March 1, 2006 (Vol. 26, No. 5)

A Standardized Expression of Benefit Is Missing from Our Risk/Benefit Analysis Paradigm

Today the problem of deciding the case for approval is fraught with intense yet supposedly unknowable perils. The FDA and other regulatory agencies globally struggle with ambiguities that typify the review process for routine submissions to the extent that these submissions reflect the state of risk analysis, risk mitigation, and risk communication, derived from the most current revisions of the internationally harmonized risk standards and terms of reference.

The greatest dilemma facing these industries now is how to proceed in the face of conflicting urgencies of patient risks, many of which represent long-term unanticipated side effects and/or co-morbidities, and compete with the clinical relevance of the therapeutic values/utility of the drug.

How does a company that is developing a new biotech product reconcile safety concerns in the process of obtaining and confirming scientific data to support market approval for an intended use? What happens during commercial distribution of this product when data arise that suggest increased risk factors are associated with a subpopulation of patients? Who should decide when a product is unsafe, and, more significantly, how?

Numerous definitions related to risk exist and are familiar to any participant in the biomedical industry. Utterly unfamiliar to the same group is any definition relating to benefit.

What is missing from the paradigm of risk/benefit analysis is a standardized expression of benefit. In preparing a regulatory submission, one is left to calculate risk in terms of process risk, patient risk, mitigated risk, and residual risk, with the implication that medical (clinical) benefit remains an unstated and unquantified (if otherwise vaguely inferred) value.

Better to Do Nothing

Citing the Hippocratic Oath, Primum non nocere (First do no harm), as industry guidance, this justifies not making a product if the risk of hazard leading to harm is imputed as unacceptably high. Thus, many in industry opt not to provide access to a risky medical product.

This risk aversion may be driven by the Vorsorgeprinzip (precautionary principle), by which it is considered better to do nothing than to do something that may also be harmful. Moreover, the decision to accept risk is deeply influenced by our societys values.

Nevertheless, there is a need for deciding the relative effect of a medical device, drug, or other biotech product using a comparative and balanced method whereby residual risk is associated with corresponding medical benefit. Such a systematic approach could save industry time and costs in drug development during the pre-market phase, and the public time and expense in achieving access to new drugs during the post-market phase.

A clearly defined and standardized expression of medical benefit should not serve as a substitute for the conventional expression of risk, rather as a supplement. This supplement to comprehending patient risk should enable a balance that currently does not exist in evaluating the overall suitability of a medical product for the marketplace.

Absence of this balance has led to some recent spectacles in the medical marketplace, not the least of which has been the case of Vioxx. In this case, Merck pulled the drug off the market due to risk factors that made continued sales unacceptably risky, despite FDA approval and continuing regard for the drugs utility.

Ten months ago, participants in clinical studies and their physicians sued Amgen for pulling an investigational new drug from development. Amgen cited risk factors in stopping the development program.

Evaluating Risk

The common denominator for evaluating risk is societys values, and in the U.S., as elsewhere in the modernizing and increasingly cosmopolitan world, knowing and agreeing upon values is fundamentally challenging. For some, proposing that death is a better outcome than continuation of a debilitating and dignity-robbing condition is obvious, while for others it is appalling.

Ours is a society that is evermore pain-averse, and currently we use a quality of life measurement for which only physical and emotional fitness is examined as it relates to function and comfort.

Financial well-being is not considered. Therefore, an effective painkiller that depletes a life savings over time, because it is priced so high, is nevertheless considered to improve the quality of life. If the painkiller has lingering dangerous side effects or increases other health risks or co-morbidities, these are not counted as heavily as the pain reduction.

A Balanced Analysis

I propose a concept of a balanced analysis of risk and benefit. While we have explored standardized measures to express the subjective and dynamic term Quality of Life, few have served as well as the quality adjusted life year, or QALY, in referencing clinical benefit over time. Relating this measure to patient risk is the task at hand, in order to balance the precautionary perspective with a supplemental perspective regarding clinical utility or benefit of any medical product.

The medical industry has been shaped for decades by regulation, reimbursement constraints, and risk-aversion into competing regimes. These camps have been trained to respect, if not embrace, the costs and time applied to investigating product consequences in advance of product availability. Enormous amounts of time and mind power are spent on labeling and risk communication, with an ever-narrowing acceptability of the associated risks of use.

All this effort is to satisfy a market whose values often do not preclude the acceptance of risk, even unto death, in its struggle to obtain benefit, even potential benefit. The Abigail Alliance, an advocacy group comprised of late-stage cancer patients, is pointedly asking for access to cancer drugs under investigation regardless of the risks. However, the choice of taking unapproved drugs for even potential improvement in quality of life is not allowed.

With a medical industry that felt confident enough to offer a new paradigm prospectively to the FDA, there might be a pre-market submission composed of less risk-related data and more quantitative expression of the benefit of the proposed product within its intended uses.

The fact is that, although risk-mitigation is a zero-sum exercise, there is always some residual risk. Current efforts to amplify risk management throughout the life cycle of a medical product ought to be supplemented by achieving a working standard for measuring the intended and actual improvement in the quality of life, and for how long the improvement is likely to endure, so as to factor into premarket submissions and subsequently postmarket surveillance activities.

The FDA currently regulates for safety over effectiveness, and if the U.S. medical industry and its market desire to see improvements in medicine, for which our nation is certainly capable, then it will task itself with establishing a standard of risk acceptability as measured in the context of corresponding clinical benefit.

Upon completing this task, the process of drug development and regulatory market approval would be improved due to the increased clarity in decision-making. There could be far less waste, less cost, and less anguish in adopting such a standard and applying it to rule making. Such a system would increase our knowledge of risks as they relate to benefits over time, whether intended or unintended. This data, expressed comparatively or semi-quantitatively, would use scales that take into consideration that, in certain cases, the quality of life gained by the medical treatment may be considered worse than death.

Moreover, the utility of a medical treatment in prolonging such conditions and/or co-morbidities rather than improving the quality of healthful living is of a negative benefit. Such data, expressed in summary form for consideration by panels and the public, are valuable and urgently necessary. There are some models for using a new method of risk/benefit calculus for the life sciences. Before a new method is applied, however, the medical industry must be bold enough to demand it.

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