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The advent of blockbuster drugs by jfm16066


									                                                                                                    Update 2008, Issue 3
                                                                                                    With Permission from FDLI,

   What Drug Companies Can Do
    by Mei Sheng Duh, Sc.D., Paul E. Greenberg, and Lucia Antràs, Ph.D.

        he advent of blockbuster drugs      patients of potential side effects. More-   steeper than the increase in the total
        in the 1990s revolutionized         over, an increasing number of popular       number of outpatient prescriptions over
        American medicine. An aging         drugs (most recently Merck’s pain-          the same eight-year period, driving
population now relies on popular            killer Vioxx and Novartis’ Zelnorm          researchers to search for explanations.2
medications to treat a variety of com-      for irritable bowel syndrome) have been     One contributing factor may be that
mon conditions, such as hypertension,       withdrawn due to concerns over cardiac      many chronically ill patients now take
high cholesterol, type II diabetes, and     safety. It should come as no surprise       a given drug daily over the course of
arthritis. One perhaps unavoidable          to industry observers that high-stakes      many years. Another is the number of
consequence has been an increase in         mass tort litigations against pharmaceu-    patients taking multiple prescriptions,
the number of adverse events (AEs),         tical companies are now increasingly        increasing the potential for drug-drug
defined by the Food and Drug Admin-         common.                                     interactions. And, unlike the small test
istration (FDA) as events requiring            On the regulatory front, the FDA         groups in clinical trials, which tend to
medical intervention to prevent harm.       Amendments Act, signed into law             be homogenous and carefully selected,
   According to FDA’s Center for Drug       in September 2007, has set forth risk       users of on-market drugs are highly het-
Evaluation and Research (CDER),1 the        identification, evaluation, and mitiga-     erogeneous, bringing a complex range
number of AEs reported from 1995 to         tion objectives for the FDA regard-         of potential co-morbidities into play.
2005 increased at a compound an-            ing postmarket drugs. The combined             Given the inherent difficulty of pin-
nual growth rate of 11.5 percent, from      impact of these factors has led phar-       pointing the precise cause or causes of
156,500 to 464,000. At least partially as   maceutical companies to incorporate         AEs in diverse populations, pharmaceu-
a result of this increase and the surge     greater attention to drug safety into       tical companies cannot realistically try
of scrutiny by public health regulators,    their pre-market approval processes as      to eliminate risks to all patients; instead,
about one-fifth of prescription drugs       well as post-marketing surveillance.        they must determine the best strat-
now carry a “black-box warning,” issued        The recent spike in reported ad-         egy for addressing the particular risk
by the FDA, the most serious label a        verse events, as an Archives of Internal    potentially associated with every new
drug can bear to inform prescribers and     Medicine study notes, is four times         and existing drug. But risk assessment,

                   Dr. Duh, Sc.D.                             Mr. Greenberg                                Dr. Antràs, Ph.D.
                   is a Vice President                        is a Managing                                is a Manager at
                   at Analysis Group,                         Principal at Analysis                        Analysis Group,
                   Boston, MA. She is                         Group, Boston, MA.                           Boston, MA.
                   a pharmacoepide-                           He is also Co-direc-
                   miologist.                                 tor of its Health Care

FDLI                                                                                                       May/June 2008   Update      35
       A Risk Management Roadmap                                                              to “first, do no harm,” today’s demand-
                                                                                              ing patients seek perfect pills that can
                                                                                              cure the most persistent diseases.
       1. Review clinical trials. In the wake of what happened to                                 The safety standards for pharmaceu-
            Zelnorm and Avandia, it is especially important that pooled
            analyses be carefully examined.                                                   tical products are significantly higher
                                                                                              than those imposed on nearly all other
       2.	Implement a signal monitoring program, using MedWatch                               industries. As a result, even when the
            data, to determine if your drugs are on a watch list, and
                                                                                              incidence of AEs is extremely low,
            therefore likely to be under scrutiny
                                                                                              drugs can still be withdrawn from the
       3. If you get a signal, identify it and the adverse event that                         market. And, in our litigious society,
            could potentially occur. Note that the nature of the data                         if a drug is used widely, the scope
            allows a high number of spurious signals to be sent                               alone makes it likely that litigation will
       4.	Validate the signal with a quick, denominator-based claims                          ensue, even if only a small proportion
            analysis. The result will be a propensity score matching,                         of patients is affected. As University
            adjusted for demographic variables such as age and gender.                        of California researcher Robert Kagan
                                                                                              points out in American and European
       5. If elevated risk is still being returned, a more sophisticated                      Ways of Law: Six Entrenched Differ-
            epidemiological study is required, to combine claims data
            with patient chart data.                                                          ences, “the United States is distinctive
                                                                                              in the relative ease with which entre-
       6. Determine whether the signal was a chance finding by                                preneurial lawyers can aggregate tort
            trying to replicate it using another claims database; if not,
                                                                                              claims by persons injured by the same
            determine relative risk, using U.S. population data.
                                                                                              product, accident, or technology into a
       7. Before undertaking the most difficult and costly analysis                           single case, demanding millions … or
            —randomized safety trials—companies can develop an                                billions of dollars in damages.”3 The
            information and education program of outreach to pre-                             business implications of possible litiga-
            scribing physicians and patients.                                                 tion must therefore inform any risk
       8. Undertake randomized safety trials, if the cost-benefit                             management discussion.
            analysis merits it.                                                                   Pharmaceutical companies clearly
                                                                                              need to develop a pragmatic approach
                                                                                              to managing the safety of on-market
     which epidemiologists define as the        considerations, with unwavering at-
                                                                                              drugs. Unfortunately, they can’t yet
     probability of the occurrence of harm      tention to maintaining the public’s
                                                                                              turn to any standard protocols for help
     and the severity of that potential harm,   trust. In this article, we lay out a simple
                                                                                              in managing risk during the post-
     requires expert judgment combined          roadmap, based in epidemiology, that
                                                                                              marketing period. In 2005, the FDA
     with input from many parties: company      drug companies can use to design and
                                                                                              published some nonbinding recom-
     scientists and clinicians, executives,     implement a risk-management program           mendations on pharmacoepidemiolog-
     general counsel, and perhaps external      tailored to their specific products.          ic assessment, but this guidance does
     counsel and strategic advisors as well.                                                  little more than define basic concepts,
        A comprehensive approach must also      Building a Risk
                                                                                              stating, for example, that “pharma-
     take into account the unique role drug     Management Program                            covigilance principally involves the
     companies play not only as providers       Pharmaceutical companies are at-
                                                                                              identification and evaluation of safety
     of products critical to public health      tempting to address the challenges            signals.”4
     and disease prevention, but also as        of on-market drug risk management                 Absent formal guidelines, pharma-
     viable businesses with obligations to      within complicated and often highly           ceutical companies must strike a bal-
     shareholders. Ultimately, risk manage-     charged business, social and political        ance between benefit and risk. That
     ment decisions must be based on both       contexts. While drug manufacturers            means evaluating the positive treat-
     epidemiologic concerns and business        and healthcare providers must pledge          ment efficacy of products that will

36   Update    May/June 2008                                                                                   
help the majority of patients who take       ment program continues to be largely        Strategic Decisions in
them alongside the potentially nega-         a qualitative effort, dependent more        Balancing Risk and Benefit
tive side effects, or AEs, which typi-       on judgment calls than on fact-based        Pharmaceutical companies may decide,
cally occur in a minority of patients.       findings. Determining the appropriate       based on corporate strategy, to manage
Ideally, drugs would be administered         risk-benefit balance always involves the    the results of an AE signal related to one
only to patients not likely to suffer side   judgment and preferences of the deci-       drug retrospectively, while they may
effects; however, the ability to predict     sion maker as well as some uncertainty      need to choose a proactive approach with
this accurately and consistently is well     around the true benefits and risks of a     regard to a different drug. Some drug
beyond the limits of current medical         given drug. Quantitative methodolo-         companies develop safety programs that
knowledge and technology. In addi-           gies, building upon existing methods        are implemented from the moment drugs
tion, a side effect that might appear
to be a random adverse event at one
point in time may later—with hind-                    Once researchers begin linking
sight bias (the medical equivalent of
                                                        adverse events to the known
Monday-morning quarterbacking)—
be interpreted as a signal of an adverse              properties of a drug, it becomes
event that should have been detected                   easy for critics to accuse drug
and managed. Once researchers begin
linking adverse events to the known
                                                   companies of not having done enough
properties of a drug, it becomes easy                to safeguard the public all along.
for critics to accuse drug companies of
not having done enough to safeguard
the public all along.
   In designing risk management              for analyzing cost-effectiveness, could     enter the product pipeline, preferring to
strategies, drug company executives          serve as a possible way to allow decision   gather and analyze data in advance of
need to conduct a cost-benefit analysis      makers to evaluate the net benefit of a     potential FDA requests or investigations.
based on multiple possible scenarios.        drug given different risk-benefit accept-      Whatever the approach selected,
H. Gregg Claycamp, Associate Director        ability thresholds.6                        each program needs to be appropri-
for Risk Analysis and Strategic Policy          As noted earlier, the context in         ate to the specific nature of the risk.
                                             which these decisions are being made        Whenever a pharmaceutical company
Assessment at CDER and an expert on
                                             has changed significantly: the risk         identifies a signal of a potential side
risk management, suggests that any
                                             benefit calculus often now takes place      effect (from monitoring MedWatch
such program must, at a minimum,
                                             under intense scrutiny from public          for example,) it will often develop and
address the following questions:
                                             health crusaders, industry watchers         document a response. However, since
■ 	Does the risk exceed an acceptable
                                             and regulators, competitors, media and      risk management programs can be ex-
   level? Or is it already below current
                                             the general public. In the face of this     tremely expensive, companies cannot
   regulatory concerns … or has it been
                                             pressure, some companies are begin-         afford to follow up on every signal, or
   reduced by risk management pro-
                                             ning to adopt more formal quantitative      to investigate each to the same extent.
   grams to a currently acceptable level?
                                             methods for weighing risk and benefit,      Consider the case of two drugs for
■ 	What steps might be taken to reduce       identifying thresholds for drug safety      which the manufacturer has identified
   or eliminate remaining risks?             in much the same way that they evalu-       similar AE signals, one with a history
■ 	What is an appropriate balance            ate drug cost-effectiveness. The impact     of annual sales in the $5 billion range,
   among risks, benefits, and resources      and results of these methods are,           and a newer product with first-year
   to manage risks?5                         however, still being studied, and defin-    sales of $100 million. A very different
   The broad nature of these con-            ing the relative term “acceptable risk”     risk-benefit ratio may apply to each,
siderations underscores the fact that        therefore remains for many companies        resulting in two separate risk manage-
assessing the needs of a risk manage-        a qualitative challenge.                    ment approaches.

FDLI                                                                                                       May/June 2008   Update     37
         For some pharmaceutical companies, the        drug safety is unlikely to diminish,          ing and drug regulations will not fully be
     threat of lawsuits over product safety is the     and pharmaceutical companies may be           known in the foreseeable future. In the
     primary catalyst for establishing a risk man-     forced to devote greater resources to         interim, in order to survive and succeed,
     agement strategy. In litigation, a proactive      risk management programs. However,            drug companies may have to focus as
     approach can be key. A solid risk manage-         the precise shape of programs imple-          much energy on strategic risk manage-
     ment program will have identified and             mented can be expected to evolve in           ment as they historically have on such
     assembled a set of well-researched studies,       accordance with advances in both sci-         core areas as drug development, innova-
     published in reputable health care journals,      ence and risk management.                     tion, and growth. FDLI
     well in advance of any suits being filed. This        In the future, part of every company’s
                                                                                                     1   FDA, CDER Report to the Nation, Post-marketing
     might involve gathering data-based evidence
                                                       risk management strategy may involve              adverse event reports, 2005
     on the population level—in other words,                                                         2   See
                                                       reducing the number of AEs, for example,
     epidemiological evidence, not just clinical                                                         stract/167/16/1752
                                                       by applying new insights into the genetic     3   Robert A. Kagan, “American and European Ways
     trial outcomes. Such evidence can be used to                                                        of Law: Six Entrenched Differences.” Institute
                                                       basis of drug safety problems. That’s the
     demonstrate, for example, the incremental                                                           of European Studies, http:/repositories.cdlib.
                                                       goal of the newly established International       org/ies/060407
     risk of a specific drug relative to established                                                 4   FDA, available at
                                                       Serious Adverse Events Consortium,
     baselines. As was the case in the Vioxx trials,                                                     GUIDANCE/6359OCC.pdf
                                                       funded by seven of the world’s largest        5   Gregg Claycamp, Perspective on Quality Risk
     having this kind of evidence in hand at the                                                         Management of Pharmaceutical Quality, Drug
                                                       drug companies, that is already searching
     outset can help companies attain critical                                                           Information Journal 353; Vol 41, Issue 3, July 1,

     early wins in mass torts.                         for a genetic cause of liver-toxicity and         2007
                                                                                                     6   Lynd LD, O’Brien BJ. Advances in Risk-Ben-
                                                       plans to focus next on heart and kidney
                                                                                                         efit Evaluation Using Probabilistic Simulation
     Conclusion                                        problems related to drug side effects. But        Methods: An Application to the Prophylaxis of
                                                                                                         Deep Vein Thrombosis. J Clin Epidemiol. 2004
     With Americans taking more prescrip-              the science of pharmacogenetics is still in
     tion drugs each year, concern about               its infancy, and its impact on policy-mak-

                                                                                                                                                     FOOD CRISIS
                                                                                                                 FOOD CRISIS

                                                                                                                                                           T MANUAL
                                                                                                                                                           2nd Edition
                                                                                                                                                     Prof. James T. O’R


38   Update      May/June 2008                                                                                                                           

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