E-drug: Re: WHO launches new ORS (cont)
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[E-drug posted the Press release from WHO on the new formula 11 May and
Wilbert commented that it was not brought to the meeting in April revising
the Essential Drugs List. See also postings by Andy Gray and Hilbrand Haak
14 May. Hilbrand argues that new formulations should not be reviewed as a
new essential drug (that is a strange view in my opinion), he is also in
favour of the new formula. Obviously, this is a controversial topic, cf.
this letter to the Lancet criticising the formula and the process. Whether
the new formula represents an improvement or not, it may seem that WHO still
has a way to go in making its decisions evidence-based and open to
independent review. Copied as fair use. KM]
Lancet 2002; 360(9329): 340-1 (27 July)
Correspondence
Formulation of oral rehydration solution
Sir--WHO's recommendation to change the formula of oral rehydration solution
(ORS) to contain less salt and sugar (1) is ill advised. The original
formulation has been effective for more than 25 years, and successfully
implemented in many national programmes.
The change is motivated by a desire to lessen stool output and the rate of
resuming intravenous fluid. The studies said to support such improvements
provide only marginal or non-existent evidence for either outcome. (2-4)
The theoretical benefits of ORS with less salt and reduced osmolarity are
offset by a negative net salt balance and its consequences. Predictably, in
adult cholera, the lower salt formula is inadequate to maintain salt
balance, and results in a substantial rise in the risk of hyponatraemia;2 in
one study, twice as many children had serum sodium concentrations falling to
less than 125 mmol/L compared with the group receiving the standard
solution. (3)
We are troubled that such an important modification is being recommended
without review by independent experts not involved in the various studies. A
so-called expert consultation on ORS formulation was held in 2001, in which
many of the participants were co-workers on the various studies. (5)
The US Food and Drug Administration (FDA) requires a protocol to assess
safety as well as efficacy of new drugs or formulations before approval for
use. For ORS, a large-scale study with a sample size big enough for a power
of 80% is needed to find out whether the two formulations differ by ten
percentage points for rate of hyponatraemia (serum sodium 130 mmol/L) during
treatment. None of the precedent studies achieved such size, and only one
investigated adults with cholera. The planned use of the low-salt formula
without rigorous study of its safety has the potential to harm the most
severely ill patients, and to discredit national rehydration programmes. The
FDA also requires postmarketing surveillance of any new drug or formula. We
seriously doubt a system for such surveillance is in place anywhere that
cholera or other severe diarrhoeal illnesses are common.
In addition, if the new policy eventually leads to two formulae in different
packaging, one for mild and the other for severe diarrhoea, or one for
children and another for adults, the decades-long proven simplicity and
safety of the single formulation will be lost.
We urge WHO to revisit the decision, and to do the necessary additional
safety studies.
*Norbert Hirschhorn, David R Nalin, Richard A Cash, William B Greenough III
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*1044 Chapel Street #502, New Haven, CT 06510, USA; 100 Lucky Hill Road,
West Chester, PA; Harvard School of Public Health, Boston, MA; Department of
Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
(e-mail:bertzpoet@yahoo.com)
1 WHO. New formula for oral rehydration salts will save millions of lives:
number of deaths and severity of illness will be reduced.
http://www.who.int/inf/en/pr-2002-35.html (accessed July 15, 2002).
2 Alam NH, Majumder RN, Fuchs GJ, and the CHOICE study group. Efficacy and
safety of oral rehydration solution with reduced osmolality in adults with
cholera: a randomised double-blind clinical trial Lancet 1999; 354: 296-99.
3 CHOICE Study Group. Multicenter, randomized double-blind clinical trial to
evaluate the efficacy and safety of a reduced osmolarity oral rehydration
salts solution in children with acute watery diarrhea. Pediatrics 2001;
107: 613-18.
4 Hahn S, Kim Y, Garner P. Reduced osmolarity oral rehydration solution for
treating dehydration due to diarrhoea in children: systematic review. BMJ
2001; 323: 81-85.
5 WHO/UNICEF. Expert consultation on oral rehydration salts (ORS)
formulation. WHO/FCH/CAH/01.22. 18 July 2001.
http://www.who.int/child-adolescent-health/New_Publications/CHILD_HEALTH/Exp
ert_consultation.htm (accessed July 10, 2002).
Kirsten Myhr, MScPharm, MPH
Head, RELIS Ost Drug Information Centre
Ulleval University Hospital
0407 OSLO, Norway
Tel: +47 23 01 64 11 Fax: +47 23 01 64 10
kirsten.myhr@relis.ulleval.no
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