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.

Financial Remuneration of Clinical Study Investigators

In November 2009, the Center for Health & Pharmaceutical Law & Policy, in its White Paper, Conflicts of Interest in Clinical Trial Recruitment & Enrollment: A Call for Increased Oversight, explored payments to investigators — and other potential motivators — to conduct research.  A study in this month’s IRB: Ethics & Human Research explores the impact payments may have on researchers to conduct and complete studies.  In Motivated by Money? The Impact of Financial Incentive for the Research Team on Study Recruitment, Sharon Unger and her colleagues examine the effect financial remuneration has on researchers in a neonatal intensive care unit (NICU).

Taking advantage of a “fortuitous set of circumstances” in which two separate clinical trials with nearly identical inclusion criteria were conducted simultaneously in an NICU in Canada, the authors looked at two issues: 1) whether financial remuneration impacted the rate at which the research team approached parents about research participation, and 2) whether financial remuneration impacted the rate at which parents provided consent to participate.

In the first study (Study A), a placebo-controlled trial involving a medication that was the standard of care for treatment of newborns nearing extubation to prevent apnea of prematurity, members of the research team were financially compensated for their time if they were successful in obtaining parental consent (parents were unaware of this arrangement).  In the second study (Study B), which involved two different forms of noninvasive respiratory support following extubation, there was no financial compensation of the research team.  Both studies had the same recruiting team.  Study A was federally funded, multicentered and high-profile, while Study B was a single-center, unfunded trial.

The payments in Study A were per capita, which, while creating a direct incentive to recruit individual enrollees, is usually not problematic as long as the payment is not excessive.  The Center recommends “that the benchmark for compensation for physician services for research should be comparable payment for time and services for treatment. This will compensate physicians fairly for their time and services, and will assure that there are no hidden bonuses or incentives for physicians to recruit patients into research or to refer them to research rather than treatment.”  As noted in the study, finder’s fees are increasingly considered “ethically problematic;” the Center recommends a wholesale bar on finder’s fees because they can create conflicts of interest that can incentivize investigators to recruit and retain individuals who do not meet the study’s inclusion and exclusion criteria.

As the authors noted, and as acknowledged in the Center’s White Paper, potential enrollees are increasingly vulnerable as increasing numbers of individuals seek to participate in research either as a primary means of access to treatment or as a form of income.  The results of this study indicate a much higher likelihood of approach when there was a prospect of financial remuneration.  These results are concerning, and were anticipated by the Center’s White Paper, which noted the potential for poor compliance with inclusion and exclusion criteria and pressure to enter or remain in a clinical trial.

However, surprisingly, the authors found that, despite the much higher likelihood of approach for Study A than Study B, parents were much more likely to actually agree to enroll their newborn in Study B — for which there was no financial remuneration of the research team.  The authors explored various explanations for this result, including that the research team was overly cautious about giving the appearance that their approach for consent was motivated by financial compensation, or that parents chose to withhold consent  due to the research team’s  increased pressure.

The authors do acknowledge other potential factors — beyond financial remuneration –  that could have affected the study’s results.  For example, parents’ hesitancy to enroll their newborn in a placebo-controlled drug trial could explain the discrepancy between enrollment in the studies.  Likewise, the authors consider that parents may not have been able to differentiate between the two modes of support being investigated in Study B.  In addition, the recruiting team, when presented with the results of the study, did not recall feeling influenced by the financial arrangement of Study A, but did “recall being highly motivated to ensure the success of Study A as it was part of a high-profile, multicentered trial.”

The authors concluded by noting concerns that “there may be a point at which the amount of the financial remuneration or the manner in which it is assigned could negatively impact the ethical conduct of the researcher,” but cautions that these concerns should be balanced with the value of conducting research in patients’ best interests.  This balancing act is considerably important.  As the Center notes,

Research is critical to the advancement of medical treatment and health. It must be structured to produce high quality data that facilitates the assessment of safety and efficacy in the population for whom the treatment will be used. The good of the enterprise requires that the clinical trial system sufficiently balance the costs and benefits to physicians and prospec­tive trial participants to ensure the continued sufficient supply of researchers and subjects. The system must also be imbued with actual and perceived integrity — so that it produces scientifi­cally reliable results, participants are safe, and people trust the system sufficiently to be willing to participate.

Medical Marijuana Act Signed Into Law: Some Chronically Ill New Jerseyans Rejoice While Others Continue to Wait

As expected, on January 18, 2010, Governor Jon Corzine signed the New Jersey Compassionate Use Medical Marijuana Act into law, making New Jersey the 14^th state to legalize marijuana for medical use.  Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy endorsed the Act in a position paper distributed to key lawmakers in June 2009.

The Act’s backers celebrated its passage with “hugs and tears,” while its opponents expressed continued concerns, including that the for-profit “alternative treatment centers” that the Act will allow to grow and distribute marijuana will have negative effects on the neighborhoods where they are established.  An interesting abcnews.com article by Susan Donaldson James highlights a third constituency: New Jerseyans with chronic illnesses that are responsive to treatment with marijuana but who are not considered to have debilitating medical conditions under the Act.

The article profiles Jack O’Brien of Laurel Lake, New Jersey who was born without fingers and toes and suffers from “crushing neuropathic pain.”  He wakes up to shooting pain in his arms and legs and can only walk short distances on his deformed feet.  According to O’Brien, smoking marijuana is “like having a valve on the forearm, turning it and having the coolness of relief through my extremities. … I try to walk on these feet and I can go four or five blocks, with my wife. With marijuana, I can go forever.”  State Assemblyman Reed Gusciora, who was a prime sponsor of the Act, explained that while he had empathy for O’Brien and others in his position, the legislature “had to do a measured approach,” citing fears that New Jersey could become another California, where medical marijuana “seemed to be spiraling out of control.”   Assemblyman Gusciora promised that in two years the legislature would “revisit the issue and add ailments.”

Addendum:

While Jack O’Brien’s case provides only anecdotal evidence of marijuana’s efficacy against neuropathic pain, as the Center noted in its position paper, “in the past two years, three placebo-controlled, randomized, double-blind clinical trials published in the medical literature have demonstrated that smoked marijuana is effective against neuropathic pain, including for patients who have tried the available conventional treatments and are still in pain.”   The existence of this evidence is remarkable because, as recent articles in the New York Times and Wall Street Journal explain, researchers must surmount formidable hurdles to study marijuana’s potential medical uses.

For those who are curious, under the compromise version of the Act which was signed into law January 18^th, “debilitating medical condition” is defined to include the following:

• Seizure disorder, including epilepsy, if resistant to conventional medical therapy;
• Intractable skeletal muscular spasticity, if resistant to conventional medical therapy;
• Glaucoma, if resistant to conventional medical therapy;
• HIV or the treatment of HIV, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• AIDS or the treatment of AIDS, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• Cancer or the treatment of cancer, if it causes severe or chronic pain, severe nausea or vomiting, cachexia, or wasting syndrome;
• Amyotrophic lateral sclerosis;
• Multiple sclerosis;
• Terminal cancer;
• Muscular dystrophy;
• Inflammatory bowel disease, including Crohn’s disease; and
• Terminal illness, if the physician has determined a prognosis of less than 12 months of life.

New Jersey Legislature Passes Medical Marijuana Bill

Yesterday, the last day of its 2008-2009 legislative session, the New Jersey legislature voted to legalize the use of medical marijuana by New Jersey residents suffering from debilitating medical conditions.

The version of the New Jersey Compassionate Use Medical Marijuana Act passed yesterday represents a compromise between the version that the state Senate passed in February of 2009, which Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy endorsed in a position paper distributed to key lawmakers, and the Assembly version, which included a number of amendments intended to bolster the Act’s already strict safeguards against abuse and diversion.  (The differences between the Assembly and Senate versions are outlined here; a summary of the changes made in the final legislation is posted here on the Legislature’s website.)   Governor Corzine is expected to sign the Act into law before he leaves office next week.

Among other changes, the final legislation:

• revises the definition of “debilitating medical condition” to specify that severe or chronic pain, severe nausea or vomiting, and cachexia or wasting syndrome qualify a patient to use medical marijuana if they are symptoms of cancer, HIV/AIDS, “or the treatment thereof.” The new definition also adds inflammatory bowel disease, including Crohn’s disease, muscular dystrophy, and terminal illnesses expected to cause death in 12 months or less to the list of debilitating conditions;

• deletes the Assembly provision that allowed patients to designate an individual to transport marijuana to them in an emergency, and reverts to the Senate language allowing patients to designate a primary caregiver to assist them with their use of medical marijuana on an ongoing basis; and

• preserves the Assembly version’s requirement that patients obtain their marijuana from “medical marijuana alternative treatment centers,” i.e., that they not be allowed to grow their own, but increases the amount of marijuana that patients can be dispensed in a 30-day period from one ounce to two ounces.

Interestingly, the final legislation also requires that the system the Division of Consumer Affairs in the Department of Law and Public Safety establishes to monitor the dispensation of marijuana for medical use must “serve the same purpose as, and be cross-referenced with” the Division’s system for monitoring the dispensation of certain prescription drugs with the potential for abuse.  This is further evidence that marijuana is slowly but surely, as Fordham Law Professor Kimani Paul-Emile writes, “migrating from the criminal regulatory regime into the public health regulatory regime.”

Of Electric Eyes, $20 Knees & Flying Cars

CNN recently featured what it called the Top 10 Health Innovations of 2009. From a $20 knee joint replacement developed by Stanford students (which may in time at least partially replace the titanium versions currently marketed with price tags from $10,000 to $100,000), to a microchip developed by MIT researchers which may, as an “electric eye,” help blind people to regain partial sight. There’s also a smart stethoscope which can transfer monitored data directly to a computer where that which has been transmitted can be further analyzed; a new found process which uses pieces of wood to regenerate broken bones; and a Transcranial Magnetic Stimulation Therapy System which has shown promising results in treating the depression of those who have not been able to obtain relief through anti-depressants. The electromagnetic headpiece “pulses magnetic fields into a patient’s prefrontal cortex, the part of the brain that regulates mood” and “stimulates the neurons to make more mood enhancing chemicals.”  The technology may offer relief to millions of people who suffer from depression. Amazing really.

The award winning New Jersey Journalist Paul Milo has just published a fascinating book entitled “Your Flying Car Awaits: Robot Butlers, Lunar Vacations, and Other Dead-Wrong Predictions of the Twentieth Century.” Milo has produced what Harper Collins has aptly referred to as an “insightful compendium of the most outrageous and completely ridiculous predictions of the 20th Century.” And as I, having grown up in the late Sixties and Seventies, ponder this present dire lack of flying robot cars (we were veritably promised), I can’t help but be amazed that we’ve reached a point where machinery may offer sight to the blind and knees to the poor.

And if still upset about the flying robot cars, there’s always the Transcranial Magnetic Stimulation Therapy System.

The CNN graphic showing the Top 10 Health Innovations is well worth a quick look.

Pharma Marketing, Advanced

With the Senate’s bill clearing late night hurdles, the coverage in the mainstream media is, at least for the moment, broad. But there was a segment on NPR’s All Things Considered in the midst of all that Health Reform bill coverage that is well worth a listen. The segment, “How A Bone Disease Grew To Fit The Prescription,” (transcript linked, audio below) functions as a sort of biography of the evolution of both a drug and a disease– which was not, it seems, an entirely independent process.

The drug is Merck’s Fosomax, the disease is Osteopenia. Fosomax had sales in 1996 of $281.8 million; by 2005, on the heels of what qualifies as a comprehensive and wildly successfull marketing effort, the drug had sales of $3.2 billion.  Osteopenia derives its origin as somewhat of an afterthought, when in 1992 “a group of osteoporosis experts gathered under the auspices of the World Health Organization” and drew a somewhat arbitray bright line to determine what level of bone mass loss was normal and what amount constituted a disease. The term “Osteopenia” was coined, on the spot, to give clinical researchers a term which described those whose bone loss was considered normal, but was close to the line. They never imagined that Osteopenia would come to be considered a disease in itself, but it did. Millions of women are said to have it; millions treat it with Fosomax. The story of how this came to be (and the implications regarding the role of Pharma in health care) is fascinating.

The FDA Steps In: Regulating Prescription Drug Promotion on the Internet

The FDA has been widely criticized for not providing guidance for drug companies eager to promote their products on the internet.  Earlier this year, the FDA expressed the view that the message was what was important, not the medium, meaning that companies should simply apply the rules governing prescription drug advertising in print media to the internet.  On April 2, 2009 the agency issued Notice of Violation letters to 14 companies who sponsored links on internet search engines advertising their products; the links gave the name of the drug and, in some cases, its indicated use, without including the required “fair balance,” i.e., safety information such as contraindications and potential side effects.  In reliance on the so-called “one-click rule” — which had never actually been adopted by the FDA — the companies had put the required safety information one click away on a separate page.

In recent months, the FDA has indicated that it is open to providing internet-specific marketing guidance.  Yesterday and today (November 13^th) the agency is holding a hearing on “Promotion of FDA–Regulated Medical Products Using the Internet and Social Media Tools.”  Representatives from advertising agencies, consumer groups, health-related websites, pharmaceutical companies, and search engines are scheduled to testify.

In written testimony released before the hearing, PhRMA, the pharmaceutical industry’s trade group, proposed that the FDA approve a standard universal warning: PhRMA suggests “All drugs have risks.  Click here for more information from the manufacturer.” — for use “in places throughout the Web where there is not enough room for complete disclosure of all warnings, indications, and contraindications (e.g., search results and microblog posts.)”  Such a warning would, PhRMA argues, allow companies to take advantage of sponsored links, make full use of Twitter, etcetera, while also providing easy access to safety information.  PhRMA even suggests that the warning incorporate the FDA’s logo, arguing that this could mitigate against “the dangers posed by illegal Internet drug sellers.”

It will be interesting to see whether and how the proposals of the other groups represented at the hearing differ from PhRMA’s, and, of course, whether the FDA in the end decides that its “fair balance” requirements should be modified for the web.  Among the other interesting issues FDA may address is companies’ responsibility for web content they do not control.  Google’s introduction of Sidewiki, which allows anyone visiting a pharmaceutical company’s website to leave a comment, has brought this issue to the fore, raising, for example, the prospect of doctors discussing a product’s off-label uses on the manufacturer’s site.

Anyone who wishes to comment on these or other internet-specific promotion issues may do so through February 28, 2010.

ACCME: Showing Some Teeth?

This week, the New York Times reported on efforts by the Accreditation Council for Continuing Medical Education (ACCME) to step up its enforcement of its Standards for Commercial Support.  Drug and device companies spent over a billion dollars on accredited continuing medical education (CME) courses in 2008; ACCME’s Standards for Commercial Support are meant to ensure that industry funding does not translate into commercially-biased content.  ACCME’s new focus on enforcement comes in the wake of a Senate Committee on Aging hearing over the summer at which Dr. Steven Nissen of the Cleveland Clinic testified that ACCME should be abolished because it is a toothless watchdog, “uninterested or incapable” of enforcing its Standards.  And that was not the first time ACCME’s oversight of CME has attracted congressional attention.  A 2007 Senate Finance Committee investigation uncovered numerous cases in which drug and device companies violated ACCME’s Standards and expressed concern about ACCME’s years-long delays in imposing penalties for compliance failures.

While noting that medical education is largely self-regulated, Dr. Murray Kopelow, ACCME’s head, told the New York Times that, relative to years past, ACCME was active in 2008 and 2009, investigating twelve complaints and finding five courses to be commercially biased.  In addition, the organization will soon post to its website a list of CME courses and providers found to be biased.  ACCME will also consider a proposal that providers whose courses are found to be commercially biased be required to alert the doctors who attended and provide them with corrective materials.

While these efforts are salutary, an effective enforcement program would require a significant commitment of time and resources (in 2008, there were just under 50,000 accredited CME activities), which ACCME may not have.  Well-known critic of industry-funded CME Daniel Carlat (author of “Dr. Drug Rep,” a fascinating piece about his experience giving paid promotional talks for a drug company) had this  to say about the prospects for effective enforcement:

…if the Atypical Antipsychotic program is bad enough to be pulled for commercial [bias], my conservative estimate is that at least half, probably more, of all industry funded psychiatry CME will also need the retraction treatment. The problem is, who on earth has the time to police these things? Certainly not ACCME. Dr. Carroll and I try to keep on top of the worst of the worst, but we have other things to do in order to make a living. The best and simplest solution would be to end industry funding of medical education altogether.

Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy has recommended just that — that industry funding be ended altogether, on the grounds that drug and device industry funding too often leads to bias and that such bias is incompatible with CME’s educational aims.  Dr. Nissen makes the additional argument that ending bias in CME would reduce inappropriate prescribing of branded prescription drugs, which would in turn yield significant cost savings.  As Dr. Nissen told the Senate Committee on Aging, “That’s one of the ways we can pay for healthcare reform.”

Under the Radar: Health Care Reform & Drug Advertising & Marketing

At the Food and Drug Law Institute’s 21^st Annual Advertising & Promotion Conference John Kamp of the pro-industry Coalition for Healthcare Communication discussed four proposals addressing drug advertising and marketing issues that may be incorporated into the final health care reform bill but have not been widely debated.  Mr. Kamp’s presentation is available here.  

Off the Table (For Now)

Of most concern to industry is an oft-floated proposal to eliminate the tax deduction for drug advertising.  (See, for example, bills sponsored by Representative Jerrold Nadler (D-NY) and Representative Daniel Lipinski (D-IL) here and here.)  Most recently, on September 11, 2009 Senator Bill Nelson (D-FL), a member of the Senate Finance Committee, announced his plan to put forth an amendment to the Baucus Bill that would eliminate the “tax break drugmakers get for TV advertising.”

Direct-to-consumer advertising is a prime target because, as the New York Times put it, for many “the ads are a daily reminder of a health care system run amok,” which “prompt people to diagnose themselves with chronic quality-of-life problems like insomnia or restless leg syndrome; lead people to pressure their doctors for prescriptions for expensive brand-name drugs to treat these conditions; and steer people away from cheaper generic pills.”   There is also concern that DTC ads do not present an accurate picture of drug risks and benefits and that they drive uptake of new drugs before their safety is fully known.

Another obvious driver is the need to pay for health care reform.  Senator Nelson echoed a claim made earlier this year by Congressman Charles Rangel (D-NY) that eliminating the tax break for TV ads would free up $37 billion over the next ten years.  Industry representatives contest the $37 billion figure, arguing that drug companies spend far too little on direct-to-consumer advertising to achieve that level of additional tax revenue.  They contend that Congress would have to eliminate the tax deduction for physician advertising and other marketing expenditures to garner $37 billion.

Less than a week after he announced it, Senator Nelson backed off his plan, perhaps under pressure from other members of Congress who come from districts with a strong media presence and have spoken out against eliminating the deduction.  According to Mr. Kamp, however: “Somebody else will raise this again before it’s over, you bet … Baucus says the reforms will cost $850 billion, the Congressional budget office $750 billion. Three-quarters of a trillion dollars is a lot of real money in Washington. The $37 billion will continue to be in the buffet of options as they try and figure out healthcare.”  

Still on the Table

Three proposals related to drug and device promotion are still on the table, with varying chances for inclusion in the final health care reform bill.

First, health care reform bills in both the House and the Senate contain transparency provisions akin to those in the Physicians Payments Sunshine Act of 2009 introduced in January by Senator Chuck Grassley (R-IA).  Seton Hall Law’s Center for Health & Pharmaceutical Law & Policy recommended that disclosure of drug and device company payments to doctors be federally mandated in its January 2009 white paper.  As the Sunshine Act has widespread support, including from industry, transparency provisions are likely to be included in the final bill.

Second, Section 138 of the health care reform bill reported out of the House Education and Labor Committee   bans the commercial use of “prescription information containing patient identifiable and prescriber identifiable data,” essentially adopting as federal law New Hampshire’s ban on prescription data mining which survived a First Amendment challenge in the First Circuit.  If passed, Section 138 would end drug reps’ current practice of tailoring their sales messages to each doctor’s prescribing history, which many believe creates undue pressure on doctors to prescribe newer more expensive medications.

Third, a bill sponsored by Senator Jack Reed (D-RI) would authorize the FDA to evaluate whether use of a “drug facts box” format for presenting a drug’s benefits and risks would improve healthcare decision making and, if so, to promulgate regulations requiring that drug facts boxes be added to drug labels.  Senator Reed’s bill also empowers the FDA to set standards for comparative clinical effectiveness information included in drug labeling and advertising.

It is difficult to predict whether the data mining ban or Senator Reed’s bill will be included in the final health care reform bill.  Mr. Kamp calls Senator Reed’s bill’s chances a “toss up;” regarding the data mining ban, he has “no idea.”

Alternative Revenue Stream for Private Practice Physicians – Research Investigator

Clinical research is the only way [for a physician in the managed care era] to make a boat payment, quips David Stark, M.D.

With increasing frequency, pharmaceutical and medical device companies are turning to physicians in private practice, rather than academic medical centers, to serve as investigators overseeing the 60,000-odd clinical trials each year, between 80 and 90% of which are funded by industry as opposed to, say, NIH. Academic medical centers are losing the “business,” having fallen from 63% to 26% as the site for clinical research between 1994 and 2004. While it might be argued that trials in the private practice setting produce superior results because they occur under circumstances that more closely resemble how the drug or device will actually be used if approved by the FDA, there are significant risks attendant to this phenomenon that have received too little attention.

The ultimate question is whether physicians can compartmentalize the competing incentives that exist in advising patients about whether to pursue conventional therapy or participate in a clinical trial. This is especially true if the physician is being handsomely compensated for each patient she recruits into a trial, and is exacerbated when the physician also has other financial relationships with the trial sponsor (the drug or device company) for, say, speaking and consulting gigs. Clinical Research in the Private Office Setting — Ethical Issues The recruitment process for clinical trials is the longest and most costly part of the process - prospective participants have to undergo testing to see if they qualify for the study, and federal law requires that they receive significant amounts of information and have ample opportunity to have their questions answered pre-enrollment. A per capita payment contingent upon successful enrollment of the patient will tempt a physician to fudge on this process and enroll unqualified subjects. This not only may put them at risk because they are too sick, but also skew the research results because they’re not sick enough. Bonuses for meeting enrollment goals only make it worse.

Without impugning physician integrity, how realistic it is for physicians to serve in the dual capacity of treating physician and researcher? Studies have repeatedly confirmed “therapeutic misconception” whereby study participants believe, no matter how clearly told to the contrary, that they are “patients” receiving treatment, rather than “subjects” of research who may be receiving a placebo or an experimental drug. This phenomenon is certainly exacerbated when the patient’s treating physician is doubling as the investigator of the clinical trial. Most patients continue to believe that their own personal physician would be driven solely by their best interests. Ironically, some people have more faith in an experimental intervention when they learn that the investigator has a “piece of the action.”

Obviously, significant policy and legal questions arise from this practice, and a more holistic approach to the question of the best way to encourage clinical trials while safeguarding the interests of trial subjects is beyond what I can attempt here. But one possible approach could be drawn from informed consent law — whether statutory or common law, which should require physician disclosure of conflicts of interest to patients. Imagine the beginning of a conversation between doctor and patient/potential research subject:

Doctor: “Just so you know, if you agree to participate in this clinical trial, I get paid $1000 by the manufacturer of the product being tested, but if you don’t, and you just want regular treatment, I’ll only get paid $60 by your insurance company. But, in fairness, that’s because a clinical trial is a lot more work for me….”

But to be honest, I don’t really believe in this solution either. Most recipients of this information either don’t understand it, or have no idea what to do with it, or both. Some fear that too much confusing information might kill trials altogether, which would be a terrible outcome. And there are certainly reasons to fear that such trials are becoming harder to run, to the point where they’re not worth the money. Ultimately, I guess, I want to control how physicians get paid to serve as investigators — the Goldilocks Solution — not too much, and not too little. I want them to be paid just right, so that they are willing to conduct clinical trials, but aren’t tempted to act other than in the patient’s best interest. Of course, what is just right and how to enforce it poses its own problems.

Seton Hall Law School, the author’s employer, is the recipient of grants, donations and endowments from the pharmaceutical industry. No part of the author’s compensation is funded by these gifts.

x-posted at Concurring Opinions

Drug Study Fails to Mention Risk of Death to Test Subjects

[Ed. Note: Today's Post is by Maansi K. Raswant, a Seton Hall Law student pursuing the Health Law concentration. She is a research assistant to the Center for Health & Pharmaceutical Law & Policy and an intern at the NYC Health and Hospitals Corporation.]

As reported recently in the Boston Globe, a federal probe found that heart attack survivors enrolled in a clinical trial conducted in over 120 sites nationally had not been adequately informed of the safety risks of the study, including the risk of death.

The process under study, chelation, involves “periodic infusions of a drug– in this case, disodium EDTA.” The infusions are being tested in conjunction with the ingestion of high doses of  vitamins and minerals. However, according to the federal probe, “in 2008 FDA removed disodium EDTA from the FDA’s approved list and withdrew of approval of new drug applications for disodium EDTA.” Test subjects were not informed that disdodium EDTA “is no longer FDA approved for any use and has been removed from the market because of safety concerns.”

Funded by the National Heart, Lung and Blood Institute and the National Center for Complementary and Alternative Medicine, the study has over 1,500 subjects. Though researchers suspended enrollment last August due to the investigation, federal officials allowed the study to continue pending further findings of the probe, a decision that has been highly criticized.

In addition to the deficiencies regarding the  informed consent of study participants, the Boston Globe reported that the investigation found that several co-investigators involved in the study had been disciplined for “substandard practices” or had been involved in insurance fraud. Three were convicted felons. Federal officials explained that they found the substandard practices and convictions of the principal investigators “concerning” but not a reason to “automatically preclude an investigator from participating in research.”

The U.S. Office of Human Research Protections detailed the findings of the investigation and required corrective actions in a letter to the three medical institutions heading the study. In response to the investigation’s findings, the study modified the consent form to recognize death as a “rare complication of the EDTA [chelation] infusions.” The Office of Human Research Protections has also requested further modification of the form to disclose that disodium EDTA had been removed from the market.

Despite the change in consent form, questions remain about the acceptability of the risks posed by the study. As the Globe reports, critics of the study, including the head of bioethics at the University of Pennsylvania, Arthur Caplan, have charged that the risks posed by the study are unethical. The complaint against the study filed with the Office of Human Research Protections noted that since “the mid-1970’s court documents and newspapers have reported at least 30 deaths associated with intravenous EDTA.”

The probe is the lastest in a string of major investigations of clinical trials, including the continuing investigation into payments by device maker Medtronic to Dr. Timothy Kulko (who is accused of falsifying author names and  study results), and the Synthes indictment for allegations that its subsidiary, Norian, conspired to conduct unauthorized clinical trials that placed subjects at risk of death without properly informing them of the risks. In the Synthes/Norian matter, three patients are believed to have died as a result of the use of the companies’ bone cement products.

Medical Science Liaisons: Walking the Line between Scientific Exchange and Promotion

[Ed. note: As noted in the post above, we are very pleased to welcome Kate Greenwood, J.D., to the blog today.]

As the Wall Street Journal recently reported, at a time when the ranks of pharmaceutical sales representatives are thinning, the number of medical science liaisons (MSLs) is (or was until very recently) growing.  MSLs are doctors, pharmacists, or scientists employed by drug companies to disseminate scientific information about the companies’ drugs — including information about off-label uses of those drugs — usually to physicians who are key opinion leaders.  MSLs are, at most companies, part of the medical affairs or research and development departments and, unlike sales reps, they are not typically evaluated or compensated based on increases in market share or prescription volume in their regions.  Still, as suggested by this PharmExec article on permissible metrics for measuring the value to companies of both MSLs and the thought leaders they court, it is not always clear how the work MSLs do differs from that of a sales rep.

FDA regulations ban companies from “represent[ing] in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation” but explicitly allow companies to engage in “the full exchange of scientific information.”  Sales reps cannot take advantage of the scientific exchange safe harbor to discuss off-label uses with physicians, but MSLs can, as long as they do so in response to a physician’s unsolicited request.  Jeff Patrick, who holds a doctorate in pharmacy and is Director of Medical Scientists at the biopharmaceutical company Dyax, explained to the Wall Street Journal that, unlike a sales rep, he could respond to a question like “Were there pediatrics in your trial?” even if the drug being evaluated was not approved for pediatric use.

Because MSLs are out in the field engaging doctors in free-ranging and difficult to police discussions, they present evident compliance challenges for companies attempting to follow the rules regarding off-label promotion.  On the other hand, their scientific expertise and established relationships with thought leaders may also present compliance opportunities.  For example, earlier this year, the FDA approved the use of MSLs in the Risk Evaluation and Mitigation Strategy (REMS) for UCB’s Cimzia, a drug used to treat Crohn’s disease and rheumatoid arthritis which carries with it a risk of serious infection.  The Cimzia REMS requires as part of its communication plan that the company’s MSLs make a presentation about the drug’s risks to all of the nation’s approximately 500 gastroenterology key opinion leaders.

Synthes Legal Troubles –Again

[Today's Post is by Maansi K. Raswant, a Seton Hall Law student pursuing the Health Law concentration. She is a research assistant to the Center for Health & Pharmaceutical Law & Policy and an intern at the NYC Health and Hospitals Corporation.]

Recently, the Synthes corporation has been garnering a lot of attention, but for all the wrong reasons. A June 17^th indictment comes a little over a month after the New Jersey Attorney General announced that the medical device maker had entered into a settlement agreement for failing to disclose financial conflicts of interests held by physicians conducting clinical trials for its products (see prior post, “Clinical Research: When the Compensation Begs the Answer“). Filed by the United States Attorney for the Eastern District of Pennsylvania, the recent 52-count indictment alleges that from May 2002 to Fall 2004, the Swiss company Norian, and its parent company Synthes, (both based in West Chester, Pennsylvania) conspired to conduct unauthorized clinical trials of Norian XR and Norian SRS, bone cement products used in surgery to treat vertebral compression fractures of the spine. Not only did the trials lack FDA authorization, but the FDA had specifically warned Synthes against using Norian XR for spinal surgery due to safety concerns.

The indictment explains that preliminary studies using human blood in test tubes found that the bone cement products chemically reacted with the blood to create blood clots. In further studies of the prod in a pig, the clots became wedged in the lungs. Despite this knowledge, Synthes continued to market the Norian products for use in spinal surgery, and did not stop doing so until after three patients had died on the operating table.  According to the indictment, rather than recall the products following the patient deaths, the company engaged in a cover up by lying to FDA officers during an official inspection in May and June 2004.

The two recent legal actions against Synthes break new ground, and represent significant inroads by prosecutors in the arena of clinical research. Among other remedies, the settlement with the State of New Jersey required Synthes to disclose all relevant financial interests of its investigators on a public website, and barred the company from compensating investigators with stock, a practice the Attorney General called widespread in the industry. The latest indictment contains not just the usual charges against the corporations, but also criminal charges against four corporate executives charged with shipment of unauthorized devices. If found guilty, each executive faces up to a year in prison.

Rationing or Cost Effectiveness?

In today’s Wall Street Journal, Scott Gottlieb, a former senior official with both the FDA and the Centers for Medicare and Medicaid Services (CMS), warns that “Government Health Plans Always Ration Care.” Aside from recasting the same old aspersions about “rationing,” Gottlieb warns that if reform efforts can’t tame health care costs, the “government will turn to a less appealing but more familiar tool to cut costs: the regulation of access to drugs and medical services.”

Of course, “access” can mean many things. Theoretically, Americans have “access” to the best medical technologies in the world. But practically, most Americans-including those with health insurance-don’t actually access this type of care and couldn’t even if they tried. The bottom line is that every health insurer in the world, public or private, has to “ration” for the simple fact that health care resources are not unlimited. Only wealthy citizens truly have “access” to the best medical care money can buy, regardless of the country they live in or the health system they live under. That won’t change with or without major health reform.

Gottlieb is worried that reformers might formally embrace recommendations by the Medicare Payment Advisory Committee (MedPAC), which currently has a broad statutory mandate to advise Congress on the Medicare program. He also warns that rationing is “a European import,” as if no health insurer in the United States has ever had to draw the line somewhere and decide what not to pay for. For example, Gottlieb warns about organizations like the Committee for the Evaluation of Medicines in France and the Institute for Quality and Efficiency in Health Care in Germany. He doesn’t mention the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom, but it drew similar scorn after the economic stimulus package funded comparative effectiveness research here in the United States. Gottlieb cautions that European countries “aren’t shy about rationing.”

Gottlieb is correct in one aspect: these organizations are prevalent in Europe. However, he misses three important points.

First, the countries in Europe that Gottlieb warns about spend considerably less than we do on health care (and don’t suffer negative health consequences for it).

Second, wealthy residents in pretty much all of these countries can purchase services and technologies over and above what the organizations that Gottlieb warns us about approve.

And third, we’re not exactly strangers to these organizations in the United States. Gottlieb is concerned about European imports, but he’s ignoring our home grown organizations, like the Agency for Healthcare Research and Quality (AHRQ), which makes new technology assessments for Gottlieb’s old agency, CMS, and supports comparative effectiveness research. Or the Medicare Evidence Development and Coverage Advisory Committee (MEDCAC), which also performs new technology assessments. In fact, it’s no secret in Washington that Medicare has long considered some amalgam of cost effectiveness and comparative effectiveness in its coverage decisions, even if nothing in the Medicare statute explicitly allows it to do so. (CMS has long stretched the definition of “reasonable and necessary” in section 1862(a)(1)(A) of the Social Security Act to fit its fiscal realities, even if CMS or its precursor, HCFA, haven’t been successful in cementing cost effectiveness as a formal criterion, as evidenced through failed rulemaking in 1989 (54 Fed. Reg. 4,302) and 2000 (65 Fed. Reg. 31,124)).

And just as importantly, private insurers make cost and comparative effectiveness determinations too, either by following Medicare’s lead, as expressed through national and local coverage determinations (NCDs and LCDs), or by setting up their own new technology evaluation systems, like BlueCross BlueShield has with its Technology Evaluation Center. Though the offical duties and decisionmaking processes of these organizations differ, the health care community generally understands these decisions as implicitly factoring in cost effectiveness or at least clinical effectiveness-thus doing precisely what the anti-reformers like Gottlieb warn about.

PhRMA Shows Its Committment to Transparency With Revised Principles on Conduct of Clinical Trials

The Pharmaceutical Research and Manufacturers of America (PhRMA) Board of Directors announced yesterday their unanimous endorsement of revised principles to increase transparency in medical research through their newly revised PhRMA Principles of Conduct of Clinical Trials and Communication of Clinical Trial Results.  The revised principles are part of an effort to encourage behavior that benefits the healthcare community and the public through objectivity in research and strengthened transparency in medical studies.

PhRMA states that the Principles of Conduct, which are to take effect on October 1, 2009, will:

Fortify our commitment to patients and healthcare professionals by increasing transparency in clinical trials, enhancing standards for medical research authorship and improving disclosure to manage potential conflicts of interest in medical research.

The pharmaceutical and biotech industries have been under recent pressure to become more transparent, specifically concerning the disclosure and publication of clinical trial results, the disclosure of physician payments/reimbursement for conducting clinical trials, and authorship standards.

Read more

Next Page »