2005D-0122 Guidance for Industry on Exploratory IND Studies
FDA Comment Number : EC11
Submitter : Dr. Anna Wu Date & Time: 07/15/2005 01:07:21
Organization : David Geffen School of Medicine at UCLA
Category : Academia
Issue Areas/Comments
RE: 2005D-0122

Guidance for Industry, Investigators and Reviewers
Exploratory IND Studies

I appreciate the opportunity to comment on the proposed Guidance on Exploratory IND Studies. This document represents an important step in streamlining the development and evaluation of drugs and biologicals in humans. My comments are narrow and reflect my background as an academic investigator developing engineered anti-cancer antibodies for imaging.

One important class of molecules that is not adequately addressed in the document is comprised of recombinant proteins that are being developed as imaging agents, where no therapeutic use is intended. In particular, this class includes recombinant antibody-based proteins with specificity for biomarkers of disease. These would be radiolabeled for use in clinical imaging studies. Development of these proteins can be envisioned along three paths: where the ultimate use is solely as imaging agents (to determine whether a biomarker is present); where targeting, biodistribution and clearance are studied, to determine whether an analogous protein could be considered for future development as a therapeutic; or in co-development with a paired, essentially similar therapeutic protein, as a means to assess targeting and dosimetry of the paired therapeutic (examples include Zevalin and Bexxar, where clinical use includes administration of an imaging dose prior to the therapeutic dose). Regardless, the initial exploratory stages would involve administration of small doses of protein in a limited number of patients. These studies would be very low risk due to the doses administered and the known distribution, clearance, and metabolism of proteins and antibodies in general.

The definition of a microdose and in particular the setting of the maximum dose at less than or equal to 100 micrograms (lines 310-311) is problematic, and should be revised when the agent in question is an antibody as opposed to a small molecule compound. A maximum dose in the range of 5 mg is more reasonable for the following reasons:

A) 100 micrograms of a small molecule with a molecular weight of 1000 Da represents 100 nanomoles of material. On a molar basis, the equivalent amount (100 nanomoles) of a protein with a molecular weight of 150,000 Da (e.g., IgG) would be 15 mg.

B) Examples of typical administered therapeutic doses of antibodies might range from 200 mg (based on 4 mg/kg in a 50 kg female) of trastuzumab to 675 mg (based on 375 mg/m2 in a 1.8 m2 male) of rituximab; thus, 1/100th of the therapeutic dose would be 2-6.75 mg.

Other areas of the draft guidance are in need of clarification. Line 173 refers to ?a compound (or compounds)? and a corresponding ?single trial or related trials.? A clearer definition of when multiple compounds can be included in a single Exploratory IND application is needed. An example where this may be relevant would be in the evaluation of a series of engineered antibody fragments, with identical frameworks and formats, that differ only in the peptide loops that determine the antibody specificity. Would these be considered related compounds?

An especially critical area is lines 210-213, which describes the Agency?s plans to develop guidance explaining the stepwise approach to meeting cGMP regulations. This is a key area for those who aspire to develop recombinant proteins as imaging agents, especially when sponsors are academic and non-profit organizations with limited resources.

Respectfully submitted,

Anna M. Wu, Ph.D.
Associate Director, Crump Institute for Molecular Imaging
Associate Professor, Dept. of Molecular and Medical Pharmacology
David Geffen School of Medicine at UCLA
700 Westwood Plaza
Box 951770
Los Angeles, CA 90095