Safety Net

One basic assumption we must make in the new Culture of Drug Safety is that there will be continuing focus on drug risk and hazards throughout a drug's marketing. The Culture of Safety raises many questions for pharmaceutical companies: What types of studies and which risk-mitigation tools will be employed? What will be their direct impact on drug use and their indirect impact on the general acceptance and use of medications? How do we provide sufficient information to regulators, prescribers, and drug users about the benefits of our products so that a fair decision can be made on the marketing, prescribing, and usage of our drugs? Generally, how do we steward our drugs in the dynamic but "hazard heavy" environment so that they can be used appropriately?

Underlying all these questions is a sea change in how the risk/benefit ratio is perceived by key stakeholders. We've known all along that the risk/benefit ratio is not fixed, that it can evolve through time. But now, the perception has shifted in a very important way. Now, FDA's leadership is expressing the idea that risk/benefit is dynamic and fundamentally unknowable premarketing. Here, for example, is how FDA's Deputy Commissioner and Chief Medical Officer Janet Woodcock expressed the idea at a recent hearing:

"The premarket clinical trials that are done to get products onto the market can't identify all the potential risks, as we know, or even the future changes in use patterns that are going to occur once that product gets out there," she said. "Therefore, full knowledge of benefit/risk doesn't exist at the time of product approval, and often not at the time of treatment decision making.... Therefore, timely and effective postmarket surveillance and risk communication—in other words, communication of the evolving information as rapidly as possible—is critical to reduce the knowledge gap and foster better-informed treatment decisions and actually keep people safe."

The emphasis in the new Culture of Drug Safety will be on reassessing and recalculating the risk/benefit ratio through the life cycle of a drug. One area where we can look for innovations is in the way we generate new postmarketing safety signals. FDA has already held hearings on creating a new "Sentinel Network"—a virtual, integrated, electronic nationwide medical-product-safety network. It is highly likely that new systems will be developed based on computer review and data mining of very large databases—perhaps 100 million lives or more. It's also likely that new methods of collecting information from physicians will be sought, so we aren't simply relying on the passive submission of adverse-event reporting forms.

As these systems develop, they will catch subtler safety signals and catch them much faster than today's adverse-event reporting system. How much faster? At the FDA hearing on the Sentinel System, Richard Platt, a professor at Harvard Medical School and principal investigator of the HMO Research Network, Centers for Education and Research on Therapeutics, said, using existing databases, it would be possible to assemble a network of 100 million lives. With such a system, he predicted, the link between Vioxx and heart attack would have been discovered in two or three months rather than 34.

Even if Platt is correct, is also likely that the focus on early detection will lower our threshold for signaling when an observed increase in drug hazards is the sign of a serious adverse reaction. This can result in false positives and a loss of credibility. "People reach different judgments on when to shout and when not to shout," said Robert Temple, medical director at FDA. "It's the hardest single thing—the value and danger to screaming early."

The View from FDA

Rewriting the Safety Equation

Currently, to have a new drug application (NDA) approved, a company has to demonstrate that the product's benefits (B) outweigh its risks (R), so B/R>1. In the new Culture of Drug Safety, more danger signals will be detected and more safety studies undertaken, not only for the drugs we are championing as if our livelihood depended on it (and, of course, it does) but also for other drugs both within and outside the class.

As a given drug moves through time, two things can happen:

» R or B may change due to the discovery or verification of new information (either positive or negative).

» The perception or interpretation of R or B may change, not because of new information about the drug but because of the context in which the information is conveyed. For example, a competitive drug for the same condition has been approved in the period between initial approval and the new risk/benefit analysis. Although comparative risk/benefit analyses are not supposed to influence drug safety analyses, they clearly do—and they will continue to influence safety decisions.

The Institute of Medicine (IOM) called for a fixed time for review of risk/benefit (such as five years after approval). However, the continued search for drug risks will increase the frequency with which new safety questions are discovered or verified. For most drugs, the risk/benefit ratio will become steadily more unfavorable unless companies take steps to ensure that new information about benefits is provided to balance or overcome new information about risks. The question is how to do that.

Currently, life cycle plans are viewed as a marketing-focused template that helps to identify sales and profit goals, new uses to be investigated, and long-term strategies to stave off therapeutic and generic competition. In the new Culture of Drug Safety, we will need to modify and adapt life cycle planning to meet the challenges posed by the continued discovery and analysis of drug risks. There are several goals we will need to integrate into our life cycle planning. These goals include benefit identification, benefit and risk quantification, and benefit augmentation.

Benefit Identification

In many instances, the intended uses of a drug are also its benefits. For example, if a drug is approved to treat pain, its benefit is that it treats pain. In cases like this, the benefit of a drug is said to have "face validity," and if there are no other effective drugs in a class, face validity is usually sufficient for approval.

But there are many effective drugs in many classes, and a manufacturer who wants to add an additional drug to the class must look to additional benefits. In the case of a pain drug, for example, the benefit may be that it treats pain more rapidly, more conveniently, with fewer minor side effects, or with less chance of addiction or abuse. These are clearly benefits, but they are much more difficult to analyze in a R/B equation.

In the past, manufacturers have argued successfully that providing an alternative treatment option is sufficient benefit to justify approval. Recent cases, however, suggest that that may no longer be true. During the FDA advisory-committee meeting to review Merck's proposed new COX-2, Arcoxia (etoricoxib), the company made just that argument. FDA and the committee, however, wanted evidence that people who have failed on one pain reliever would benefit from a new product. Without it, they were unable to quantify the benefit of the product. (Disclosure: I served on the Arcoxia advisory committee and voted against approval.)

How do we translate drug effects into benefits, and how do we make these benefits tangible? This will be a major problem for the industry. The most likely candidate for providing this perspective is some form of patient-reported outcome (PRO) or health-related quality-of-life (HRQL) measure. These scales are commonly used in clinical trials as secondary end points to help characterize the disease and the drug's impact on the disease. A new class of scales that can help capture drug effects—not necessarily disease impacts, as quality-of-life instruments currently do—will likely be needed to identify the meaning of the drug's benefits to patients.

Let's say we can demonstrate that a drug improves patients' functioning, social interactions, and physical well-being. How do we now add sufficient meaning to these outcomes so that physicians in FDA or on its advisory committees can place those benefits into a perspective that will balance the perceived negative physical impact of severe adverse effects?

Benefit and Risk Quantification

Efficacy measures are not directly comparable to efficacy outcomes. Thus, R/B analyses are usually subjective exercises. Data on the disease burden, benchmarking against other drugs, or measuring the quality-of-life impact of the drug (both positive and negative) may help provide a perspective when interpreting risks or benefits. While some have argued in favor of putting all benefits and all risks into a single equation—using metrics such as health utilities or quality-adjusted life years (QUALYs)—these analyses are likely to be too broad and insensitive to be informative because too much information is lost in translating drug benefits and risks into one directly comparable metric.

Drug benefits are usually looked at from a medical perspective in which physiological outcomes dominate. However, that's more difficult to do for drugs that treat cosmetic problems (such as hair growth or removal), lifestyle issues (erectile dysfunction or birth control), or complex conditions whose medical impact is difficult to evaluate (depression or irritable bowel syndrome). Historically, the National Institute of Mental Health (NIMH) has had a very difficult time convincing the public of the large negative impact that depression has had on our society. Data from the Medical Outcomes Study that compared the impact of several diseases, including depression, on quality of life helped to put these issues into perspective. But such benchmarking across diseases is rare for FDA.

To quantify pharmaceutical benefits and risks, it will be important to link both positive medical outcomes (such as lower blood pressure or lowered cholesterol) and side effects to intermediate values of importance to patients. For example, even though patients may not feel the benefits of a blood pressure treatment, they know (or they should know) that lowering blood pressure is in their best interest. They also know that experienced or possible future side effects can be harmful or difficult to bear. Understanding how patients appraise and evaluate these positive and negative outcomes—in other words, how they view risk and benefit—will become important.

Benefit and risk quantification will require a better understanding of how physicians and patients make decisions about using medications. Marketing research techniques, such as conjoint analyses, can help to identify how factors are weighted, and decision-analysis techniques may be used to understand how these factors are combined to select an appropriate course of action. New insights into the holy grail of patient compliance, redefined as patient decision-making over time, may provide a new understanding of how to improve drug utilization—a serendipitous outcome of this new research.

Benefit Augmentation

Traditionally, drug companies have added benefits to their drugs by discovering new uses or developing new dosage forms. This clearly increases the real value of new products, and it will continue. But the industry will also need to build value or perceived benefits by understanding to an even greater extent how a drug affects a patient's lifestyle. Again, manufacturers will need to turn to market research techniques—such as ethnographic observations coupled with studies that measure beliefs, emotional reactions/adjustments, and values.

Quality-of-life scales may be highly valuable. But we will likely need more sensitive and customized studies that provide precise measures of how the drug (rather than the disease) affects the patient. For labeling or promotional purposes, FDA requires that such scales have pristine psychometric qualities. It is unclear how well-validated such customized scales will need to be to augment the perceived benefit of the product. Companies will need to better understand how the information they collect will be used in order to plan a program of research.

Because regulatory R/B analyses may be conducted at unpredictable times, it will be important to continuously collect, analyze, and store these benefit analyses in a dossier. Without active project management, we would expect much slippage in time schedules for the completion of such studies. Unlikely outcomes can easily slip down the hierarchy of our to-do list. However, as Nassim Taleb has discussed in his book The Black Swan, it is precisely these highly improbable events that have a massive impact.

Benefit Communication

Finally, we need to consider how the collection of information about the benefits of drugs can be communicated publicly. Any information that impinges on the safety of drugs must be incorporated into the product's label as rapidly as possible. But benefit information presents significant challenges. If companies want to be able to use it in labeling or promotions, they will have to employ careful study design, a systematic research program, and rigorous data-collection processes and analyses. FDA's recent guidance on PRO's incorporation in labeling demonstrates that FDA considers any benefit information equivalent to gaining a new indication. "Substantial evidence" in the form of adequate and well-controlled clinical trials is necessary to convince FDA that such measured benefits are real and worthy of incorporation on the label.

Even if the information is intended for promotional use and not incorporated into the label, FDA will insist on the same level of evidence. Thus, for specific promotional claims about a drug's effects, companies must collect sufficiently rigorous and reliable evidence. Without such evidence, companies will be limited to presenting the information at scientific meetings or publishing the data in scientific journals.

However, much of the new information pharmaceutical companies will need to collect about the benefits of drugs won't necessarily describe their drugs. Rather, it will measure patients' and prescribers' perception of those benefits and how those perceptions influence adoption decisions and use of the medicine.

For example, John Calfee, resident scholar at the American Enterprise Institute, recently published a survey of patients' perceptions of the risks and benefits of therapy for multiple sclerosis (MS). He asked patients if they would be likely or unlikely to use a medicine that was more effective at slowing down the progression of disability (or preventing relapses) but that caused 1 in 1,000 patients to die. He then modified the question to vary the number of people who would die from taking the drug (i.e., 1 in 500, 1 in 100, and 1 in 10). He found that slightly over half the patients (53 to 55 percent) probably would take the drug if 1 in 1,000 died, but that only a third or less would likely take the drug if the death rate was 1 out of 500 or fewer.

Such a study provides insight into how patients make trade-offs between the benefits and risks of therapy. Information of this sort does not have to be consistent with the product label in order to be communicated to the public. Yet it clearly has direct implications for how patients evaluate the risks and benefits of MS therapy.

It will be important to conduct further research into what types of patients are risk-sensitive or -insensitive and how to identify and communicate to them. Decades of research on risk perception has shown us that it's not just objective analyses of severity and probability that influence how people make decisions about undertaking risk. Patients also make use of their expectations about the perceived "dreadedness" of possible outcomes and their ability to control risks and cope with hazards. By understanding the criteria patients use to evaluate the risks and benefits of prescription medicines—and segmenting populations by risk/benefit perceptions—companies will be able to target prescribers and patients better and provide them with more meaningful information.

Conclusion

The pharmaceutical industry has perceived life cycle planning primarily as an aspect of marketing. We seek to jump-start product sales with a rapid introduction and uptake, we seek to maintain growth and sustain maturity of sales as long as possible, and we seek to stave off decline by morphing the product into some new use, with new dosage forms or delivery mechanisms or by switching the product to an OTC version.

In the new Culture of Drug Safety, life cycle planning will have new functions. It will need to define drug benefits in a much more structured and communicable form. It will need to place those benefits into a more logical and analytical framework along with drug risks. It will need to track public perceptions of the product in a fashion that will permit a better understanding of how attitudes about risks and benefits are formed. It will need to provide a much more complete understanding of how drug-use decisions are made and how various risk and benefit communications influence those decisions.

Maintaining a drug on the market will necessitate greater efforts by the industry. We have tended to regard the discovery of unexpected adverse drug effects as a matter of bad luck. This is not true. Rather, it is the result of careful vigilance and systematic study. Similarly, the discovery of the true benefits of a drug will also require creative research and a more thorough understanding of the meaning of the products we produce.

This is the second of three articles on the Culture of Drug Safety. In the final installment, we will focus on how risk and benefit communications will need to be researched, framed, integrated, and monitored in both safety and marketing communications. The first article, "Culture Shock," appeared in our July 2007 issue.

Louis A. Morris is president of Louis A. Morris & Associates. He provides consulting and research services to pharmaceutical and communications companies and has authored more than 100 articles and book chapters on health and risk communications. He can be reached at lmorris@optonline.net.