Perspective: Information, Inspiration and Advocacy for People Living with HIV/AIDS

Simplar Dcosing

The Science and
Marketing of Simpler Dosing
Adherence to difficult drug regimens is a critical issue for people
using combination therapies. As data have accumulated about
the need for reasonably strict adherence to drug dosing regimens, so too has the demand for simpler, easier-to-use drugs.

Pharmaceutical companies have gotten the
message that people want less frequent dosing and fewer pills to simplify their complex daily routines. But rather than see new
drugs designed with this in mind, we are
instead beginning to see old "TID" (three
times per day) drugs simply redefined or
relabeled as "BID" (two times per day)
drugs. Changes in AZT dosing led this
trend. This in turn made it possible for
Glaxo Wellcome to begin marketing a new
single pill combining both AZT and 3TC
(called Combivir@) in a convenient, twicedaily dosing package. Very soon, we will
see similar efforts to redefine some of the
protease inhibitors. Studies are underway
seeking to redefine both indinavir (Crixivan@) and nelfinavir (Viracept~) as drugs
that can be taken only twice daily. Abacavir
(formerly GW1592), the new Glaxo Wellcome nucleoside analogue, will be marketed
from the start in twice daily doses and
efavirenz (Sustiva@), a new non-nucleoside
from Dupont Merck will be the first AIDS
drug prescribed for once daily use.
People generally welcome changes that
make drugs easier to use. But few people so
far seem to acknowledge that the stakes here
are considerably higher than just a matter
of personal convenience and that this issue
warrants great caution. At stake is the longterm success or failure of therapy, which
may or may not be jeopardized by reduced
dosing frequencies of some drugs. Were
convenience the only issue, having the flexibility to dose twice daily would always be
superior to three times daily. But first and
foremost, the goal of any dosing strategy
must be to keep a steady and adequate level
of the drug in the bloodstream from one
dose to the next. If that goal is not met, at
least two serious problems may be created:
1. Because of the longer times between
doses, the blood level of a drug used only
twice daily may fall below the minimum
needed to sustain full suppression of HIV.
When this occurs, it creates repeated daily
periods of inadequate dosing, a condition which actively favors the development of drug resistant virus.

* 2. The switch to fewer daily doses makes it
even more critical that people strictly adhere to the schedule. If skipping one dose
* out of a day's three doses is a problem,
as everyone agrees, skipping one of a
day's two daily recommended doses is
likely to be even more so as one dose
represents half a day's entire requirement.
* The hope is that easier dosing will result in. higher levels of adherence, that many people
who are incapable or unwilling to adhere
to a thrice daily regimen will be able and
willing to adhere to twice daily dosing. This
may or may not be so, but it is certain that
the consequence of non-adherence will be
more severe when fewer daily doses are
used. There will be even less room for occasional error.
Scientific CoDncerns. If changes to simplify dosing are supported. by sound scientific evidence that adequate
* drug levels are being maintained throughout the day, the duration of treatment effectiveness will not be shortened. If such
evidence is lacking, changing to a more
convenient dosing regimen runs the risk of
doing more harm than good. At the moment, the companies seem anxious to rush
these changes through the FDA approval. process based on as little data as possible.. In the hotly competitive market for AIDS
drugs, pharmaceutical companies face an
inherent conflict of interest over this issue.
Simpler dosing is not just a scientific matter, nor just an issue of patient convenience.
It is, from the manufacturer's point a view,
a very important marketing consideration.. Companies that can offer simpler, BID
(twice daily) dosing establish an important
marketing advantage compared to competitors who might still be selling a TID (three
times per day) drug. This inherent conflict
pits the interests of the Marketing Department against the beliefs of the research personnel, and ultimately against the interests
of the patients.
* In order to change their product labels to
recommend twice-daily dosing, they must
*. first convince the Food and Drug Adminis* tration (FDA) that the dosing change pro
* duces results equivalent to their previously
approved dosing schedule. While this
sounds reassuring, it is not convincing on a
scientific level. In short-term testing, there
is likely to be little difference between the
dosing schedules. Both should work well,
for a while. The real question is the longterm duration of effectiveness. Over time,
if the new dosing schedules result in daily
* periods of inadequate dosing, it will almost
certainly add up to quicker development of
resistant strains of virus. The real test is. how well people are doing after a year, or
* perhaps two years of treatment on the two
* different regimens. Unless the FDA demands
clinical testing which is capable of showing
this kind of information, patients and physicians can only be misled by the outcome.
All of this has become even more critical in
the last year as awareness has grown of the
widespread cross-resistance between drugs. in the same families. For practical purposes,
people have only one good shot at using a
protease inhibitor. It could easily be ruined
* by an inadequate dosing schedule, and the
patient is left with little or nothing to pick
up the pieces when the failure comes.. Once they get FDA approval, manufacturers will rush to make bold new advertising
claims touting the new "advantage" of their. drugs. One possible outcome might be that. the simpler dosing will improve adherence
among people who are inclined to miss a
dose now and then. This group might
achieve a net benefit, since they aren't likely
to be getting the best long-term benefits
anyway. However, if marketing and advertising suggests that the new dose is "best"
for everyone, it could cause those who currently are not having trouble with adherence to switch to what is for them a less
effective regimen, resulting in more rapid
failure. Nothing in currently planned studies will be capable of sorting out these ques-. tions. Simpler dosing might provide a net
* benefit for some and a net loss for others.
* For now, the FDA is gambling, with very
* little evidence, that the differences between
two dosing schedules will show up with a
year-long study. Perhaps so, perhaps not.
" There simply is no way to know. It may be
*impractical to demand that the FDA require. true, long-term studies to fully test these
* new, easier regimens. However, it may be
possible to demand that the companies per-.form continuous, long-term follow-up of the
* people who participate in the dosing regimen trials. Records should be kept for two
Syears or longer to determine the real long-term outcome, and they should attempt to
* distinguish between the effects in patients
with varying degrees of adherence.

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PI PERSPECTIVE NUIVBER 23 NOVEIVBER 1997