2003D-0206 - Draft Guidance for Industry on Exocrine Pancreatic Insufficiency Drug Products--Submitting New Drug Application; Availability
FDA Comment Number : EC9
Submitter : Dr. T. Sipos Date & Time: 07/12/2004 12:07:40
Organization : Digestive Care, Inc.
Drug Industry
Category :
Issue Areas/Comments
PART 8 OF 10
DOCKET NO. 2003D-0206 (2003N-0205)

The employment of the intubation procedure to demonstrate delivery of exogenous enzymes into the intestine in their biologically active state is complex, time-consuming and prohibitively expensive. Intubations are invasive, damages the lining of the esophagus, stimulate the gagging reflexes, are uncomfortable and painful. Furthermore, intubations in children are extremely difficult and, in most cases, parental permission is denied. Institutional Review Board (IRB) approval is also unlikely since the gained information contributes very little to our knowledge of intraluminal digestion of a meal and the resolution of steatorrhea. Therefore, intubation procedures are unjustified and not recommended for the in situ analysis of pancrelipase containing drug products. We urge the Agency to waive this requirement for measuring aspirates from the gastrointestinal tract and replace it with measurements of acceptable pharmacodynamic endpoints. The primary end point of clinical effectiveness is the resolution of steatorrhea and that is a readily measured parameter.

At the FDA-sponsored meeting of April 23, 1992 (?Exocrine Pancreatic Insufficiency Drug Product Workshop, FDA Memorandum of Meeting?), it was also stated ?in vitro measurement of enzyme activity complements the clinical efficacy determination, and in vivo measurement of enzyme activity is possible but is not a reliable indicator. The end point is not the enzyme activity that you will measure in the duodenal fluid. The end point is the steatorrhea that you are resolving? (Lebenthal, pg. 48).


We concur with many points in this section of the guideline as it relates to clinical trial considerations, patient population, endpoints, safety, and design. We shall only comment on those sections which we believe needs further consideration.

Considerations for Clinical Trial Development:

 Dose-response relationship in clinical trials is not achievable with pancrelipase due to patient variability (patients are normally titrated by physicians).

Establishing an empirical dose-response relationship in clinical trials, in our opinion, is not warranted with pancrelipase drug products due to large differences in between-subject variability and the fat content of meals on which the efficacy parameter is based. In addition, all patients, in conjunction with medical care, determine their optimal dose. Further, in order to establish such a relationship, a minimum of four dose levels are
needed. The sample size required for such a trial would be extremely large. Given that the FDA has recognized that 10-25 patients are sufficient for pivotal trials, the necessity for conducting such a large dose-response trial is not necessary, onerous, impractical, and probably not achievable.

There are numerous example of drugs, both in the classical biologics category; e.g. menotropins, as well as chemically synthesized drugs; e.g. antidepressants approved by the FDA that do not or have not been able to demonstrate dose-response relationships.