E-drug: Strategies for Pharmaceutical Cost Containment (cont)
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In respect to strategies for cost-containment, one that is rather widely
practiced, though not widely publicized, is the search by formulary
committees in US managed care organizations for sound bases for
cutting recommended doses.
One product that was dramatically cost-reduced by this maneuver
several years ago was the adoption of the 'pulse-dosing' regimen for
itraconazole for fungal infections of the nails. An astute clinical
pharmacist, as the story goes, serving on the formulary committee of
an MCO, came across a paper in the research dermatology literature on
the turnover of itraconazole in the nailbed, and concluded that the
turnover kinetics were slow enough that the drug could be given,
instead of daily for 3 months, as recommended, daily for 7 days
repeated monthly for 3 months, in other words one-quarter the number
of doses, and thus one-quarter the acquisition cost of drug. That
regimen was adopted and enforced by prescribing guidelines within the
MCO in question. Soon many MCO's were doing the same thing. As the
practice spread, FDA requested the company (J&J-Janssen) to carry out
comparative efficacy testing of the pulse-regimen vs the originally
recommended one, the results of which confirmed the efficacy of the
pulse-regimen. The official labeling was then revised, but of course
the economic impact remained.
Post-marketing dose reductions are fairly common -- Cross, Peck and
colleagues had a poster on these at the ASCPT meetings in Orlando
last month, and one can see from the website of the WHO Collaborating
Centre on Drug Statistics & Methodology in Oslo that there have been
many drugs whose 'defined daily doses' (a parameter used in drug
utilization research, reflecting what is being prescribed in actual
practice in many countries) have been reduced by half or more since
1980, when the Oslo group starting compiling such data. It amounts
to 1 drug in about 4 having had its originally recommended daily dose
reduced, either de facto or de jure, depending on whether or not the
regulators sanctioned the changes or not. From the Oslo data, one
can see that increases in defined daily doses, which were fewer in
number, occurred almost exclusively with anti-infective agents,
possibly reflecting, in part at least, changes in microbial
resistance.
In pre-market development of new drugs, there is a rather strong,
systematic bias toward setting the recommended dose too high.. Back
in 'the good old days' when prescription drugs were inexpensive,
setting the dose too high incurred mainly the potential matter of
avoidable, dose-dependent
side-effects. In today's world of ever more pricey new drugs, it is
perforce a major economic issue.
A rather simple way to assess whether the recommended dose has been
set too high is to follow a group of treated patients in routine
practice using a
reliable measure of their compliance (which means electronic monitoring, the
only method both practical and reliable), and observe the clinical correlates
of their actual drug intake. Given that the prevailing patterns of compliance
are strongly downwardly skewed in drugs that have no abuse potential, one is
thus able to observe in this 'natural experiment' the clinical correlates of
varying degrees of underdosing. If you observe that the underdosers
seem to be doing no less well than the full-dosers, then the next
step is to formulate a
hypothesis about what the optimal drug regimen seems to be, and go on
to design and execute a formal trial of the new vs the old regimen to
test for the
non-inferiority of the new, lower-dose regimen vs the recommended
regimen. One must pay careful attention to the issues of assay
sensitivity in such trials.
For a full discussion of that matter, see the ICH E10 document, Choices of
control group in clinical trials, which can be found at the either the website
of the International Conference on Harmonisation of Drug Regulation or in its
trascription in the US Federal Register, September 24, 1999, Volume
64, Number 185, Pages 51767-51780.
Of course the pharma companies can run this same type of study during
pre-market development, to confirm or challenge their choice of
recommended doses before pricing is set, thus preventing them from
being blind-sided by a post-marketing dose and revenues reduction.
But they have lagged in adopting this approach, with the result that
running the compliance-outcome protocol in the post-marketing arena
is fairly likely to turn up some opportunities for dose cutting.
Since most drugs are priced on a weight basis, cutting the dose cuts
the acquisition cost. Moreover, once pricing is set in the major
countries, it is essentially impossible to revise pricing to
compensate for halving or quartering of recommended doses.
One could lump this approach under 'rational prescribing', but I think it
deserves separate status. I would call it: "Systematic challenge of
recommended doses" if one wanted to take the aggressive approach, or
"Post-marketing validation of recommended doses" if one wanted a more
neutral approach.
John Urquhart, MD, FRCP(Edin)
Professor of Pharmaco-epidemiology, Maastricht University, Maastricht, NL
Chief Scientist, AARDEX Ltd/APREX Corp, Zug CH & Union City, CA, USA
Professor of Biopharmaceutical Sciences, UCSF, San Francisco
home office: 975 Hamilton Ave, Palo Alto, CA 94301 USA
tel: +1-650-321-3961; fax: +1-650-324-9739
email: urquhart@ix.netcom.com
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