I would encourage Craig to provide some evidence that my comments are
largely untrue.

While phase-2 trials may incorporate some aspects of dose ranging, these
trials are rarely if ever done in the elderly, or patients with concomitant
disease states or abnormal liver or renal function - populations that often
need lower doses. Regardless of this frequently "untested" group, "average"
patients also very often require lower doses. There is a lot of evidence
showing that virtually every antihypertensive (eg. hydrochlororthiazide,
captopril, reserpine, nadolol, atenolol, most calcium channel blockers)
almost every sleeping/antianxiety pill (eg. lorazepam, triazolam), most
NSAIDs, some antibiotics (antibiotics for UTI's - primarily duration, strep
throat) AZT, ASA, many antidepressants, and so on and so on that are now
routinely dosed lower than when they were initially marketed. I'm sure Craig
is aware of an excellent and fairly recent example from his own company -
when Imitrex (sumatriptan) first came on the market, the recommended oral
dose was 100 mg - we now know that many patients respond to 25 and 50 mg
doses. If Glaxo did appropriate dose ranging studies, why did the product
monograph not initially recommend a 25 and 50 mg dose. While there are a few
examples of drugs for which recommended drug doses are higher than when the
drug first came on the market (eg. inhaled corticosteroids - although in the
last few years the push has been to use lower doses of inhaled
corticosteroids because of toxicity concerns) there are very few of these
examples. I would be interested in hearing of others.

Two of the reasons for suggesting lower doses are as follows

1) given that there is a response rate of 20-40% of patients in the placebo
group of most clinical trials, 20-40% of patients have shown that they
respond to the ultimate low dose.
2) as pointed out in the letter on our website
http://www.ti.ubc.ca/pages/letter10.html the drug industry needs to show
that their drug is more effective (statistically) than placebo to get
licensed. The only way to do this, unless clinical trials involve 1000's of
patients is to use a dose that the majority of people will respond to - if
that is the case, then the majority of patients would have done better with
a lower dose. That is simply the way the dose-response curve works. I am not
blaming either the drug industry or the regulatory bodies - it is just the
way the system has been set-up.

Clinicians need to recognise this reality and consider either staring with
lower than the monograph recommended doses or once a response has been
achieved with product monograph doses they or the patient should attempt
dose reduction in an attempt to find the lowest effective dose.


Dr James McCormack
Associate Professor
Faculty of Pharmaceutical Sciences
University of British Columbia
Vancouver, B.C.
604) 822-1710


-----Original Message-----
From: Currie, Craig [mailto:[log in to unmask]]
Sent: Sunday, January 16, 2000 10:47 AM
To: [log in to unmask]; EBM
Subject: RE: evidence on pill splitting


...this is largely untrue.  Phase-2 clinical trials are specifically
designed as dose-ranging studies, and the dose(s) must be justified to the
regulatory authorities.  I think the contrary situation often occurs though
i.e., patients frequently receive sub-clinical doses of drugs.

Cheers, Craig

> 	Craig Currie Ph.D.
> 	Manager- GI & Metabolic Diseases
> 	Global Health Outcomes
> 	GlaxoWellcome
> 	Greenford
> 	London UB6 OHE
> 	Tel:  44 (0) 208 9662800 (Direct)/ 9662206 (Secretary [Rhoda Luer])
> 	Fax:  44 (0) 208 9662193
> 	Email:  [log in to unmask]
>
> -----Original Message-----
> From:	James McCormack [SMTP:[log in to unmask]]
> Sent:	Thursday, January 13, 2000 6:02 PM
> To:	EBM
> Subject:	RE: evidence on pill splitting
>
> The issue of pill cutting is closely linked to another very important
issue
> of drug dosing -  that is, almost without exception, when a drug first
comes
> to market, the doses recommended in the product monograph are too high for
> the majority of patients. Many patients would do just as well with 1/4 or
> 1/8 of the recommended dose. In other words, we are likely exposing
patients
> to potentially unnecessary side effects and excessive costs if one isn't
> routinely getting patients to split pills (especially for newly released
> medications). For a brief, but certainly not complete discussion of this
> important issue, please see http://www.ti.ubc.ca/pages/letter10.html .Any
> comments would be welcome.
>
> -----Original Message-----
> From: [log in to unmask]
> [mailto:[log in to unmask]]On Behalf Of
> Currie, Craig
> Sent: Tuesday, January 11, 2000 7:47 AM
> To: 'Adams, Elizabeth'; 'INAHTA listserv';
> [log in to unmask]
> Subject: RE: evidence on pill splitting
>
>
> ...it does go on quite frequently.  This occurs not only with differential
> dosing of a drug but  where also a drug has more than one indication and
the
> drugs are then differentially priced.  An example that springs to mind is
> the alpha-reductase inhibitor (ARI) finasteride marketed as proscar for
> benign prostatic hyperplasia (BPH), and propecia for alopecia.  This may
> have been documented.
>
> Safety issues are associated specifically with the individual drug,
however,
> the regulatory authorities consider carefully any drug where the
> differential indication/pricing issue occurs.
>
> You can buy pill cutters specifically for the purpose you describe.
>
> Warm wishes, Craig
>
> > 	Craig Currie Ph.D.
> > 	Manager- GI & Metabolic Diseases
> > 	Global Health Outcomes
> > 	GlaxoWellcome
> > 	Greenford
> > 	London UB6 OHE
> > 	Tel:  44 (0) 208 9662800 (Direct)/ 9662206 (Secretary [Rhoda Luer])
> > 	Fax:  44 (0) 208 9662193
> > 	Email:  [log in to unmask]
> >
> > -----Original Message-----
> > From:	Adams, Elizabeth [SMTP:[log in to unmask]]
> > Sent:	Tuesday, January 11, 2000 3:16 PM
> > To:	'INAHTA listserv'; [log in to unmask]
> > Subject:	evidence on pill splitting
> >
> > Dear colleague,
> >
> > Is anyone aware of evidence for increased risk or reduced safety from
pill
> > splitting (halving a pill or tablet)?  I am particularly concerned with
> the
> > differences between scored vs. non-scored pills in accuracy of dosing,
> > absorption, assessing patients' ability to split, etc.
> >
> > I look forward to your comments.  Thank you in advance.
> >
> > Liz Adams
> > Management and Program Analyst
> > VA Technology Assessment Program
> > 150 S. Huntington Ave. Bldg 4 (152M)
> > Boston, MA  02130
> > Tel. (617) 278-4469  Fax (617) 278-4438
> > [log in to unmask] <mailto:[log in to unmask]>



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