Culture Shift
by Elisa Ludwig
April 2008
Drug safety monitoring needs to begin early in the development process and continue throughout the product’s entire lifecycle.
With the passage of the Food and Drug Administration Amendments Act (FDAAA) last September, the pharmaceutical industry, regulators and consumers are looking at ways to improve post-marketing safety surveillance. “Certainly I think we’re going to be seeing more requests for post-marketing studies and possible risk evaluation and mitigation strategies,” says Dr. Annette Stemhagen, vice president of Epidemiology and Risk Management at United BioSource Corporation in Blue Bell, Pa., USA. “At the same time, there’s also a movement in terms of consumer empowerment and expectations about product safety that is likely to increase pressure on companies for safety information. After Vioxx, everyone wants to know how products that are unsafe can end up on the market.”
The industry’s safety perception problems — between high-profile cases like Vioxx, Avandia, and selective serotonin reuptake inhibitors and the Institute of Medicine’s recommendations to the FDA in its 2006 report The Future of Drug Safety — have been well documented. Dr. Sidney Kahn, president of Pharmacovigilance & Risk Management Inc., a consulting firm based in Huntingdon Valley, Pa., USA, has seen the failures of a reactive approach to safety firsthand.
“I know of a situation where a company observed events in studies that were well known to be associated with this type of product,” Kahn says. “When cases of the expected event were reported, they were not required to be submitted in 15-day reports. The New Drug Application was pending when the FDA identified the issue, resulting in withdrawal of the application and a calamitous fall in company market capitalization, which still has not recovered many years later.”
Shortsightedness has been the industry’s fatal flaw, Kahn says. “Pharmaceutical companies can be schizophrenic. On the one hand you have people in R&D who are really trying their best to improve the public health with a consciousness of safety supported by regulatory requirements. But people in the sales and marketing side are judged and evaluated according to their short-term sales figures. We need to make the shift for pharma as a whole to become more invested in the idea that doing safety proactively, thoroughly and openly is the best marketing tool you’ve got.”
Power in Knowledge
That shift is happening, though it may be moving at a cautious pace, says Axel Olsen, Ph.D., executive director of global pharmacovigilance and risk management for Quintiles, in Durham, N.C., USA. “Industry is seeing that the FDA is going to be increasing capabilities and infrastructure, but there’s a bit of a ‘wait and see’ attitude about what kind of change there will be in the regulatory framework,” Olsen says. “But they’re learning that, in order to be responsive to the marketplace, industry needs to be more proactive about safety.”
Many companies already are expanding their pharmacovigilance and signal detection programs to encompass a product’s lifecycle, from pre-clinical through early studies and onward. “Sponsors are thinking more proactively about their post-marketing commitments, and they’re also volunteering to do more studies to give them more potential latitude in negotiating with FDA,” Stemhagen says.
A proactive approach to safety, dovetailing with the FDA’s concept of the “science of safety,” includes creating a risk management plan early on. “If you’re talking about a therapeutic class of drugs, many times there are comparator data that can be used in Phase II and Phase III to create a risk management plan, rather than waiting until post-marketing,” Stemhagen says.
The new science of safety also includes establishing signal assessment and data mining during the pre-marketing phases of development. “We work with a couple of sponsors who are doing that—not only within a specific study but across multiple studies, creating a data warehouse for products and developing methodologies to look for safety signals earlier on,” Stemhagen says, though she adds that this is far from the industry standard.
Through adaptive trial design, researchers can reach a better understanding of both drugs and disease at the molecular level, identify a target trial population and help predict safety issues before they become adverse events. “Today we have an increased awareness of the role and importance of pharmacoepidemiology,” Kahn says. “But even now, it is too often an afterthought for some companies.”
Better Safety Through Better Design
Though many of the largest companies are modernizing their practices and incorporating programs and methodologies for creative signal detection and evaluation, smaller firms that lack in-house epidemiological resources may be lagging behind, Olsen says.
“As an epidemiologist, I’m always on my soapbox about creating a natural history of the disease study early on in a product lifecycle,” Stemhagen says. “It sounds counterintuitive—most people creating a drug for osteoporosis think they know everything about the disease, but there is not always enough data about the condition to understand the safety profile of how a drug can impact the disease.”
The disease itself often presents risks, Stemhagen says. “For example, when Merck was developing a treatment for benign prostatic hyperplasia (BPH), at the time little was known about the condition, including case fatality rate and co-morbidities or how frequently men were hospitalized, so Merck did a series of natural history studies,” she says. “Ultimately, all of this information helps you understand how to place your drug and how to mitigate safety risks.”
Conversely, a natural history study will reveal more about the patient population that isn’t covered in efficacy studies. “Often you’re leaving out the elderly or children or people with concurrent medical conditions such as impaired renal function in the pivotal studies because you need a ‘clean’ or homogenous sample,” Stemhagen says. “So you need to understand who you studied and who you did not, since this latter population will take your drug and should be studied in peri-approval safety studies.”
As scrutiny of product safety increases, a proactive approach to monitoring will have to be adopted across the board and not solely on a product-by-product basis, Olsen says. “I’m not sure that any new questions need to be asked as much as there needs to be more analysis of findings across the stages of drug development that will apply to the population in a broader sense, and not just the ideal patient.”
Send us Your Comments
Web Exclusives
- An Unbalanced Burden
-
A Q&A with Dr. Kathleen Squires, director of the infectious disease department at Jefferson Medical College in Philadelphia, illuminates the gender differences in the diagnosis and treatment of HIV.
- Turning the Corner
-
After decades of neglect, leading to a rapid increase in incidence, tuberculosis started gaining attention from industrialized nations over the past 10 years. With this new focus, TB’s incidence has started to decrease—but barely.