Center for Health & Pharmaceutical Law & Policy Submits Comments on Conflicts of Interest in Research to the National Institutes of Health

On August 19, 2010, on behalf of Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy, Seton Hall Law Professors Kathleen Boozang and Carl Coleman, along with Research Fellow Kate Greenwood, submitted comments on the National Institutes of Health’s proposed revisions to its regulations governing conflicts of interest in federally-funded research.  While the Center’s November 2009 White Paper Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight endorsed limits on conflicts of interest beyond those that the NIH has proposed, the revised regulations are a step in the right direction and in its comments the Center commends the NIH for its decisive action on this issue.


Briefly, the Center:

• Supports the NIH’s proposal that that researchers disclose to their institutions any significant financial interest that “reasonably appears to be related to the Investigator’s institutional responsibilities,” with “institutional responsibilities” defined to include “activities such as research, research consultation, teaching, professional practice, institutional committee memberships, and service on panels such as Institutional Review Boards or Data and Safety Monitoring Boards.” This comports with the Center’s recommendation in the White Paper that investigators not be charged with determining for themselves whether one or more of their financial interests could be affected by a specific research project.

• Supports the NIH’s decision to significantly lower the monetary threshold at which a researcher’s financial interest becomes “significant” to $5,000, but argues that a lower threshold would be better. Collection of data about all of a researcher’s relationships with industry, even those that fall below the proposed $5,000 threshold, would facilitate better conflict of interest assessment and management and make possible research into the effects of conflicts on research integrity and human subject welfare.

• Supports the NIH’s decision not to exclude income from non-profit entities for lectures and similar engagements from the definition of significant financial interest and its conclusion that any equity interest in a non-publicly traded entity is significant, as are any and all intellectual property rights, but encourages the agency to revisit its decision to shield from disclosure (1) equity interests held by investigators in commercial or for-profit institutions and (2) royalties and other remuneration other than salary paid to an investigator by an institution that appoints or employs him or her.

• Notes that the draft revised regulations do not address the White Paper’s criticisms that the conflict of interest regulations place no “substantive limits on the kinds of conflicts that may exist” and fail to put forth “a required minimum response for conflicts that pose the greatest risks to participants and the integrity of the research” and encourages the NIH to consider again the benefits of setting forth required minimum responses to those conflicts that are the most problematic.

• Supports the NIH’s decision to require that grantees provide “sufficient information to enable the [agency] to understand the nature and extent of the financial conflict, and to assess the appropriateness of the Institution’s management plan.”

• Supports the requirement in the draft revised regulations that any significant financial interest that (1) is still held by a principal investigator or senior/key person, (2) is related to PHS-funded research, and (3) is a financial conflict of interest must be disclosed to the public via the world wide web.

• Supports the draft revised regulations’ requirement that investigators complete training on “the Institution’s policy on financial conflicts of interest, the Investigator’s responsibilities regarding disclosure of significant financial interests, and of these regulations” before the commencement of research and then at least once every two years. As recommended in the Center’s White Paper, it would be beneficial for the training to include as well a discussion of the nature of conflicts of interest and their potential for harm.

• Recommends that the agency adopt its own suggestion that institutions be required to “maintain up-to-date, written, enforced policies” on institutional conflicts of interest, as they are for investigator conflicts, and that these policies be made publicly available via the world wide web. The nudge this requirement would provide is necessary because institutions have been slow to develop and adopt policies on institutional conflicts.

• Recommends that the section of the regulations devoted to remedies be revised to include a non-exclusive list of potential enforcement actions such as temporary withholding of cash payments pending correction of the deficiency, suspension or termination of the contract or grant in whole or in part, monetary assessments and penalties, and suspension or debarment from eligibility for future contracts or grants.

The Center’s comments in their entirety are available here.

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy. The Center is a think tank that fosters dialogue, scholarship, and policy solutions to critical issues in health and pharmaceutical law. As part of its mission, it convenes policymakers, consumer advocates, the medical profession, industry, and government in the search for concrete solutions to the ethical, legal, and social questions presented in the health and pharmaceutical arenas. The Center also runs a compliance training program covering the state and federal laws governing the development and marketing of drugs and medical devices.

PPACA and the Growing Shortage of Pediatric Subspecialists

Over the course of this year, a spate of articles and op eds have highlighted a growing shortage of pediatric subspecialists.  Earlier his month, Amy Mansue, CEO of Children’s Specialized Hospital here in New Jersey, addressed the problem in a very interesting post on the National Association of Children’s Hospitals’ With All Our Might blog.  Ms. Mansue describes a recent visit to Capitol Hill during which she discussed the implementation of the Patient Protection and Affordable Care Act, explaining to the staffers that:

[t]he differences between strategies to address the needs of the newly insured children versus strategies to address the needs of adults couldn’t be more different.  Start with the basic fact that there is a critical shortage of specialists in pediatrics, where the biggest issue facing adults is how to access primary care. There can be a utilization of physician extenders in the short run until more primary care physicians are trained; there is no similar ‘quick fix’ in pediatrics.

Pediatric neurologists and developmental-behavioral pediatricians are in especially short supply.  A survey of children’s hospitals conducted by the National Association of Children’s Hospitals and Related Institutions in December 2009 revealed average wait times of 9 weeks for an appointment with a pediatric neurologist and 13 weeks for an appointment with a developmental-behavioral pediatrician.  An earlier study published in Pediatrics found that, in addition to enduring long waits, parents and children also travel long distances to see these specialists–on average 73 miles to see a subspecialist in neurodevelopmental disabilities and 44 miles to see a developmental pediatrician.

This is concerning for a host of reasons, including the importance of early, appropriate intervention to the future success of children with developmental delays.  As I discussed previously here and here, the “right” medical diagnosis can be key to accessing needed services, as can a thorough written evaluation and a doctor willing to advocate on a child’s behalf.  This is true whether a family is fighting for publicly-provided disability benefits or special education services or to get a private insurance plan to pay for medically necessary therapies.

What explains the subspecialist shortage?  As Ms. Mansue puts it, “it is all about math.  There is no incentive to go through an additional decade of training to get paid less than what a pediatric nurse practitioner is now demanding in my home state of New Jersey.”  Congress has tried to change the equation.  PPACA provides for loan forgiveness of up to $35,000 per year for up to three years for pediatric subspecialists who “work for a provider serving in a [Health Professional Shortage Area] or medically underserved area, or among a medically underserved population that has a shortage of the specified pediatric specialty and a sufficient pediatric population, as determined by [HHS], to support the specified pediatric specialty.”  But funding for this measure has not yet been appropriated.  The federal government has also attacked the problem through its Children’s Hospitals Graduate Medical Education Payment Program, which provides funding for specialty training for pediatricians.  According to a recent New York Times op ed, however, this program’s funding is also uncertain, suggesting that an end to the shortage of pediatric subspecialists may not be in sight.

Recommended Reading: Recent Legal Scholarship on Issues in Global Public Health

Redressing the Unconscionable Health Gap: A Global Plan for Justice (published in the Harvard Law & Policy Review). In this article Lawrence Gostin brings a big picture issue — the vast global health gap between rich and poor — into perfect focus. Professor Gostin reminds us of an “uncomfortable truth” — “that closing the health gap is well within the means of the international community” — and he proposes a simple (in concept if not execution) plan to do just that.  No international treaty would be required; Professor Gostin’s Global Plan for Justice would take the form of a World Health Assembly resolution.  No new organization or governance structure would be required either; rather, the World Health Organization would “assume its place as the global health leader.”  States would be asked to contribute a small percentage — Professor Gostin suggests 0.25% — of their Gross National Income each year to a Global Health Fund.  The WHO would then allocate the Fund’s resources based on “the health needs of developing countries measured by poverty, morbidity, and premature mortality.”  Professor Gostin suggests that the mission of the Fund be threefold: “(1) ensure the fair allocation of essential vaccines and medicines, with particular attention to low- and middle-income countries in a public health emergency; (2) meet basic survival needs [e.g. food, water, sanitation, and vector controls] and create the conditions in which people can be healthy; and (3) help countries that will suffer most to adapt to the health impacts of climate change.”  Existing efforts, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria, demonstrate the power of voluntary collective action; unlike the proposed Global Health Fund, however, they are too narrowly-targeted and inconsistent to close the global health gap.  Professor Gostin’s article is short (it’s based on the text of a speech), straightforward, and provocative in the best sense of the word.  I highly recommend it.

I also highly recommend Kevin Outterson’s The Legal Ecology of Resistance: The Role of Antibiotic Resistance in Pharmaceutical Innovation (published in the Cardozo Law Review) in which he uses proprietary sales and volume data for the important hospital antibiotic vancomycin to test a number of widely-propounded theories about the interplay between antibiotic resistance and intellectual property law.  The vancomycin case study fails to support the hypothesis that a patent holder is likely to zealously market an antibiotic with an eye to the drug’s dwindling patent term, without regard for the risk that increased uptake could accelerate the evolution of antibiotic-resistant bacteria.  It also fails to support the hypothesis that if patent terms for antibiotics were extended, patent holders would better manage the sales and use of their drugs to forestall the development of resistance.  By contrast, the story of vancomycin is consistent with the hypothesis that antibiotic resistance stimulates innovation — as bacteria evolve that are resistant to an existing antibiotic a market for a new antibiotic arises.  All of this suggests that “tinker[ing] with the patent system” is unnecessary and could even backfire.  Professor Outterson concludes that a more direct and potentially more effective approach to preserving the antibacterial effectiveness of our antibiotics would be to fix our broken health care reimbursement system, under which infection control is an unreimbursed cost and “hospitals and doctors have generally gained revenues from additional infections[.]“

Recommended Reading: Recent Scholarship on Medical Decisionmaking for Children

Alicia Ouellette’s Shaping Parental Authority over Children’s Bodies (published in the Summer 2010 issue of the Indiana Law Journal and available on SSRN) highlights four “shaping cases,” including “a case involving a white father who used surgery to reshape the eyes of his adopted Asian child; another in which parents used human growth hormone to add a few inches onto the adult height of their young son; a third in which a mother consented to liposuction for her twelve-year old daughter; and the case of Ashley X, a young girl with profound disabilities whose parents elected to stunt her growth and remove her breasts and uterus in order to continue caring for her at home.”  Professor Ouellette argues that these cases reveal that the “traditional hierarchical model of the family at play in the health-care setting, which starts from an assumption of parental power” and “take[s] as a given that, absent grievous harm or death, parents have a right to modify a child’s body,” fails to adequately protect or respect children.  She advocates instead the adoption of a “trust-based construct,” under which parents would be conceived of as trustees of their children’s welfare (e.g., their need for food, safety, and nurturing) and developing autonomy rights (e.g., the right to self-determination that will be theirs once they reach adulthood).  Under Professor Ouellette’s trust-based construct, the four shaping cases she identifies would trigger third-party review, because of the potential for conflict between the parents’ trustee-like duties to their children and the parents’ personal interests.  This is not to say that the parents’ decision to “shape” their children would be overruled in all four cases; Professor Ouellette argues that the outcomes of the third-party reviews would likely vary.  Overall, this is a fascinating (and very readable) article in which facts that might seem sensationalistic at first blush are used as a launching pad for a thoughtful theoretical analysis with broad potential applicability.

Rachel Camp’s A Mistreated Epidemic: State and Federal Failure to Adequately Regulate Psychotropic Medications Prescribed to Children in Foster Care (forthcoming in the Temple Law Review and available on SSRN) also takes on the issue of medical decisionmaking for children, focusing on children in foster care for whom psychotropic medication has been recommended.  Professor Camp persuasively argues that parents whose children have been removed and placed in foster care have a right to consent before their children begin taking such medications, because they fall outside the bounds of “ordinary” medical care.  “[W]hen a parent is unwilling or unable to consent,” Professor Camp advocates for “[c]ourt review with an evidentiary burden on the party seeking the medication, not agency acquiescence[.]“  A meaningful and enforced consent requirement would “force[] a check on a system that has become complacent about how psychotropic medications are administered to children in care;” it could also “empower parents to parent — to assess risks, benefits, and make decisions for their children.”  Professor Camp’s article provides an excellent summary of the (startling) facts about the extremely high rates of use of psychotropic medication by children in foster care, a nuanced and thorough accounting of the possible explanations for these high rates, a helpful overview of the applicable law, and concrete recommendations for state-level legal and policy change.

Ethical Marketing Measures in Access to Medicines Index: An Important First Step

Earlier this week, the Access to Medicine Foundation released its 2010 Access to Medicine Index, “a ranking of the world´s largest pharmaceutical companies on their efforts to increase access to medicine for societies in need.”

In a change from the 2008 Index, which was the first to be issued, the 2010 Index includes measures designed to assess companies’ commitment to, and practice of, ethical marketing behavior.  Per the report accompanying the Index, “[t]he marketing and promotion of drugs can have a significant influence on the type of medicines that patients receive.  Particularly in Index Countries [88 countries with low or medium levels of development] with less robust regulatory enforcement and consumer protection, the marketing behavior of pharmaceutical companies can shape access to both appropriate and affordable medicines.  Unethical marketing can lead to suboptimal clinical decisions, prescription of more expensive drugs and irrational use of medicines by consumers, which can result in reduced treatment efficacy and other complications, such as adverse drug reaction and drug resistance.”

The Index ranks pharmaceutical companies’ marketing behavior along three axes: (1) commitments, (2) transparency, and (3) performance.  In the commitments category, companies are assigned points for the marketing codes and standards they have adopted and that they require their local third party sales agents to adopt.  For example, “originators,” i.e., research-based pharmaceutical companies, receive 5 points on a scale of 1-5 for committing to the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) Code of Pharmaceutical Marketing Practices, the WHO Ethical Criteria for Medicinal Drug Promotion, “or an equivalent industry code.”  Originators that have not committed to any external codes but that have an internal code which covers the same core principles receive 2.5 points.  (The scoring is different for generics on this measure because they do not have a “viable up to date and auditable external code.”)  With regard to third party sales agents, both originator and generic companies can receive all 5 points if they make “specific ethical marketing demands” of their sales agents and then audit the agents’ practices to ensure compliance.

For transparency, the Index gives points to companies that “publicly disclose[] detailed information regarding [their] marketing and promotional programs in the Index Countries, such as payments to physicians or other key opinion leaders and also its promotional activities for other healthcare providers, distributors, etc.”  None of the companies earned any points in this category.  While some have started to disclose payments made in the United States, no company has disclosed payments made in any of the Index Countries.  According to the report, three companies — GlaxoSmithKline, Merck, and Roche — have pledged to disclose payments made in the Index Countries soon.  Companies can also earn disclosure points for revealing breaches of marketing codes and marketing-related litigation in the Index Countries.

For the third category, performance, companies lose points if they breach the IFPMA Code or if they are sued or subjected to fines for marketing behavior.  Companies can earn points for including binding ethical marketing requirements in their agreements with their sales agents and by establishing employee codes of conduct in the Index Countries equivalent to the codes they have in place in other markets.  Despite the fact that issues have been raised “about pharmaceutical marketing practices in the Index Countries, especially regarding clear mention of … adverse side effects,” none of the companies studied lost any points in this category.

As the title of this post suggests, I think that the Index’s attempt to rank companies’ commitment to and practice of ethical marketing practices is important.  Anyone who works in a law school knows how influential rankings can be — for better or for worse.  It is easy to imagine the Access to Medicine rankings providing an additional nudge to companies to begin disclosing payments to healthcare providers around the world not just here in the United States.  At the same time, there is ample room for refinement.  In the performance category, for example, measures, in addition to breaching the IFPMA Code/being sued/ being fined, are needed to expose differences that surely exist in companies’ approaches to marketing in the Index Countries.

Lingering Questions about Mild Traumatic Brain Injury: A Medical Research Priority

For anyone who missed it, I highly recommend the eye opening series NPR has been running this week, reported by T. Christian Miller and Daniel Zwerdling, on the military’s failure to diagnose and treat soldiers with mild traumatic brain injury, defined by the Department of Defense as a blow or jolt to the head that results in a brief change in mental status or consciousness.

As Miller and Zwerdling explain, “[b]etter armor and battlefield medicine mean troops survive explosions that would have killed an earlier generation. But blast waves from roadside bombs, insurgents’ most common weapon, can still damage the brain.  The shockwaves can pass through helmets, skulls and through the brain, damaging its cells and circuits in ways that are still not fully understood. Then, secondary trauma can follow, such as sending a soldier tumbling inside a vehicle or hurling into a wall, shaking the brain against the skull.”  While most sufferers of mild traumatic brain injury make a full recovery, some — termed the “miserable minority” — experience a devastating array of chronic, disabling symptoms, including balance issues, dizziness, headaches, memory and reasoning deficits, and vertigo.  Among Miller and Zwerdling’s findings are that “[w]ithout diagnosis and official documentation [a distinct possibility given the weaknesses of the diagnostic tests used and the fact that handheld recordkeeping devices fail and paper records are burned] soldiers with head wounds have had to battle for appropriate treatment.”

Complicating matters is a lingering controversy over what the appropriate treatment is for mild traumatic brain injury.  In a 2009 opinion piece in the New England Journal of Medicine, Charles Hoge — a retired Army psychiatrist whom Miller and Zwerdling note is a high-level advisor to Lt. Gen. Eric Schoomaker, the Army’s most senior medical officer — argued that (1) there are no validated diagnostic criteria for clinicians to use in diagnosing mild traumatic brain injury, (2) the physical, neurocognitive, and behavioral symptoms believed to be associated with mild traumatic brain injury are more strongly associated with post-traumatic stress disorder and depression, and (3) that misattributing “postwar health conditions that have been described for centuries” to mild traumatic brain injury could result in “a failure to address underlying conditions (e.g., depression, PTSD, or substance abuse), the use of unproven rehabilitation procedures, and the prescribing of medications for nonapproved indications (e.g., an atypical antipsychotic for sleep).”  On the other hand, Miller and Zwerdling report that “[a]n increasing number of brain-injury specialists say the best way to treat patients with lasting symptoms is to get them into cognitive rehabilitation therapy as soon as possible. That was the consensus recommendation of 50 civilian and military experts gathered by the Pentagon in 2009 to discuss how to treat soldiers.”

Given the high number of veterans of the wars in Iraq and Afghanistan who are affected, resolving the debate over the diagnosis and treatment of mild traumatic brain injury is a medical research priority of the highest order.  Miller and Zwerdling quote Congressman Bill Pascrell (D-NJ) as follows: “We are not doing service to our bravest.  There needs to be a sense of urgency on this issue.”

Bad Ads and Doctor Deputies

Earlier this month, the FDA launched a new initiative — the Bad Ad Program — to “help health care providers recognize misleading prescription drug promotion and provide them with an easy way to report this activity to the agency.”  In an article appearing earlier this week in Advertising Age, advertising executives and others decry the program as a “publicity stunt” with the potential to lead to physician “vigilantism” and to become “unbridled and messy.”  Also quoted in the article is PhRMA Senior Vice President Ken Johnson, who states that PhRMA views the Bad Ad Program as “another step to help educate — and receive feedback from — healthcare providers about prescription drug advertising and promotion.”  The Advertising Age article, correctly I think, characterizes this statement as offering only “tepid support.”

There appear to be two central criticisms of the Bad Ad Program: (1) that it is not as low-cost as it seems because it will take up physicians’ time and create more work for the FDA’s already overburdened Division of Drug Marketing, Advertising, and Communications (DDMAC) and (2) that it will be an ineffective compliance tool either because doctors cannot tell the difference between compliant and noncompliant advertising or because doctors will “go on personal jihads on ads they don’t like - ads that very well might be in perfect compliance.”

Both concerns seem overblown.  Doctors do not have to participate if they do not have the time or inclination — it seems likely that most will not — and pharmaceutical companies have been reporting each other’s marketing abuses to DDMAC for years, so the Division has experience sifting through more and less credible information.  Doctors may well have difficulty discerning which ads are compliant and which are not — see, e.g., this study revealing that doctors could not accurately identify the FDA-approval status of a significant percentage of the drugs they prescribe — but this is not an argument against the FDA’s effort to educate them.

The bottom line is that while pharmaceutical companies track what happens in physician offices in multiple ways, including through sales rep call notes and sales message recall studies, they do not, at least not consistently and/or voluntarily, use the information gathered in service of compliance, as opposed to sales, goals.  In the words of Arnie Friede, to the extent that the FDA’s Bad Ad Program creates “an additional incentive for a company to closely monitor and control communications by their sales people” it is “an understandable, perhaps even brilliant move.”

Recent Empirical Research Suggests Rise in Cesarean Section Rates Not Caused by Malpractice Liability Pressure

In my recent post on the NIH’s consensus development conference on vaginal birth after cesarean, I noted that one of the recommendations coming out of the conference was that “medico-legal” reforms “be developed, implemented, and evaluated” to determine their effect on cesarean section rates.  Recent empirical research indicates that such reforms are likely to have little impact.

Prior work suggested that medico-legal reforms could play a significant, if supporting, role in efforts to reduce the number of unnecessary cesarean sections.  For example, the authors of a 2006 study published in Health Affairs analyzed the disturbingly large disparities in cesarean rates from county to county and concluded that, for normal weight births, 14.5 percent of the variance in rates was attributable to variance in malpractice premiums and the number and size of malpractice payouts.  Another study published in the journal Medical Care in 2009 found, among other things, a small negative association between cesarean section rates and two types of tort reforms — caps on noneconomic damages and pre-trial screening panels.

In an article in the latest volume of American Law and Economics Review, Influence and Deterrence: How Obstetricians Respond to Litigation Against Themselves and Their Colleagues, Northwestern University researchers David Dranove and Yasutora Watanabe move beyond “macro measures of the malpractice environment” and “tak[e] a micro look at the data, examining on a quarterly basis how physicians respond to claims lodged against themselves and their immediate colleagues.”  Using two rich data sets from Florida, one of all hospital births between 1994-2000 and another of every resolved malpractice claim from that state from 1979-2003, Dranove and Watanabe generate answers to three provocative questions:  Do obstetricians perform proportionally more cesarean sections after they have been sued?  Do their cesarean section rates increase in the wake of suits against other obstetricians at their hospital?  What about when the number of lawsuits filed against non-obstetricians in their county goes up?  The answer to the first two questions is yes, but the “effects are both small in magnitude and very short-lived.”  Moreover, the effect disappears after an obstetrician has been sued once; subsequent suits have no effect.  The answer to the third question is no.

Dranove and Watanabe theorize that “[t]he fact that [the effect of a physician's own history] is short-lived and limited to obstetricians with no previous contacts may indicate that obstetricians overreact to their first contact.  It is possible, for example, that they rapidly discover that the litigation process is neither costly nor particularly painful.  For example, physicians rarely make a financial payment to the plaintiff and do not appear to lose any income as a result of being sued (Danzon et al. 1990; Zeiler et al., 2008).”  They conclude that “[w]hatever has caused the pronounced upswing in [c]esareans, it is not due to the influence of individual, hospital-wide, or regional contacts with the legal system.”  This, of course, causes one to wonder what has caused the “pronounced upswing;” in a subsequent post, I will look at other possible explanations, including reasons related to health care finance and organization.

Solving the Mysteries of Pregnancy

In last week’s JAMA, the Pandemic H1N1 Influenza in Pregnancy Working Group reported that their analysis of nationwide data on 2009 influenza A (H1N1) in pregnant women revealed that “early antiviral treatment appeared to be associated with fewer admissions to an ICU and fewer deaths.”  Pregnant women who were not treated with antiviral medication until 3-4 days after they began experiencing flu symptoms were more likely to die than those who were treated within 2 days of symptom onset.  Women who were first treated with medication more than 4 days after symptom onset were 54 times more likely to die than those who were treated within 2 days.

The authors speculate that the “reasons for delayed treatment … could include reluctance of pregnant women or clinicians to use antiviral medication because of concern for risk to the fetus, despite available evidence suggesting that treatment benefit likely outweighs the potential risk.”  Given the shocking 54-fold increased risk of death associated with late initiation of antiviral medication, the authors’ use of the qualifiers “suggesting” and “likely” is noteworthy.  They are forced to hedge because, as a group of experts convened by the CDC acknowledged in late 2009, “[l]ittle is known about the effects of the four currently available influenza medications on the fetus.”

In my article The Mysteries of Pregnancy: The Role of Law in Solving the Problem of Unknown But Knowable Maternal-Fetal Medication Risk (forthcoming in the University of Cincinnati Law Review), I point out that this information gap is not unique to antivirals.  We lack data on the efficacy or safety or both of most drugs when used by pregnant women.  A frequent shorthand explanation for the dearth of information is that you cannot test drugs on pregnant women because of ethical concerns.  Without denying or dismissing the real moral conundrums that arise in maternal-fetal medicine, the information gap is deeper and wider than that.  As Ruth Faden puts it: “Everyone thinks, Oh, my God, research on pregnant women!  All kinds of ethical flags go up.  We don’t have to start with high drama.  [There's enough] low-hanging fruit that we could keep lots of medical researchers busy for a long time.”

Two FDA-led efforts promise to begin connecting the dots: the Medication Exposure in Pregnancy Risk Evaluation Program, which will conduct epidemiological research using data on approximately 1 million births gathered by the 11 participating research sites, and the Sentinel Initiative, which is creating a national electronic system with the goal of, among other things, allowing for prompt investigation of the safety of newly-approved drugs in pregnant women.  Other government agencies also have roles to play.  For example, the house committee report accompanying the Departments of Labor, Health and Human Services and Education Fiscal 2010 Appropriations measure encouraged the NIH “to  expand research on pregnant women with the goals of better understanding the long-term health effects on women of disease states in pregnancy, the proper therapeutics for pharmacologic treatments for pregnant women who face illness, and the safety and efficacy of medications administered to pregnant women and fetuses.”   Finally, industry can and should do more.  Congress should empower FDA to require pharmaceutical companies to sponsor maternal-fetal medication research in appropriate cases, authority the agency already has in the pediatric arena.

Study Demonstrates Link Between Physician Surgicenter Ownership and Volume of Surgeries

There has long been a concern — reflected in the federal Stark Law and its state law analogues — that a conflict of interest arises when a physician refers patients to an ambulatory surgery center he or she owns.  Prior research established that a doctor’s rate of referrals of patients for surgery and other hospital-based services is positively correlated with an ownership stake in a specialty hospital; now there is similarly concrete, empirical evidence of the deleterious effect of the conflict created when doctors own surgicenters.

In an article in the April issue of Health Affairs, John M. Hollingsworth and his co-authors present the results of a study comparing “the practice patterns of physician-owners of surgicenters, before and after they acquired ownership, to those of physician-nonowners over the same time period.”  Using data from Florida for the years 2003-2005, the authors identified all patients who underwent one of five ambulatory procedures — carpal tunnel release, cataract excision, colonoscopy, knee arthroscopy, and ear tube surgery.  The procedures were chosen because “substantial variation exists … in their use,” making them “susceptible to the influences of financial incentives associated with surgicenter ownership.”  After accounting for differences in the populations served by physician-owners and physician-nonowners, the authors found that “the mean annual caseloads for owners … were at least twofold greater than those for nonowners.”  Even more telling, using earlier data, from 1998-2000, the authors found that, even after accounting for the fact that some of the eventual owners had higher-volume practices before they invested in a surgicenter, for four of the five procedures studied, “acquisition of ownership status kicked owners’ already high volumes even higher.”

In an earlier post, I noted that a 2009 New Jersey law conditions physicians’ ability to refer patients to surgicenters on the following: (1) for patients they refer, they personally perform the surgery; (2) they be paid in proportion to their ownership interests, not the number of patients they refer; (3) they and their physician partners make all healthcare decisions, leaving non-physician partners without a say; and (4) they inform their patients in writing of their ownership interest at the time they make the referral.

The work done by Hollingsworth and his co-authors suggests that while the first and second conditions might eliminate certain especially troubling payment arrangements, a “relationship between surgicenter ownership and surgical volume” can persist even when physician-owners personally perform the surgeries.  Similarly, while the third condition would require that physicians make healthcare decisions, it would do nothing to ensure that those decisions are uninfluenced by conflicts of interest.  The fourth condition — which puts the burden on patients to suss out which referrals are medically necessary and which result from a physician-owner inappropriately lowering his or her threshold for intervention due to a financial conflict of interest — is also unlikely to reduce “physician-induced demand.”  There is no evidence that patients are able to perform such a sifting function.  To the contrary, existing evidence suggests that they are not.

Ultimately, as Hollingsworth and his co-authors suggest, the government may need to “intervene through physician reimbursement.”  “[P]artial capitation or global payment schemes, or both, implemented in the context of proposed delivery system reforms (such as accountable care organizations) may be needed to discourage the over-use that fee-for-service payment rewards.”

Health Care Reform Law: Help for Hospitals?

Last week, Samuel Maizel, a bankruptcy lawyer specializing in representing health care businesses in distress, gave a great talk here at Seton Hall Law on “Hospitals in Crisis: Debt Restructuring Options & Issues for Financial Survival.”  Mr. Maizel painted a grim picture of the financial pressures facing hospitals and said he does not believe the situation is going to improve in the near term despite the overall economic recovery.

Near the end of his talk, Mr. Maizel told us that hospitals across the country are combing through the health reform legislation looking for anything that could improve their bottom lines.  This piqued my interest and made me wonder what they will find.  Using the House Committees’ summary of the provisions in the bill relating to delivery system reform as a guide, I came up with the following.

Sec. 3001.  Rewarding High-Quality and Efficient Care.

This provision, which applies to patients discharged on or after October 1, 2012, establishes “value-based purchasing,” meaning that the government will make “value-based incentive payments” to hospitals that provide care to Medicare patients that meets or exceeds certain performance standards to be established by the Secretary of Health and Human Services.  Initially the standards must relate to at least the following five conditions: heart attack, heart failure, pneumonia, surgery, and healthcare-associated infections.  Eventually (by fiscal year 2014) the standards are to incorporate “efficiency measures,” that is Medicare spending per beneficiary must be a factor.

Sec. 3022.  Medicare Shared Savings Program.

This provision, which Jordan Cohen analyzed at length here, directs the Secretary of Health and Human Services to establish a program by January 1, 2012 through which accountable care organizations that save Medicare money would be entitled to a cut of the savings they achieve.  Hospitals are eligible to participate in the program through a partnership or joint venture arrangement with physicians or as employers of physicians.

Sec. 3023.  National Pilot Program on Payment Bundling.

Under this 5-year long pilot program, which the Secretary must establish by January 1, 2013, the government will make one bundled payment “for integrated care during an episode of care provided to an applicable beneficiary around a hospitalization in order to improve the coordination, quality, and efficiency of health care services.”  Episodes of care begin 3 days prior to hospitalization and end 30 days after discharge.  Hospitals can apply to participate in the program (and/or submit a bid) as part of “[a]n entity comprised of … a hospital, a physician group, a skilled nursing facility, and a home health agency.”

While the above three provisions hold out hope of improvement to hospitals’ bottom lines, the House Committees’ summary also highlights two provisions which establish negative incentives.  Section 3008 on Hospital Acquired Conditions provides that, beginning in fiscal year 2015, the government will cut by 1% the payments it makes to hospitals in the top quartile for hospital acquired conditions.  Similarly, Section 3025, the Hospital Readmissions Reduction Program, provides that, after October 1, 2012, the government will begin reducing the amount it pays to hospitals with “excess readmissions.”

NIH Panel Recommends Medico-Legal Reform to Reduce Elective Repeat Cesarean Delivery Rate

In December 2009, an Arizona woman made the news when, in her ninth month of pregnancy, she left her husband and three sons behind and traveled to Phoenix, six hours away from her home, to await the birth of her fourth child.  She took these drastic measures because she wanted to give birth vaginally but her local hospital did not allow women who have had a cesarean section to attempt a vaginal delivery.

Last week, the NIH held a consensus development conference on vaginal birth after cesarean (”VBAC”) to evaluate, among other things, the sharp increase in elective repeat cesarean deliveries in the United States and the medical and non-medical factors that have caused it.  The panel convened by the NIH found that both a trial of labor in women who have had a prior cesarean and an elective repeat cesarean delivery have “important risks and benefits” that “differ for the woman and her fetus.”  A trial of labor is associated with a statistically significant increase in risk of uterine rupture and in risk of perinatal death.  Elective repeat cesarean delivery, on the other hand, is associated with a statistically significant increase in risk of maternal death.  Moreover, as the number of prior cesareans goes up, the risk of serious harm to both mother and baby does too, which is of particular concern to women who hope to have large families.  As the panel notes, these facts and figures pose “a profound ethical dilemma for the woman as well as her caregivers, because benefit for the woman may come at the price of increased risk for the fetus and vice versa.”

The panel concluded that for certain women — those with a “prior low transverse uterine incision” — a trial of labor is a reasonable choice, albeit one that it increasingly constrained by difficulty accessing clinicians and facilities able and willing to offer it. Among the non-medical barriers to VBAC is a recommendation made by the American College of Obstetricians and Gynecologists and the American Society of Anesthesiologists that women with a prior cesarean not be permitted to attempt a vaginal delivery unless the hospital has “immediately available” surgical and anesthesia personnel.  The panel concluded that this recommendation should be reassessed in light of “other obstetrical complications of comparable risk, risk stratification, and in light of limited physician and nursing resources.”

The panel also found that “medico-legal considerations add to, as well as exacerbate” barriers to VBAC.  Midwife Amy Romano, who writes the Science & Sensibility blog for Lamaze International, explains that because “lawsuits focus entirely on the counseling around [uterine] rupture rates, and doctors are sued if that counseling isn’t done or documented effectively, then the doctor has a financial incentive to focus on rupture likelihood[.]“  This steers women toward elective repeat cesarean delivery and exacerbates the already formidable liability barrier to VBAC.  The panel predicted that “caps on noneconomic damages and reductions in physician malpractice premiums would result in fewer cesarean deliveries” and recommended that these and other interventions to reduce the liability barrier be developed, implemented, and evaluated to determine their efficacy.

An Autism Diagnosis: Key to Unlocking Needed Services?

Michael Poreda’s excellent post yesterday called attention to what looks to be a fascinating panel discussion — “Serving Urban Students With Autism: Newark, New Jersey” — to be held here at Seton Hall Law on April 5th.  Michael interviewed Leslie Long and Michele Adubato — Adubato will be speaking on the panel — of Newark’s North Ward Center which plans a 2011 launch of a new initiative to better serve individuals living with autism in Newark.

In his post, Michael writes that he “wanted to know if students with autism in Newark were getting the same services as students elsewhere in the New Jersey, and if not, whether law or policy played a role in the disparity.”  He goes on to highlight a number of areas of potential disparity between Newark and New Jersey’s suburbs and towns, all disturbing.

I was particularly troubled by Michael’s report that the Newark schools’ wait-and-see approach to diagnosing children with autism leads to children from birth to age three being denied (or simply not accessing) early intervention services.  There is nothing wrong in theory with waiting and seeing with regard to diagnosing an infant or toddler with autism.  I believe the choice to wait-and-see is one that parents should be free to make in consultation with their baby or child’s healthcare providers.  That choice is in no way free if advocating for and/or accepting an autism diagnosis is the key to accessing needed services.  (My previous post on the pressure parents can face to accept the diagnosis is here.)

In my opinion, early intervention services should never be linked to a diagnosis; they should always be based on the demonstrated needs of the individual child.  A key takeway from the dispute over the inclusion of Asperger’s Disease in the DSM-V is that while diagnoses of mental disorders can no doubt be useful in certain contexts, they are also mutable and political, describing and potentially shaping a complicated reality.  They seem a shaky basis for divvying up scarce educational resources amongst very young children.

In New Jersey children do not, legally, need to be diagnosed with autism — or any other   -ism — to access early intervention services.  A child with an autism diagnosis is presumptively eligible for early intervention services, but that same child could also qualify without the diagnosis, based only on his or her individual developmental delays.  After a child turns 3 and is no longer eligible for early intervention, a diagnosis is still not (supposed) to be the key to services.  In New Jersey, a child between the ages of 3 and 5 with developmental delays can qualify for special education as a “preschooler with a disability.”  N.J.A.C. 6A:14-3.5(c)(10).  I wonder whether the use of these avenues to accessing services is more common in the New Jersey suburbs than in Newark– and whether this is yet another disparity.

Rising Maternal Death Rate: A Sentinel Event

California Watch, a project of the Center for Investigative Reporting, reported earlier this month that the rate of maternal deaths directly related to pregnancy and birth nearly tripled in California between 1996 and 2006– from 5.6 maternal deaths per 100,000 live births to 16.9 per 100,000.  Even after accounting for improved information gathering, the rate has more than doubled and “[c]hanges in the population — obese mothers, older mothers and fertility treatments — cannot completely account for the rise … said Dr. Elliott Main, the principal investigator for the task force” that prepared the report.  While the reason or reasons for the rise in deaths are not yet understood, Dr. Main notes that the rate of Cesarean sections increased by 50 percent over the 1996-2006 time period.

Sadly, California is unlikely to be unique in this regard.  Maternal death rates have probably increased in other states and in the country as a whole as well.  On January 26th, the Joint Commission issued a Sentinel Event Alert to hospitals, notifying them that “current trends and evidence suggest that maternal mortality rates may be increasing in the U.S.”  The Commission acknowledged that that incidence of maternal death remains low — at an estimated 13.3 deaths per 100,000 live births — and that a possible reason for the increases seen is better identification of women who die during or shortly after pregnancy.  Still, the Commission quoted the CDC’s Dr. William M. Callaghan as follows: “[T]here clearly has been no decrease in maternal mortality in recent years, and we are not moving toward the U.S. government’s Healthy People 2010 target of no more than 3.3 maternal deaths per 100,000 live births[].”  Moreover, “[m]aternal deaths are the tip of the iceberg for they are a signal that there are likely bigger problems beneath — some of which are preventable,” says Dr. Callaghan. “It is important to consider the women who get very, very sick and do not die, because for every woman who dies, there are 50 who are very ill, suffering significant complications of pregnancy, labor and delivery.”

Not all maternal deaths are preventable, of course.  To reduce the rate of those that are, the Joint Commission suggests a number of actions for hospitals and physicians to take, including participating in state-level maternal mortality reviews and developing protocols (and holding drills to train staff on the protocols) for responding to conditions such as hemorrhage and pre-eclampsia.  More concretely, the Commission quotes Dr. Steven L. Clark of the Hospital Corporation of America who argues that the “only cause of maternal death amenable to nationwide systematic prevention efforts is pulmonary embolism [a blood clot in the lung].”  Disappointingly, while nearly all adult patients undergoing major surgery receive prophylactic measures for the prevention of venous thromboembolism (VTE) — even patients with no risk factors for the condition — pregnant women undergoing Cesarean delivery traditionally do not, despite the fact that they are at increased risk.   In light of the Commission’s Sentinel Event Alert, it seems to me that hospitals would be well-advised to adopt VTE prophylactic measures for all pregnant women undergoing Cesarean sections at once.  Is there a downside I am missing?

Allergan v. FDA: Where Does Disseminating Safety Information End and Promotion Begin?

In the Fall of 2009, the drugmaker Allergan made waves when it sued the FDA alleging that the ban on off-label promotion was chilling its “First Amendment right to share truthful medical information with physicians about how to safely use Botox off-label [to treat muscle spasticity] to achieve a benefit while minimizing risk of serious adverse events.”  Allergan was back in the news last week when the LA Times reported that trial was set to begin in a case brought against Allergan by the mother of Kristen Spears, a seven-year-old girl with cerebral palsy who died after being injected with Botox to treat muscle spasticity in her legs.

Allergan manufactures two FDA-approved botulinum toxin products, Botox Cosmetic, the well-known anti-wrinkle treatment, and Botox, which is approved to treat, among other conditions, cervical dystonia, “a movement disorder that causes [the muscles of the neck and shoulders] to contract and spasm involuntarily.”  Botox is also frequently used “off-label” for conditions it is not approved to treat, including muscle spasticity.  Per the NIH,  locally-injected Botox “has become a standard treatment for overactive muscles in children with spastic movement disorders such as cerebral palsy.”  The FDA agrees.  An agency physician describes Botox as a “commonly used” and “very effective” treatment for spasticity, which he characterizes as a “significant disability[y.]“  Per the LA Times, Botox can “sometimes help young patients walk without surgery.”

While the NIH’s website states that the undesirable side effects of Botox are “mild and short-lived,” the FDA’s informs physicians that “a Boxed Warning has been added to the prescribing information to highlight that botulinum toxin may spread from the area of injection to produce symptoms consistent with botulism,” “that swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effects of spread of botulinum toxin,” and “that children treated for spasticity are at greatest risk for these symptoms[.]”

In addition to requiring the addition of the black box warning to the Botox label, the FDA has ordered Allergan and other manufacturers of botulinum toxin products to adopt a Risk Evaluation and Mitigation Strategy (REMS) which includes “a Medication Guide [for patients] and Communication Plan, including a Dear Health Care Provider letter, and a timetable for submission of assessments.”

In its complaint against the FDA, Allergan alleges that while “the boxed warning and REMS materials identify the risk of potential distant spread of toxin effect, … they do not give physicians using Botox for spasticity specific guidance about how to further minimize that risk while still obtaining an acceptable therapeutic effect.”  Allergan wants to provide physicians with specific information about treating spasticity including “proper dosing, patient selection, and injection technique.”  Allergan argues, with good reason I believe, that if it were to, say, develop a slide deck about dosing, patient selection, and injection technique in treating spasticity and present it to physicians it would be exposing itself to criminal liability for promoting an off-label use.  In its brief in opposition, the FDA disagrees — sort of — arguing that disseminating safety information about unapproved uses is “not necessarily” promotion and that Allergan has “ample room” “to disseminate truthful, non-promotional information about dangers associated with unapproved uses of Botox.”  (I will have more to say about the parties’ legal arguments in a subsequent post.)

In an interesting twist, the LA Times reports that Kristen Spears’ pediatrician and his nurse practitioner wife testified in depositions that they “learned to use Botox on children with cerebral palsy at Allergan-sponsored seminars in 2000 and 2001″ and that “Allergan’s sales agents discussed the use of Botox for juvenile cerebral palsy patients … repeatedly, visiting the practice about 50 times over several years.”  They also claimed that they were told by sales representatives that other doctors were using “in range of 10 to 15 units” of Botox per kilogram to treat their pediatric patients.  Dr. Mitchell Brin, Allergan’s Chief Scientific Officer for Botox, testified that fifteen units per kilogram, which is the dose given Kristen Spears, is nearly twice the maximum dose that the company considers safe for children.  He also testified that, because of the ban on off-label promotion, Allergan did not disseminate its maximum dosage information to physicians.  If it is true that Allergan’s sales force was providing doctors with dosing information gleaned from anecdotal reports from other doctors they called on while the experts in the company’s medical department kept their dosing knowledge to themselves, it is an example of an all-too-common disconnect between the field and headquarters that in this case may have had tragic consequences.

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