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.

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.

Reform Rodeo

1. The HITECH Act’s Breach Notification rules are now in effect. As is noted in the article, many are questioning some of the limitations in the act– which may reduce the Act’s impact on protecting privacy.

2. Eugene Volokh’s blog discusses the constitutionality of an individual mandate.

3. A persuasive article from Fortune Magazine describing how Baucus’ Finance Committee bill will raise taxes on the middle class, and in dong so violate the core tenets of the Obama administration.

4. A nicely compiled listing of the amendments that have been put forward during the Finance Bill’s mark up.

5. A FiveThirtyEight post questions those who presume that health reform is inevitable, raising some sobering thoughts.

6. Under the Obama administration, The FDA has provided a black box warning for the anti-nausea drug Phenergan, presumably in light of the Supreme Court’s recent rejection of the drug manufacturer’s claim that federal regulations preempt state court’s from suing drug manufacturers for defective warnings.

7. In case you missed it: A post from Health Reform Watch by Professor Timothy S. Jost on Health Care Cooperatives was cited by Jacob S. Hacker in an article over at the New England Journal of Medicine’s web site. Hacker’s article, “Poor Substitutes–Why Cooperatives and Triggers Can’t Achieve the Goals of a Public Option,” is well written and well read.

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.

Clinical Research: When the Compensation Begs the Answer

The New York Times reports that New Jersey Attorney General Anne Milgram announced a settlement agreement with medical device maker, Synthes, for failing to disclose the financial conflicts of interest of doctors researching its products. Synthes is the maker of the ProDisc, an artificial spinal disk.

The settlement agreement with Synthes was described in the AG’s press release, which quoted Ms. Milgram, as “the first of its kind because of its disclosure provisions, as well as its ban on compensating clinical researchers with company stock. She said the latter provision runs counter to widespread industry practice — a practice she called unacceptable.” Notably, the state pursued the case as a matter of consumer fraud. The premise being that the failure to fully disclose such conflicts constituted such for both human trial subjects and the purchasing public.

In a letter to the FDA, critical of the FDA and cc’d to key members of Congress, Ms. Milgram described the results of the AG’s investigation into the business and research practices of Synthes. The letter states:

The investigation revealed that a majority of the physicians who participated in these clinical trials had significant investments in the products -investments that would have been worthless had the product failed to obtain regulatory approval from the FDA. And, the investigation revealed that Synthes, which acquired ProDisc while the clinical trials were underway, failed to disclose these financial conflicts of interest to the FDA.

Yet, despite the fact that Synthes’ failure to adequately disclose these interests should have been obvious from even a cursory review of its FDA submissions, the FDA did nothing to regulate these conflicts. A number of the disclosure forms were signed and dated, but were otherwise left blank. Others indicated that the clinical investigator had a significant equity interest in the product, but did not attach the requisite details. But the FDA approved Synthes’ applications for premarket approval without any delay or further inquiry into this issue.

Leaving aside for the moment the criticism of the FDA (the State of New Jersey joins a long list of increasingly vocal complainants, including the Program on Government Oversight (citing “dramatically reduced inspections of ‘good laboratory practices’ at facilities that do the earliest testing of medical devices. Such inspections declined from 33 in 2005, to seven in 2007, to just one last year”),  and FDA scientists from the Center for Devices and  Radiological Health, who have openly proclaimed that the FDA “is fundamentally broken.”), it’s worth a moment to consider that Synthes has agreed to “stop paying doctors who are conducting clinical trials of its products with stock or stock options,” and that AG Milgram described the compensation of research doctors with stock as being “apparently common” and a “widespread industry practice.”

Compensating a  doctor with stock or stock options financially tied to the results of his research may well be the antithesis of an impetus for objective clinical research.

The basic proposition is this: you, doctor, are charged with investigating whether or not this medical device is safe and fit and shows efficacy for human use. For doing so, we will give you a portion of the company (stock or stock options) which owns the medical device. If the medical device is efficacious and fit for human use, the company will stand to profit. As a holder of stock and/or stock options in the company, you will be paid a portion of that profit and/or the value of your holdings in the company will increase correspondent to your determination of safety for human use and efficacy. If you determine that the device is not safe for human use and/or not efficacious, your holdings in the company will be worth much less, if not worthless. “Is the device safe for human use and efficacious?” Does an answer of “Yes” surprise anyone?

It is also not an answer to say that the doctors may have merely been compensated in cash and then later converted that cash into stock or stock options independently. My guess is that in constructing these compensation packages, as with most securities matters, timing and knowledge is important. That the stock or stock options must be issued or at least contracted for by the researcher simultaneous with the hiring so as to avoid SEC difficulty regarding the particulars of the researchers’ “inside” and “confidential” knowledge regarding the device and the research itself. Researchers who have purchased interested stock (or who have had stock purchased by others) before news of their research has been made public have often paid a price.

And obviously, once the doctor’s research has been made public, any positive results will have been already reflected in the market price of the stock, all but foreclosing the research doctor from reaping profits tied directly to his research determinations.

As part of A.G. Milgram’s “Assurance of Voluntary Compliance agreement (the Synthes case was handled by Deputy Attorney General Megan Lewis, Chief of the Division of Law’s Affirmative Litigation Section, and Deputy Attorney General Michelle T. Weiner) Synthes must disclose any future payments made by the company to physicians conducting clinical trials on its devices, as well as any investments held by such physicians in the devices they test. A $3 billion global company, Synthes has also agreed to stop paying clinical trial physicians with company stock or stock options.”

Attorney General Milgram said that “the Synthes agreement should serve as a template for the entire industry,” and in her letter to the FDA remarked that she was “hopeful the Synthes terms will become “best practices” for disclosure among medical device makers.”

In addition to signifying her hope, Ms. Milgram announced that her office issued subpoenas “to five major medical device manufacturing companies seeking information about their business practices.”

The FDA to Evaluate 25 Medical Devices Marketed Before 1976 Without Premarket Approval

The FDA announced last week that they are requiring the makers of 25 medical devices marketed before 1976 to submit safety and effectiveness information regarding their devices.   These devices were allowed onto the market without undergoing the current FDA testing and classification because they were first manufactured before the Medical Device Amendments to the Food, Drug, and Cosmetic Act of 1976, and include many of the riskiest devices — defibrillators, pacemakers accessories, and heart valves.

The FDA classifies medical devices into three categories, with class III being the riskiest devices– as such, they require premarket approval.  Currently, the 25 pre-amendment devices in question are class III, but based on the 1976 law these devices were not required to undergo premarket approval at the time.

The FDA will use the submitted safety and effectiveness data to review the devices and classify them into what they deem to be the appropriate risk category.  According to the FDA, if a device is found to be a class III device, the manufacturer will need to submit a premarket approval application.  If the device is moved to class I or II, it will not require premarket approval.

The FDA’s announcement comes after the Government Accountability Office reported in January that the FDA was not doing enough to thoroughly evaluate the safety and effectiveness of many medical devices marketed before 1976.  They urged the FDA to review the devices and said that “it is imperative that FDA take immediate steps” to fix this review and approval process for devices.

Daniel G. Schultz, M.D., director of the FDA’s Center for Devices and Radiological Health, said regarding the FDA’s new requirement:

We are taking the necessary steps to complete this very complex process while continuing to protect public health by thoroughly reviewing and evaluating all medical device submissions presented to the agency.  New premarket notification submissions for devices of these 25 types will continue to receive an appropriate level of scrutiny to ensure safety and effectiveness.

This decision to evaluate these devices and further public safety comes after recent criticism of the agency, such as the opinion expressed publicly by a number of  FDA scientists that the “FDA is fundamentally broken.”  We have blogged about the much maligned agency on numerous occasions, with specific emphasis upon the Center for Devices and Radiological Health and a decline in medical device lab inspections.

U.S. District Court Says FDA Decision on Plan B Was Influenced by Political Pressure

A U.S. District Court ordered yesterday that the Food and Drug Administration (FDA) allow for the sale of the Plan B morning-after pill to females 17 years old and older without a prescription.  Since 2006, based on a FDA decision during the Bush administration, Plan B has been available over the counter only to women over the age of 18.  The FDA must comply with the order within 30 days.  Plan B is a back-up birth control pill that can reduce the chance of pregnancy when taken within 72 hours of unprotected sex or contraceptive failure.  It is manufactured by Duramed, a subsidiary of Barr Pharmaceuticals.

Judge Edward Korman of the Eastern District of New York wrote in his decision that the FDA was influenced by political pressure and their conclusion was not based on the scientific evidence available concerning the drug.  Judge Korman wrote that:

These political considerations, delays, and implausible justifications for decision-making are not the only evidence of a lack of good faith and reasoned decision-making.  Indeed, the record is clear that the FDA’s course of conduct regarding Plan B departed in significant ways from the agency’s normal procedures regarding similar applications to switch a drug product from prescription to non-prescription use.

Judge Korman’s statements echo similar sentiments expressed as of late that the “FDA is fundamentally broken.” We have blogged about the subject, and the alleged political influences on FDA, in a number of posts most recently.

The WSJ Health Blog wrote today that the ruling specifically blasts past and current FDA officials such as acting Surgeon General and acting Secretary for Health and Human Services, Dr. Steven Galson, and then-FDA Commissioner Lester Crawford.

The FDA is reviewing the decision and the WSJ reports that “If the Obama White House doesn’t appeal the ruling, it would mark the fourth significant departure from Bush administration positions on controversial health-care issues since President Barack Obama took office.”

Susan Woods was a top FDA official who resigned in 2005 due to the delays surrounding a FDA decision on the pill.  The Associated Press quoted her as saying:

What happened with Plan B demonstrated that the agency was off track, and was not being allowed to do its job properly.  This is telling the FDA to move forward with a focus on good science.

The President and CEO of the Reproductive Health Technologies Project, Kristen Moore, said “This ruling validates what we have known all along - politicians trumped the scientists when it came to the FDA’s handling of Plan B.”

Naturally, many conservative groups are angered over the ruling.

Unpublished 1997 Study Linked Drug to Weight Gain and Diabetes, Now Thousands Sue Claiming They Were Not Warned of Side Effects

The Washington Post reported today on the “silenced drug study” of AstraZeneca’s antipsychotic drug, Seroquel.   The study, known as Study 15, was conducted in 1997 and showed an increase in weight gain and diabetes among Seroquel users.  The results were never published and the information was not released to the public or physicians.  The study was, however, provided to the FDA but they did not have the authority to publish the results.  Seroquel was approved by the FDA in 1997 after they received the study’s findings.

AstraZeneca contends that they did disclose the drug’s health risks on the label, as required by the FDA.  Spokesperson Tony Jewell wrote in an email to The Washington Post that the results of Study 15 “did not identify any safety concerns.”  Study 15 compared Seroquel to another similar drug, Haldol.  Jewell also wrote that “A large proportion of patients dropped out in both groups, which the company felt made the results difficult to interpret.”

Over 9,000 lawsuits have been filed against the drug by patients who experienced weight gain, hyperglycemia and diabetes.  It is through these lawsuits that internal documents and details regarding the buried study have emerged.  Internal documents show that AstraZeneca was well aware of the results indicating significant weight gain and worked to spin the results favorably.  The company presented information that Seroquel caused patients to lose weight at two meetings in 1999. This data was based on a much smaller company-sponsored study even though AstraZeneca had concerns with the study and the doctor who conducted it.

The Washington Post says:

The saga of Study 15 has become a case study in how drug companies can control the publicly available research about their products, along with other practices that recently have prompted hand-wringing at universities and scientific journals, remonstrations by medical groups about conflicts of interest, and threats of exposure by trial lawyers and congressional watchdogs.

An obvious concern with unpublished or silenced studies is that they may lead physicians to make medical decisions without all the information that should be available to them.  As the Center for Health and Pharmaceutical Law & Policy recommends in its recently-released whitepaper:

All those engaged in medical research and publication, including medical professionals and institutions, medical journals, and industry, should undertake reforms to ensure the integrity of the medical literature.  Transparency in the relationship of industry and physicians would be critical tool in this effort.

Supreme Court Rules that Preemption Does Not Exist in Drug Labeling Case

The Supreme Court held today, in a 6-3 decision, that FDA federal approval of drug warning labels does not preempt state regulations and therefore does not prohibit claims of insufficient drug warnings brought under state law.  The ruling in Wyeth v. Levine upheld a $6.7 million award to Diane Levine, whose arm was amputated after a flawed injection of Wyeth’s anti-nausea drug, Phenergan.

The case centered on the drug’s labeling, as Ms. Levine argued that the label did not warn of the risks associated with administering the drug through “IV push” and that it must contain these warnings in accordance with Vermont law.   The NY Times reported that Wyeth wrote in their brief that they “could not change Phenergan’s labeling to comply with Vermont law without violating federal law.”   They argued that because the drug label was approved by the FDA, a federal agency, Levine’s state law claims were preempted by federal regulations.  The Supreme Court disagreed with this argument, holding that Wyeth could have complied with both state and federal regulations, and reaffirmed the ruling of the Vermont Supreme Court.

Senate Judiciary Committee Chairman Senator Patrick Leahy (D-Vt.) filed an amicus brief for this case in August, 2008.  Today he issued the following statement regarding the Court’s decision:

This decision to uphold the Vermont Supreme Court’s ruling in Wyeth v. Levine has far-reaching effects on the ability of countless Americans to seek justice in their courts. Diana Levine’s life and career have suffered irreparable - yet preventable - damage. The Court’s decision soundly rejects the anti-consumer position of the Bush administration, and reaffirms Congress’ primacy concerning the extraordinary power to preempt state law. Most of all, the decision reclaims for all American citizens the ability to seek justice in their courts of law.

In the 110th Congress, the Senate Judiciary Committee held several hearings to examine the way in which federal agencies have overstepped their authority in the area of preemption, and, given what I viewed as an untenable position by the drug maker and the former administration, I filed an amicus brief with the United States Supreme Court in Ms. Levine’s case. I am gratified that the Court has spoken so clearly on this issue. While recent Supreme Court decisions have shielded big business from accountability and have undermined stronger state consumer protections, this ruling alters that earlier course and affirms that Congress never intended to preempt state laws in the way claimed by Wyeth and the Bush-Cheney administration, claimed. This is a clear victory for Ms. Levine, and for all American consumers. It is also a clear vindication for our own laws and courts in Vermont.

Wyeth’s comments on the decision can be found here.

The DOJ Sets Its Sights On Forest Laboratories

Forbes reports in its article, “Forest says 11 states will join fraud lawsuit,” and the New York Times reports in its article, “Drug Maker Is Accused of Fraud,” that a civil claim was filed against Forest Laboratories Inc. under the False Claims Act. The claim relates to the advertisement of the  “off-label” use of certain drugs.

Forbes reports:

The Justice Department said Forest promoted Lexapro and Celexa for use by children even though it is not allowed to do so. While doctors are allowed to prescribe drugs for uses not listed on the labels, companies are not allowed to actively promote the drugs for that kind of “off-label” use.

This suit is similar to the qui tam actions against Scios.  Both the cases against Scios and the suits against Forest Laboratories involve the off-label marketing of the unapproved uses of certain prescription drugs.  And like the claims against Scios, it appears that the case against Forrest Laboratories began as a qui tam action.

The NY Times reports:

The filing follows a long-running federal investigation that began with complaints filed by two former company officials. Under the civil charges brought against Forest, the government is seeking to recover up to three times the amount of money spent by federal programs to pay for pediatric prescriptions of Celexa and Lexapro, but did not specify a figure.

This case is consistent with the DOJ’s heightened investigation of the pharmaceutical industry and shows the federal government’s reliance on qui tam actions.  As the number of cases against pharmaceutical companies for the off-label advertising of the unapproved uses of drugs increases, the gap between the FDA approval of the use of drugs and the actions of pharmaceutical companies is becoming more apparent.

To some extent, the Civil False Claims Act is bridging this compliance gap by functioning as a mechanism to enforce FDA decisions on the uses of drugs. But perhaps a legitimate question to ask is whether this increasing reliance upon an “outsourcing” of regulatory compliance is the appropriate mechanism by which to fix this inefficiency. Or, might we consider, as recommended by the recent Center for Health & Pharmaceutical Law & Policy whitepaper, being that “estimates suggest that as many as 40% of all prescriptions are for off-label uses,” that we give the “FDA the authority to mandate scientific studies for off-label medications and devices that have high sales volumes or large profits but lack needed evidence of efficacy or safety?”

As the Center stated, “this would protect the interests of patients and advance sound choices about the risks, benefits, and economic value of off-label uses.”

Seton Hall Law School’s Center for Health & Pharmaceutical Law & Policy Releases White Paper Recommending Reform of Drug and Device Promotion

Seton Hall University School of Law’s Center for Health & Pharmaceutical Law & Policy has called for broad reforms in the marketing of drugs and devices. In a whitepaper, entitled, “Drug and Device Promotion: Charting a Course for Policy Reform,” the Center proposes legal and policy changes to address conflicts of interest in the relationship of medicine and industry. “The time is right for reform in the marketing of drugs and devices to doctors,” said Center Executive Director Tracy Miller. “Conflicts of interest have become pervasive in medical practice. Reform is needed to ensure that patients’ interests are at the heart of medical education, practice, and research,” she said.

The Center recommends: (1) making payments by drug and device companies to doctors transparent, with public disclosure by industry and physicians of their financial relationships; (2) adopting federal legislation to ban gifts, meals and other benefits provided to doctors as part of the current marketing model; (3) setting new policies to give FDA the authority to require studies of safety and efficacy of drugs and devices used off-label; and (4) undertaking a fundamental change in funding for continuing medical education to end industry support.

Moving to Transparency. The Center recommends that payments by drug and device companies to doctors should be publicly disclosed. “Transparency is critical to shore up public trust in physicians and the collaboration of industry and medicine,” said Tracy Miller. Transparency would also foster better practices by doctors and industry, advance government oversight, and provide information to the press and public. Pending federal legislation, the Physician Payments Sunshine Act, would require industry to disclose payments to doctors.

The Center supports this approach. It also recommends that states undertake disclosure by doctors, and decide how information about physician financial relationships with industry could best be shared with patients. Law Professor Kathleen Boozang adds that, “If doctors had to disclose payments from industry it would prompt them to examine their practices through the eyes of their patients and peers.”

Banning Gifts, Meals, Perks. The Center proposes adoption of federal legislation to ban the use of gifts, meals, and other perks to promote drugs and devices. The states have taken the lead to date–Massachusetts, California, Minnesota, and the District of Columbia have passed laws to limit or ban gifts and meals that are now routine in marketing practices. Concluding that industry self-regulation is not sufficient, the Center calls for national legislation to create uniform practices by industry and physicians. As urged by Professor Boozang, “the benefits of drugs and devices should drive promotion and physicians’ decision to prescribe, not a marketing model that depends on gifts and meals.”

Promoting Scientific Study of Off-Label Uses. The Center proposes that national policy should be redesigned to assure that physicians, patients and government have reliable information to make informed choices about off-label medications. Estimates suggest that as many as 40% of all prescriptions are for off-label uses. The FDA has recently issued guidelines to promote integrity and accuracy in medical articles that drug and device companies give to doctors. The Center urges that this policy guidance, while useful, does not go far enough to provide crucial information about the safety and efficacy of drugs and devices prescribed by doctors for uses other than those approved by the FDA.

The Center proposes giving FDA the authority to mandate scientific studies for off-label medications and devices that have high sales volumes or large profits but lack needed evidence of efficacy or safety. This would protect the interests of patients and advance sound choices about the risks, benefits, and economic value of off-label uses.

Reforming Funding for Continuing Medical Education (CME). Most states require physicians to undertake continuing medical education to maintain their medical license. The drug and device industry currently funds over half of the accredited CME courses available to physicians. The Center recommends that industry funding for continuing medical education should be phased out, and replaced by an educational process driven by physicians. As stated by Tracy Miller, “Physicians need to retake control of their professional education. CME should focus on doctors as professionals caring for the whole patient, not just as prescribers of drugs and devices.” While the transition to new funding occurs, the Center recommends that speakers at CME events should disclose more information about their financial interests, and physicians who are paid to promote drugs and devices should not speak at CME events about those products.

Factual Background for the Recommendations

• Ninety-four percent of physicians have some kind of financial relationship with industry, as reported in a major recent national study.

• Five states–Maine, Massachusetts, Minnesota, Vermont and West Virginia– have required industry to disclose financial relationships with physicians.

• As shown by a recent Congressional investigation of payments by industry to prominent psychiatrists, even at universities with strong disclosure policies, practices have not kept pace, leaving the public in the dark about financial ties between physicians and industry.

• Medications are widely used off-label, especially in certain fields such as psychiatry, pediatrics, and oncology. A recent study found that 73% of off-label uses lack evidence of efficacy.

• Commercial support for accredited CME, nearly all of it from drug and device manufacturers, grew from $302 million in 1998 to $1.2 billion in 2006.

Read Whitepaper here.

How the FDA is “Fundamentally Broken”

AP has run a story on FDA investigatory practices that lends additional credence to the assertions of a number of FDA scientists who have publicly claimed that the FDA is “fundamentally broken.”

The article focuses on a recent report by the Project on Government Oversight (POGO) which exposes a dramatic decrease in medical device lab inspections over the course of the last few years.

AP writes:

“Medical devices are overseen by an FDA division called the Center for Devices and Radiological Health. The center has been shaken by recent complaints from its own scientists that managers squelched debate, leading to the approval of devices that were of questionable effectiveness and perhaps not entirely safe.”

The Center has also been accused of allowing political influence to be a determinate factor in the approval process of medical devices.

The decline in laboratory inspections outlined by the POGO report is both precipitous and alarming. AP writes that the report shows that

“…the Food and Drug Administration has dramatically reduced inspections of “good laboratory practices” at facilities that do the earliest testing of medical devices. Such inspections declined from 33 in 2005, to seven in 2007, to just one last year, according to a report the group was releasing Wednesday. No inspections are planned for this year, the report said.”

Read the full POGO report here.

FDA Scientists Say FDA is “Fundamentally [More] Broken”

Just this last week we posted that a group of nine FDA scientists from the Center for Devices and Radiological Health– which is responsible for medical devices ranging from stents and breast implants to MRIs and other imaging machinery-authored a letter which asserted that “The FDA is “fundamentally broken” and requires reforms.”

We wrote:

With what A.P refers to as an “unusually blunt letter,” the group of federal scientists contacted “John Podesta, head of the transition team, as well as former Senate Majority Leader and HHS Secretary-designate Tom Daschle (D-S.D.); Baltimore Health Commissioner Joshua Sharfstein, who has led a team assembled by Obama to assess FDA; Senate Health, Education, Labor and Pensions Committee Chair Edward Kennedy (D-Mass.); and eight other lawmakers,” according to Kaiser.

In that post, we also called attention to the contention of the scientists that “Managers with incompatible, discordant and irrelevant scientific and clinical expertise in devices…have ignored serious safety and effectiveness concerns of FDA experts.”

Noting that

To say that these managers had “incompatible” and “discordant” scientific and clinical expertise in devices is one thing. One expects a certain degree of disagreement within the scientific community-and to some extent, one reasonably relies upon the crucible of such “discordant” viewpoints in scientific debate to provide tested answers to real problems. But the scientists who wrote this letter added one more word: “irrelevant.” And in this context, that leaves us uncomfortably with the knowledge that in the estimation of these nine scientists, the determining force in these particular scientific inquiries-the managers-lack relevant scientific expertise in the pertinent subject matter-medical devices.

Apparently, the “expertise” at issue in the approval of a breast cancer imaging device is alleged to go somewhat beyond the scientific.

The New York Times reports that it has obtained various FDA emails and internal documents which underlie the scientists’ complaint and are the present subject of both an FDA internal inquiry and a congressional investigation. The emails and documents are said to provide details of the investigations which had not previously been made public.

The New York Times reports that

An official at the Food and Drug Administration overruled front-line agency scientists and approved the sale of an imaging device for breast cancer after receiving a phone call from a Connecticut congressman, according to internal agency documents.

The congressman is Republican Chris Shay, who lost re-election in November. A component of the imaging device was produced by a Fujifilm Medical Systems, which “is based in Stamford, Conn., the heart of Mr. Shays’s former district,” according to the NY Times.

The article also states that

The legislator’s call and its effect on what is supposed to be a science-based approval process is only one of many of accusations in a trove of documents regarding disputes within the agency’s office of device evaluation.
Read more here.

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