All Articles Leadership Challenges in Developing Biologics

Challenges in Developing Biologics

5 min read


Shawn Heidel

Shawn Heidel, DVM, PhD, is Executive Director, Global Lead Optimization and Program Management at Covance. In this role, he is responsible for scientific and business strategy for the pathology, toxicology, pharmacology and imaging groups involved in preclinical development. He also works across Covance’s business units to ensure delivery of client solutions for nonclinical development. In this post, sponsored by Covance, Heidel talks about the nonclinical challenges of developing biologics and other industry issues.

Question: We’ve seen the new Covance advertisement with the slogan that “No Two Are Ever the Same” for biologics.  What does this mean?

Answer: Biologics are medicines that are manufactured in living cells and are structurally unique depending on the conditions under which they are manufactured. You can manufacture the same biologic in different cell lines and get a structurally different biologic because the manufacturing conditions can change them.

Biologics [today] have varying degrees of human gene sequence. If you go back 20 years ago, most biologics had substantial non-human sequences.  Now, there are fully humanized sequences and a wide array of constructs that contain both human and non-human sequences.

To sum it up, the physicochemical structure, the intended target, the immunogenicity potential and the species selectivity of each biologic makes them unique.

Q: Building on this theme, how does this apply to development examples in the lead optimization space? 

A: Lead optimization is a critical—and time-consuming—phase in the process of drug discovery. Each biologic, each program has to have a [unique] series of studies. Some biologics will need a battery of tests, which may include extensive toxicology testing, and some will only need a simple, single-dose pharmacokinetic/pharmacodynamic (PK/PD) study. One commonality that all biologics share is that all of them will need reagent development for quantitation in enzyme-linked immunosorbant assays (ELISAs). But knowing which reagents are needed to build very unique bioanalytical assays requires development experience. Development experience is absolutely critical to understanding which way to turn, what are the right assays.

You need to consider the complexity of bioanalytical method development, as well as the tests that will be needed for pharmacology, toxicology, and PK/PD for the specific biologic. And it may be some [of those tests] or none of them, such as in vivo pharmacology. And you don’t know until you see what the biologic is—and characterize it and know the target.

Q: How does this apply to good laboratory practice (GLP) study designs?

A: Going back to the notion that no two biologics are the same, the GLP studies that directly support that first-in-human clinical trial aren’t like boxes that you can just tick off. Some programs will have a single study in a nonhuman primate. Some will have a set of studies, including a rodent study, a large animal study and a complete battery of safety pharmacology studies. And designing the appropriate study goes back to the issue of experience. You have to have the experience of which set of studies to design and, more to the point, how to design each study.

Q: What are the nonclinical challenges of developing some of the more novel classes of biologics, such as cell-based or gene-based therapies?

A: First, as far as the challenges go, there’s no ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) program to guide development. What that means is that there isn’t an overarching worldwide guidance. The other thing is that cell-based or gene-based therapies are by definition designed to modify or replace cell function and that means that you have to be concerned about cell proliferation and creating cells that could cause cancer. Therefore, parameters in the study must look for things like tumorgenicity, or the potential of causing cancer within humans.

To summarize some of the key nonclinical challenges: 1) There are no ICH regulations to design the program; and 2) there are different considerations for safety when compared to more traditional molecules, like monoclonal antibodies, cancer risk being the greatest concern.

Q: Are you seeing a shift in what clients are asking for from Covance?

A: What we are finding is that clients are asking for development experience. To design a biologics program, you need deep experience, 10 years at a minimum. We have gone to great lengths to hire those experienced people. In addition, clients are looking for people trained in immunotoxicology because biologics are inherently immunogenic and frequently have targets in which immunotoxicology experience is needed. Finally, clients are looking for CROs [contract research organizations] that have vertical integration: CROs with experience in toxicology, pharmacology, biologics chemistry, manufacturing and controls, and clinical experience, and that can put together a team of experts that covers all the disciplines.

It comes back to that notion of no two are ever the same: you have to have that experience, whether it is for nonclinical or clinical. You need experience to design the right development program that gives the right answers to the client.