Wyeth v. Levine: Should the FDA be held responsible for adverse events?

Diana Levine, a musician, went to the hospital with severe nausea associated with a migraine headache. She was given Phenergan, a Wyeth drug, by intramuscular injection. When the nausea persisted, the drug was administered by IV push into a vein. Unfortunately some of the drug made contact with arteries in the arm, resulting in arterial damage (a known risk), gangrene and eventual amputation.

Levine’s case against Wyeth is based on the fact the product label did not mention dangers associated with the IV push method of administration, and that Wyeth knew about these risks. A Vermont jury awarded Ms. Levine $6.7 million dollars.

Wyeth did know about the risks associated with IV push administration of Phenergan but did not include a statement of these risks on the product label, nor did the FDA require Wyeth to include this warning. (It is unclear is the FDA was aware of the risks.) Wyeth appealed to the Vermont Supreme Court and lost. The company then appealed to the US Supreme Court which will hear the case next week.

The case is of considerable interest to pharmaceutical companies in the US. If the Supreme Court rules that FDA approval of a drug and the content of its labeling and warnings, means that the pharmaceutical companies can not be libel for adverse events the companies will be permanently off the hook for any resulting damages that arise in use of their products.

There is precedent for the Supreme Court to decide in favour of Wyeth. Only recently the Court ruled that companies making medical devices that received FDA device and labelling approvals could not be held liable for injuries associated with use of these products. (The case involved an angioplasty ballon catheter that burst during a procedure.) Although the Court based its decision on a narrow and rather literal interpretation of US federal law governing medical devices, the decision was 8 to 1, with Justice Ruth Bader-Ginsburg dissenting. Some Democrats in Congress will try to amend the law so that device manufacturing companies would once again be held liable.

There are several problems with assigning complete responsibility for product safety and labelling to the FDA. While recognizing that the Supreme Court narrowly interpreted this responsibility and may render a different opinion in the case of drugs (which are governed by a different federal law), it is useful to consider some of these difficulties.

First are the countervailing pressures on the FDA: a) to ensure that the products they approve are safe, and b) to do so quickly so that patients can benefit from new drugs and devices. The first requires patience, abundant data and analysis, and prudence: The second, speed, limited data and analysis, and imprudence.

Companies only grudgingly provide data to the FDA. More data means more studies, longer delays in approval and marketing, and greater chances that additional evidence will negate approval or reduce subsequent sales. The company goal is to provide the minimum of amount of information that will yield approval for the widest possible uses and users. If legal responsibility for approval and use can be passed to the FDA, then companies will further pressure the Agency to proceed with less not more information.

Developing new drugs or getting approvals for new uses of drugs already approved is costly to companies; although the costs are likely exaggerated and blended indecipherably with marketing costs. Still, many candidate chemicals (drugs) fail and have to be abandoned when they are subjected to clinical trials. Drug development costs, rightly, are passed along to patients and drug plans in the form of higher prices. If the Supreme Court rules in favour of Wyeth, rejecting Diana Levine’s claim, then it is very likely that the FDA will raise the approval bar. Drug development and approval costs - funded in large part directly by pharmaceutical companies seeking FDA approval - will increase, but perhaps less than the substantial reductions in cost that will accrue to companies from reduced legal fees, court costs and liability settlements often in billions of dollars. (I presume that patients can’t sue the FDA and that the government will not compensate them for adverse events they suffer.)

It should also be remembered that many and indeed most pharmaceutical companies have been considerably less than forthright in sharing information with the FDA. More information means more vigilance and greater probability of discovering something wrong or dangerous about the product. It is only during the legal discovery process in liability cases that new information comes to light, including evidence of deliberate cover-up and hiding information from the FDA. A case involving alleged fraudulent data submitted (or not submitted) to the FDA is also before the Supreme Court. This involves Warner-Lambert Company and Pfizer Inc. v. Kimberly Kent et al. in a class action law suit in Michigan claiming that the company submitted fraudulent data to the FDA about the diabetic drug Rezulin (rosiglitazone). Michigan laws grant immunity from product liability for drug manufacturers unless the FDA approval was obtained through fraudulently withholding or misrepresenting information. This is obviously a catch-22, for to prove that Warner-Lambert withheld or misrepresented data requires the law suit to go forward and the company be forced to release all relevant documents. This can’t be done without the case being heard.

Thus the Supreme Court decision on Wyeth v. Levine, and Warner-Lambert/Pfizer v Kent will alter not only the drug approval process and drug safety and availability, but pharmaceutical company balance sheets as well.

The precedent established in the case involving the angioplasty device hinged on federal law that precisely forbids states from establishing any additional requirement different from or in addition to the FDA requirements. This makes sense. Otherwise, companies would need to seek approval in each state creating a redundant, costly and slow approval process for new products. But did the law mean that the states could not consider other factors in liability cases? Only a narrow reading of the law would yield this meaning. Supreme court justice Antonin Scalia, writing for the majority took this view.

There is a wider view to support the Supreme Court if it decides on the narrow interpretation and maintains that product liability for pharmaceuticals can’t be pursued for FDA approved drugs. The current situation permitting these liability law suits in most states can be seen as second-guessing the FDA, as all cases involve drugs approved the Agency, and thus perhaps weakening its credibility. Having the courts decide if products are safe (or were safe) is not a robust way to evaluate scientific evidence. Dramatic adverse events affecting a few people may lead to the withdrawl form the market of genuinely useful drugs for the majority.

The Court, however, will also take cognizance of the burden that will be placed on the FDA if it grants pharmaceutical companies immunity from product liability law suits in all states.And have to grapple with the resulting axiom that there will be no recourse or compensation for individuals harmed by drugs, individuals like Ms. Levine.

Sources

Cornell Law School http://www.law.cornell.edu/supct/cert/06-1498.html

Cristina Carmody Tilley Wyeth v. Leine Northwestern University Medill Journalism Supreme Court Cases by Year http://docket.medill.northwestern.edu/archives/004674.php

Linda Greenhouse, Barnaby Feder: Justices Shield Medical Devices from Lawsuits New York Times, February 21, 2008

Photo of Diana Levine from her appearance on CBS Morning Show, Feb 25, 2008 available at
http://www.wcax.com/Global/story.asp?S=7921065

US FDA sets standards for medical journals and peer review

Photo Credit vaneska~tHOmz's
In seeking to define standards for ‘good reprint practices’ by pharmaceutical companies seeking to provide copies of journal articles to doctors the FDA has had to grapple with the quality of articles and of journals. That they have failed is hardly a surprise, but that they even tried is quite astonishing given their intimate knowledge of the hundreds (if not thousands) of flimsy and misleading research reports submitted to the agency from these same companies seeking drug approvals, most of which are published in these same journals.

The FDA has a legislated role not only to approve new pharmaceuticals, but to do so quickly. The agency is under pressure from all sides except the ranks of the cautious and skeptical to approve drugs and new usages with minimal delay and minimum of assurance they are effective and safe. Once approved, pharmaceutical companies market these drugs to physicians and patients for use.

Pharmaceutical companies (and some physicians and sick patients) are anxious to see if drugs approved for one indication - say epilepsy in adults - might just work for other health problems - say Parkinson’s disease or among groups of individuals (such as children and pregnant women) where there are often few clinical trials.

These ‘off-label’ (non-FDA approved) uses are the target of this FDA Guidance for Industry on Good Reprint Practices for the Distribution of Journal Articles.... The guidance on good reprint practices is a set of suggestions that pharmaceutical companies should use when they are promoting drugs for unapproved uses. The FDA claims that:

“public health may be advanced by healthcare professionals’ receipt of medical journal articles ... on unapproved or new uses of approved or cleared medical products that are truthful and not misleading.”

This is ludicrous. That pharmaceutical companies would select journal articles that are “truthful and not misleading” is irrational from the companies point of view - they will select articles that support use of the product, that emphasize benefit and minimize harm - and naive or blind from the FDA point of view.

There is a wealth of evidence that the published literature looks like a shipwreck of clinical trials that have been shown to be wrong. First of all it is clear even from the perspective of the FDA that published studies sponsored by pharmaceutical companies show a terrific bias towards benefit and against harm. Studies showing benefit of a product are published, those showing no benefit or harm are not. The astonishing thing is that the FDA is intimately aware of this sham evidence base, for it has the only complete record of all clinical trials done to explore new uses of existing products.

For example of 74 clinical trials of antidepressants (involving 12 drugs for which companies sought approval 31% were never published. Published clinical trials show that the drugs are on average 31% better than the comparison drugs or placebos; however, when all the evidence is examined - published and unpublished - the 12 drugs on average showed no benefit over the comparison group.<1> Ludicrous is not too extreme an adjective to describe a belief that pharmaceutical companies will show doctors the complete evidence, on anything.

In its disconnect from reality the FDA goes further by listing a set of criteria that pharmaceutical companies can use (are not required to use) when choosing articles to flog to doctors and their patients. Under the rubric “Good Reprint Practices” we find that:

The Journal should:
1. Have an editorial board that uses experts.
2. Have an editor and board independent of the journal owners
3. Have a policy of full disclosure of conflict of interest or biases.
4. Be peer reviewed

The Journal article should not:
1. Be false or misleading
2. Be a drug company funded special supplement.
3. Have been withdrawn by the journal
4. (Promote a product) that poses a significant risk

I know of few journals that would; a) not have these policies in place; b) publish articles known to be false or misleading and; c) not know and understand that they regularly violate them all, despite their best intentions.

Even well funded journals like the New England Journal of Medicine and JAMA get duped and make mistakes. And they know that they are publishing but part of the evidence, mostly the part showing benefit.

The vast vast majority of journals, however, are small, employ a part-time editor and have but limited time and resources to provide effective oversight of the material they are publishing. They can't guarantee to effectively sort the excellent science from the sloppy, and even less to detect purposeful deceit by funding sponsors with embedded conflicts of interest. Yet, the FDA criteria render virtually all medical journals eligible for cherry picking of articles by company marketing departments and peddling of it to practicing physicians and their patients.

This is not an effective or safe way to improve the health of the public. It is a an effective and now legally protected way ("the FDA said we should") for pharmaceutical and device manufacturing companies to expand markets for unapproved uses.

Further there is no need to promote selected research publications on specific drugs to physicians. Although individual practitioners ought to be able to recognize the conflict of interest of the pharmaceutical company salesperson, they don’t. The majority continue to accept visits and advice form various peddlers. The average practitioner (and patient) has little training, experience or frankly interest in reading and understanding research articles.

In fact, individual practitioners should be encouraged to not read research articles involving randomized trials of a single drug, for there is a reasonable probability that any one study will be flawed or subsequently disproved by accumulating further evidence. Average practitioners are encouraged to stick to guidelines which while themselves are still susceptible to bias and influence by pharmaceutical companies are at least one-half degree of freedom removed from Wall Street.

The FDA criteria for choosing a journal and article do not reflect the very flawed reality of current medical publishing nor of the sad state of market driven medical research, nor of the abilities, availabilities and interests of practitioners to read an understand. The FDA does not have to cave to pressure from Wall Street to let pharmaceutical companies market directly to individual practitioners and their patients by flogging journal articles. Ethical pharmaceutical companies should act responsibly and urge the FDA to drop this guidance.

Reference

Turner EH, Matthews AM, Linardatos E, Tell RA, Rosenthal R. Selective publication of antidepressant trials and its influence on apparent efficacy. N Engl J Med 2008;358:252-60.