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Damned if you donít
by Randall C Willis  |  Email the author

It sometimes seems that it doesn't matter how the pharmaceutical industry approaches the development of new drugs; no matter what it does, it is wrong. Over the last few decades, the industry has faced lawsuit after lawsuit regarding unexpected side effects from drugs that it has put onto the market; drugs that met with regulatory approvalóa fact often ignored in these discussions. Clearly a situation of damned if you do.
To complete the expression, a commentary published last week in the British Medical Journal now argues that drug companies and regulators aren't doing enough to get treatments into markets where they can immediately save thousands or millions of lives. The article argues that too much time is being spent on randomized controlled trials in situations where a drug or treatment has a history in the literature of efficacy against a disease or condition.
Among their examples, the public health specialists from the University of California, Berkeley examined the impact of the stomach ulcer drug misoprostol on postpartum hemorrhage, a leading cause of maternal death, particularly in the developing world. The authors argue that study after study has shown the drug to be effective in treating women giving birth in remote locations but that the drug has yet to be approved by regulatory agencies for use in home settings (as opposed to in medical clinics) because thorough randomized controlled trials have yet to be completed.
"Good science, we suggest, is taking the research to the problem rather than conducting the research in the tallest ivory tower the investigator can find," the authors write. "The question is how much evidence is needed to move from research to practice, when the matter is life-saving interventions in poor settings."
While I believe that the authors' arguments have some merit, I am concerned that they too suffer from an ivory tower approach that doesn't take into account the realities that drug companies face in trying to put a new therapeutic out into the field. Already, some activists are complaining that in performing clinical trials in resource-poor settings, the pharmaceutical industry is "experimenting" on these people. They argue that the industry (and the West, in general) views the developing world as a source of expendable guinea pigs. Witness John Le Carre's The Constant Gardener, a very well written but politically slanted fictional book. (I also liked the movie, but didn't think it did the ethical dilemma justice.)
Given this already hostile environment, I wonder how quickly the pharmaceutical industry would be pilloried if just one of these drugs, rushed to market to satisfy a health crisis in the developing world, produced undesirable side effects downstream. Who then would stand up for the individual companies or the industry as a whole?
"The yardstick for decision-making should take into account the risks and benefits in the local conditions, not those of an ideal situation," the authors conclude.
I agree, and in principle, at least, I think that this is the basic premise under which most (if not all) companies and regulatory agencies work. And mechanisms exist to push for early drug approval based on conditions of critical need or superior clinical results. Usually these mechanisms are used by drug companies to argue their case, but patient advocacy groups are also starting to use the same steps to plead for early release.
But these examples are the exception to the rule and controlled trials remain the best way to stack the deck in favor of safer drugs. If the authors wish to take on the clinical trials process, which are almost universally accepted as excessive and onerous, then I fully support their efforts.
Until there is a mechanism to indemnify pharmaceutical firms against lawsuits for adverse drug events to save lives in a health crisis, however, I am confident that companies will continue to push for thorough controlled trials before going ahead with marketing. And I can't say that I blame them.
RE: Out of Order: Dammed If You Don't; October 11, 2006, DDN Online
Your cover article on "Dammed If You Don't" caught my eyeóbut one key facet was missing!†
While randomized controlled trials (RCTs) are certainly the accepted method for assessing efficacy and safety by global regulatory authorities, regulatory approvals are relatively straightforward compared to a bigger bottleneck that may already be impacting the drug development process.† In a word: economics.† Someone has to pay for all the new drugs, which are increasingly more costly.†
Public payers in all first-world countries are now demanding RCTs versus current treatments (rather than the regulator standard of placebo-control), and furthermore are requiring outcomes dataóexactly what you spoke ofóthe real-world large-scale safety (and "effectiveness" data that tells you how safe and effective the drug really is in a mass population (a "Phase V" trial.)† Except payers are demanding these data PRIOR to market (which is clearly ridiculous, not "do-able").† The net result of this is that pharma companies are increasingly able to access only 50 percent of their markets (private payers), which has all kinds of impacts on profits and corporate budgets.†
Something to think about, because even at the R&D/regulatory stage, pharma and biotec need to become educated about how to get their products paid for.† An extreme example is the enzyme replacement therapies, some of which cost up to $1 million per person per year.† All that development success, but very few can, and are, paying.† Profit expectations not met, no more money for R&D.†
I see the solution as requiring a global reassessment and realignment of industry with regulators and payers on the requirements for approval and coverage of new products.† These discussions should begin as soon as a company is considering moving into Phase I testing.† Everyone has always focused on regulatory approval.† Companies need to get with the times and think beyond that to coverage.†
Cures for many diseases, including possibly death, are around the corner (i.e., next 50 years), but the key question is: What is the cost of this innovation, and will there be anyone able to pay for it? 
Tania MacLeod, President, Market Access Solutions
RE: Out of Order: Dammed If You Don't; October 11, 2006, DDN Online
You might look at the saga of the introduction of Tysabri (Elan; Biogen) for MS. In particular, its introduction, its withdrawal upon progressive multifocal leukoencephalopathy (PML) infections in three trial patients, two of whom were also on Avonex (dual Av + Ty trial), and one other Crohn's patient, who was highly immunosuppressed. †In the opinion of some, the withdrawal was an overreaction, noting that no trial participant solely on Tysabri (about 6000-7000) has ever experienced †PML (often fatal) infections.
Tysabri is back (after 18 months more), but is highly restricted and believed by many to be lethal due to its "checkered" background †and has a quoted "risk" factor of 1000:1 (in apparent disregard of its clean monotherapy experience. †On the other hand, most MS sufferers (60-75 percent) who have experience (trials and initial intro) are willing to accept this (purported) risk factor according to several recent polls.

All of this is lamentable in that Tysabri is clearly demonstrated to be twice as effective in reduction of exacerbations as Avonex, Copaxone, Betaseron and other treatments , all of which have, for many (most) highly undesirable side-effects.

Perhaps this will find this another worthwhile addition to your gallery of pharma-disasters.

Dr. Alfred Hortmann, Professor, Washington University of St. Louis



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