Legal: May 2010 Archives

David Walk of the Drug and Device Law Blog performed a major takedown of the hallowed NEJM and its publication of an interview study (or "study," depending on your perspective) of successful anti-pharma whistleblowers, which was also criticized 2 weeks ago at this blog.

Walk correctly assails the authors' methodology, or lack thereof; their inherent bias in only interviewing prevailing whistleblowers; and findings (or "findings") that might be found in any lazy magazine piece—like, "a typical day could be meeting an FBI agent in a parkway rest stop. Sitting in his car with the windows rolled up. Neither heat nor air conditioning."

Neither heat nor air conditioning? Walk's pithy response: "Wow."

Another wry criticism of the authors' findings: Questioning how some whistleblowers "accidentally" "fell into the qui tam process." Walk responds, "As lawyers, we know it’s pretty hard to file a lawsuit accidentally," and "Try that argument at home to excuse some dumb thing you did."

And if it truly, really, verily isn't about the money, as the interviewed whistleblowers would like us to believe, then revamp the whole process. Walk logically concludes,

Then the qui tam system urgently needs revision. We're wasting millions that could be benefiting us as taxpayers. Obviously, these relators didn’t need the millions of dollars they received to motivate them to bring qui tam lawsuits. All that money can go back to the taxpayers or, better yet, our clients, the pharmaceutical companies.

Last Walk snipes at the authors' conclusion that the qui tam system should be revamped on the basis of their interviews.

What a great idea – deciding important public policy questions based only on a few interviews of one of many interested groups. Maybe someone will follow this NEJM-approved "scientific" approach to public policymaking and make serious proposals to reform the nation’s regulation of doctors based solely on 30 to 45 minute interviews of 26 successful medical malpractice plaintiffs.

Image of Saint Sebastian by Guido Reni from Wikipedia.

Monday the Drug and Device Law Blog cited a new lawsuit in the "Judicial Hellhole," Madison County, Illinois (and you know how the DDLB feels about Judicial Hellholes). The suit, covered by the Madison and St. Clair Record* and filed by 19 plaintiffs "from across the country," alleges that Novartis, CIBA, and Sandoz failed to warn African Americans of their genetically increased risk of Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and other severe skin disorders during carbamazepine therapy (brand name, Tegretol; abbreviated CBZ). The plaintiffs are represented by Christopher Cueto of neighboring St. Clair county, the brother of controversial circuit court judge Lloyd A. Cueto and the disbarred Amiel Cueto.

In clumsy language, the suit stipulates, according to the Record:

"Defendants knew or should have known a significant portion of deaths and severe side effects, described herein, resulted from carbamazepine products have included African American persons and children who were found to have increased risks of carbamazepine SJS and TEN in the medical literature..."

And,

"Different races, such as African Americans, Hispanics, native Indians, Asians and Caucasians, face an increased risk of developing SJS and TEN because of their genetics. African Americans and Asians remain especially prone to developing the life-threatening skin conditions because of a gene they have a tendency to carry."

The paper also outlines the long, "storied" history of Tegretol's approval, which is evidently solely based on what's written in the complaint.

Problem is: While there are compelling data linking CBZ-induced SJS and TEN in southeast Asians and the presence of the HLA-B*1502 genetic allele, to my knowledge, there are no comparable data in African Americans, persons of African descent, or black Africans. Nor are there comparable data for Hispanics or Native Americans. In fact, published data indicate a negligible or extrememly low rate of the HLA-B*1502 allele in these non-Asian ethnic groups.

The HLA-B*1502 link was first made in 2004 in the journal Nature. Taiwanese investigators showed an astronomical association between the allele and CBZ-related SJS and TEN in Han Chinese (see also, Hung et al). The link was also subsequently found in a Thai population and, to a much lesser extent, in East Indians. The HLA-B*1502 allele, however, does not appear to be a risk factor for SJS/TEN in Caucasians.**  

In other words, the allele is neither necessary nor sufficient for the development of CBZ-related skin disorders: meaning that persons who don't carry the allele can develop SJS and TEN, and persons with the allele don't always develop drug-induced skin disorders. Also an association between HLA-B*1502 and severe skin disorders with other anticonvulsants (eg, oxcarbazepine, phenytoin) was recently reported in Han Chinese.

In December 2007, the FDA issued an alert, informing physicians of the link between HLA-B*1502 and CBZ-induced SJS or TEN. The agency reported, "This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians." Genetic testing was advised in "[p]atients with ancestry from areas in which HLA-B*1502 is present," before starting treatment with CBZ. However, "[p]atients who have been taking carbamazepine for more than a few months without developing skin reactions are at low risk of these events ever developing from carbamazepine. This is true for patients of any ethnicity or genotype, including patients positive for HLA-B*1502," the FDA advised. Labeling for CBZ products was accordingly changed with black-box warnings.

Also according to the FDA in 2007, the frequency of the HLA-B*1502 allele in ethnic populations is as follows.

• Chinese, Thai, Malaysians, Indonesians, Filipinos, Taiwanese: 10%-15%
• Other southeast Asians, including Indians: 2%-4%
• Japanese, Koreans: <1%

In 2008, Ferrel and McLeod updated the frequencies of the HLA-B*1502 allele in various Asian and North American populations. Attorney Cueto is evidently hanging his hat on a 0.2% allele rate in African Americans, which hardly constitutes a "tendency." (One at least hopes that the plaintiffs have been tested for the allele.) Curiously enough, Native Americans, who are most likely to have at least a remote Asian ancestry, show a negligible frequency.

Continent	Population/Ethnicity	Allele Frequency (%)	N
Asia	Singapore	11.6	86
	Han Chinese	10.2	572
	Malay	8.4	101
	Thai	6.1	99
	Filipino	5.3	94
	India Khandesh Pawra	6	50
	India North Hindi	2	91
	India Mumbai Marathas	1	72
	Korean	0.5	200
North America	Asian	5.1	396
	African	0.2	251
	European	0	287
	Hispanic	0	240
	Native American	0	235

* Which, by the way, reports that "Pharmaceuticals failed to warn African Americans of drug's dangers" (italics added).

** Nor does the allele increase the risk of maculopapular exanthema in Han Chinese.

Image of bottom-feeding channel catfish from Wikipedia.

Successful whistleblowers in qui tam suits against pharma weren't in it for the money. At least that's what they say in hindsight, according to a newly published interview study of 26 such "relators" in the NEJM. (Did anybody expect them to admit otherwise?) The semi-structured study was conducted by investigators at Harvard and the University of Melbourne, one of whom (Kesselbaum) has served as an expert witness in litigation against Merck.*

The 26 interviewed relators, who received a median of $3 million ($100,000-$42 million), were reportedly motivated by their senses of justice, altruism, or integrity, according to the study. In other cases, whistleblowing was viewed as a way to avert possible future accusations of engaging in illegal activity (eg, off-label promotion). They also cited heavy personal and professional costs during the qui tam investigation and litigation.

However, one sentence in the NEJM article, in particular, suggests that whistleblowers are at least initially motivated by the prospect of a financial windfall and don't accurately anticipate the direct and indirect costs of the qui tam process. In a concluding statement to the section, "Settlement and Life Afterward," the authors report the relators' advice to would-be whistleblowers:

Some offered strategic suggestions, such as hiring an experienced personal attorney, and many suggested a need to mentally prepare for a process more protracted, stressful, and conflict-ridden, and less financially rewarding, than prospective whistle-blowers might expect.

The authors also note that if the Justice Department decides to intervene in whistleblowers' qui tam suits, almost all result in settlements or judgments against the pharma defendant. So once the DoJ picks up a case, it's highly unlikely that the whistleblower would decide to back out, whatever the upfront headaches.

* Related to the alleged improper promotion of Vioxx.

Image of Saint Sebastian by Guido Reni from Wikipedia.

Addendum: In a highly revealing statement, one interviewee "likened his large settlement to 'hitting the lottery,'" which, as we all know, has the sole upfront cost of forking over a buck or two for a ticket.

I have a hard time believing that cosmetic doses* of Botox caused the multitude of neurologic and other problems claimed by former OB/GYN Sharla Helton, 48. But yesterday, an Oklahoma jury decided otherwise and granted Helton $15 million, according to the Orange County Register (a paper diligently covering alleged Botox-injury cases). Allergan will reportedly appeal the verdict. (Coverage of the verdict is also provided by NewsOK.com, which shows a photo of a nearly wrinkle-less, smiling Sharla Helton in 2006.)

Helton, who claims to have experienced double vision, respiratory problems, and persistent limb pain from injected Botox, was represented by Ray Chester of the Texas-based firm McGinnis, Lochridge, and Kilgore. Chester also represented the mother of Kristen Spears, who lost her wrongful-death suit against Allergan in March. (For background on this story, start here.) In April, the OC Register reported that Allergan was suing Spears's mother for legal fees.

The Oklahoma jury evidently decided in favor of Allergan with respect to Helton's product liability claim, however. According to a quoted Allergan spokesperson, the jury concluded that "Botox Cosmetic was not a defective product and did not have defective warnings." Consequently "it is not possible for Allergan to have been found negligent in this case," the company reasoned. Punitive damages were apparently not awarded by the jury.

During the 3-week Oklahoma trial, the plaintiff's expert witness, toxicologist Shayne Gad, PhD, was publicly humiliated when it was revealed by Allergan's counsel that Gad had misstated his military record. Gad was convicted of a misdemeanor for falsely claiming that he had been awarded a number of medals, including 3 Purple Hearts. In a plea bargain with the US District Court for eastern North Carolina, Gad avoided prison time and was placed on an 8-month probation, from February to April of last year. A dramatic courtroom apology from Gad to Chester and the plaintiff was printed by the OC Register last month.

Chester's next case (now 3 of 15, if I'm counting correctly) is that of Sondra Bryant, a 70-year-old nurse who died in 2008 after receiving Botox injections for neck pain. The nurse was from Texas, but the trial will begin in Santa Ana, California, in the fall.

Allergan's free-speech case against the government remains pending, but today's search of the court calendar still reveals nothing on the schedule for the remainder of the year.

* Even at somewhat-higher-than-approved doses. According to the OC Register, Helton received a 50-unit treatment for wrinkles in her upper face. The FDA approved total treatment dose is 20 units. It was not reported if Helton was treated by another physician or treated herself.