across the world at any given time.1–3By its own estimation,
the pharmaceutical industry in Canada spent Can$501.8 mil-
lion on clinical trials in 2004.4In comparison, in 2003/04 the
Canadian Institutes of Health Research spent Can$31.8 mil-
lion in direct grants to RCTs.5
The RCT business is profitable for private pharmaceutical
companies because the large trials they invest in are focused
on patentable drugs. The patent system enables innovator
firms to charge consumers prices that are above marginal
cost and make a profit.2,6In contrast, research on drugs with-
out patent (i.e., nonpatentable or off-patent drugs) or with in-
sufficient marketing prospects (orphan drugs) is funded by
nonprofit or charitable organizations only. The numbers pre-
sented above show that for economic reasons alone, drugs
for which a patent cannot be granted are not being developed,
even when they respond to a public health need. Patients,
pharmacists, physicians and other caregivers consequently
cannot take full advantage of potentially effective treatments.
Must we remain ignorant of the potential efficacy of drugs
simply because of their nonpatentability?
Omega-3 polyunsaturated fatty acids (n-3 fatty acids) for the
prevention and treatment of Alzheimer’s disease are a good
example of this problem. These chemicals are essential for
synapse function, but their concentrations in our cellular mem-
branes depend on our dietary intake. Underconsumption of n-
3 fatty acids is commonplace in our modern society; indeed, in
the United States the average intake of docosahexaenoic acid
(DHA) is 60–80 mg/d, in contrast to expert-panel recommen-
dations of 200–300 mg/d.7,8Several preclinical and epidemio-
logic studies suggest that long-chain n-3 fatty acids such as
DHA may be beneficial for Alzheimer’s-related dementia.7,9–11
In animal models, DHA deprivation leads to aggravation of
pathological signs of Alzheimer’s disease, especially at the
level of the synapses.9,10In an epidemiologic study,11patients
with a diet high in DHA (a median of 0.10 g/d) were at lower
risk of Alzheimer’s disease than those who consumed less
DHA (median 0.03 g/d; relative risk 0.3, 95% confidence in-
terval 0.1–0.9) after adjustments for sex, race, education, total
energy intake and the presence of the ε4 polymorphism of the
apolipoprotein E gene, the ApoE ε4 allele. Furthermore, vari-
ous studies12–15(though not all of them)16have indicated that
blood concentrations of DHA and other n-3 fatty acids are
lower in patients with Alzheimer’s-related dementia. Because
n-3 fatty acids are readily incorporated in cellular mem-
branes, adverse effects from high consumption are rare.17
To translate these observations into evidence-based rec-
ommendations, we need large, state-of-the-art RCTs. For pri-
he pharmaceutical industry spends over US$10 billion
to fund some 90% of the 40 000–80 000 randomized
controlled clinical trials (RCTs) being conducted
mary prevention trials, it is reasonable to estimate (assuming
an annual probability of Alzheimer’s of 3% in the placebo-
treated population) that sample sizes of at least 4500 patient-
years per group are required to achieve sufficient statistical
power (80%) to detect a 25% relative difference in the risk of
Alzheimer’s disease.18RCT costs average some $5000/yr per
patient; investments in the area of $50 million are therefore
required, which, because n-3 fatty acids are a natural product
that cannot be patented, could come only from nonprofit
agencies. The cost of these studies nevertheless constitutes a
fraction of the money spent around the world on mildly effi-
cient palliative drugs for treatment of Alzheimer’s disease,
such as cholinesterase inhibitors. Indeed, if we assume that
1 million patients worldwide who have Alzheimer’s disease
are treated with cholinesterase inhibitors at an annual cost of
Can$1000 per patient, this amounts to more than Can$1 bil-
lion yearly.19–21Pfizer’s own data22state that 717 million pa-
tient-days of Aricept were purchased in 1997–2002; assuming
$3 per patient-day, this represents more than Can$2 billion.
Meanwhile, it is quite possible that suboptimal consumption
of n-3 fatty acids, in combination with population aging, will
soon translate into increasingly more patients with dementia
related to Alzheimer’s disease.
Studies of omega-3 fatty
acids would cost a fraction
of what is spent on pallia-
tive drugs for Alzheimer’s.
Can we afford to invest in clinical research for nonpatented
drugs? The answer, in many cases, is yes. What we tend to
forget is that everyone pays at the pharmacy for the cost of
private pharmaceutical research. By entrusting drug develop-
ment almost entirely to the pharmaceutical companies, we
may enjoy short-term savings; but in the long term, either as
citizens or as patients, we will have to pay.2
Competition between manufacturers generally causes the
pharmacy prices of nonpatentable drugs to be lower than
those of patented ones.23,24Thus, many nonpatentable drugs
such as n-3 fatty acids may turn out to be cheaper in the long
term than a patentable drug of the same efficacy. Folic acid,
mineral and vitamin supplements are good examples of low-
cost nonpatentable drugs commonly recommended by health
professionals. It is estimated, for example, that 1.5 million
• February 14, 2006 • 174(4) | 483
© 2006 CMA Media Inc. or its licensors
Nonpatentable drugs and the cost of our ignorance
Americans experience osteoporotic fractures each year, with
an annual cost of nearly US$14 billion in health care alone
(ignoring lost income and other indirect costs).25,26A 400-UI
vitamin D and 1000-mg calcium supplement, which has been
shown to reduce the risk of fracture by at least 15%,27,28costs
less than Can$200/patient/yr.29This example, like possibly
that of n-3 fatty acids in Alzheimer’s disease, suggests that
some (perhaps many) nonpatentable drugs can reduce phar-
macy and other health care costs.
Pharmaceutical companies play a pivotal role in drug dis-
covery; yet they develop and test only those drugs for which
they can get a patent.30Instead of relying exclusively on phar-
maceutical companies to determine the effectiveness of drugs
and to develop new treatments, nonprofit agencies should
take up the relay for nonpatentable, off-patent and orphan
drugs. As of today, such propositions seem utopian, but the
problem calls for economic studies on a global scale to deter-
mine where public money for health research is better inves-
ted. Since the benefit of research-generated knowledge is not
limited to a nation’s borders, funding could come from inter-
national organizations as well as individual governments.
To meet the health research challenges of tomorrow, the
present dynamic, in which public money is focused on basic
research while private funding is concentrated on clinical re-
search, should be carefully analyzed and revised if necessary.
At present, we all should realize that ignoring the potential
efficacy of nonpatentable or orphan drugs carries a social cost
that clearly needs recognition.
1. CenterWatch Clinical Trials Listing Service. Thomson CenterWatch Analysis.
Available: www.centerwatch.com (accessed 2005 Sept 8).
2. Angell M. The truth about the drug companies. New York: Random House; 2005.
3. Moher D, Bernstein A. Registering CIHR-funded randomized controlled trials: a
global public good. CMAJ2004;171(7):750-1.
4. Patented Medicine Prices Review Board (Canada). Annex 3, table 15. In: 2004
PMPRB annual report. Available: www.pmprb-cepmb.gc.ca/english/view.asp?x
=436(accessed 2006 Jan 11).
5. Canadian Institutes of Health Research. Schedule 1 to the [auditor's report and]
financial statements — grants and awards for the year ended March 31 . In:
CIHR annual report 2003–2004: exceptional value for Canadians. Ottawa: CIHR;
2004. Available: www.cihr-irsc.gc.ca/e/25727.html (accessed 2006 Jan11).
6. Danzon PM, Towse A. Differential pricing for pharmaceuticals: reconciling access,
R&D and patents. Int J Health Care Finance Econ 2003;3:183-205.
7. Maclean CH, Issa AM, Newberry SJ, et al. Effects of omega-3 fatty acids on cogni-
tive function with aging, dementia, and neurological diseases. Evidence Report/
Technology Assessment No. 114. Rockville (MD): National Library of Medicine;
8. Simopoulos AP. n-3 fatty acids and human health: defining strategies for public
policy. Lipids 2001;36(Suppl):S83-9.
9. Calon F, Lim GP, Yang F, et al. Docosahexaenoic acid protects from dendritic
pathology in an Alzheimer’s disease mouse model. Neuron 2004;43:633-45.
10. Lim GP, Calon F, Morihara T, et al. A diet enriched with the omega-3 fatty acid
docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse
model. J Neurosci 2005;25:3032-40.
11.Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids
and risk of incident Alzheimer disease.Arch Neurol 2003;60:940-6.
Laurin D, Verreault R, Lindsay J, et al. Omega-3 fatty acids and risk of cognitive im-
pairment and dementia. J Alzheimers Dis 2003;5:315-22.
13. Tully AM, Roche HM, Doyle R, et al. Low serum cholesteryl ester–docosahexaenoic
acid levels in Alzheimer’s disease: a case–control study. Br J Nutr 2003;89:483-90.
Kyle DJ, Schaefer E, Patton G, et al. Low serum docosahexaenoic acid is a signifi-
cant risk factor for Alzheimer’s dementia. Lipids 1999;34(Suppl):S245.
15.Heude B, Ducimetiere P, Berr C; l’Étude du Vieillissement Artériel (EVA) Study
Group. Cognitive decline and fatty acid composition of erythrocyte membranes —
the EVA Study. Am J Clin Nutr 2003;77:803-8.
Wheaton DH, Hoffman DR, Locke KG, et al. Biological safety assessment of
docosahexaenoic acid supplementation in a randomized clinical trial for X-linked
retinitis pigmentosa. Arch Ophthalmol 2003;121:1269-78.
Lenth RV. Some practical guidelines for effective sample-size determination. Am
18. Conquer JA, Tierney MC, Zecevic J, et al. Fatty acid analysis of blood plasma of pa-
tients with Alzheimer’s disease, other types of dementia, and cognitive impair-
ment. Lipids 2000;35:1305-12.
Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients
with Alzheimer’s disease (AD2000): randomised double-blind trial. Lancet 2004;
20. Lanctot KL, Herrmann N, Yau KK, et al. Efficacy and safety of cholinesterase inhi-
bitors in Alzheimer’s disease: a meta-analysis [review]. CMAJ2003;169(6):557-64.
21.Sambrook R, Herrmann N, Hebert R, et al. Canadian Outcomes Study in Demen-
tia: study methods and patient characteristics. Can J Psychiatry 2004;49:417-27.
22. Pfizer Canada Inc. 5th year milestone for first Alzheimer drug approved in Canada
[press release]. Montreal: Pfizer; 2002Aug 21.
23. IMS Health Canada. 2004 [e.g., www.imshealthcanada.com/htmen/4_2_1_42
24. The Henry J. Kaiser Foundation. Prescription drug trends: a chartbook update.
Menlo Park (CA): The Foundation; 2001.
25. International Osteoporosis Foundation. Facts and statistics about osteoporosis
and its impact. Available: www.osteofound.org(accessed 2005 Sept 13).
26. Brown JP, Josse RG. 2002 clinical practice guidelines for the diagnosis and man-
agement of osteoporosis in Canada [published errata appear in CMAJ 2003;168
(4):400, CMAJ 2003;168(5):544 and CMAJ 2003;168(6):676]. CMAJ 2002;167(10
27. Reginster JY. The high prevalence of inadequate serum vitamin D levels and impli-
cations for bone health.Curr Med Res Opin 2005;21:579-86.
28. Larsen ER, Mosekilde L, Foldspang A. Vitamin D and calcium supplementation pre-
vents osteoporotic fractures in elderly community dwelling residents: a pragmatic
population-based 3-year intervention study. J Bone Miner Res 2004;19:370-8.
29. Régie de l’assurance maladie du Québec (RAMQ). Liste de médicaments. Sainte-
Foy (QC): Conseil du médicament; 2005.
30. Sackett DL. Time to put the Canadian Institutes of Health Research on trial [pub-
lished erratum inCMAJ 2000;162(3):319]. CMAJ 1999;161(11):1414-5.
• February 14, 2006 • 174(4) | 484
Frédéric Calon is Assistant Professor, Molecular Endocrinology and Oncol-
ogy Research Center, Laval University Medical Center (CHUL), and the Fac-
ulty of Pharmacy, Laval University, Sainte-Foy, Qué.
Competing interests: None declared.
Acknowledgement: Frédéric Calon is a recipient of a New Investigator
Award (Clinician) from the Canadian Institutes of Health Research.
Correspondence to: Dr. Frédéric Calon, Molecular Endocrinology
and Oncology Research Center, Laval University Medical Center
(CHUL), 2705 blvd. Laurier, Sainte-Foy QC G1V4G2;
fax 418 654-2761; firstname.lastname@example.org
We doctors need to learn how to Download full-text
help ourselves if we are to be able to
continue helping others.
CMA Office for Leadership
Sex ratio for medical
Mark Baerlocher and Allan Detsky re-
port that, between 1995 and 2004, men
were more likely than women to be re-
jected from their top-ranked discipline
when applying to Canadian residency
programs.1They suggest that female
residency applicants might have had a
competitive edge on their male coun-
terparts or that selection committees
might have been consciously or uncon-
sciously exhibiting bias.
Another factor might be sex-related
differences in admissions to Canadian
medical schools. Of the 10 957 appli-
cants receiving at least one offer of ad-
mission from 2000/01 to 2004/05, 4554
were men and 6403 were women.2Two
factors appear to have contributed to
this imbalance. First, fewer men
(18 277) than women (23 620) applied
to Canadian medical schools over that
period.2Second, male applicants were
less likely than female applicants to be
granted admission: 24.9% of the male
applicants and 27.1% of female appli-
cants received at least one offer of ad-
mission.2The net result is that female
medical students outnumbered male
medical students (by a ratio of 7:5) over
this 5-year period.
Being outnumbered by the competi-
tively superior and/or preferred sex
suggests that men may continue to ex-
perience greater difficulty than women
in acquiring a residency position in
their top-ranked discipline.
Wesley D. Block
University of Alberta
1. Baerlocher MO, Detsky AS. Are applicants to Cana-
dian residency programs rejected because of their
2. Association of Faculties of Medicine of Canada. Ad-
mission requirements of Canadian faculties of med-
icine: admission in 2006. Ottawa: The Association.
_book.pdf(accessed 2006 Mar 20).
Yes to “febrile,” no to
I would like to suggest that all physi-
cians make an effort to stop referring to
febrile illnesses as “flu-like.” This habit
gives the lay public an incorrect idea of
the symptoms of influenza.
Ihave read numerous articles on gas-
troenteritis in the lay press that contain
phrases such as “many people think
they have the flu, since the symptoms
are similar” or “it can be tricky to iden-
tify a food-borne illness, since symp-
toms are similar to flu symptoms.”
If the people of Walkerton, Ontario,
had known that there is no nausea, vom-
iting, or diarrhea associated with in-
fluenza, maybe they would have sought
medical help much sooner and lived.
So, doctors, please make an effort to
call an illness with fever and myalgia a
In our recent article on hepatitis C,1the
correct sentence is “For analgesia, small
doses of ASA (< 2 g/d) are vastly prefer-
able to NSAIDs in patients with liver
disease.” The medication is acetamino-
phen instead of ASA as printed. Also,
the correct e-mail address for Dr. Tom
Wong is email@example.com.
1. Wong T, Lee SS. Hepatitis C: a review for primary
care physicians. CMAJ 2006;174(5):649-59.
In the References section on page 484,1
listings 12–18 are out of order. Citation
12 in the text actually refers to number
16 in the References listing; citation 13,
to the listing numbered 12; citation 16,
to listing 17; citation 17, to listing 18;
and text citation 18, to listing 13.
1. Calon F. Nonpatentable drugs and the cost of our
The DOI published in a recent News
item1was mistakenly listed as
10.1503/cmaj.06022. It should have
been read 10.1503/cmaj.060229.
1. Hass J. Nurse practitioners now able to work
across Canada. CMAJ174(7):911-2.
• May 9, 2006 • 174(10) | 1450
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