PI Perspective #23

November 1997     View PDF     En español

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, twice-daily 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 long-term 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:

• 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.
• 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 Concerns
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 Administration (FDA) that the dosing change produces 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 long-term 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 questions. 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 perform continuous, long-term follow-up of the people who participate in the dosing regimen trials. Records should be kept for two years 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.

A Recommendation
For now, it is wise to assume that there was a good reason for the dosing schedule recommended when a drug was first approved. People should stick to that schedule until someone proves that a different schedule is truly equivalent over the long term. Once sufficient data exist that a simpler regimen may be useful, it should be cautiously offered as an alternative by the sponsors—not aggressively marketed—to people having trouble adhering to the proven, initial regimen. Then perhaps if long-term follow-up proves true long-term clinical equivalence, a time may come when the new dosing may be recommended for standard use.

The desire for easier dosing regimens is not a bad thing. But the goal should be achieved the right way—by designing new and better formulations, not just by changing the labels on older drugs after rushed, short-term studies. Simply changing the label on an existing drug is a very tempting short cut, but it is not necessarily in the real interests of people whose lives depend upon long-term success of drug regimens.

Finally, patients and physicians should note that switching one or another drug to twice daily dosing doesn’t necessarily simplify a person’s daily routine. It can just as easily complicate it. For example, if the other drugs a person takes require a thrice-daily regimen, changing to a twice daily antiviral might result in a person now having 5 distinct “drug taking” periods in the day.

Project Inform urges anyone who is asked to participate in marketing surveys or focus groups on this subject to consider the more complex issues involved above and beyond the simple desire for easier dosing. Simpler dosing is a reasonable objective, but should not come at the cost of the long-term durability of therapy.

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