Act’s Medicaid maintenance-of-effort requirement, which Maine Governor Paul LePage has challenged, the Clean Air Act, the No Child Left Behind Act, Mitt Romney’s education reform proposal, and Section 504 of the Rehabilitation Act, and concludes that the Clean Air Act, which requires states to comply with certain provisions on pain of losing federal highway funding, is particularly vulnerable post-NFIB.

Stepping away from the constitutional questions addressed by the Supreme Court in NFIB, Jessica L. Roberts’ article Health Law as Disability Rights Law, which is forthcoming in the Minnesota Law Review, views the Medicaid expansion and other changes the ACA makes through the lens of “the historical division between the health and civil rights paradigms within disability law.”  As Professor Roberts explains, in the 1970s and beyond, disability rights activists actively rejected the health paradigm as grounded in an outdated, medical model of disability that failed to recognize that the barriers to access that people with disabilities faced had a strong social component.  The civil rights paradigm has its limits, though.  Courts have been reluctant to apply civil rights legislation such as the Rehabilitation Act and the Americans with Disabilities Act to Medicaid and other public programs “in a manner that ensures health-care services for people with disabilities.”  In the landmark Supreme Court case Alexander v. Choate, for example, the Court found that a state Medicaid program’s fourteen-day limit on in-patient hospital care did not discriminate against people with disabilities.  In so doing, the Court “construed the benefit at stake as a ‘package of health care services,’ not adequate, equitable, or accessible health care.”  Professor Roberts argues that “the ACA’s changes to public health insurance hold the promise to eliminate those barriers previously experienced by people with disabilities and, consequently, to reduce existing health disparities.”  Thus, while the Medicaid expansion and certain of the Act’s other changes “fall under the health law umbrella substantively, insofar as they promote access and equality for people with disabilities, they make a civil rights law impact.”  Professor Roberts’ article is thoroughgoing and thoughtful; I highly recommend it.

New Jersey’s Medical Marijuana Program: (Almost) Off and Running

Three summers ago, Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy issued a position paper in support of New Jersey’s then-pending “New Jersey Compassionate Use Medical Marijuana Act.”  The Act passed the following January but the road to implementation has been rocky, as I blogged about here and here.  In April of this year, a prospective patient and physician sued the state’s Department of Health and Senior Services and Department officials alleging that the “selection of six nonprofit groups to grow and sell the drug at alternative treatment centers was ‘arbitrary and capricious,’ and that the regulations it created to govern the program were not consistent with the law’s intent and were ‘intentionally designed with the intent to interfere with the medical marijuana program.’”

There are, however, signs of progress.  Yesterday, the Wall Street Journal reported that: “[f]or the first time in generations, marijuana is legally growing in New Jersey.”  According to the Journal, the Greenleaf Compassion Center, the first and only nonprofit to secure a permit from the Department of Health to grow marijuana, has for about a month been growing its first plants in a secure 5,000-square-foot warehouse in an undisclosed location.  By September, Greenleaf expects to begin serving patients at a dispensary to be located in Montclair, which is in the northern part of the state.

Another nonprofit, the Compassionate Care Foundation, was denied permission to set up shop by the zoning board of one town earlier this year, but was subsequently given the go ahead by officials in another town, Egg Harbor Township, which is in the southern part of the state just inland from Atlantic City.   Compassionate Care’s Chief Executive Officer William J. Thomas told the Journal that “New Jersey’s Division of Gaming Enforcement, which typically vets casino owners for possible organized crime ties, is nearly finished with extensive background checks[.]“  Mr. Thomas “hopes to have a permit to grow pot by the end of August” and “to harvest a crop around November.”

The remaining four nonprofits which were selected by the Department of Health in March of 2011 have yet to find permanent homes. Breakwater Alternative Treatment Center, which was approved to operate in the central part of the state, was rejected last year by one town and is, according to Republican Assemblyman Declan O’Scanlon, a supporter of medical marijuana in New Jersey, “going ahead with talks with several municipalities.”  The Journal was not able to find out where the three other nonprofits are in the process.

Democratic Assemblyman Reed Gusciora, who sponsored New Jersey’s medical marijuana legislation, has called for hearings on the cause of the ongoing delay.  In April, Governor Christopher J. Christie explained that the state has taken its time because he does not want New Jersey to “become Colorado or California.”  Interestingly, recent research suggests that even in those very liberal states the legalization of medical marijuana was not accompanied by increases, and may have even been accompanied by decreases, in the use of marijuana or other substances such as alcohol and cocaine among high school students.  This should provide some comfort to Governor Christie and others concerned about the ancillary effects of legalization as New Jersey’s program moves closer to full implementation.

A Weak Mandate That’s Strong Enough?

In Chief Justice John Roberts’ decision in National Federation of Independent Business v. Sebelius, he explains that, in arguing that the individual mandate should be “upheld as within Congress’s enumerated power to “lay and collect Taxes[,]” the Government did not claim that the taxing power allows it to mandate that individuals purchase insurance.  Rather, the Chief Justice explains, the Government contended that “the mandate is not a legal command to buy insurance.”  Under this argument, “going without insurance [is] just another thing the Government taxes, like buying gasoline or earn­ing income.”

As Nathan Cortez highlighted, Chief Justice Roberts’ conclusion that the “shared re­sponsibility payment” that individuals who do not secure health insurance will owe is a tax hinged in part on the fact that “for most Americans the amount due will be far less than the price of insur­ance, and, by statute, it can never be more.”  The Chief Justice emphasized that “[i]t may often be a reasonable financial decision to make the payment rather than purchase insurance…”  The shared responsibility payment is more tax than penalty because it lacks a scienter requirement and because it “is collected solely by the IRS through the normal means of taxation–except that the Service is not allowed to use those means most sugges­tive of a punitive sanction, such as criminal prosecution.”

That “[t]he individual mandate survives as a tax” is for sure a victory for those who support the Patient Protection and Affordable Care Act.  Yet, as Dave Hoffman points out here, victory in a broader sense will hinge on the Act’s success.  And the very fact that the individual mandate is weak enough to be characterized, fairly, as not a mandate at all, raises the spectre of, as Professor Hoffman puts it, “disastrously bad adverse selection problems, coupled with a talking point (taxes & costs going up) to hammer liberals with for the next decade.”

The possibility that relatively healthy individuals and small employers with relatively healthy employees will opt out of purchasing health insurance — at all or through the Act’s health insurance exchanges — causing health insurance premiums to rise, the market to contract, and the exchanges to be destabilized is not a new concern.  In March of this year, for example, Avik Roy argued at his blog at Forbes that “[b]ecause the mandate is weakly enforced, small in size, and gradually put into place, whereas the pre-existing condition mandate takes effect immediately, Obamacare creates the recipe for an adverse selection death spiral.”  Now that the Supreme Court has upheld the Act, these concerns will take on a new urgency for federal and state regulators, insurers, and others.

In fact, just hours after the Court handed down its decision, John Reichard and Rebecca Adams at CQ HealthBeat were reporting that Cigna is planning a lobbying campaign with the goal of convincing lawmakers to strengthen the mandate.  Reichard and Adams report that

“Cigna also plans to lobby state governors, state legislatures, the Obama administration and Congress to require waiting periods of up to six months if a health care plan enrollee decides to drop out of a plan and then decides he or she wants to get back in, said Tom Richards, president of Cigna’s individual and family plan division. Efforts in Congress likely won’t occur until next year, he said.

In other words, a person who dropped out of a plan could come back into it during the next open enrollment period but would have to wait for some specified period — perhaps six months — before they would be covered for a pre-existing medical condition. That would keep people from dropping coverage and then re-enrolling quickly if they got sick so they could be covered for that illness.”

Reichard and Adams quote Ron Pollack, the Executive Director of Families USA, who noted that instead of or in addition to pre-existing condition waiting periods, those who wait to purchase health insurance could be charged a higher rate, as is the case with Medicare Part B.

The individual mandate is not the only arrow in the Affordable Care Act’s quiver, however, and it remains to be seen whether these additional measures are necessary.  The Act’s premium subsidies, for example, will provide a strong incentive to individuals to participate in the health insurance market.  The “3 Rs” — the reinsurance, risk corridor, and risk adjustment programs — are also important, as they are designed to, as Timothy Jost explains here, ease the transition to the exchanges and to a market without medical underwriting and with premium tax credits.  The final “R,” risk adjustment, will provide a mechanism to reduce problematic concentration of risk in the exchanges on an ongoing basis.

“The reinsurance program will [ease the transition] by collecting assessments from insured and self-insured group health plans and paying out funds to individual plans that cover high-risk individuals. The risk corridor program will collect funds from issuers of qualified health plans (primarily but not exclusively plans in the exchanges) that have lower-than-expected claims costs and pay out those funds to issuers of qualified health plans with higher-than-expected costs. It will thus stabilize the experience of these plans over the first three years when insurers will have a difficult time predicting exactly how to set their premiums.

Finally, the third ‘R’ program, risk adjustment, will on a permanent basis move funds from issuers in the nongroup and small group market (other than grandfathered plans) with lower-than-average-risk populations to those with higher-risk populations; this will discourage risk selection and compensate insurers that cover sicker enrollees.”

If the 3 Rs, and, in particular, the risk adjustment program, work as intended, a weak individual mandate may be strong enough.

Recommended Reading (and a Lawsuit to Watch) on Prisoner Physical and Mental Health Issues

• In The Ninth Circle of Hell: An Eighth Amendment Analysis of Imposing Prolonged Supermax Solitary Confinement of Inmates with a Mental Illness (forthcoming in the Denver University Law Review), Thomas Hafemeister and Jeff George provide a fascinating history of prolonged solitary confinement and helpful reviews of the empirical research establishing that such confinement “is virtually guaranteed” to cause significant psychological harm and of the Eighth Amendment jurisprudence addressing the practice. Tragically, the limited extant empirical evidence indicates that our “supermax” facilities and units house not the worst of the worst but rather “a disproportionally large number of inmates suffering from a serious mental illness.” Hafemeister and George conclude that prolonged solitary confinement, without more, is not unconstitutional under the Supreme Court’s current standard. Inmates who are mentally ill or highly vulnerable to becoming so, however, “can readily establish the requisite deliberate indifference on the part of [prison] officials with regard to the impact of prolonged solitary confinement[.]“

• On May 31, 2012, the Center for Constitutional Rights filed an amended complaint in Ruiz v. Brown, a proposed class action lawsuit brought on behalf of prisoners at California’s Pelican Bay State Prison who claim “that prolonged solitary confinement violates Eight Amendment prohibitions against cruel and unusual punishment, and that the absence of meaningful review for [Security Housing Unit ("SHU")] placement violates the prisoners’ right to due process.” In its press release announcing the suit, CCR highlighted the following allegations: “SHU prisoners spent 22 ½ to 24 hours every day in a cramped, concrete, windowless cell. They are denied telephone calls, contact visits, and vocational, recreational or educational programming. Food is often rotten and barely edible, and medical care is frequently withheld. More than 500 Pelican Bay SHU prisoners have been isolated under these conditions for over 10 years, more than 200 of them for over 15 years; and 78 have been isolated in the SHU for more than 20 years. Today’s suit claims that prolonged confinement under these conditions has caused “harmful and predictable psychological deterioration” among SHU prisoners. Solitary confinement for as little as 15 days is now widely recognized to cause lasting psychological damage to human beings and is analyzed under international law as torture.”

• Priscilla Ocen’s article Punishing Pregnancy: Race, Incarceration and the Shackling of Pregnant Prisoners (forthcoming in the California Law Review) is also well worth reading. Ocen contends that because our Eighth Amendment jurisprudence is racially blind, the historical and ideological foundations of the practice of shackling pregnant prisoners during labor, childbirth, and recovery have been obscured. She argues, compellingly, for an “antisubordination” reading of the prohibition on cruel and unusual punishments, one that would take account of “the racial and gender stereotypes of women prisoners that render then vulnerable to shackling practices.”

• I also recommend Lisa Heinzerling’s searing blog post on the cost-benefit analysis which accompanied the Department of Justice’s recently-released final rule implementing the Prison Rape Elimination Act. Heinzerling describes the DOJ’s analysis as “a labored, distasteful, and gratuitous essay on the economics of rape and sexual abuse.” In it, she writes,  DOJ finds “itself in the remarkable position of asking how much money the victims of rape would be willing to pay to avoid rape and also asking how much money these victims would be willing to accept in exchange for being raped. … Never mind that rape is a serious crime, not a market transaction. Never mind that framing rape as a market transaction strips it of the coercion that defines it. Never mind that the law under which DOJ was acting is the Prison Rape Elimination Act, not the Prison Rape Optimization Act. In the topsy-turvy world of cost-benefit analysis, DOJ was compelled to treat rape as just another market exchange, coercion as a side note, and the elimination of prison rape as a good idea only if the economic numbers happened to come out that way.”

• Finally, Rick Hills’ response to Heinzerling’s post is also provocative and worth a read. Hills argues that the DOJ’s analysis should have gone further down the road of quantifying the benefits of prison rape regulation, in order to support additional, costly, reforms. Hills writes “that it is better to ‘feel violated’ by facing up to the need to choose between costly reforms and substantial benefits than to refrain from adopting any costly reforms at all in order to avoid the comparison. Put more generally, sometimes it is impossible to induce judges, legislators, and the voters at large to bear big burdens unless one makes explicit the benefits that such burdens will produce.”

The Treatment of Neonates in Pending Legislation Permanently Reauthorizing the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act

Last week, the United States Senate took up debate of The Food and Drug Innovation and Safety Act, S 3187.  A similar bill, HR 5651, was voted out of the House Energy and Commerce committee earlier this month. In addition to re-authorizing user fees for drug and devices and newly authorizing user fees for biologics and generic drugs, the bills include provisions reauthorizing and making permanent both the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA). As reported here, S 3187 and HR 5651 are expected to pass the House and Senate in the coming weeks and to go to a conference committee in June. Lawmakers hope to present the final version of the legislation to President Obama before the Fourth of July.

The BPCA and the PREA are often described as taking a carrot and stick approach.  The BPCA is the “carrot,” providing a drug’s manufacturer with six additional months of protection from generic competition in return for studying the drug in children.  The PREA is the “stick,” requiring, as I explained here, “that, as a condition of FDA approval of a new drug application or supplemental drug application for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration, drugs be studied in children. Applicants must submit a ‘pediatric assessment’ which evaluates the drug’s safety and effectiveness for use in children and ‘supports dosing and administration’ for any pediatric sub-populations for which the drug is found to be safe and effective.  The PREA also requires applicants to request approval of the formulations appropriate for those sub-populations for which the drug is found to be safe and effective.”

While not without their flaws, the BPCA and the PREA have increased our knowledge of the safety and effectiveness of drugs when used in children.  As Daniel Frattarelli of the American Academy of Pediatrics testified before Congress earlier this year, as a “direct result of BPCA and PREA[,]” “we have gone from a situation where about eighty percent of time, the drugs we were using in children did not have FDA-approved pediatric labeling to today where that number is down to about fifty percent.”

In addition to reauthorizing permanently the BPCA and PREA, both S 3187 and HR 5651 make minor changes to the laws, addressing some but not all of the concerns raised in the Institute of Medicine’s February 2012 report, Safe and Effective Medicines for Children: Pediatric Studies Conducted under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. For example, the IOM suggested that “[m]ore timely planning, initiation, and completion of pediatric studies would benefit children[,]” and both bills require that companies submit the pediatric research plans required under PREA earlier in the process than they currently do.  The bills also include provisions designed to, in the words of one of the sponsors of HR 5651, “increase[] transparency on the status of pediatric clinical trials required under PREA” and to provide FDA the necessary enforcement tools to ensure that trials are completed on time.

One problem that the IOM discussed in its report that is only partially addressed in the draft legislation is the need for more studies of drugs in neonates, that is, infants up to four weeks old.  Per the IOM, “[f]rom 1998 through 2010, only 23 of the more than 350 labeling changes resulting from [studies conducted pursuant to the BPCA and the PREA] included information from studies with neonates.”  There were also “five products [that] had been studied in neonates and companies had received exclusivity, but no information from the neonatal studies was added to the labeling.”

The draft legislation incorporates the following provisions relating to neonates:

• Both the House and the Senate bills provide that if the FDA issues a request pursuant to the BPCA and “does not request studies in neonates, such request shall include a statement describing the rationale for not requesting studies in neonates.”

• Both the House and the Senate bills require that the reports that the FDA will be required to make to Congress every five years include a discussion of “the efforts made by the Secretary to increase the number of studies conducted in the neonatal population (including efforts made to encourage the conduct of appropriate studies in neonates by companies with products that have sufficient safety and other information to make the conduct of the studies ethical and safe)[.]“

• The House bill includes a provision that would ensure that the Pediatric Review Committee (PeRC), which is responsible for carrying out the BPCA and PREA, has as a member an agency employee with expertise in neonatology.

• The House bill also includes a provision requiring that the staff of the Office of Pediatric Therapeutics, which is “responsible for coordination and facilitation of all activities of the Food and Drug Administration that may have any effect on a pediatric population or the practice of pediatrics or may in any other way involve pediatric issues, including increasing pediatric access to medical devices[,]” 21 U.S.C. § 393a, include “one or more additional individuals with expertise in neonatology[.]“

Ensuring that individuals with expertise in neonatology serve on the Pediatric Review Committee and staff the Office of Pediatric Therapeutics will not guarantee that studies in neonates are conducted where appropriate.  The IOM concluded in its report that it did not have enough information to know whether additional expertise would have made a difference in the quality of the FDA’s review of studies in neonates.  It also wrote, however, that it “had some concerns about whether sufficient expertise in neonatology and neonatal pharmacology was brought to bear on some requests, for example, those for bacterial conjunctivitis and GERD.”   Common sense suggests that expertise in neonatology is a necessary but not sufficient condition for high quality review; the bill that comes out of conference committee should incorporate the two provisions from the House bill.

As the IOM emphasizes, industry-funded research conducted pursuant to the BPCA and the PREA will never be enough to build an adequate evidence base for drug treatment of neonates, because the BPCA and the PREA only apply to relatively new drugs.  This has a disproportionate effect, because, as the IOM explains, “[m]any drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.”  The IOM discusses an ongoing study of caffeine citrate, which is used to treat apnea of prematurity, which is following children treated with the drug through the age of twelve.  As the IOM notes, “[t]he study, which was funded by the Canadian Institute for Health Research, illustrates the importance of long-term studies of the benefits and risks of neonatal therapies and the importance of public funding for such studies, particularly for long-marketed drugs.”

First Circuit Finds Generic Drugmaker Had State Law Duty to Stop Selling Unsafe Drug

Earlier this month, the First Circuit surprised observers when it held, in Bartlett v. Mutual Pharmaceutical, that a state law product liability suit founded on the claim that a generic drug was unreasonably dangerous due to a design defect was not preempted by the Federal Food, Drug, and Cosmetic Act (FDCA).  In coming to its decision, the First Circuit distinguished Pliva v. Mensing, in which the Supreme Court held that the FDCA does preempt a state law product liability suit founded on the claim that a generic drug was unreasonably dangerous due to a label that failed to warn of the drug’s dangers.

Pliva hinged on the fact that the FDCA and its implementing regulations “require that the warning labels of a brand-name drug and its generic copy must always be the same– thus, generic drug manufacturers have an ongoing federal duty of ‘sameness.’”  Because the defendant in Pliva could not fulfill its alleged state law duty to add stronger warnings to its label without violating the federal duty of sameness, the Supreme Court held that the state law product liability suits at issue could not go forward.  As the First Circuit put it in Bartlett, “Congress cannot have wanted the generic to pay damages under state law for a label that the FDA required.”

The defendant in Bartlett argued that, because generic manufacturers cannot alter the composition of a drug, “[Pliva's] policy of encouraging generics by preempting state tort claims should extend to design defect as well as claims based on inadequate warning.”  The First Circuit rejected this argument, finding that

“…although Mutual cannot legally make [the drug at issue] in another composition (nor is it apparent how it could alter a one-molecule drug anyway), it certainly can choose not to make the drug at all; and the FDCA might permit states to tell Mutual it ought not be doing so if risk-benefit analysis weights against the drug, despite what the Supreme Court made of similar arguments in the labeling context.”

James M. Beck, at the defense-oriented blog Drug and Device Law calls this result “startling[,]” pointing out that “before Bartlett the post-[Pliva] precedents had universally rejected arguments that supposed state-law duties (no state high court has ever recognized such a duty) to remove generic drugs from the market altogether could survive preemption.”  Beck argues that

“[a]nybody could always avoid liability by not selling any products at all — but that would make preemption ‘illusory,’ and also totally defeat the purpose of the Hatch-Waxman Amendments to encourage production of generic drugs. Sooner or later, one plaintiff or another will argue that every generic drug ever approved should be removed from the market.”

While plaintiffs may argue that generic drugs have design defects and should be removed, their arguments are unlikely to succeed.  As the First Circuit explains, many state courts refuse to review claims that FDA-approved prescription drugs are defectively designed.  Even where such claims are permitted, manufacturers can defend against them by showing that a drug “was unavoidably unsafe but was highly useful and had an adequate safety warning[.]“  For unknown reasons, the defendant in Bartlett “abandoned that defense on the eve of trial.”

That said, Bartlett highlights a number of important questions.  Should generic manufacturers, as the First Circuit decision suggests, have a duty to perform their own continuous risk-benefit analysis of the drugs that the FDA has approved them to sell?  They may be in the best position to do so, although monitoring is likely to be more complicated the more manufacturers of a single drug there are.  Should they have a duty to stop selling a drug as soon as the risk-benefit balance — in their sole estimation — tips?  Maybe, maybe not.  Drugs are, after all, “highly useful” and there are inevitably winners as well as losers when manufacturing is discontinued.  Such a decision might be better entrusted to the FDA.

Legislation is pending in Congress that would overturn Pliva by giving generic manufacturers the same authority that branded manufacturers have to add warnings to their labels.  Perhaps Congress should also clarify manufacturers’ obligations (or lack thereof) with regard to removing drugs from the market.

Next Page »