2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC11
Submitter : Dr. Tibor Sipos Date & Time: 07/12/2004 12:07:14
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
PART 9 OF 10
DOCKET NO. 2003D-0206 (2003N-0205)


 A 72-hour stool analysis is one established and valid quantitative measure of steatorrhea.
 Baseline can be more suitably established by stool markers.

It is appropriate that the FDA has considered several designs to establish efficacy, as well as the use of other active PEPs as comparators. A 72- hour stool analysis is an established and valid quantitative measure and remains a standard for the primary efficacy endpoint, the resolution of steatorrhea. The concept that baseline conditions should be re-established in this indication does not make clinical sense. The effects on GI symptoms and fat malabsorption are instantaneous, localized, and short lived. Patients need to take their medication with each meal and this drug class has a short half life in the GI tract, their site of action, due to normal protease activity that hydrolyzes all proteins to peptides and amino acids. To account for any carryover effects, studies should be designed so that fecal fat is measured over the course of three days and should be done at the end of at least seven days of treatment. Stool markers can then be used to confirm that the stool measurements are taken at the correct time points and intervals.

End Points (Outcome Measures) Efficacy:

Clinical benefit can only be demonstrated under carefully defined conditions, such as control of defined diet with adequate intake of fat/protein/carbohydrates, use of stool markers for the 72-hour stool collection under supervised condition and preferably in the metabolic ward (Brady SM, et.al., Twelfth Annual North American CF Conference, 1998). The use of placebo as a reference control is unethical and unwarranted. We recommend the use of the commercially available enteric-coated pancrelipase product as reference controls. The positive control should be from a single lot, and before use, the lipase potency should be determined. Likewise, the test product?s lipase potency should also be determined and matched up to the positive control lipase potency. This would ensure a dose-to-dose comparison of the test product to the reference positive control drug. We agree that the study population should include not more than 10 to 25 pancreatic enzyme insufficient cystic fibrosis patients. Fecal elastase assay should be evaluated as a potential pre-screening tool to confirm pancreatic enzyme insufficiency.

Once any product is demonstrated to be effective by the fecal fat analysis to resolve steatorrhea, additional product line extensions, e.g. change in dosage unit, two capsules reduced to one dosage unit, different capsule sizes, change in packaging, etc., demonstration of effectiveness could be
done with use of appropriate PD endpoints. These PD endpoints include common digestive signs and symptoms of stool frequency, stool consistency, urgency of bowel movements, intestinal gas and cramps, etc. This should be sufficient to demonstrate clinical effectiveness of the line extension of clinically proven products.


Since pediatric patients form a large part of the target population, it is essential to include this age group in PEP studies. Rather than using separate studies, however, we would like the Agency to allow the use of pediatric subgroup analysis for clinical trials. Perhaps this was understood as a general procedure for clinical trials; nevertheless, we would like to encourage the FDA to include this in their guideline.

We hope that the Agency seriously considers our proposed recommendation in a positive light as improvement to the regulation of PEP products and not as overt criticism.