Problems in planning and analyzing the common cold trials
by Harri Hemilä
This text is
based on pp 58-59 of Hemilä
(2006)
These documents have up to date links to documents that are available
via
the net.
Harri Hemilä
Department of Public Health
University of Helsinki,
Helsinki, Finland
harri.hemila@helsinki.fi
Although a large number of trials was published on the vitamin C and
common cold relationship, rather less understanding was generated
compared with the time and effort invested. Most of the literature
related to vitamin C and the common cold is the product of
investigators with only a transient interest in the topic.
Lack of carefully formulated questions has been a problem typical of
the published trials. In most cases a group of authors carried out a
single trial without a proper look at those already published. The
major exceptions to this problem are Anderson, who carried out 3 large
trials (Anderson et al. 1972, 1974, 1975), and Clegg, who carried out 2
trials (Charleston & Clegg 1972; Clegg & Macdonald 1975). Both
of these authors changed their settings on the basis of their earlier
trials. Coulehan et al. (1974, 1976) carried out 2 trials, but the
second does not consider the dose-response tendency observed in the
first.
In most cases the question in the trials has been oversimplified;
whether Pauling was wrong or not, or whether vitamin C has any effects
on colds or not. When there already is a large set of trials with
conflicting results, it is difficult to see that any single new trial
could provide meaningful progress without explicitly formulated
questions based on the older findings. Hypotheses could be generated to
explain the older conflicting results and such hypotheses could be
tested in a new trial, but in most cases no such hypotheses were
formulated by the authors before initiating their own trial. With the
existence of a large set of published trials, the meta-analytical
approach, extensively used in this thesis, may be useful.
The problem of planning individual trials is seen in several aspects of
the published trials. Pauling (1970a) suggested that vitamin C would
substantially reduce the incidence of colds. The large-scale trial by
Anderson et al. (1972) showed that vitamin C had no meaningful
preventive effects in the general population, but did find a
statistically highly significant reduction in common cold severity.
After such a finding it would appear reasonable to plan new trials
explicitly to test the possible therapeutic effect of vitamin C.
Essentially all of the later trials (see Hemilä 1992a, 1994a,
1999a; Hemilä, et al. 2007), however, used regular
supplementation without any hypothesis about why the subjects or
experimental conditions in these new trials might yield a different
result on common cold incidence compared with the Anderson trial
(1972). Consequently, there is a gross shortage of therapeutic trials.
A dose-response relation was observed in schoolchildren by Coulehan et
al. (1974), who reported that 2 g/day of vitamin C shortened colds by
29%, whereas 1 g/day shortened colds by only 12%. Karlowski et al.
(1975) found that 6 g/day was about twice as effective as 3 g/day
(Table 8). Although these two trials do not establish dose-dependency,
they should have justified further trials to investigate whether there
actually is dose-dependency in the high dose region. Essentially all
later trials, however, employed only a single dose, in most cases only
1 g/day (Hemilä 1992a, 1999a). Thus, here also many authors did
not look at the previous literature to formulate proper questions for
their own trials.
Most of the vitamin C trials did not appropriately consider the type of
subject that might be meaningful. In this respect, the Anderson (1972)
trial is one of the positive exceptions, since Anderson selected
subjects who had usually at least one cold during winter. This kind of
selection seems sound as the role of vitamin C appears to be quite
small, and there is no point in examining the effect of vitamin C on
people that usually have no problems with colds in winter. It seems
that most authors were simply enrolling subjects who were easy to
reach, rather than subjects for whom there was a sound biological
rationalization.
Thus, problems in planning and analysis of trials have led to a
considerable waste of man-years of work on the subject of vitamin C and
the common cold. Detailed description of the randomization method,
double-blindness and other technical features are no substitutes for a
meaningful biological question, even though the technical features are
relevant for the validity of the trial. However, some of the recent
trials are of limited use because of severe technical deficiencies.
In one recent trial, the ‘control group’ data was collected in 1990
with one group of students, whereas the ‘vitamin C’ group data was
collected in 1991 with a different group, and, moreover, the protocols
of data collection differed between 1990 and 1991 (Gorton & Jarvis
1999). Given the variability of cold experience from year to year, the
claim by the authors that the observed differences were attributable to
vitamin C must be disputed.
Another recent trial (Himmelstein et al. 1998) started with 52 marathon
runners in two groups, but 42% (22 of 52) of the vitamin C group and
75% (38 of 52) of the placebo group dropped out during the trial. With
such an extreme and significantly divergent drop-out rate (mid-P[2-t] =
0.002), and such a small number of participants in the treatment
groups, it makes no sense to draw any conclusions from the differences
in the incidence or severity of upper respiratory tract infections
between them, although the authors have done so.
References
Anderson TW, Beaton GH, Corey PN, Spero L (1975) Winter illness and
vitamin C: the effect of relatively low doses. Can
Med
Assoc J 112:823-6
Anderson TW, Reid DBW, Beaton GH (1972) Vitamin C and the common cold:
a double-blind trial. Can
Med
Assoc J 107:503-8
Anderson TW, Suranyi G, Beaton GH (1974) The effect on winter illness
of large doses of vitamin C. Can
Med
Assoc J 111:31-6
Charleston SS, Clegg KM (1972) Ascorbic acid and the common cold
[letter]. Lancet
299:1401-2 [see also: Clegg (1974)
]
Clegg KM, Macdonald JM (1975) L-ascorbic acid and D-isoascorbic acid in
a common cold survey. Am J Clin
Nutr 28:973-6
Coulehan JL, Reisinger KS, Rogers KD, et al. (1974) Vitamin C
prophylaxis in a boarding school. N
Engl
J Med 290:6-10
Coulehan 1976
Gorton HC, Jarvis K (1999) The effectiveness of vitamin C in preventing
and relieving the symptoms of virus-induced respiratory infections. J
Manipulative Physiol Ther 22:530-3
Karlowski TR, Chalmers TC, Frenkel LD, Kapikian AZ, Lewis TL, Lynch JM
(1975) Ascorbic acid for the common cold: a prophylactic and
therapeutic trial. JAMA
231:1038-42
Pauling L (1970a) Vitamin C and the
Common Cold. San Francisco: Freeman
* See
Book
Reviews * Pauling's comments on book reviews:
Pauling (1971c,
1971d)
