PharmExec Blog

Understanding Serious Adverse Events Takes Serious Cooperation

What if the technology is at hand to prevent adverse reactions to medicines before they start?

The International Serious Adverse Events Consortium (iSAEC) came together in 2007 to research the cause of certain drug-induced serious adverse reactions, posing the question, “What if the identification of risk for adverse events were not a random development, but instead something that is linked to a genetic factor?” If genetic factors are determined to contribute to these events, the Consortium contends, “those at risk could be identified and exposure to the adverse event avoided.”

What this leads to, “if we’re incredibly lucky and the science works out,” says iSAEC founder, chairman, and CEO Arthur Holden, is the idea that there will be certain markers by which patients can be characterized before they ever take a drug. Ideally, this will minimize risk to patients by preventing many SAE reactions from occurring, and minimize risk to Big Pharma by ensuring that drugs don’t get pulled off the market for SAEs that are caused by genetic factors. In this way, the continuing work of the iSAEC could lead to a win-win situation.

The founding members of this Consortium include Abbot Laboratories, GlaxoSmithKline, Johnson & Johnson Pharmaceutical Research and Development, Pfizer, Roche, Sanofi-Aventis, and Wyeth. When some of the biggest names in Big Pharma put aside their differences and forego their natural competitive relationships to work together, the initial cause—and the eventual results—of such collaboration must be something special.

When Holden first brought the group together to study serious adverse events—many of which are related to the immune system and can cause hypersensitivity, serious skin rashes, and drug-induced liver injury—his idea was to form a privately funded, non-government-run group to get the research done quickly and effectively with no cost to the public. “We have not—nor do we intend to—take any taxpayer funding,” says Holden. “Particularly in these times of enormous government spending and deficit concerns in the developing market, some way, some how, we’re going to have to get past the idea that everything can be funded just by throwing taxes on people.”

And so in order to generate funds, ideas, research, and data for such a large project, Holden approached Big Pharma for help and had to answer a vital question—what’s in it for them? “I decided to go right to the head of R&D at most of the major pharmaceutical companies—I had one-on-one discussions with them about what they felt were the most pressing needs that, together as an industry, we would want to pool some resources to work on,” recalls Holden. The pitch, he said, was an easy one, driven from a common frustration. “All of us within the industry have experienced the failure of a product in development—or worse, the failure of a product once it gets out on the market—as a result of these drug-induced, very serious adverse events,” he explains. And so, if the iSAEC could prove that these events were not solely the result of some property of the drug itself, but of “a certain genetic heritage that puts the patients at risk,” then certain patients could simply avoid the drug in question, and these drugs would not be stopped in trials or taken off the market—potentially saving Big Pharma big money.

From the very beginning, however, gathering the data on SAEs had some inherent problems that needed to be solved. According to a recent White Paper from the iSAEC titled “Harnessing the Power of the Genome To Address Drug Safety in Pharmaceutical Development and Delivery”:

• SAEs are quite rare, making the number of well-phenotyped cases (obvious clinical cases that could not be mistaken for other adverse events) available for research very small;

• Often, even the largest of pharmaceutical clinical development trials are not large enough to experience enough cases of an SAE to support genomic exploration of the event;

• SAEs will likely vary in both incidence and frequency across ethnic groups; and

• Genome research undertaken by groups with appropriate data analysis capabilities is still a rarity

Collaboration, Holden discovered, was largely the solution to these problems. “The only way to do all this—and it’s a big bridge to cross—is to develop new research channels,” says Holden. “We need to move past the traditional one-institution mentality. The only way to do this is as a team sport.” Big Pharma has been willing to be a part of Holden’s team, he says, because “people will collaborate if it’s compellingly in their own interest to do so. The more we understand about these types of events and the better our capability to understand and to hopefully predict SAEs, the more we improve new product development productivity in the industry.”

The role that Big Pharma plays in the iSAEC is threefold, says Holden. First is a governance role—“They help shape and decide on the execution of the strategy,” he says. Second, each Big Pharma member contributes relatively small amounts of funds, providing the financial underpinning for the consortium. Lastly, it’s a matter of reputation; “It gives us a certain amount of credibility by having as much of the industry as we’ve been able to have involved,” says Holden.

Branching out beyond Big Pharma, Holden recognizes that academic and regulatory support are also essential pieces of the SAE puzzle. Holden calls Wellcome Trust, a funding member, essential to the consortium. “They’re a strategic member,” he says. “We’ve been doing this together a long time. They’re also certainly very heavily involved in the governance.”

The FDA, though they aren’t providing any funding for the Consortium’s research, also plays an integral role, and Holden calls their support unwavering. “They’ve been at literally every single meeting we’ve had,” he says. FDA is there to provide regulatory perspective and council and to share ideas. Similar to one of the roles Big Pharma plays, knowing that FDA backs and takes part in the Consortium’s research goes a long way in establishing credibility. “Their endorsement, saying that our research is vital, certainly helps us in bringing the membership together, too,” explains Holden.

Phase 1 of the Consortium’s research aimed to find out whether or not there were, in fact, common genetic mutations—across multiple drugs and ethnicities—that tend to predispose patients to certain Serious Adverse Events. Before this research, Holden says, “There were a lot of people who believed that you needed thousands of cases in order to characterize a genetic effect. What we proved—definitively—is that if there’s a genetic effect that’s strong enough to be clinically significant, you’re going to see it in as few as 50 cases.” This means that, if the Consortium can get access to a relatively small number of well-characterized cases (which is where the collaborative nature of the research comes in), accurate results can easily be determined.

Phase 2 will, according to the iSAEC White Paper, “focus on achieving a more integrated biological understanding of the genetics associated with drug-induced immunological SAEs.” In phase two, the iSAEC aims to:

• Complete an SAE Phenotype Standardization Project (PSP) on the target SAEs, with the Wellcome Trust and the FDA;

• Partner with large-scale HMO and government healthcare systems to enhance SAE case recruitment and better establish long-term SAE research channels for individual pharmaceutical safety research;

• Complete two genome-wide genotyping studies to investigate the role of low-frequency variants in SAE risk; and

• Continue the development of optimal genotyping and sequencing approaches for SAE genetic research

The ultimate goal of the Consortium, says Holden, is to “get whole genome-wide studies done across multiple drugs on most of the major conditions that involve the immune system and cause adverse safety reactions.” The practical upshot of all this research comes in the form of data that is publicly available “to all companies, all researchers, with no intellectual property … so the composition could never be patented.”

Holden believes that only a highly collaborative organization such as the iSAEC can achieve these goals quickly, effectively, and relatively inexpensively. “Here, you can set up a situation where you have a relatively small amount of money from multiple parties—so your investment is low, and the risk is diversified across a number of different members. No one entity can do this alone,” he says.

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