By Wayne Koberstein
Safety and innovation have become the twin poles of a dynamic struggle that both embattles and empowers the FDA’s Center for Drug Evaluation and Research (CDER). Of all the changes CDER Director Janet Woodcock, M.D., has witnessed during her 20+ years at the FDA, emergence of the center’s lightning-rod role in drug safety and its assumption of new responsibilities for innovative treatments reveal the struggle most clearly. We spoke to Dr. Woodcock during a whirlwind season of political agitation, controversial FDA decisions, and her own congressional testimony, just to name a few hotspots of the time.
The FDA famously oversees one quarter of the U.S. economy. But for much of the life sciences industry, the most important part of the agency is CDER, which in the past decade has assumed or shared increasing authority with the sister centers that regulate biologics and medical devices. In 2003, CDER took on the oversight of all biological therapeutics from the Center for Biologics Evaluation and Research (CBER). As more and more therapeutics have been linked to diagnostic, delivery, and other medical devices, CDER’s overlapping authority with the Center for Devices and Radiological Health (CDRH) has also continued to expand. Meanwhile, largely under Woodcock’s direction, CDER has assumed leadership in the perennial issue of safety versus innovation: Does regulation to protect patients from side effects in fact deny them the benefits of new therapies, as well as impede economic growth?
Though Woodcock argues that science has pushed the agency into the safety arena, economics and politics often invade the debate. Likewise, nonscientific issues tend to dominate the discourse over specific biotech or alternative-technology therapeutics, the overall pace of innovation, and the very mission of the agency itself. The FDA, CDER, and Woodcock toil away at the center of the storm, where in politics, unlike nature, no still waters can be found.
In June, BIO President James Greenwood proposed a legal change of the FDA’s mission from its current emphasis on protecting public health to achieving faster drug approvals. His statement resonated with the current conservative bloc in Congress; Senator Scott Brown (R-MA) and other Tea Party Republicans piled on to threaten legal action that would transform the FDA into an “approval-first, safety later” culture.
Conversely, a previous Congress passed the 2007 FDA Amendments Act, which mandates more aggressive safety initiatives at the agency, and the Institute of Medicine later issued a report exhorting the FDA to establish a safety-first culture. Attempting to address both sides of the issue, with Woodcock then as the Deputy Commissioner, the FDA had already launched the Critical Path Initiative, a collaboration with industry and others to promote science-based improvements in all phases of regulated-product development. The agency has since followed with numerous other programs based, like Critical Path, on broad public, industry, and scientific input.
The waters were not calmed. “The fact is, you can’t please all of the people all of the time,” she says. She cites both a recent article in the Annals of Internal Medicine that advocates increasing the FDA’s efficacy standard and an op/ed piece in the Wall Street Journal saying the agency should abandon the efficacy standard altogether because it impedes innovation.
Is a third way possible? Could the agency do both — promote greater drug safety and a speedier review process at the same time? Woodcock believes it could, not with a politicized mission but through better new-drug submissions.
“What we put forth under Critical Path is that the only way out of this problem is science. If we have better signs of safety and efficacy in development, and companies can submit safer and more effective drugs, we will get out of the conflict we are having now, and I believe we are starting to see that,” she says.
Do Less Harm
Much criticism of the FDA focuses on its rising standards, aka “hurdles,” that make it more difficult for already strapped start-ups to win product approvals. It is no secret that drug approvals fell and review times lengthened after safety-related product withdrawals ended a post-PDUFA (Prescription Drug User Fee Act of 1992) spike several years ago. Also, some drugs marketed under the accelerated approval program failed at some point, and others have been subject to long delays in the required postmarketing studies. But, the most visible FDA initiatives that address safety and efficacy, for example REMS (risk evaluation and mitigation strategies), do so in the context of actual use rather than intrinsic quality.
All of the initiatives may affect companies from development to the market. For example, although REMS is still in its relative infancy, it already requires companies to generate reams of usage information as well as an evaluation of each REMS package’s effectiveness. Woodcock says CDER’s plan is to standardize the form, content, and evaluation of REMS packages in the future. A series of public meetings will continue to guide the program’s refinement.
“Even for some of the REMS already put in place for existing drugs, such as Accutane, it has been very difficult to discern actually how much benefit the REMS provided,” Woodcock says. “It is everybody’s problem to evaluate whether these programs are actually making a difference because they are costly, and they are somewhat cumbersome.”
Nevertheless, Woodcock agrees REMS and other patient-focused initiatives represent a big step beyond the traditional industry practice of ignoring the real-life experience of those on the receiving end of medicines. “Back in the old days, when we ran the premarket review program, it was like we threw the approved drug over the wall and told the healthcare system, let us know if anything goes wrong!”
But, the initiative’s focus on use does not mean CDER is ignoring the emerging science of drug safety, with its exploration of drug mechanisms, which in turn may hold keys to increasing efficacy as well. Scientifically and technologically, now may be the right time to address the common channels by which drugs harm people and what can be done about it. Can we look forward to a day when drugs overall are intrinsically safer to use?
Woodcock believes we can. She says drug targeting, not just for optimum benefits but for side-effect avoidance, is a hopeful path. Four years ago, she helped start the International Serious Adverse Event Consortium (ISAEC) [www.saeconsortium.org] to explore the genetic basis of SAEs (serious adverse events). Since then, the ISAEC has researched and discovered HLA (human leukocyte antigen) alleles linked to susceptibility to drug-induced liver injury (DILI), Steven-Johnson Syndrome, and toxic epidermal necrolysis.
The research has now been applied to the antibiotics Augmentin (amoxicillin/clavulanate) and flucloxacillin with DILI. It has also led the FDA to recommend patient screening for an HLA allele associated with Steven-Johnson Syndrome on the label for CNS (central nervous system) drug Tegretol (carbamazepine). In principal, the same approach ISAEC uses for rare SAEs could be scaled up to allow screening for the more widespread side effects of drugs and drug groups.
Perhaps, as the small victories lead to bigger ones, companies will begin to look at higher safety and efficacy standards as something not to compete against but upon which to compete. Woodcock agrees: “Drugs that offer no additional benefit — I just don’t think they can compete in the marketplace anymore.”
Weight of Evidence
Woodcock’s basic concept of drug safety would encounter little disagreement in the biopharmaceutical research community. “We all recognize that safety does not stand alone; it’s part of the benefit/risk assessment of any given drug,” she says. “And, there is an evolution of knowledge — from the beginning of drug development, all the way through the life cycle of a drug, even with the generic versions we may still be learning more about its benefits and harms.”
Not that CDER is yet fully equipped for such long-term oversight. “We have an application-driven process, premarket, but we recognize we need to have a more global and seamless look at benefit/risk throughout the life cycle of the drug. We need to integrate the various functions we have around the center and have a better way of responding to safety problems that arise postmarket, prioritizing them and having risk-management activities similar to REMS and the other initiatives.” Woodcock says CDER is now conducting a pilot program to develop a “framework” for judging “whether the benefits outweigh the risks in any given time period or around any given event.”
The framework would build on the tight premarket review system created as a result of PDUFA, extending it to all drugs and to postmarket surveillance. Woodcock believes the plan will take years to implement, but that CDER has made significant progress already with a risk-prioritization system that helps it determine timelines for response to new safety signals.
One outside proposal for weighing benefit/risk is to use statistical science to develop a numerical ratio, or index, the FDA would apply to every approved new drug. The index would quantify benefit/risk in a standard way to allow a relative comparison of one drug against another. Based on a wide enough consensus, the index could ease approvals but motivate companies to compete for the best “scores,” rather than striving for a simple binary, up-or-down decision. Physicians, patients, and payers could use the index as a treatment decision guide. Woodcock is less than enthusiastic about the proposal.
“People have tried a numerical approach, but we are not going quite so far, because we believe a single number lacks face validity. We are trying to quantify therapies, or semiquantify, the benefits and the risks and the uncertainties, in our pilot. But, the big thing lacking (and something we will do if the PDUFA program agreed to between industry and the FDA is put into law) is the patient values or preferences. Different patients can value benefits and risks very differently.”
She cites a survey by the International Foundation for Functional Gastrointestinal Disorders [www.iffgd.org], in which 6% of patients would accept a 1/100 chance of “serious and disabling side effects” from a treatment to relieve their IBS symptoms; 8% would accept a 1/100 chance of death. “Our society and our approval system says, within certain parameters, people should be able to make a choice if they are fully informed and decide to take that risk. It shouldn’t be withheld from them if the drug has a benefit. So our pilot collects much more patient input into how those benefit/risks are weighted.”
Woodcock observes, however, that some consumer groups object to the idea of any patient input or participation in prescribing decisions, instead advocating such a strict review system that approved drugs in general would have essentially zero risk. Of course, that is what critics on the other side accuse the agency of doing already — another case, perhaps, of you can’t please everybody.
“On the other hand, there are always some patients who will take any medicine if there is any hope at all, no matter what the evidence says about whether it will benefit them or hurt them,” Woodcock notes. “People should be able to make choices, but they shouldn’t be conned into ‘selling the farm’ for something that has no benefit. Yet, in a polarized political environment, it is very difficult to have a sensible conversation about patient choice and information.”
Woodcock also has a more fundamental answer to the safety question. “What will really improve drug safety is for us to improve the science of safety, and we are working on that. We are working on better ways to detect safety signals, and we’re working on the mechanistic side to figure out what causes drug-safety problems and how they could be prevented.”
It is a message that resonates with the commissioner’s overarching drive to keep science in the driver’s seat. In August, the FDA released “Advancing Regulatory Science at FDA: A Strategic Plan” to augment its late-2010 Regulatory Science Initiative with detailed steps in key “science priority” areas such as stimulating personalized medicine, implementing new medical countermeasures to global security threats, and ensuring its readiness to evaluate innovative emerging technologies.
That CDER having become a lightning rod for the safety vs. innovation debate is largely due to its expanding authority over therapeutics of all kinds. In 2003, the drug center became the regulator of biotechnology and the critical gatekeeper for small entrepreneurial companies as well as the industry giants. Since then, CDER has assumed responsibility for many products and companies outside traditional definitions.
Woodcock has played a central role in the transformation and, even aside from her current position, is probably the ideal person at the FDA to assess its progress. Even before the transition of biologics authority, she headed CBER’s Office of Therapeutics. Now, she says, the integration of cutting-edge therapeutics into CDER is nearly complete — save some IT systems, which typically lag behind any big organizational change. Biotech and other high-tech products represent a large and ever-growing portion of CDER’s workload.
In hindsight, the transfer of biologics to CDER makes a lot of sense. As time goes on, the line between small-molecule and bio-engineered therapeutics continues to blur.
“We may approve a small molecule and a biologic for very similar indications, say, for cancer,” Woodcock explains. “There are also some areas that overlap; for example, determining how small a large molecule can be and so forth, and we’re seeing small molecules with very complex delivery systems. So, all of these therapeutics are in a mix together, and we try to have the same standards for efficacy and safety for whatever intervention it is.”
New challenges constantly arise to tax the center’s organizations and resources. Chief among them are combination products: medicines that incorporate diagnostics, delivery technology, and novel procedures as integral elements in their therapeutic strategy.
“We anticipate that over time there will be multiple combinations and permutations,” says Woodcock. “Our Office of Combination Products is supposed to deal with regulatory assignments and pathways. But, when it gets down to actual reviews, for example with drug-diagnostic combinations, we are setting up procedures to deal with the device center so that everybody knows what their role is, even at the IND [investigational new drug] stage. There will be new kinds of drugs and devices, too, that we must learn to handle together without confusion between the centers.”
As the regulatory arena grows ever more complex, the political tug-of-war between those who see an unresolvable dichotomy of drug safety or efficacy versus innovation will only intensify. Perhaps the debate will rage on to the point that the historic partnership of private industry and the U.S. government in the life sciences breaks down entirely, and that the FDA itself abandons its traditional scientific role. Recalls and lawsuits would then be the only recourse when, as history predicts, the inevitable happens with serious adverse effects of drugs on the market.
It is doubtful that industry will enjoy such a Wild West environment. History also shows that biopharma companies generally prefer a high barrier of entry to the market based on scientific merit — if only to weed out competitors with frivolous claims. And, abandoning the quest for major advances in drug safety/efficacy simply flies in the face of science. Equally, to the extent that selling medicines ultimately relies entirely on public trust, making safety standards a scapegoat makes no sense as an investment- or job-producing strategy. Woodcock and her team at CDER are counting on science to show a new way, a new path by which safety and innovation can work hand in hand.