The impact of the growth of biopharmaceuticals on preclinical CROs

By Scott Boley

The only thing certain is change. This axiom holds true for many aspects of today’s world, but it is a central tenet for drug development. Fifteen years ago, small molecules (chemically synthesized molecules designed to interact with a specific cellular receptor) represented the majority of pharmaceuticals under development. During the past 10 years, however, the number of therapies being developed that fall into the category of biopharmaceuticals has exploded, with predictions that the majority of therapies developed in the next 10 years will fall into this class.

For purposes of this article, the term biopharmaceutical is used interchangeably with the terms biotechnology-derived pharmaceutical, large molecule, biologic or biotherapeutic. In the most general sense, the term biopharmaceutical can be used to refer to anything that was produced by a living cell (bacterial, yeast, mammalian, insect or plant) and may include antibodies, peptides, intact proteins, oligonucleotides, vaccines and stem cells.

The nonclinical safety program used to support development of a biopharmaceutical can differ significantly from that used to support development of traditional small molecules.

Some of the key considerations include:

Study design: With small molecules, general toxicology studies and reproductive toxicology studies would typically be conducted in rodent and nonrodent species based on in vitro metabolism profiles. For biopharmaceuticals, regulatory bodies allow the animal studies to be conducted in a single species if the biopharmaceutical is pharmacologically active in only a single species.

Safety pharmacology studies: In the case of small molecules, a standard battery of separate safety pharmacology studies is conducted, where the potential for the test article to affect the major physiological systems is examined. For biopharmaceuticals these studies may not be conducted as stand-alone studies; rather, safety pharmacology endpoints may be included in the design of the general toxicology studies. If the biopharmaceutical has known effects on a physiological system, stand-alone safety pharmacology studies will likely still be needed.

Reproductive toxicology studies: For small molecules, reproductive toxicity testing is conducted in two species. If the pharmacological activity of the biopharmaceutical is limited to one species, typically nonhuman primates (NHP), reproductive toxicology studies can be conducted solely in NHP, with the rationale being that if there is no pharmacological activity of the test article in a particular species, conducting reproductive toxicology studies in that species would not provide meaningful data.

Dosing solutions: The preparation of dosing solutions used for nonclinical safety studies with biopharmaceuticals also differs from that used for small molecules. For example, biopharmaceuticals are more prone to “adhesion” than are small molecules and may, therefore, require specific materials during their formulation (for example, glass instead of plastic, etc.). In addition, vigorous homogenization procedures used during the preparation of small molecules are not used in the preparation of biopharmaceuticals, because of homogenization’s propensity to create bubbles that can denature a protein.

Delivery methods: The delivery of biopharmaceuticals presents its own challenges. Biopharmaceuticals cannot be administered orally, because they would be broken down in the acidic environment of the stomach before they had an opportunity to become systemically available. Therefore, the common routes of administration are parenteral (subcutaneous, intravenous, intraperitoneal, intramuscular).

These are just a few of the important considerations affecting the nonclinical research industry, which, instead of being driven by small molecules as it has been over the past decade, will now have its growth largely fueled by biopharmaceuticals.

It is critical that the CRO selected by pharma and biotech companies have the experience, expertise, and equipment necessary to meet the nonclinical safety evaluation needs with this emerging class of compounds.

Biography

Scott E. Boley, PhD, DABT, is Senior Director of General Toxicology and Infusion Toxicology at MPI Research. He received his PhD in biochemistry and environmental toxicology from Michigan State University and did postdoctoral work at CIIT Centers for Health Research. Contact Dr. Boley at Scott.Boley@mpiresearch.com or +1-269-668-3336, extension 1887.