New Evidence on Smoking Marijuana and Lung Function; Update on New Jersey’s Nascent Medical Marijuana Program

This week’s JAMA includes an article reporting on new evidence that smoking marijuana does not negatively affect lung function. Smoking tobacco has long been known to harm the lungs and to increase the risk of developing chronic obstructive pulmonary disease and lung cancer, both leading causes of death. The risks posed by smoking marijuana, on the other hand, have largely been assumed, based on the fact that “[m]arijuana smoke contains many of the same constituents as tobacco smoke[.]”

The authors of the JAMA article analyzed data from a 20-year longitudinal study of 5,115 people in 4 American cities who “comprise a broad cross-section of typical tobacco and marijuana use patterns” and found that “[w]ith up to 7 joint-years of lifetime exposure (e.g., 1 joint [a day] for 7 years or 1 joint [a week] for 49 years)” there was no evidence of an adverse effect on the lungs. Very heavy marijuana use in excess of 7 joint-years of lifetime exposure could prove harmful, but there were not enough heavy users in the study to demonstrate this.

High-quality epidemiological evidence like this latest JAMA study will be key to filling in the gaps in our knowledge about marijuana’s safety profile. While double-blinded randomized controlled trials are considered the gold standard for evaluating the safety and efficacy of drugs, they are not always an option, particularly where the goal is to gather data over many years. Marijuana’s classification as a Schedule 1 controlled substance adds to the difficulty of mounting clinical trials. Given this, it is (or will be) a very good thing that New Jersey’s still-nascent medical marijuana program will include a registry of de-identified patient treatment and outcomes data that will allow researchers to learn more about the drug’s safety and efficacy.

The statute authorizing New Jersey’s medical marijuana program was passed two full years ago, in January 2010, but the road to implantation has been a long and rocky one. (My previous posts on the subject are here, here, here, and here.) While the Christie Administration is now on board, local towns have proved resistant to efforts to site alternative treatment centers that would grow and/or dispense marijuana there. In the Associated Press earlier this week, Geoff Mulvihill writes that “[s]o far, only one [of the six groups authorized by the state to operate alternative treatment centers] has announced that it has secured local approvals. … Three others have been shut out of their chosen locations by local government bodies, despite assurances that security at the dispensaries would be tight and that pot would be given only to patients who are truly sick.”

The state may be fighting back. Nina Rizzo reports in the Asbury Park Press that Assemblyman Declan O’Scanlon has announced “that he will introduce legislation next week that would prohibit counties and municipalities from interfering with the development of medical marijuana cultivation and distribution centers by extending their protections under the Right to Farm Act.”

Such a heavy-handed approach may be necessary in the short term, to ensure that all six authorized alternative treatment centers can get off the ground. If the New Jersey Compassionate Use Medical Marijuana Act and its regulations work as they are intended to, however, public confidence in the program should grow.

Venture Capitalists Complain of ‘Regulatory Challenges,’ FDA Responds

Writing in this month’s Fortune, Dan Primack is the latest to raise the alarm about indications that venture capital funding of life sciences startups is on the decline.  The decline in funding is cause for concern because venture capital-funded startups are, in the words of Tracy Lefteroff of PricewaterhouseCoopers, “where all the drugs are coming from[.]“  “[L]arge pharma[,]” Lefteroff explains, has “been extremely ineffective at developing pipeline drugs internally.”

While there are still “plenty of venture dollars … going into the [life sciences] sector,” Primack reports, they are going to mature companies.  Startups, on the other hand, “are having a much tougher go of it, with 17% fewer raising venture capital during the first three quarters of 2011 than during the same period in 2010.”  According to Primack, “a number of veteran VC firms are formally ending their pursuit of pharma startups.”

What explains the increasing reluctance to invest in the life sciences sector?  The venture capitalists blame “regulatory challenges,” primarily “the hostile FDA.”   Primack quotes Kate Mitchell, co-founder and Managing Director of Scale Venture Partners, a venture capital firm which recently announced that it will make no new healthcare investments, as follows: “It just takes a lot longer now to get approval than it used to, or to even know what the [Food & Drug Administration] is thinking.  One of our companies, Prestwick Pharmaceuticals, supposedly was put on a ‘fast track,’ but it still took another three years before receiving FDA approval.  It’s incredibly frustrating and means we need to invest more to keep the companies running.”

The Medical Innovation and Competitiveness (MedIC) Coalition, a group of “life science investors, innovators and entrepreneurs,” has been lobbying hard for the FDA to approve more drugs and devices more quickly, that is, without the careful review of efficacy and safety that it currently undertakes.  Specifically, they have prioritized “[r]ebalancing benefit-risk assessments in the drug and device approval processes to appropriately reflect the value of new therapies to patients in need” and “[e]xpanding the accelerated approval pathway into a progressive approval system for drugs, diagnostics and medical devices.”  MedIC also believes that the FDA’s conflict of interest policy threatens to “hinder[] patient access to new treatments.”  It argues for increased “utilization of non-government outside experts to facilitate and strengthen the FDA review and approval process,” presumably experts who would be barred from serving by the FDA’s current conflicts policy.

Not all of MedIC’s priorities are so extreme.  They have also called for more timely, consistent, and transparent decision-making at FDA, while acknowledging that to achieve these ends the agency must be “well resourced and endowed with state-of-the-art scientific tools, clinical input, processes and procedures.”  With this, even the most ardent consumer advocate can agree, and the FDA has recently acted to improve its decision-making in ways that do not risk sacrificing health and safety.  This is a promising development.  The results of a recent survey of venture capitalists suggests that increasing the predictability and speed of the FDA’s decision-making would have a higher impact on their willingness to invest in the life sciences sector than would “rebalancing” the agency’s weighing of safety and efficacy.

Recommended Reading: Recent Scholarship on Drug and Device Regulation

In Patients Over Politics: Addressing Legislative Failure in the Regulation of Medical Products (forthcoming in the 2011 volume of the Wisconsin Law Review and available on SSRN), Efthimios Parasidis proposes a significant expansion of drug and device companies’ responsibility to engage in “active post-market analysis” of drugs and devices, to be coupled with a new rule that only companies that conducted such analysis would benefit from preemption of state tort claims.  Professor Parasidis’ article includes a nuanced and revealing analysis of the historical and other reasons for the Food and Drug Administration’s heavy focus on pre-market review of drugs at the expense of post-market surveillance, as well as useful updates on both the caselaw regarding the preemption of claims involving branded drugs, generic drugs, devices, and vaccines and the ongoing efforts to use health information technology to glean information about the safety and efficacy of marketed products.  Most notable, though, is the article’s thorough explication of Professor Parasidis’ interesting proposal that “preemption laws, which often are enacted pursuant to industry lobbying efforts [be linked to] protocols that further the public health.”

In Enforcing Integrity (forthcoming in the 2011 volume of the Indiana Law Journal and available on SSRN), Katrice Bridges Copeland makes a strong case for her conclusion that neither the exclusion of pharmaceutical manufacturers from Medicare and Medicaid — a punishment which the government is reluctant to impose because it would spell the end for the company — nor the use of corporate integrity agreements coupled with large fines — which manufacturers agree to in order to avoid exclusion — works to deter illegal marketing activities.  As Professor Copeland notes, numerous companies have learned that “the punishment for multiple offenses is simply another CIA and another fine.”  She recommends that the government consider a number of alternative penalties for repeat offenders, including (1) requiring that manufacturers fund clinical trials studying the off-label uses for which they promoted their products, (2) requiring that they license the product or products at issue to other manufacturers, (3) holding high-level individuals criminally liable under the responsible corporate officer doctrine, and (4) amending the Social Security Act to allow for the exclusion of particular drugs (as opposed to entire companies) from Medicare and Medicaid.

Finally, I recommend Seton Hall Law’s own Jordan Paradise’s fascinating article, Claiming Nanotechnology: Improving USPTO Efforts at Classification of Emerging Nano-Enabled Pharmaceutical Technologies (forthcoming in the 2011 volume of the Northwestern Journal of Technology and Intellectual Property and available on SSRN), in which she argues that the United States Patent and Trademark Office’s system for classifying patents on nanotechnology-related inventions, “[w]hile undoubtedly helpful for internal purposes,” cedes too much to the courts.  Reviewing the facts of the recent case Elan Pharma International v. Abraxis Bioscience, which involved a dispute over two patents describing nano or near-nano scale versions of the same existing cancer-fighting agent and was tried to a jury verdict, Professor Paradise points out several ways in which the patents’ claims potentially overlap.  She argues that the courts are “a clumsy forum” for sorting out the “complex patent law issues that arise based on scale, size, and interactions at the nanoscale that transcend previously envisioned physical and chemical boundaries[,]” and offers concrete recommendations for steps the USPTO can take to improve its classification efforts to reduce the number of patents with potentially overlapping claims thereby making court involvement less necessary.

Recommended Reading: Recent Scholarship with Implications for Pharmaceutical Pricing and Access

Bundles in the Pharmaceutical Industry: A Case Study of Pediatric Vaccines, by Kevin W. Caves and Hal J. Singer of Navigant Economics, provides a technical but still accessible analysis of the anticompetitive effects of vaccine manufacturers’ practice of conditioning price discounts on physician buying groups agreeing to purchase the manufacturers’ vaccines in a bundle and agreeing not to purchase other manufacturers’ products.  The article begins with an interesting overview of the characteristics of the vaccine market, an introduction to the physician buying groups that purchase vaccines and to the anti-kickback concerns they raise, and a summary of the (somewhat up in the air) legal standard for when bundled discounting becomes an antitrust violation.

The authors then present their analysis of the uphill battle Novartis (a source of funding for the article) will have to fight to induce physicians to “break the bundle” and buy its new meningitis vaccine.  The authors conclude that even if Novartis were to give away its meningitis vaccine for free, “buyers defecting from [Sanofi Pasteur's bundle of vaccines, which includes Sanofi's meningitis vaccine,] would still lose $14.05 per patient in expected value.”  They present data indicating “that buyers unencumbered by … Sanofi’s loyalty contracts are over three times as likely to purchase [Novartis' vaccine], relative to encumbered buyers…” and conclude that enough of the market is foreclosed to Novartis to establish a presumption of anticompetitive effects and concomitant harm to consumers.  Per the authors, “[i]n an industry served almost exclusively by large, multi-product incumbents, with no prospects for generic competition and extremely limited entry by competitive rivals of any kind, these findings have significant implications for public policy and antitrust enforcement.”

Somewhat less accessible (due to a plethora of equations) but still well worth reading is Tort Liability and the Market for Prescription Drugs by Eric Helland, Darius Lakdawalla, Anup Malani, and Seth Seabury.  Helland and his co-authors present the results of an empirical study of the relationship between product liability rules and drug price and utilization.  While the effect of a liability rule can often be studied by comparing a state that makes a change to the rule with one that does not, the authors had to modify this approach because drugs are sold nationally.  They determined the exposure to punitive damages caps of each of nearly 16,000 drugs by first determining each drug’s geographic distribution of sales, a figure which varies from drug to drug due to geographic variation in the prevalence of disease.  The authors found that the degree of exposure to caps was correlated with an increase in drug prices but also with an increase in drug utilization.  Tighter liability standards also correlate with a reduction in adverse drug reactions.  The authors write that their numbers “imply that if every remaining state adopted some reform, there would be a 23% increase in all [adverse] events and a 25% increase in serious [adverse] events … among branded drugs.”  They conclude that “on balance, liability improves consumer and social welfare.”

FDA’s ‘Bad Ad’ Program is in Full Effect

Last spring, the Food and Drug Administration (FDA) launched the Truthful Prescription Drug Advertising and Promotion Program (known more accessibly as the “Bad Ad Program“). The goal of the program is to enlist the help of health care professionals, consumers, and industry representatives in noting FDA violations and reporting activities and messages that are false or misleading. Common drug marketing violations include omitting or downplaying risk, overstating effectiveness, promoting off-label uses and making misleading drug comparisons. The program is run by the FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC), which is responsible for “ensuring truthful advertising and promotion of prescription drugs.”

The FDA published a year-end report in May noting that the program has been successful in raising awareness. DDMAC received 328 reports of potentially untruthful or misleading promotions in one year, with the majority of those submitted by health care professionals (188 reports) and consumers (116 reports). The report notes that prior to the Bad Ad program, the FDA received an average of about 104 reports per year.

And the Bad Ad tips are still coming in. Just at the end of last month, DDMAC issued a reprimand letter to Pfizer’s Vice President of US Regulatory Affairs regarding misleading advertising of drugs on the company’s Lipitor website. A complaint to the Bad Ad program observed that the links from the Lipitor site led to pages for the drugs Caduet (for high cholesterol and blood pressure), Norvasc (for high blood pressure), and Chantix (for smoking cessation). But each of those pages failed to note any of the risk information associated with the drugs, which is a violation of the Federal Food, Drug, and Cosmetic Act.

The FDA states that “by omitting the most serious and frequently occurring risks associated with Caduet, Chantix, and Norvasc, the webpage misleadingly suggests that these drugs are safer than have been demonstrated.” The letter ends with a request that Pfizer immediately stop the dissemination of violative promotional materials for the drugs. The company was to have submitted a written response to the complaint by September 14^th that states how they will comply with the request.

While the Bad Ad program may be working to raise awareness among health professionals and consumers, one violation may not be enough to induce compliance from pharmaceutical companies. In fact, DDMAC already chided Pfizer in March of 2009 for omitting risk information for Caduet and Chantix. In that case, Pfizer sponsored links for the drugs on Internet search engines. The sites linked to did not mention any risk information and therefore, presumably,  can be said to have also represented the products in a manner which, as above, suggests that these drugs are safer than have been demonstrated.” The most recent letter states that “DDMAC is concerned that Pfizer is continuing to promote its products in a similarly violative manner.” A citizen’s task force is a good way for the FDA to multiply their eyes and ears to keep tabs on misleading and/or violative advertisement. We’ll see what further successes the next year-end report for the Bad Ad program can show. Or, perhaps, success might also be measured in the absence of violations.

Generic Drugs, Cost-Effectiveness, and Confidence

Smarter prescribing and better medication management are linchpins of current efforts to care for those with chronic medical conditions in a more consistent, coordinated, and, it is hoped, affordable manner.  A study reported in last month’s Health Affairs found that using medication to control patients’ blood sugar levels and lower their blood pressure and cholesterol is not just cost-effective, it can actually save money by reducing “downstream complications and the use of health services that outweigh the cost of the medications themselves.”  Notably, these cost savings can only be achieved if the medications in question are generics.  The authors conclude that “in a health care system strapped for resources, physicians will increasingly use generics, and patients will have to expect that most of their medications will be generic.”

As the authors also note, resistance to generics, on the part of both patients and their doctors, is longstanding and persistent.  Some of this can be chalked up to the intense and wide-ranging marketing campaigns that innovator companies mount on behalf of branded drugs.  Branded medications used to treat chronic conditions are especially heavily marketed, including through the use of free samples.  Numerous studies (here’s a recent one out of Vermont) show that physicians with sample closets in their offices are less likely than those without sample closets to prescribe generics where appropriate.

Interestingly, the Centers for Medicare and Medicaid Services announced earlier this year that Medicaid Part D prescription drug plans “may incur expenses related to distribution of and reporting on generic drug samples, provided to members within a physician’s office setting, under the plan’s administrative cost structure if doing so is consistent with a cost effective drug utilization management program.”  CMS explained that generic samples have the potential to reduce the government’s overall costs and to promote compliance with drug therapies by reducing enrollees’ current and future cost sharing expenses.  (George Van Antwerp argues here that CMS overstates the benefits of generic samples, but only because generic fill rates are rising so fast without them.)

Marketing is not the whole story behind lingering resistance to generics, though.  As the New York Times recently reported, most generic drugs are manufactured in “a shadowy network of facilities in China and India that are rarely visited by government inspectors, who sometimes cannot even find the plants.”  While plants in the United States are inspected at least once every two years, the Food and Drug Administration has historically lacked the resources to provide the same level of oversight to foreign facilities.  An “epoch-making” agreement between the FDA and generic drug manufacturers will, assuming it is approved by Congress, change this.  The manufacturers have agreed to pay $299 million in annual fees to, among other things, fund inspections of foreign plants on the same schedule that applies to domestic plants.  As the Times notes: “[T]he generic drug industry is no longer a motley collection of struggling mom-and-pop companies.  Years of consolidation have created giants like Israel-based Teva Pharmaceuticals that understand that their businesses depend on winning the confidence of patients and regulators alike, and they can afford to pay the fees needed to achieve that confidence.”

The Ban on Off-Label Promotion after Sorrell v. IMS Health

In the wake of Sorrell v. IMS Health, in which the Supreme Court invalidated on First Amendment grounds a Vermont law barring drug companies from using physician-specific prescribing data to craft physician-specific sales pitches, lawyers on both sides of the case have weighed in on the opinion’s implications for the Food & Drug Administration’s ban on off-label promotion.  In doing so, they build upon an exchange between the dissent and the majority in Sorrell.  Writing in dissent, Justice Breyer argued that the fact that the Vermont ban is “speaker-based” (i.e., that it only applies to drug companies) should not mean that it is subject to heightened scrutiny, because in the regulatory context it is not unusual for rules to apply only to regulated entities.  By way of example, Justice Breyer cites the ban on off-label promotion, which limits what manufacturers but not others can say to doctors about unapproved uses.  In response, the majority suggests that the government “might defend” the ban on the ground that it “will prevent false or misleading speech.”  The majority then reiterates that Vermont’s interest in banning data mining “instead turns on nothing more than a difference of opinion” between the state and the companies about the truthful marketing messages to which doctors should be exposed.

In an article for BNA’s Pharmaceutical Law & Industry Report, Lisa Blatt and colleagues (who represented PhRMA, one of the respondents in the case) contend that: “Sorrell builds on prior Supreme Court precedent in establishing a strong foundation to argue that a pharmaceutical company’s truthful, non-misleading information about its products cannot be subjected to content-based and speaker-based restrictions.”  And they predict (correctly) that “[t]he implications of Sorrell for the FDA’s off-label promotion regulatory regime may be tested in litigation, as well as in new regulations, in the months ahead.”  On July 14, 2011, as reported here, the Second Circuit ordered supplemental briefing on the implications of Sorrell for its pending decision in United States v. Caronia, a criminal case in which a sales representative was convicted of conspiring to misbrand the sleep aid Xyrem by promoting it for a number of off-label uses.  On the regulatory front, on July 5, 2011, seven leading pharmaceutical companies filed a citizen petition asking “the Commissioner of Food and Drugs to clarify FDA regulations and policies with respect to manufacturer dissemination of information relating to new uses of marketed drugs and medical devices.”

In a very provocative blog post at The Incidental Economist, Kevin Outterson (who wrote an amicus brief on the side of the petitioner in Sorrell on behalf of, among others, the New England Journal of Medicine) appears to concur with Blatt that “[i]n the wake of Sorrell … we can expect the FDA to relax rules against off-label promotion.”  Professor Outterson characterizes the Supreme Court’s decision as a radical adjustment of the regulatory balance between the FDA and the companies it regulates.  Under our current system, data on the safety and efficacy of drugs is largely generated privately, as a condition of marketing approval.  The ban on off-label promotion is a key component of the system, because it provides manufacturers with a powerful push to continue to study their products after they are initially approved for sale.  Without it (or, even more radically, without any requirement that a manufacturer establish that a drug is efficacious before marketing it), we’ll either need to find other ways to incentivize private sector research or spend more public money on the study of drugs, both easier said than done.  Professor Outterson suggests a third way, that: “the US could simply free ride off the studies produced to satisfy Europe’s Phase III approval process.”  As he points out, however, “[t]hat would work only so long as the EU didn’t make the same changes.”

Perhaps naively, I am hopeful that the ban on off-label promotion will survive the coming wave of legal challenges largely intact.  In addition to its role in incentivizing research (a neutral function which distinguishes it from the data mining law at issue in Sorrell), I think that the ban serves as an important prophylactic against false and misleading product promotion.  (I elaborate on this argument here.)  This preventive role further distinguishes the ban on off-label promotion from the law invalidated in Sorrell.

Of Pain and Suffering, Morphine and Global Shortages

In recovery for more than 18 years, up until yesterday I had little good to say about narcotics. Having seen over the years at close quarters what drug and alcohol abuse can do to people and families, I could be considered almost virulently anti-drug. I have no patience for abuse– which may well have spilled over into use. The constant barrage of Pharma commercials which promise that I can avoid any of the discomfort associated with daily life has only added to my distaste. I receive dozens of spam messages through this blog each day promising me cheap oxycontin and the like through internet clearing houses. We are a Pharma Nation. But yesterday, as is so often the case, born of personal experience, I came to appreciate the pain relief that properly administered drugs can bring– and to also appreciate the gravity of the lack of such medicines across the globe.

I woke up and broke out in a cold sweat and quickly began writhing around and wailing in pain like a wild animal caught in a bear trap. The pain came in excruciating waves radiating as though I had just been punched below the belt– repeatedly. Afraid it may have been appendicitis or something equally as dire, I had my son call 911. The police showed up immediately, but the all volunteer ambulance squad took close to 40 minutes to get here. I cursed, hollered, moaned, pled– and even shrieked, the whole time. I did the same even after we reached the Emergency Room, though there I peppered my plaints with apologies.

Convinced it was a kidney stone, the nurse and doctor insisted I take something for the pain. Explaining my recovery status I  protested, but ultimately relented asking if they could make the drug/dose “as little as possible.” They gave me morphine and Toradol. Moments later I became human again. It stopped the pain, it didn’t get me “high.”

The CT scan showed the stone to be making its may down to my urinary tract– all 4 painful millimeters of it. It would need to be 5 millimeters, however, for it to be surgically removed. As such, I longingly wait for it to pass.

Over the years, because I’ve seen so many alcoholics and addicts relapse after using prescription drugs, despite severe pain I’ve eschewed the use of prescription pain relief– always risky to wake a sleeping dragon. But this was something else entirely.

So what does this all have to do with health reform and law? Outside the U.S. there are severe shortages of morphine. Although a dose costs only pennies, the “War on Drugs” is said to have rendered the drug largely unavailable for medical use. In India, morphine is said to be “almost impossible” to get. In the video below,  Diedrick Lohman of Human Rights Watch asserts that “freedom from medical pain should be a basic human right.” I’m not sure how that would be defined legally, but conceptually, I agree. If you ever find yourself within the grips of an unrelenting pain– a pain so great you no longer even feel human–you may too. The video below details the problem, in excruciating terms.

Auditing Studies of Anti-Depressants

Marcia Angell has kicked off another set of controversies for the pharmaceutical sector in two recent review essays in the New York Review of Books. She favorably reviews meta-research that calls into question the effectiveness of many antidepressant drugs:

Kirsch and his colleagues used the Freedom of Information Act to obtain FDA reviews of all placebo-controlled clinical trials, whether positive or negative, submitted for the initial approval of the six most widely used antidepressant drugs approved between 1987 and 1999—Prozac, Paxil, Zoloft, Celexa, Serzone, and Effexor. . . .Altogether, there were forty-two trials of the six drugs. Most of them were negative. Overall, placebos were 82 percent as effective as the drugs, as measured by the Hamilton Depression Scale (HAM-D), a widely used score of symptoms of depression. The average difference between drug and placebo was only 1.8 points on the HAM-D, a difference that, while statistically significant, was clinically meaningless. The results were much the same for all six drugs: they were all equally unimpressive. Yet because the positive studies were extensively publicized, while the negative ones were hidden, the public and the medical profession came to believe that these drugs were highly effective antidepressants.

Angell discusses other research that indicates that placebos can often be nearly as effective as drugs for conditions like depression. Psychiatrist Peter Kramer, a long-time advocate of anti-depressant therapy, responded to her last Sunday. He admits that “placebo responses . . . have been steadily on the rise” in FDA data; “in some studies, 40 percent of subjects not receiving medication get better.” But he believes that is only because the studies focus on the mildly depressed:

The problem is so big that entrepreneurs have founded businesses promising to identify genuinely ill research subjects. The companies use video links to screen patients at central locations where (contrary to the practice at centers where trials are run) reviewers have no incentives for enrolling subjects. In early comparisons, off-site raters rejected about 40 percent of subjects who had been accepted locally — on the ground that those subjects did not have severe enough symptoms to qualify for treatment. If this result is typical, many subjects labeled mildly depressed in the F.D.A. data don’t have depression and might well respond to placebos as readily as to antidepressants.

Yves Smith finds Kramer’s response unconvincing:

The research is clear: the efficacy of antidepressants is (contrary to what [Kramer's] article suggests) lower than most drugs (70% is a typical efficacy rate; for antidepressants, it’s about 50%. The placebo rate is 20% to 30% for antidepressants). And since most antidepressants produce side effects, patients in trials can often guess successfully as to whether they are getting real drugs. If a placebo is chosen that produces a symptom, say dry mouth, the efficacy of antidepressants v. placebos is almost indistinguishable. The argument made in [Kramer's] article to try to deal with this inconvenient fact, that many of the people chosen for clinical trials really weren’t depressed (thus contending that the placebo effect was simply bad sampling) is utter[ly wrong]. You’d see the mildly/short-term depressed people getting both placebos and real drugs. You would therefore expect to see the efficacy rate of both the placebo and the real drug boosted by the inclusion of people who just happened to get better anyhow.

Felix Salmon also challenges Kramer’s logic:

[Kramer's view is that] lots of people were diagnosed with depression and put onto a trial of antidepressant drugs, even when they were perfectly healthy. Which sounds very much like the kind of thing that Angell is complaining about: the way in which, for instance, the number of children so disabled by mental disorders that they qualify for Supplemental Security Income (SSI) or Social Security Disability Insurance (SSDI) was 35 times higher in 2007 than it was in 1987. And it’s getting worse: the editors of DSM-V, to be published in 2013, have written that “in primary care settings, approximately 30 percent to 50 percent of patients have prominent mental health symptoms or identifiable mental disorders, which have significant adverse consequences if left untreated.”

Those who would defend psychopharmacology, then, seem to want to have their cake and eat it: on the one hand it seems that serious mental health disorders have reached pandemic proportions, but on the other hand we’re told that a lot of people diagnosed with those disorders never really had them in the first place.

That is a very challenging point for the industry to consider as it responds to concerns like Angell’s. The diagnosis of mental illness will always have ineradicably economic dimensions and politically contestable aims. But doctors and researchers should insulate professional expertise and the interpretation of maladies as much as possible from inappropriate pressures.

How can they maintain that kind of independent clinical judgment? I think one key is to assure that data from all trials is open to all researchers. Consider, for instance, these findings from a NEJM study on “selective publication:”

We obtained reviews from the Food and Drug Administration (FDA) for studies of 12 antidepressant agents involving 12,564 patients. . . . Among 74 FDA-registered studies, 31%, accounting for 3449 study participants, were not published. Whether and how the studies were published were associated with the study outcome. A total of 37 studies viewed by the FDA as having positive results were published; 1 study viewed as positive was not published. Studies viewed by the FDA as having negative or questionable results were, with 3 exceptions, either not published (22 studies) or published in a way that, in our opinion, conveyed a positive outcome (11 studies). According to the published literature, it appeared that 94% of the trials conducted were positive. By contrast, the FDA analysis showed that 51% were positive. Separate meta-analyses of the FDA and journal data sets showed that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall. (emphasis added).

Melander, et al. also worried (in 2003) that, since “The degree of multiple publication, selective publication, and selective reporting differed between products,” “any attempt to recommend a specific selective serotonin reuptake inhibitor from the publicly available data only is likely to be based on biased evidence.” Without clearer “best practices” for data publication, clinical judgment may be impaired.

Full disclosure of study funding should also be mandatory and conspicuous, wherever results are published. Ernest R. House has reported that, “In a study of 370 ‘randomized’ drug trials, studies recommended the experimental drug as the ‘treatment of choice’ in 51% of trials sponsored by for-profit organizations compared to 16% sponsored by nonprofits.” The commodification of research has made it too easy to manipulate results, as Bartlett & Steele have argued:

One big factor in the shift of clinical trials to foreign countries is a loophole in F.D.A. regulations: if studies in the United States suggest that a drug has no benefit, trials from abroad can often be used in their stead to secure F.D.A. approval. There’s even a term for countries that have shown themselves to be especially amenable when drug companies need positive data fast: they’re called “rescue countries.” Rescue countries came to the aid of Ketek, the first of a new generation of widely heralded antibiotics to treat respiratory-tract infections. Ketek was developed in the 1990s by Aventis Pharmaceuticals, now Sanofi-Aventis. In 2004 . . . the F.D.A. certified Ketek as safe and effective. The F.D.A.’s decision was based heavily on the results of studies in Hungary, Morocco, Tunisia, and Turkey.

The approval came less than one month after a researcher in the United States was sentenced to 57 months in prison for falsifying her own Ketek data. . . . As the months ticked by, and the number of people taking the drug climbed steadily, the F.D.A. began to get reports of adverse reactions, including serious liver damage that sometimes led to death. . . . [C]ritics were especially concerned about an ongoing trial in which 4,000 infants and children, some as young as six months, were recruited in more than a dozen countries for an experiment to assess Ketek’s effectiveness in treating ear infections and tonsillitis. The trial had been sanctioned over the objections of the F.D.A.’s own reviewers. . . . In 2006, after inquiries from Congress, the F.D.A. asked Sanofi-Aventis to halt the trial. Less than a year later, one day before the start of a congressional hearing on the F.D.A.’s approval of the drug, the agency suddenly slapped a so-called black-box warning on the label of Ketek, restricting its use. (A black-box warning is the most serious step the F.D.A. can take short of removing a drug from the market.) By then the F.D.A. had received 93 reports of severe adverse reactions to Ketek, resulting in 12 deaths.

The great anti-depressant debate is part of a much larger “re-think” of the validity of data. Medical claims can spread virally without much evidence. According to a notable meta-researcher, “much of what medical researchers conclude in their studies is misleading, exaggerated, or flat-out wrong.” The “decline effect” dogs science generally. Statisticians are also debunking ballyhooed efforts to target cancer treatments.

Max Weber once said that “radical doubt is the father of knowledge.” Perhaps DSM-VI will include a diagnosis for such debilitating skepticism. But I think there’s much to be learned from an insistence that true science is open, inspectable, and replicable. Harvard’s program on “Digital Scholarship” and the Yale Roundtable on Data and Code Sharing* have taken up this cause, as has the work of Victoria Stodden.

We often hear that the academic sector has to become more “corporate” if it is to survive and thrive. At least when it comes to health data, the reverse is true: corporations must become much more open about the sources and limits of the studies they conduct. We can’t resolve the “great anti-depressant debate,” or prevent future questioning of pharma’s bona fides, without such commitments.

*In the spirit of full disclosure: I did participate in this roundtable.

Distribution Controls: A Potentially Powerful Weapon Against Inappropriate or Dangerous Off-Label Use

When supplies of sodium thiopental dried up earlier this year, states turned to other drugs to carry out executions by lethal injection.  The anti-seizure drug pentobarbital, marketed as Nembutal, is one such drug.  An estimated two-thirds of the thirty-four states with the death penalty have switched or considered switching to Nembutal; states that have made the switch include Georgia, Ohio, Oklahoma, South Carolina, and Texas.  As of earlier this month, Nembutal had been used in eighteen executions this year.

Like sodium thiopental, Nembutal is an off-patent drug that serves a relatively small market.  The sole company licensed to manufacture Nembutal in the United States, the Danish firm Lundbeck Inc., has been the target of a public relations and investment campaign by human rights activists calling for the end to the use of the drug in executions.  Lundbeck has never sold Nembutal directly to prisons, however, and initially the company said that there was nothing it could do to control the drug’s re-sale.  As a spokesperson explained:

We can’t withdraw the product because it is used for treating severe epilepsy and sometimes it’s the only treatment option.  All we can do is write to the prisons urging them to stop misusing using our product which was designed to help sick people.  It’s a really unfortunate situation.

Earlier this month, Lundbeck announced that it had determined that there were steps it could take beyond letter writing.  The company considered ceasing production of the drug altogether–it represents less than one percent of the company’s sales and is, in the company’s words, “economically insignificant”–but decided against doing so in light of survey evidence that the fifty million doses of the drug it sells in the United States each year are important for treating epilepsy that is severe and refractory (that is, unresponsive to other drugs).

Lundbeck decided instead to distribute Nembutal through Cardinal Health’s Specialty Pharmaceutical Services on a “drop-ship” basis, directly to hospitals.  Less than ten percent of drugs are distributed directly to end-user customers in this way, typically “cancer treatments that are expensive, difficult to make, or not in high demand.”  Lundbeck will review each Nembutal order and deny those from “from prisons in states currently active in carrying out death penalty sentences.”  Every purchaser will be required to represent in writing “that the purchase of [Nembutal] is for its own use and that it will not redistribute any purchased product without the express written authorization of Lundbeck.”  Lundbeck’s CEO has warned that the company will take unspecified “legal action” against any purchaser who violates these terms.

Lundbeck’s decision to use a drop-ship program and purchaser agreements to take responsibility for the off-label uses to which its product is put once it leaves the company’s control raises the question whether other companies could or should be asked to do the same.  In some cases, issues of scale will foreclose such an approach.  In other cases, a company and/or regulators may have concerns about inappropriate or dangerous off-label use but not be able to link it to an easily identified class of would-be purchasers like “prisons in states currently active in carrying out death penalty sentences.”  (Note that even in Lundbeck’s case the agreements are overbroad to the extent that they deny access to Nembutal to prisoners in death penalty states who need the drug to treat severe, refractory epilepsy.)  In still other cases, however, taking control of distribution will be a feasible, and powerful, compliance tool.  The Risk Evaluation and Mitigation Strategy (REMS) for Lazanda (fentanyl) Nasal Spray, recently posted to the Food and Drug Administration website, which provides that would-be distributors enroll in the REMS program and agree to limit their distribution to specially-certified pharmacies which are also enrolled in the program, is just one example.

Power, Knowledge, and Big Pharma: Preliminary Reflections on the Sorrell Vacuum

I have previously commented on Sorrell v. IMS Health, as a co-author of an amicus brief, a Pharma FaceOff panelist, and a blogger. I’m disappointed by the Sorrell ruling, for reasons largely elaborated in Justice Breyer’s dissent. As he observes, the majority opinion “reawakens Lochner’s pre-New Deal threat of substituting judicial for democratic decision-making where ordinary economic regulation is at issue.” But I’m not surprised at the Lochner revival, given the First Amendment maximalism of the Citizens United Court. For this Court, “free expression” will have to do in the information age what “freedom of contract” did for the early decades of the 20th century: erase even small and incremental steps toward a fairer social order.

Bill McGeveran has characterized Kennedy’s majority opinion in the case as relatively limited, a surgical strike against an overreaching and incompetent state legislature. I want to respond to his interpretation in a future post, after I’ve digested the opinion a bit more. But for now, I’d like to focus a bit of attention on the types of problems Vermont was addressing, to give the case more of a human face. For behind all the familiar Kennedy rhetoric about sacred speech, deeply disturbing industry practices motivated Vermont’s law.

Both PhRMA and IMS Health want us to believe that the case is about the life-saving power of a marketer to recommend drugs to oblivious doctors once it has access to their prescribing records. Never mind that, as Dr. David Orentlicher notes, “For $98 a year . . . physicians can subscribe to The Medical Letter on Drugs and Therapeutics, a respected and independent, biweekly newsletter that provides evaluations of prescription (and over-the-counter) drugs.” Maybe detailing, on occasion, saves lives. But, as the dissent observes, Vermont’s law allowed doctors to permit distribution of their prescribing records in order to receive personalized solicitations. They only needed to opt in.

Now why did Vermont doctors petition the state to limit access to prescriber records? And why might a rational physician choose not to opt in? Hundreds of pages of empirical studies show the problems caused by detailing; many are cited in Breyer’s dissent. But to make the situation a little more concrete, consider some of the literature a physician who rarely prescribes, say, pscyhotropic drugs, may now be reading. These examples are all drawn from two recent pieces by Marcia Angell in the NYRB:

A large survey of randomly selected adults, sponsored by the National Institute of Mental Health (NIMH) and conducted between 2001 and 2003, found that an astonishing 46 percent met criteria established by the American Psychiatric Association (APA) for having had at least one mental illness within four broad categories at some time in their lives. . . . The new generation of antipsychotics, such as Risperdal, Zyprexa, and Seroquel, has replaced cholesterol-lowering agents as the top-selling class of drugs in the US. . . . [Author Robert Whitaker] is outraged by what he sees as an iatrogenic (i.e., inadvertent and medically introduced) epidemic of brain dysfunction, particularly that caused by the widespread use of the newer (“atypical”) antipsychotics.

***

The pharmaceutical industry influences psychiatrists to prescribe psychoactive drugs even for categories of patients in whom the drugs have not been found safe and effective. [There has been an] astonishing rise in the diagnosis and treatment of mental illness in children, sometimes as young as two years old.

The FDA approves drugs only for specified uses, and it is illegal for companies to market them for any other purpose—that is, “off-label.” Nevertheless, physicians are permitted to prescribe drugs for any reason they choose, and one of the most lucrative things drug companies can do is persuade physicians to prescribe drugs off-label, despite the law against it. In just the past four years, five firms have admitted to federal charges of illegally marketing psychoactive drugs. AstraZeneca marketed Seroquel off-label for children and the elderly (another vulnerable population, often administered antipsychotics in nursing homes); Pfizer faced similar charges for Geodon (an antipsychotic); Eli Lilly for Zyprexa (an antipsychotic); Bristol-Myers Squibb for Abilify (another antipsychotic); and Forest Labs for Celexa (an antidepressant).

Despite having to pay hundreds of millions of dollars to settle the charges, the companies have probably come out well ahead.

Whereas IMS Health’s counsel described detailing in oral arguments as “information about lifesaving medications where the detailer goes in and talks about double blind scientific studies that are responsible for the development of drugs that have caused 40 percent of the increase in the lifespan of the American public,” Angell marshals an impressive array of evidence on the unreliability of pharma marketing, and even the underlying studies some of it is based on. Angell also compiles surprising details about the pervasive role of pharmaceutical firm influence over the social construction of mental illness. When you consider the industry’s targeting of “key opinion leaders” (professors and practitioners at elite medical centers), civil society groups, and the DSM, Vermont’s law seems an almost trivial response to a juggernaut of profit-driven promotions for mind cures. And yet even that small step (toward allowing physicians more control over how they are approached by detailers) offended the delicate sensibilities of the majority.

The Breyer dissent’s litany of regulated industry information practices should have dampened Kennedy’s abstracted enthusiasm for a “commercial marketplace” that “provides a forum where ideas and information flourish.” But in the vacuum of First Amendment fundamentalist thought, the complex ecology of fair information practices and calibrated disclosure cannot survive. It’s all-or-nothing: as soon as some parties gain access to prescriber data, everybody has to have it. Doctors can’t choose to structure their interactions with detailers based on profiling of their practices; rather, they face the stark choice of letting in marketers with access to all the prescribing practice data the state requires pharmacies to maintain, or not to talk to them at all.

In Sorrell, privacy and free expression become clashing rights, rather than social values that have long been reconciled (and occasionally reinforced one another) in complex regulatory schemes. We need to maintain that tradition of nuance in information law. Sadly, Sorrell turns its back on it.

Contractual Liability and Clinical Trial Reimbursement in Italy

Contractual Liability and Clinical Trial Reimbursement in Italy

By: Christopher J. Asakiewicz, Esq. and Anna Pinkhas, Esq. [1]

In the Italian Ministerial Decree of July 14, 2009 (the “Decree”) the Ministry of Labour, Health and Social Policy sets forth a number of statutory requirements relating to insurance in human clinical trials conducted in Italy. In order to safeguard the clinical participants the Decree expanded on and formulized into law a requirement previously established by the European Union, which provides that a clinical trial can be initiated in the Member States only when provisions have been made for insurance or indemnity to cover the liability of the investigator and sponsor towards clinical trials subjects. [2] However prudent and protective of clinical participants the Decree is, its implementation into Italian law has led to significant delays in the negotiation of the indemnification clauses in clinical trial agreements because of improper interpretation, an interpretation that delays the introduction of possible life saving medicines into the country and the European marketplace.

Indemnification is a critical part of the clinical trial agreements between clinical trial sponsors, investigational sites and, sometimes, the principal investigator. Generally, indemnification language in any agreement seeks to impute liability to a contractual party for acts or omissions and to defend, hold harmless and compensate the other party for any loss that such party may suffer during the performance of the contract that results from said acts or omissions. Indemnification provisions in a clinical trial agreement differ among varying sponsors and investigational sites. Generally, the provisions are mutual. A mutual indemnification provision will have the sponsor indemnify for personal injury or illness to study patients that relates to the study or the study drug, and likewise, the other party will indemnify the sponsor for any negligence or willful misconduct for which it is responsible.

Drafting and negotiating an indemnification clause can be both difficult and tedious, as the clause’s meaning is particularly important during litigation. Frequent confusion, however, between indemnification and study subject reimbursement further complicates and delays negotiations. A clinical trial agreement generally also includes a provision where the sponsor agrees to reimburse the institution for any reasonable and necessary medical expenses incurred by the investigational site for the treatment of patients’ illness or injuries related to the study or the study drug.  The purpose of such subject injury language is to address reimbursement of expenses incurred to treat an adverse event. [3] This reimbursement language is meant to swiftly compensate such injuries without regard for party fault so the patient can receive care immediately or continue to receive the highest standard of care.

Indemnification, on the other hand, is to assume responsibility and the costs incurred in litigation or from claims that resulted from the fault attributable to the wrongdoing of the indemnifying party. Although these two scenarios are clearly distinguishable, confusion arises over the Italian regulation because of misunderstanding about the nuances of indemnification as compared to subject injury reimbursement. The Decree states that the promoter, or the sponsor, of the clinical trial shall provide insurance to cover “any civil liability of investigator and promotor of the clinical trial, without excluding any damage which may be unintentionally caused by accident e/o be attributed to negligence, imprudence or inexperience.” [4] In other words, the clinical trial sponsor is required by the Decree to be insured to sufficient limits for not only willful or reckless conduct, but also for negligent unintentional acts or omissions. [5] Many Italian sites interpret this language to mean they are not responsible for their own negligence and therefore remove their indemnification obligation of the sponsor, the promotor, from the clinical trial agreements. However, the Decree only governs reimbursement to study subjects by the insured in the event of injuries, and does not limit contribution as well as the investigational site’s indemnity of the sponsor for those third party claims which fault is attributable to either it or its actors.

Article 1 states: “The insurance policy is to grant specific cover in connection with the reimbursement of damages caused to the subjects by the clinical trial activities throughout the entire duration thereof.”

[6] The Decree’s purpose is therefore not to forgive or excuse liability, but only to safeguard participants by ensuring that a damaged party obtains reimbursement immediately. It is incorrect to interpret the legislation’s purpose as being a limit on the scope of the Institution’s liability with respect to its own actions, as the Decree further states “[t]his restriction shall not in any event impair the right of the damaged party to seek reimbursement of damages from the person liable therefor.” [7] Exclusion language which relates to negligence, imprudence or inexperience of the investigator serves to make the insurance policy a no-fault policy, assuring participants appropriate compensation and reimbursement for their injuries or illness without having to litigate the cause of the injury or prove fault. [8]

The patient’s clinical trial injury and treatment expenses will be immediately reimbursed by the policy. But, as the Decree does not limit the remedies at law, and corresponding insurance policy’s only purpose is to compensate the participant immediately, the site can still be held liable by a court for its actions. In the situation, when the sponsor was required to compensate, but is not the determined cause, the sponsor is entitled seek contribution or indemnity for such actions’ expenses from those actors responsible. The Italian Civil Code also supports the notion that the site can still be held liable, as Article 2053 provides that any willful or negligent conduct, causing an unjust harm to third parties, obliges the tortfeasor to compensate the damages. [9]

To resolve this confusion between indemnification and clinical trial injury reimbursement, the authors recommend that a sponsor with sites operating in Italy, (i) obtain an insurance policy covering all treatment expenses incurred by patients and associated with injuries related to the study drug or protocol procedures, and (ii) ensure that any indemnification provision in the clinical trial site’s contract does not exclude the institution or the investigators from liability. The Italian Civil Code and Decree are both in agreement that those persons liable for causing harm to a third party are obligated to compensate for those damages. The sponsor through clinical trial insurance can therefore immediately reimburse the patient’s costs, then, in accordance with the mutual indemnification, the sponsor or the insurer may seek to subrogate or recoup through contribution such expenses which are attributable to the investigational site or investigator and outside the sponsor’s control. [10]

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[1] DISCLAIMER: Both authors are admitted to practice law in the state of New Jersey and draft and negotiate international clinical agreements as well as counsel on patient disclosures for pharmaceutical companies. The views and opinions expressed are solely those of the authors and shall not be attributed to any other party, company or entity. The expressed opinions are for informational purposes only, and not meant to nor intended to be an advertisement, solicitation, legal advice, authority nor services of any kind to any Client, including any person or entity in any state, country or sovereign nation. Such information is not meant to create an attorney-client relationship. the reader must not act nor rely upon these materials without seeking professional legal counsel.

[2] See Art. 3(2)(f) Directive 2001/20, of the European Parliament and of the Council of  4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, 2001 O.J. (L 121) 34, 37 ( “provision has been made for insurance or indemnity to cover the liability of the investigator and sponsor. “); See also Art. 3(1)(f) Decreto Legislativo, 24 June 2003, n. 211, G.U. 09 Aug 2003 (It.) (”provision has been made by the trial sponsor for insurance to cover the third-party liability of the investigator and the sponsors in the event of claims for damages by trial subjects.”).

[3] “adverse event” means any untoward medical occurrence in a patient or clinical trial subject administered a medicinal product and which does not necessarily have a causal relationship with this treatment.

[4] Art. 1(2) Decreto Ministeriale 14 July 2009, n. 213, G.U. 14 September 2009 (It.) (Italian Ministerial Decree, Minimum requirements for insurance policies which safeguard participants to clinical trials of medicinal products.).

[5] See Art. 2(2) D.M. n. 213/2009 (It.) (”Insurance shall provide for an insured limit for the reimbursement of damages not lower than Euro 1 million per participant, although the following minimum limits for each individual protocol are required, not less than: a) Euro 5 million if trial participants are less than or equal to 50; b) Euro 7 million five hundred thousand if the trial participants are more than 50 but less than 200; c) Euro 10 million if the trial participants are more than 200.”).

[6] Art. 1(2) D.M. n. 213/2009 (It.) (emphasis added).

[7] Art. 1(6) D.M. n. 213/2009 (It.) (emphasis added).

[8] “no-fault insurance” is any type of insurance contract under which insured’s are compensated for losses, regardless of fault in the incident generating said losses.

[9] Art. 2043 Codice civile [C.c.] (It.) (Italian Civil Code).

[10] See Blacks Law Dictionary (9^th ed. 2009) (1) (SUBROGATION “1. The substitution of one party for another whose debt the party pays, entitling the paying party to rights, remedies, or securities that would otherwise belong to the debtor.”).

The Disturbing Rise in Drug Shortages: A “Multifactorial” Problem

With the Annual Meeting of the American Society of Clinical Oncology this past week came a wave of news stories about cancer and cancer treatment.  Frank Pasquale highlights a disturbing warning issued by oncologists at the meeting, that “cancer medicines desperately needed by sick children and adults are in short supply, undermining the ability of U.S. doctors to administer treatments.”  Supplies of other medicines are running short, too, including treatments for anaphylactic shock, attention deficit hyperactivity disorder, cardiac arrest, cystic fibrosis, and infertility.

Writing for the AP, Lauran Neergaard reports that “[t]he problem of scarce supplies or even completely unavailable medications isn’t a new one but it’s getting markedly worse.”  According to Lancet Oncology, there were a record 211 drug shortages in 2011, up from 166 in 2009, 149 in 2008, 129 in 2007, and 70 in 2006.  Neergard adds that “another 89 drug shortages have occurred in the first three months of this year[.]”

Most of the medicines that have run short are sterile injectable drugs, which are complex and time-consuming to manufacture.  (The anesthesia drug sodium thiopental which I blogged about here falls into this category.)  And, most, or even all, of the shortfall drugs are no longer subject to protection from a patent or Food & Drug Administration-administered exclusivity period, so the innovator firms that developed them are subject to competition from generic manufacturers.  The resultant lower prices and slimmer profit margins mean that, in the words of leading oncologist Dr. Richard Schilsky, the manufacturers’ return on investment is “pretty low.”

Among the reasons cited for the rise in drug shortages are the inherent challenges of manufacturing sterile injectable drugs, the low return on investment facing generic manufacturers, which has led the number of manufacturers of any given generic drug to dwindle, drug company mergers, which can result in the discontinuation of one of two similar products, the time it takes the FDA to approve applications to make manufacturing changes, for example a change in the source of a drug’s active ingredient, and the failure of the FDA to act expeditiously in investigating manufacturing problems and clearing plants to resume production once the problems have been resolved.

The Preserving Access to Lifesaving Medications Act, introduced in February by Senators Robert Casey and Amy Klobuchar, would require manufacturers to notify FDA “of a discontinuance, interruption, or other adjustment of the manufacture of the drug that would likely result in a shortage of such drug[.]“  Per Lauran Neergard, the FDA “was able to prevent 38 close calls from turning into shortages last year by speeding approval of manufacturing changes or urging competing companies to get ready to meet a shortfall.”  The FDA has even permitted (temporarily) the import of medicines approved outside the United States when necessary to mitigate shortages.

Participants in a Drug Shortages Summit convened late last year by the American Society of Clinical Oncology and others recommended that additional legislative and regulatory reforms be explored, ranging from providing incentives to manufacturers in exchange for a guarantee that they continue producing critical drugs, to charging manufacturers fees to fund expedited FDA review of applications for permission to manufacture generic drugs, to requiring manufacturing redundancies (e.g. that more than one source for a drug’s active ingredient be identified) as a condition of approval.  Interestingly, while some participants in the Drug Shortages Summit argued that products liability exposure could cause companies to withdraw drugs from the market, the manufacturers who attended denied this, calling the decision “multifactorial.”  There is evidence to support the manufacturers’ claim.  As I discussed here, in late 2004, after Chiron Corporation announced that it would not be able to provide flu vaccine for the United States market that year due to manufacturing issues, Congress brought the flu vaccine into the Vaccine Injury Compensation Program fold.  Unfortunately, liability relief did not result in an increase in the number of manufacturers in the flu vaccine market.  Targeted reforms like those that the Summit participants recommend be explored seem more likely to be effective at ensuring a steady, reliable supply of vital medicines.

Controlling the Controllers of Controlled Substances

Despite their name and extensive government regulation, controlled dangerous substances (”CDS”) are far from controlled.  Licensed  health care providers are essential cogs in the prescription drug control machine.  Many faithfully execute their responsibility to prescribe CDS only where necessary and appropriate to relieve patient pain.  But sadly, some professionals are aggravating the situation.  Significant percentages of the professional licensing cases that I prosecuted in my previous position as a deputy attorney general in New Jersey involved abuse of prescribed CDS by patients and licensed professionals.

Some professionals are completely complicit, brazenly selling prescriptions (and their professional integrity) from their offices or cars.

Others aid and abet misuse by writing prescriptions too freely, for varying reasons and to varying degrees of culpability.  Some wear rose-colored glasses and miss tell-tale warning signs or just like to make people happy and have trouble confronting their patients.   Still others lack the training to know what types of questions to ask to identify drug-seeking behavior or how to effectively and safely combine different drugs to treat patients’ particular problems. Patients can be very skilled at keeping their providers in the dark, so some providers simply do not know that they are feeding a habit.   Others rationalize that it is better to keep their patients coming back for treatment than to send them to the streets for illegal drugs.

And, of course, others conscientiously wrestle with how to balance the need to relieve the very real pain they or their patients are experiencing with the reality that they or their patients are developing addictions.  It’s a thorny thicket, for sure.

No matter the reason, the problem of prescription drug abuse is intensifying, and we need to try something new.  This Spring, the Office of National Drug Control Policy (ONDCP) unveiled “Epidemic: Responding to America’s Prescription Drug Abuse Crisis,” which is “a multi-agency plan aimed at reducing the ‘epidemic’ of prescription drug abuse in the U.S. — including the FDA-backed education program that zeros-in on reducing the misuse and misprescribing of opioids.”  This plan has four main components: improving education of patients and health care providers; expanding state-based prescription drug monitoring programs; improving means for proper disposal of unused CDS from homes; and stepping up enforcement to reduce “pill mills” and doctor-shopping.

As part the education part of the plan, the FDA is working to implement a “Risk Evaluation and Mitigation Strategy (REMS)” for extended-release and long-acting opioid products, such as OxyContin and Duragesic (full list of drugs available here).  As FDA’s consumer update regarding this initiative summarizes, “[t]he new REMS plan focuses primarily on: educating doctors about proper pain management, patient selection, and other requirements and improving patient awareness about how to use these drugs safely.”  On May 16, 2011, FDA met with an Industry Working Group to discuss these ideas, including how to assess the effectiveness of the REMS plan.

Although generally I applaud any effort to better educate practitioners about the dangers of CDS, I worry how valuable this plan will be once implemented.  For one, it requires drug companies to prepare the educational materials.    Each has an interest in presenting its drug in the best light so that doctors are not afraid to prescribe it.  Would not government-funded, unbiased academic detailers, expert in pain and addiction medicine, be more effective?

In addition, the REMS plan does not require doctor training.  If we don’t even lead the horse to water, how can we ever quench its thirst?   How can we hope to affect the prescribing practices of health care providers who do not receive critical training?  It seems indisputably reasonable to require training in CDS prescribing before a practitioner is entrusted with the phenomenal responsibility to write prescriptions for CDS.   (According to a November 18, 2010 article by Susan Okie, M.D. in the New England Journal of Medicine, two FDA advisory committees agree with this requirement.)   This is especially crucial in states like New Jersey, where a medical license is plenary, and thus any licensed physician, regardless how little training in pain management s/he has had, may prescribe pain medicine.

Reportedly, other federal agencies are lobbying Congress to require mandatory physician training as a condition to receiving the Drug Enforcement Administration registration number that doctors must have to prescribe controlled substances.  But generally, the federal DEA registration process looks to state law.  If state law permits a physician to prescribe CDS, there normally is not a separate federal requirement.  This policy respects that licensing is among the states’ traditional police powers.  I expect that Congress is well aware that individual state licensing boards would bristle at Washington dictating the rules governing the practice of professions within their borders.

Not surprisingly, then, some states are not waiting for Congress to act.  According to Dr. Okie, the licensing boards in California, Rhode Island, and West Virginia require some degree of pain-management training.  We need to know what their experiences have been.  Is the training making a difference?  Is there any evidence that requiring training is discouraging doctors from prescribing CDS to patients in pain?

Dr. Okie’s article also details a law that is scheduled to go into effect in Washington state in mid-2011 that will require doctors who prescribe opioids to enter their patients’ clinical responses to treatment in a statewide database and to consult with a pain specialist if the prescribed dose exceeds a threshold.  The hope is that physicians who have thus far not changed their prescribing in response to voluntary educational programs and treatment guidelines may respond if their treatment success is being measured.  But some fear there are too few pain specialists to satisfy the demands imposed by this law.  Some practitioners and patients fear this will just drive patients to street drugs like heroin.

Florida, too, which reportedly is the source of eighty-five percent of the nation’s oxycodone and is known as the nation’s “Pill Mill Capital,” is taking bold steps to address prescription drug abuse.  In addition to increasing oversight of clinics, pharmacies, and wholesale distributors of CDS, its new statute signed into law on June 3, 2011 subjects physicians to administrative and criminal penalties for violating prescriptive regulations governing CDS prescribing.  For example, doctors will face a minimum of a six month suspension and $10,000 fine if they overprescribe CDS.  The law also requires certain doctors to register with the State and restricts their ability to prescribe certain controlled substances.  Doctors also must meet more exacting requirements for record keeping, prescription writing, and treatment plans for those receiving CDS.

The Florida law also authorizes the state to create a prescription-drug monitoring database that will help law enforcement track which providers may be indiscriminately prescribing CDS.  Upon request, treating physicians will have access to this data to inform their treatment decisions.  Approximately 34 other states are operating similar databases, although each has its own rules regarding what entities may access the data, what drugs must be reported, etc.

It is beyond the scope of this post to address the policy pros and cons of all of the provisions in Florida’s new law.  With respect to the prescription drug monitoring database, however, I long have thought it would be valuable to provide prescribing providers access to integrated pharmacy records.  I investigated many physicians who had their patients sign agreements promising only to receive CDS from that doctor.   Investigative pharmacy sweeps helped me learn that this doctor was one of many the patients were using to feed their habit.  But doctors in New Jersey have not had any access to this information unless their patients granted it to them.

But that is about to change.  Although it took years to enact, N.J.S.A. 45:1-45 - 1-52 authorizes New Jersey’s prescription monitoring program.  Section 1-46 specifically permits New Jersey physicians to access the program’s data concerning their patients (although physicians are not required to do so).  The same section also permits New Jersey to enter interoperability agreements with other states so that each state may access the other’s data.  The database is not up and running yet, but on April 7, 2011, New Jersey awarded a four-year contract to a company in Ohio to develop the database.

Once this database is operating, it will offer NJ doctors an opportunity to identify which patients are doctor-shopping and tailor their treatment accordingly.  Undoubtedly, there are risks with this system.  Patients may resent that their doctor did not trust them, for example.  In addition, doctors who primarily treat patients in chronic pain could trigger greater scrutiny from regulators because their prescribing of CDS will outpace other providers.  Regulators will need to carefully exercise their investigative powers so as not to discourage physicians from prescribing appropriate CDS.  These risks, however, seem worth the benefit of identifying patients in need of addiction counseling and treatment and reducing diversion.

But we should not rest on assumptions and hopes.  Rather, we should keenly watch what happens in places like California, Rhode Island, West Virginia, Washington, and Florida to evaluate what works and doesn’t.  Professors Diane Hoffmann (see, e.g., here and here [subscription required]) and Anita J. Tarjian (see, e.g., here) at the University of Maryland and Interim Dean Sandra Johnson at Saint Louis University School of Law (see, e.g., here), among others, raise significant concerns that aggressive enforcement of CDS restrictions can discourage physicians from prescribing CDS, which leaves un- and under-treated patients in pain.  This is unacceptable.  We should regulate with an appreciation for the strides achieved by efforts like the Mayday Pain Project to provide better care to patients suffering in pain.  By taking measured steps and being willing to tinker with our enforcement regimes as we learn, we may ensure we do not deprive patients of needed medications or scare ethical, competent pain physicians from serving their patients’ needs.

Perhaps the Federation of State Medical Boards will help lead this effort to learn from these varied efforts at the state and federal level.   According to its 2011 Annual Report, over 40 state boards have adopted the Federation’s Model Policy for the Use of Controlled Substances for the Treatment of Pain.  Clearly, state boards, without ceding their independence, look to the Federation for guidance, akin to how states view the ABA’s Model Rules of Professional Conduct.  Its policy paints in relatively broad strokes and has not been updated in more than seven years.  It would be helpful if the Federation would update its policy to reflect the current state of law and research in this area, including the impact of various reform efforts, to help state boards find balance between reining in indiscriminate CDS prescribing and the need to provide medically appropriate palliative care to patients in need.

Review of Reconsidering Law and Policy Debates: A Public Health Perspective

Reconsidering Law and Policy Debates: A Public Health Perspective, edited by John Culhane, is a superb collection of thought-provoking essays which features some of the most well-regarded health law scholars in the US. It also includes contributors from schools of public health, public affairs, and public administration. The chapters are uniformly well-written and instructive. Though I cannot in this brief review give consideration to all of the essays, I will try to highlight contributions related to some of my own areas of interest in the intersection between public health and medico-legal research.

Several authors focus on the difficult questions raised by extreme inequality. For example, Vernellia R. Randall’s Dying While Black in America reflects on the disturbing disparity between white and black death rates in the US. A black American male can expect to live seven years less than a white American male, and black women face a four-year gap. Randall explores a number of potential explanations, including discriminatory policies and practices, lack of language and culturally competent care, inadequate inclusion in healthcare research, and hidden discrimination in rationing mechanisms. Randall argues that these disparities will never be addressed effectively until the legal system develops doctrines that can deter not only intentional discrimination, but also “negligent discrimination in healthcare:”

Negligent discrimination in healthcare would occur when healthcare providers failed to take reasonable steps to avoid discrimination based on race when they knew or should have known that their actions would result in discrimination. An example of this would be decisions to close inner-city hospitals and move them to the suburbs. (86)

Randall expertly characterizes race as a key “social determinant of health” in the United States. Countering the many current legal doctrines that promote the legitimation of discrimination, Randall envisions the type of guarantees of equality that will be necessary to realize the antisubordination and antisubjugation principles that animate the 14th Amendment properly understood.

Diane E. Hoffman also addresses stunning inequalities, this time on a global level. Hoffman’s long engagement with end-of-life care informs a consistently sensitive and insightful public health perspective. Considering the situation in the United States, Hoffman concludes that “it is not as all clear that we would want to give the state a public health justification for taking on end-of-life care,” because “we might have trouble reining in the government and preventing it from implementing increasingly more coercive measures” (59). This judgment is particularly pertinent in a political environment where extreme inequality and ever-lower taxes on the wealthiest have imperiled many important health programs for the aged.

However, Hoffman comes to a different conclusion in the case of many developing countries, where the question is less one of rationing access to life extending technologies than it is one of extending access to basic treatments for pain. In a sobering series of statistics, Hoffman presents a tragic panorama of human suffering. In India, only 1% of the 1.6 million people enduring cancer pain each year are likely to receive any type of pain medication. Morphine dispensaries are rare; Calcutta, with 14 million residents, has only one. Though nearly half its population is extremely poor, India is not an outlier. While developing countries account for 80% of world population, they use only 6% of the morphine consumed each year. Sometimes, shortages of medical personnel help explain the problem: for example, in Sierra Leone, there is only one doctor for every 54,000 people (as opposed to a 1:350 ratio in the US). But Hoffman gives several examples of easily preventable policies and business practices that keep painkillers out of the hands of the world’s poorest individuals. This is a truly neglected global crisis, generating levels of suffering that are rarely encountered or even imagined in the developed world.

Returning to the US, the last two chapters in the book are very interesting contributions to ongoing debates about the nature and role of tort doctrine. Elizabeth Weeks Leonard expertly deconstructs the usual dichotomy between tort law’s individualism and the population focus of public health. As she notes, cases involving asbestos, lead paint, silicone breast implants, the Dalkon shield, hazardous autos, tobacco, firearms, Phen-Fen, OxyContin, and Vioxx have all combined efforts by individuals to secure compensation for injuries with broader strikes against destructive products and practices. Weeks succeeds in demonstrating the “counterintuitive fit between tort law and public health law” (189), arguing that each “offers approaches to addressing inevitable conflicts in organized society between individual interests and community needs.”

Jean Macchiaroli Eggen tries to make the fit better by focusing on punitive damages. Toward the end of her chapter, she proposes that states solve the “plaintiff windfall problem” in punitive damages by requiring that “the portion of the punitive award the plaintiff does not receive [due to split-recovery statutes and other measures] be allocated to a state or private program that will enhance the deterrence of the conduct that gave rise to the warden the particular case.” The contributions of both Weeks Leonard and Macchiaroli Eggen would be of great interest to tort classes and seminars considering the difficult issues raised by judicial efforts to address public health concerns.

John Culhane is to be commended for bringing together such an illustrious group of contributors to address public health, an issue that has been neglected in law schools. Knowing full well that factors like income, race, pollution, and even commute length may have a far greater impact on health than, say, dispute resolution methods used by insurance companies, law professors nevertheless tend to focus on purely legal topics. (I am as guilty of this as anyone, and credit this book (and many interventions by Daniel Goldberg) for pushing me to do more to consider the social determinants of health in my own work.) Well after the sturm und drang surrounding the constitutionality of the ACA has dissolved, we will still face problems of balancing liberty, equality, and welfare that this book’s thoughtful contributors address. Their voices deserve to be heard in those future, more substantive, debates.

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