By Leah Voigt*
March 12, 2010
FDA Official Says Globalized Drug Production Among Agency's Top Safety Challenges
Two years after contaminated heparin killed 149 people, a top U.S. Food and Drug Administration (FDA) official said the agency does not have the resources and authority it would like to address pressing safety issues, including foreign inspections and mandatory drug recalls. "We very much want to do more," Joshua M. Sharfstein, FDA's principal deputy commissioner, told the House Energy and Commerce Subcommittee on Health March 10, answering pointed questions from John D. Dingell (D-MI). "We want more authority."
Dingell said there has been a public "confidence crisis" in FDA in recent years, but under the new administration the agency has begun to rebuild its reputation. Still, he said FDA's resources are not sufficient. In testimony intended to update Congress on FDA safety-related initiatives, Sharfstein said FDA's oversight has been complicated by foreign pharmaceutical production. He said 40% of the drugs Americans take are imported, and 80% of active pharmaceutical ingredients (API) are manufactured in other countries.
"This makes oversight significantly more difficult and leaves weaknesses through which counterfeit, adulterated, and misbranded products might infiltrate the legitimate supply chain," Sharfstein told the committee. The contamination of heparin, a blood thinner, drew attention to the issue of foreign pharmaceutical production in 2007 and 2008. A Chinese API manufacturer, which FDA did not inspect, introduced a deadly contaminant into the drug. In June 2008, FDA said 149 deaths were attributed to heparin since early 2007.
Jessica Coomes, FDA Official: Globalized Drug Production Among Agency's Top Safety Challenges, BNA's Health Care Daily Report (Mar. 11, 2010) (note: registration is required to view this content).
Disease Cause is Pinpointed with Genome
Two research teams have independently decoded the entire genome of patients to find the exact genetic cause of their diseases. The approach may offer a new start in the so far disappointing effort to identify the genetic roots of major killers like heart disease, diabetes, and Alzheimer's.
In the decade since the first full genetic code of a human was sequenced for some $500 million, less than a dozen genomes had been decoded, all of healthy people. Geneticists said the new research showed it was now possible to sequence the entire genome of a patient at reasonable cost and with sufficient accuracy to be of practical use to medical researchers. One subject's genome cost just $50,000 to decode.
Besides identifying disease genes, one team in Seattle, was able to make the first direct estimate of the number of mutations, or changes in DNA, that are passed on from parent to child. They calculate that of the three billion units in the human genome, sixty per generation are changed by random mutation--considerably less than previously thought. The three diseases analyzed in the two reports, published online on Wednesday, are caused by single, rare mutations in a gene.
More common diseases, like cancer, are thought to be caused by mutations in several genes, and finding the causes was the principal goal of the $3 billion human genome project. To that end, medical geneticists have invested heavily over the last eight years in an alluring shortcut. But the shortcut was based on a premise that is turning out to be incorrect. Scientists thought the mutations that caused common diseases would themselves be common. So they first identified the common mutations in the human population in a $100 million project called the HapMap. Then they compared patients' genomes with those of healthy genomes. The comparisons relied on ingenious devices called SNP chips, which scan just a tiny portion of the genome. (SNP, pronounced "snip," stands for single nucleotide polymorphism.) These projects, called genome-wide association studies, each cost around $10 million or more.
The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics. And in most diseases the culprit DNA was linked to only a small portion of all the cases of the disease. It seemed that natural selection has weeded out any disease-causing mutation before it becomes common. The finding implies that common diseases, surprisingly, are caused by rare, not common, mutations. In the last few months, researchers have begun to conclude that a new approach is needed, one based on decoding the entire genome of patients. The new reports, though involving only single-gene diseases, suggest that the whole-genome approach can be developed into a way of exploring the roots of the common multigene diseases.
Nicholas Wade, Disease Cause is Pinpointed with Genome, N.Y. TIMES (Mar. 10, 2010).
U.S. Supreme Court Agrees to Review Ruling that Vaccine Act Bars Design Defect Claims
Stepping into the drug and medical device arena once again, the U.S. Supreme Court agreed March 8 to review a federal appeals court ruling that the National Childhood Vaccine Injury Act preempts design defect claims against manufacturers (Bruesewitz v. Wyeth Inc., U.S., No. 09-152, 3/8/10). Chief Justice John G. Roberts Jr. took no part in the consideration or decision of the petition.
At issue is Section 22(b)(1) of the act, which provides, "No vaccine manufacturer shall be liable in a civil action for damages arising from a vaccine-related injury or death associated with the administration of a vaccine after October 1, 1988, if the injury or death resulted from side effects that were unavoidable even though the vaccine was properly prepared and was accompanied by proper directions and warnings."
In March 2009, the U.S. Court of Appeals for the Third Circuit held in Bruesewitz v. Wyeth Inc. that this language creates express preemption that categorically bars design defect claims. Russell and Robalee Bruesewitz had alleged their daughter, Hannah, suffered a permanent seizure disorder caused by a Wyeth whole-cell pertussis vaccine administered in 1992. They alleged less toxic vaccine alternatives were available.
Pfizer, the parent company of Wyeth, said it is "pleased that the U.S. Supreme Court has agreed to resolve this legal issue, which is of critical importance to national public health policy. The Company is hopeful that the Supreme Court will affirm the judgment of the Third Circuit in Wyeth's favor in the Bruesewitz case, and thereby uphold the intent of Congress to preempt all design defect claims in cases covered by the Vaccine Act."
In finding preemption, the Third Circuit rejected the reasoning of the Georgia Supreme Court, which had said in 2008 in American Home Products Corp. v. Ferrari that the act does not bar all design defect claims against vaccine makers. Instead, it requires a case-by-case inquiry to determine whether the side effects of a particular vaccine were unavoidable. The ruling was reportedly the first by a state high court to find no preemption in a vaccine case.
Julie A. Steinberg, U.S. Supreme Court Agrees to Review Ruling That Vaccine Act Bars Design Defect Claims, BNA's Health Care Daily Report (Mar. 9, 2010) (note: registration is required to view this content).
Obstructive Disease Not Found on Most Angiograms
For patients without known heart disease, the diagnostic yield of coronary angiography appears to be low, researchers found. According to a report published online by the New England Journal of Medicine, only about 38% of those referred to the cath lab for the elective procedure had obstructive coronary artery disease.
Current guidelines for triaging patients for cardiac catheterization recommend a risk assessment and noninvasive testing. Yet the methods for determining how invasive tests are ordered "are far from perfect," said one researcher at the University of North Carolina at Chapel Hill, who was not involved in the study.
To investigate patterns of noninvasive testing and the diagnostic yield of catheterization among patients with suspected coronary artery disease, the researchers assessed 398,978 patients seen at 663 hospitals between January 2004 and April 2008 who were logged in the American College of Cardiology National Cardiovascular Data Registry. They noted that this population accounts for roughly 20% of the patients going into a cath lab. The vast majority are seen for other indications including heart attack and heart failure. The researchers also excluded patients who have had a prior heart procedure such as a valve replacement or stent.
Primary source: M.R. Patel et al., Low Diagnostic Yield of Elective Coronary Angiography, 362 N ENGL J MED 886-95 (2010).
Kristina Fiore, Obstructive Disease Not Found on Most Angiograms, MedPage Today (Mar. 10, 2010).
Doctors' Workweek Getting Shorter
A study in the February 22, 2010, Journal of the American Medical Association (JAMA) found that from 1996 to 2008, hours worked per week by physicians decreased 7.2%, from fifty-five to fifty-one. In the same period, physician fees declined 25% (adjusted for inflation). Furthermore, physicians practicing in areas with the lowest paid fees worked less--fewer than forty-nine hours per week--than did those in higher-fee regions, who worked more than fifty-two hours.
Despite a strong correlation between declining fees and hours worked, one factor did not necessarily cause the other, said the study's lead author. But the origin of such a significant correlation remains a mystery.
While the JAMA study did not look at physician income, researchers said other studies have shown that, despite the decline in fees, there has not been a substantial decline in physician salary. Physicians may be working fewer hours each week, but they are packing more into those hours.
The Physician Compensation and Production Survey conducted annually by the Medical Group Management Assciation has shown productivity climbing at a much faster pace than compensation. This increase in productivity appears to be contributing to burnout, or at the very least, a less rewarding workday.
The researchers said another theory for the decreased hours is that resident work-hour limits passed in 2003 contributed to the overall decline. But that doesn't hold true, he said. The decline was across all age groups, and the group representing the largest decline in work hours was nonresidents younger than forty-five. The findings suggest that more study is needed to understand what's happening with physicians and their behavior, they said. "It's telling us something about how incentives and the work life of physicians is changing that we just weren't aware of."
Researchers said the reduction in hours over a dozen years was equivalent to a drop of 36,000 doctors.
Pamela Lewis Dolan, Doctors' Workweek Getting Shorter, Am. Med. News (Mar. 8, 2010).
Limitations of Comparative Studies Described in Analysis Published by JAMA
An analysis of comparative effectiveness (CE) studies found that only a few of the studies compare medications with non-pharmacologic interventions and even fewer examine cost effectiveness or safety, according to a report in the March 10 issue of the JAMA.
Researchers at the University of Southern California, Los Angeles; Harvard Medical School; and Cambridge Health Alliance, Boston, examined the characteristics and prevalence of comparative effectiveness research concerning medications published between June 2008 and September 2009 for their report, "Characteristics of Published Comparative Effectiveness Studies of Medications." A release from Cambridge Health Alliance said the study authors reviewed 328 medication studies published between June 2008 and September 2009 in six leading medical journals and found that 104, or 32%, qualified as CE studies.
Of the 104 comparative effectiveness studies the researchers reviewed, 43% compared two or more medications with each other; 31% compared different pharmacologic strategies; 15% compared different medication doses, durations, or frequencies of treatment, or different medication formulations; and 11% compared medications with non-pharmacologic interventions. Meanwhile, the authors found that 19% of comparative effectiveness studies focused on safety and 2% included cost-effectiveness analyses, according to the report.
CE studies were much less likely (13%-45%) than non-CE effectiveness studies to have been exclusively commercially funded, according to the report. In total, non-commercial entities funded in some part 87% of the comparative effectiveness studies, including ten of the eleven comparative effectiveness studies that compared medications with non-pharmacologic interventions, according to the report.
An abstract described CE studies as those comparing existing, active treatments, and non-CE studies as those involving novel therapies or those using an inactive control.
"Overall, this study of CE research involving medications underscores the importance of the recent legislation passed in the United States to expand public funding for CE studies," the researchers wrote, a reference to the 2009 American Recovery and Reinvestment Act. "In particular, our findings suggest government and non-commercial support should be increased for studies involving non-pharmacologic therapies, for studies comparing different therapeutic strategies, and for studies focusing on the comparative safety and cost of different therapies."
The findings also highlight the need for regulatory agencies such as the FDA to require, whenever feasible, active-comparator trials for medication approval, according to the researchers.
Thom Wilder, Limitations of Comparative Studies Described in Analysis Published by JAMA, BNA's Health Care Daily Report (Mar. 11, 2010) (note: registration is required to view this content).
AHLA Teaching Hospital Updates are intended to provide quick summaries of cutting-edge issues of interest to teaching hospitals and their counsel. Additional information and more in-depth coverage on these topics may be available from AHLA Health Lawyers Weekly and appropriate AHLA Practice Groups.
*We would like to thank Leah Voigt, Esquire (Squire Sanders & Dempsey LLP, Washington, DC), for providing this week's update.