Impact of biopharmaceuticals on preclinical CROs

Scott Boley, senior director of general toxicology and infusion toxicology at MPI Research, says the rise of biopharmaceuticals is rapidly changing the way non-clinical trials are conducted.

The only thing certain is change. This axiom holds true for most aspects of today’s world and it is certainly a central tenet for drug development. Fifteen years ago, small molecules – chemically synthesised molecules designed to interact with a specific cellular receptor – represented the majority of pharmaceuticals under development.

The landscape has changed over the last ten years and the number of therapies being developed that fall into the category of biopharmaceuticals has exploded. Analysts predict that in the next decade the majority of therapies will fall into this class. For the purposes of this article, the term biopharmaceutical is used interchangeably with the terms biotechnologyderived pharmaceutical, large molecule, biologic or biotherapeutic. In the most general sense, the term biopharmaceutical can be used to refer to anything that is produced by a living cell – bacterial, yeast, mammalian, insect or plant – and may include antibodies, peptides, intact proteins, vaccines and stem cells.

The non-clinical safety programme used to support the development of biopharmaceuticals can differ significantly from that used to support the development of small molecules. Key considerations include the following:

• Study design. With small molecules, animal studies would typically be conducted in rodent and non-rodent 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 safety pharmacology studies is conducted. 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 may 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 non-human primates (NHPs), reproductive toxicology studies can be conducted solely in NHPs, 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 non-clinical safety studies with biopharmaceuticals also differs from the preparation of those used for small molecules. For example, biopharmaceuticals are more prone to adhesion than are small molecules and may require specific materials during their formulation (for example, glass instead of plastic). In addition, vigorous homogenisation procedures used during the preparation of small molecules are not used in the preparation of biopharmaceuticals because of their 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 and intramuscular).

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

It is critical that the contract research organisation selected by pharma and biotech companies has the experience, expertise and equipment necessary to meet their non-clinical safety evaluation needs with this emerging class of compounds.

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MPI Research Inc

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