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FDA, Pharma Turn to PGx to Tackle Burden Of Adverse Events, Minimize Drug Recalls

By studying the genetic underpinnings for adverse drug reactions, the US Food and Drug Administration is hoping to avoid recalling drugs based on their negative impact on a few and depriving the greater population of beneficial treatment.
Last week, the FDA and a collection of industry and academic partners kicked off the Serious Adverse Events Consortium, a collaborative effort that hopes to identify genetic markers that might be used to identify patients at high risk for adverse reactions to particular drugs.
If tests based on these genetic markers were available, “[We] can keep the benefit of a drug and keep it available for people who are going to benefit from it, if you could identify those people who are at risk for having a very serious side effect, and make sure they don’t ever get the drug,” FDA Deputy Commissioner Janet Woodcock said during a conference call last week announcing the launch of the SAEC.
The SAEC is a non-profit entity comprised of large pharmaceutical companies, research organizations, and regulatory bodies. The FDA will guide the consortium with scientific and strategic input.
The formation of the consortium, which Pharmacogenomics Reporter wrote about in May, comes as several large pharma companies have had to pull drugs already on the market or kill investigational treatments very late in clinical development. Two SAEC partners, Pfizer and GlaxoSmithKline, have recently had such setbacks.
Pfizer last year had to suspend a large, Phase III trial for the investigational cardiovascular therapy torcetrapib, which was being studied in combination with the popular statin atorvastatin (Lipitor), due to an increased rate of mortality in patients receiving the torcetrapib/atorvastatin combination [see PGx Reporter 12-06-2007].
In the 1,188-patient ILLUSTRATE trial lead by Steven Nissen of the Cleveland Clinic Foundation, which compared atorvastatin and the torcetrapib/atorvastatin combination in the treatment of coronary disease the combination treatment raised HDL-C levels by 61 percent and lowered LDL-C levels by 20 percent compared to monotherapy. However, torcetrapib also increased systolic blood pressure by 4.6 mmHg. Adverse events related to blood pressure were reported by investigators in 23.7 percent of patients on combination therapy and in 10.6 percent using monotherapy.
In another instance, sales for GSK’s type 2 diabetes drug Avandia took a nosedive since May, when it was associated with a potentially significant increase in the risk of heart attack and heart-related deaths. On June 6 the FDA requested that a black box warning about congestive heart failure be placed on Avandia’s label. By the end of June, GSK’s quarterly US sales for Avandia had fallen 31 percent to $461 million from the previous quarter [see PGx Reporter 07-11-2007].
The controversy over Avandia was sparked by a May 2007 New England Journal of Medicine study, also by Nissen. In the study, Nissen reviewed 42 patient trials of Avandia, also known as rosiglitazone, and found the popular drug was associated with a 43-percent increase in heart attacks and possibly a 64-percent increase in cardiovascular death.
GSK, however, has challenged Nissen’s analysis as “conflicting” and “fragile” and cited results from a long-term study, A Diabetes Outcome Progression Trial. In ADOPT there were five reports of cardiovascular death out of 1,456 patients, four cases out of 1,454 patients in the metformin arm, and eight cases out of 1,441 in the glyburide arm.
“The ADOPT clinical trial did show a small increase in reports of myocardial infarction among the Avandia-treated group (Avandia: 24 out of 1,456 or 1.65 percent) vs. metformin (20 out of 1,454 or 1.38 percent) vs. glyburide (14 out of 1,441 or 0.97 percent); however, the number of events is too small to reach a reliable conclusion about the role any of the medicines may have played in this finding,” GSK stated in response to Nissen’s NEJM article.
“It’s a great tragedy when a whole drug program is closed down because one or two people experience an adverse event,” Paul Watkins, director of the Genetic Clinical Research Center at the University of North Carolina, Chapel Hill, and a participant in the SAEC, said during last week’s conference call.
At the same time, the FDA is increasingly focused on encouraging the use of pharmacogenomic strategies to improve the safety and efficacy of drugs. The agency is funding the Critical Path Institute to study the utility of genetic testing to reduce drug toxicities associated with warfarin under the Critical Path initiative.
Although the SAEC’s findings will not necessarily lead to any regulatory changes or labeling updates at the FDA, the agency has recently updated the labels of several older drugs with pharmacogenomic information and Woodcock said the agency expects “that trajectory to increase.”
According to Woodcock, the FDA has been struggling for three decades with SAEs and drugs that benefit a large number of people have been pulled from the market or removed from development programs because of the “fear” of adverse reactions experienced by a few.
“We haven’t been able to do anything about this until recently,” Woodcock said, noting that recent advances in genomics may help finally address this issue. In a year or two, she said, drugs could be labeled with information about genetic-based adverse events, and drugmakers could begin tailoring drugs for specific patient populations. 
The SAEC hopes that the results from its studies will eventually provide industry with the genetic markers that they can use to learn about the safety of investigational products earlier in drug development. In turn, physicians can use this information to make better treatment decisions by balancing the benefits and risks of therapies they are considering for their patients.
The Consortium
“Patients respond differently to medicines, and all medicines can have side effects in some people. The SAEC's work is based on the hypothesis that these differences have a genetic basis, and its research studies will examine the impact genes can have on how individuals respond to medicines,” the coalition said in a statement.
The first two studies the SAEC will focus on will address drug-related liver toxicity and Stevens-Johnson Syndrome, a rare skin condition. The results from these studies are expected to be released to the research community for further study in fall 2008 and 2009, for the Stevens-Johnson Syndrome and liver-toxicity study, respectively. According to UNC-CH’s Watkins, who is leading the liver-toxicity project, some patients have these adverse reactions to several drugs on the market.
"Given the considerable time, size, and cost of conducting safety studies, a coordinated, strategic partnership between industry, academia, and government can more rapidly advance this critical science," Woodcock said.
The consortium’s big pharma partners, including Abbott, GlaxoSmithKline, Johnson & Johnson, Pfizer, Roche, Sanofi-Aventis, and Wyeth, will contribute resources and share serious adverse events data.
The SAEC’s clinical research partners – including Newcastle University/DILIGEN, the European consortium on drug-related liver toxicity EUDRAGENE, and Illumina – will collect and analyze data from the studies. Data analysis for the first two studies will be performed at Columbia University.
The FDA, the European Agency for the Evaluation of Medicinal Products, and other regulatory bodies will guide the SAEC on study design and conduct. Researchers will ultimately link genetic variations found under the SAEC with data from the SNP Consortium and the HapMap Project.
“The SAEC plans to collect already available SAE data from the participating pharmaceutical companies and academic institutions in streamlined databases,” the consortium said in a statement. “These well-characterized databases of DNA from individuals who have experienced drug-related liver toxicity and SJS will then be compared with control cases to identify genetic variants that may be associated with these SAEs.”
Watkins said the project’s “immediate goal would be a genetic test that would allow us to identify who might have a problem with a drug,” such as liver toxicity.
Advancing PGx
Although the SAEC’s findings will not necessarily lead to any regulatory changes or labeling updates at the FDA, the effort is in line with a growing PGx focus at the agency.

“We’ve already started changing labels to put in pharmacogenetic information and we expect that trajectory to increase.”

“We’ve already started changing labels to put in pharmacogenetic information and we expect that trajectory to increase,” Woodcock said. “Via the outgrowth of science, as we learn more, we can put more information in [the label] about why different people have different responses to drugs based on their genetics.”
The FDA most recently updated with genetic testing information the label for Bristol-Myers Squibb’s anticoagulant Coumadin, more popularly known as warfarin [see PGx Reporter 09-05-2007]. The FDA also recommends the use of genotypic data to modify doses for patients using the acute lymphatic leukemia drug 6-mercaptopurine and Pfizer’s colorectal cancer agent Camptosar (irinotecan). The agency is also considering updating the label for the oncologic tamoxifen.
With these labeling updates, however, the FDA has not required physicians to use genetic tests to dose the drugs for their patients. In fact, the agency has said that it would need more outcomes data about the clinical and economic benefits of using these tests before making such a strong recommendation in labeling.
“The big question people have is: ‘When are we going to require genetic testing before you can get a drug?’ That’s a ways off because you have to have evidence, you have to have strong evidence that [the genetic test] is needed to take the drug safely or effectively,” Woodcock said during last week’s SAEC conference call.
However, a lack of education has slowed physicians’ adoption of pharmacogenetic tests and a dearth of research data has made insurance companies reluctant to cover them.
Woodcock noted that using pharmacogenomic tests would actually help reduce healthcare spending. “Often it’s very ironic [that] sometimes these pharmacogenetic tests are like a cheap date for the insurance companies because people who are slow metabolizers actually need much lower doses,” she said. “They need to take less drug to get the same effect. If we can know that, it’s going to decrease the cost of treating people because they won’t have so many bad side effects from the drug and they will actually work better because they’ll be properly dosed.”
Takes Money to Save Money
According to SAEC chief executive Arthur Holden, the consortium’s corporate partners will “provide needed financial contributions, define strategy, and organize and manage research.” However, he acknowledged during the conference call that perhaps only big pharma might be able to afford the price of membership in the consortium. 
Watkins had told Pharmacogenomics Reporter sister publication GenomeWeb Daily Newsin May that the companies were paying $500,000 each to be involved in the consortium. However, a New York Times article quoted Holden last week as saying the membership fees for industry partners were around $1 million. During the conference call, however, Holden denied making those statements and refused to disclose the membership fee amount.
Whatever the cost to join the SAEC, it may prove to be a better investment than spending the $1 billion it now costs to develop a drug with the uncertainty that it may never reach the market or that it may be pulled off of pharmacy shelves due to adverse reactions in some people.
The consortium will also encourage individual pharma companies, known for being intensely protective over proprietary data, to share certain types of genomic information with the common goal of improving drug safety for the public as a whole.
"The traditional research model only provides one piece of the puzzle in understanding the genetic variations that could lead to an increased risk of an adverse event," Holden said in a statement. "Because of the number of patients needed to tie a genetic variant to an SAE, and the resulting cost of doing these studies, no one company, research center, or agency can efficiently conduct this research on its own.
“The most efficient way to study drug-related SAEs is to create a global, publicly available 'knowledge base' that will help identify the genetic variations that may predict SAEs,” he added.
Following the completion of the studies, the SAEC will create an information technology infrastructure to make the study data available to the research community for free, so they can further validate the predictive markers.
“We have to do the basic science, generate results, validate those results, and then have them put it in a format that’s cost effective and easy to use,” Holden said. “It’s not too difficult to imagine a world where, over time, we’ll have enough of this content where you can actually have a broader panel done,” and through the establishment of common medical electronic records, “the patient would have access to … information upfront about their risk factors” before they begin taking a drug.

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