January 28, 2011

Letter on Liprotamase (Sollpura)

Janet Woodcock, M.D.
Director
Center for Drug Evaluation and Research
Food and Drug Administration
Department of Health and Human Services
WO51/Room 6133
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Dear Dr. Woodcock:

These comments from Public Citizen Health Research Group are being submitted in follow-up to our testimony presented at the January 12, 2011 meeting of the Food and Drug Administration (FDA) Gastrointestinal Drug Advisory Committee regarding the drug liprotamase (Sollpura).

(1) Liprotamase is clearly not as effective as the porcine derived pancreatic enzyme preparations (PEPs) already on the market.

(2) The previous long-term, open-label clinical trial, study 767, conducted by the sponsor was unethical, despite approval by institutional review boards (IRBs), because the subjects were withdrawn from standard treatment with a well-established track record of safety and effectiveness and administered an inadequately tested experimental product. It is also highly unlikely that subjects enrolled in this study or their parents were informed that their participation in study 767deprived them of access to a considerably more effective treatment and that little was known about the safety and effectiveness of the experimental drug they were to be given.

(3) Finally, the future study proposed by the advisory committee also would be highly unethical since subjects would be randomized to receive either a known less effective treatment or a more effective treatment (no equipoise).

As previously stated in our testimony, we strongly oppose FDA approval of Alnara Pharmaceuticals’ New Drug Application, NDA # 22,486, for liprotamase capsules. Based on currently available data, there is substantial evidence that liprotamase is less efficacious than the FDA-approved porcine derived PEPs and appears to expose patients with exocrine pancreatic insufficiency (EPI) to greater risk.[1] With regards to effectiveness, for subjects enrolled in short-term study 726 (the only randomized clinical trial conducted by the sponsor) who had a baseline coefficient of fat absorption (CFA) less than 40%, the difference in CFA levels between the liprotamase-exposed subjects and the placebo-exposed subjects was only 15%, a difference that falls far short of both FDA’s pre-specified 30% difference for clinical significance and the much less than the difference achieved in clinical trials of the FDA-approved porcine derived PEPs. With regards to risk, FDA’s medical reviewer identified significant safety concerns with liprotamase, particularly the risk of inadequate growth and malnutrition in children with cystic fibrosis (CF).[2]

The long-term, open-label study, study 767, conducted by the sponsor and involving more than 110 children with pancreatic insufficiency due to CF, as wells as adults, was unethical and violated the requirements of FDA regulations concerning the additional safeguards for children in clinical investigations.[3] Both the FDA and the sponsor acknowledged that pancreatic insufficiency in children with CF is a life-threatening condition for which treatment with PEPs is essential to ensure adequate nutrition and growth. The standard of care for management of such patients for decades has been administration of porcine derived PEPs with meals. FDA noted that “[it is] the Agency’s long-standing determination that replacement of pancreatic enzymes has clinical benefit for patients with exocrine pancreatic insufficiency (EPI), and….porcine derived PEPs have decades of safety data available, and there is considerable evidence in the literature to support [the] safety of porcine derived PEPs.”[4]

Nevertheless, to our dismay, FDA allowed the sponsor to initiate this long-term, open-label clinical trial (study 767) in which subjects, including many children with EPI due to CF, were taken off the standard of care therapy and placed on the minimally tested experimental drug liprotamase for up to one year, despite the fact that (a) there was an absence of any significant clinical data in humans supporting the safety or effectiveness of this drug; and (b) the only pivotal randomized trial, study 726 – which ultimately demonstrated that liprotamase failed to meet FDA’s pre-specified threshold for clinical significance – had not even been completed. In fact, many subjects enrolled in study 726 were rolled over into study 767.

Given these facts, study 767 clearly involved greater than a minor increase over minimal risk, and the relation of the anticipated benefits to risks of liprotamase were significantly less favorable to the subjects than those afforded by porcine derived PEPs. Therefore, study 767 was neither ethical, nor was it approvable by an IRB under the FDA regulations that provide additional safeguards for children in clinical investigations.[5] Indeed, many subjects enrolled in study 767 subsequently had a significant decline in weight and body-mass index from baseline and never recovered to baseline.[6] Study 767 only could have been conducted if the Commissioner had consulted with a panel of experts, sought public review and comment, and made certain determinations in accordance with the requirements of 21 CFR 50.54. To our knowledge, these actions did not occur. We also question whether parents, when granting permission to allow their children to be enrolled in study 767, were adequately informed about the lack of safety and efficacy data regarding liprotamase, and the fact that the limited data available indicated that liprotamase was less effective than the standard porcine derived PEPs.

We therefore call upon the FDA to promptly investigate the adequacy of the IRB review at all sites that participated in study 767, and provide a timely response to the following questions: Why did FDA allow this study to proceed prior to the completion and analysis of study 726? Under what category of research stipulated by 21 CFR part 56, subpart D did the IRBs approve study 767? Did each IRB make the required determinations under subpart D and provide a reasonable justification for its determinations? Were there any IRBs that refused to approve the study? And lastly, were parents/subjects adequately informed about the nature of this research before parental permission/informed consent was obtained? We request a copy of the sample informed consent document for study 767.

Finally, as we stated in our January 12, 2011 testimony, based on the currently available data, we believe further randomized controlled trials comparing liprotamase to one of the FDA-approved porcine derived PEPs would not be ethical because equipoise would not exist, nor would such a trial satisfy the criteria for approval under FDA regulations, at least at the doses of liprotamase used in studies 726 and 767.[7] We also doubt that properly informed parents would allow their children to enroll in such a study. If FDA decides to permit a randomized trial of liprotamase to be conducted, then we believe such a study should first be conducted in adults with EPI; only after the safety and efficacy of the drug at higher doses over a prolonged period of time has been well established in adults would it be ethical to proceed with studies involving children with CF. 

Sincerely,

Michael A. Carome, M.D.
Deputy Director

Sidney M. Wolfe, M.D.
Director
Health Research Group

cc: Dr. Margaret A. Hamburg, Commissioner, Food and Drug Administration

      Dr. Donna Griebel, Director, Division of Gastroenterology Products, Food and Drug Administration