1981N-0022

OTC Weight Control Drug Products for Human Use

FDA Comment Number :

EC2

Submitter :

Mr. Rainer Becker

Date & Time:

02/17/2006 02:02:45

Organization :

Mr. Rainer Becker

Category :

Health Professional

Issue Areas/Comments

GENERAL

The results of the "Yale study" on the correlation between PPA intake and the incidence of hemorrhagic stroke do not support the proposed rulemaking.

This is because the study did not control for outdoor temperature which is shown by literature (see attachment: see attachment: Pub Med Lit search temperature hemorrhagic stroke.pdf) to be a critical risk factor for hemorrhagic stroke. Low outdoor temperatures are associated with odd ratios up to >18 for their correlation with hemorrhagic stroke (Chen et al). Mortality from cerebral haemorrhage decreased with increasing temperature at a rate of 3.3% per 1 degree centigrade (Pan et al). Intracerebral hemorrhage in men was even significantly related to intradiurnal temperature change (Shinkawa et al).

For treatment of nasal congestion PPA mainly is being used in wintertime. Therefore the low temperature as key confounding factor was present. Temperature may vary by more than 20 degrees within a month, the time span allowed by the Yale study between the interviews for cases and controls.

This confounding by not controlled temperature differences for cases and matched controls broadens the confidence intervals for the odd ratios of the Yale study to an extent that no scientifically valid conclusions can be drawn from the study results. In particular not for therapeutic doses or doses moderately above.

Hence rulemaking for PPA treatment of common cold cannot be based on the results of the Yale study from a scientific point of view.

For the same reasons and because of lacking matched controls, case reports from vigilance systems or literature cannot be taken as a basis for the proposed rulemaking either.

For the sake of completeness:

There is also no scientific basis from the Yale study for rulemaking on PPA used as slimming aid.

This is because the study did not control for fasting and thereby malnutrition with essential nutrients which is shown by literature (see attachment: Pub Med Lit search nutrition hemorrhagic stroke.pdf) to be a clear risk factor for hemorrhagic stroke.

People who take PPA as slimming aid also reduce food intake over a longer period of time to achieve slimming. The matched controls in the Yale study did not have this need. People who are fasting longer time and are not (guided by) experts in nutritional science will inevitably experience deficiencies of important nutrients, thereby being exposed to an increased risk for hemorrhagic stroke.

Therefore the six cases of hemorrhagic stroke reported in the Yale study to have been associated with PPA use as slimming aid likely were caused by the described malnutrition, with PPA being only an indirect marker for that malnutrition.

Again, this confounding by malnutrition/fasting not controlled for cases and matched controls broadens the confidence intervals for the odd ratios of the Yale study to an extent that no scientifically valid conclusions can be drawn from the study results, in particular not for therapeutic doses or doses moderately above.

Hence rulemaking for PPA use as slimming aid cannot scientifically be based on the results of the Yale study, either.

1981N-0022-EC2-Attach-1.PDF

1981N-0022-EC2-Attach-2.PDF