As the field of biopharmaceuticals continues to expand, drug developers are faced with the critical task of planning non-clinical programs for biotherapeutics. These programs play a pivotal role in ensuring the safety and efficacy of novel drugs before they reach clinical trials. Here, we explore the essential considerations that underpin successful non-clinical programs, guiding drug developers through Investigation New Drug (IND) applications and Clinical Trial Applications (CTA).
1. Leverage expert consultation
The decision to engage a toxicology consultant often stands overlooked amidst the flurry of drug development activities, particularly in teams that don’t have in-house toxicology expertise. A toxicology consultant can help guide your nonclinical toxicology strategy for your product, including important decisions about nonclinical species selection and selection and engagement of a laboratory testing partner to conduct the in vitro and in vivo toxicology studies, helping to avoid any unforeseen pitfalls. A toxicology consultant offers invaluable insights, aiding in navigating regulatory expectations, defining study timelines, and steering the program toward success.
2. Follow regulatory guidance
Before first-in-human (FIH) clinical trials can begin, regulatory guidelines require in vivo toxicology studies, complying with Good Laboratory Practice (GLP) standards. While early exploratory toxicology studies and dose range-finding studies are typically not conducted under GLPs, it is always best to conduct all assays associated with GLP toxicity studies. In some cases, an exception can be made, and an assay can be qualified but not conducted under GLP (i.e., specialty immunophenotyping or cytokine endpoints). These exceptions will be noted in study protocols and final reports submitted to health authorities.
On the other hand, in vivo pharmacokinetics (PK) studies are not required to be conducted under GLPs. Pharmacokinetic/toxicokinetic assessments (drug concentration and anti-drug antibody [ADA] assays) conducted as part of a GLP toxicity study do require validated assays and must meet GLP standards.
A toxicology consultant can help guide which in vivo or in vitro studies regulators require to be conducted under GLPs and the level of characterization of the drug substance necessary to support non-GLP and GLP studies. By aligning with regulatory standards, drug developers bolster the integrity of their non-clinical programs, laying a solid foundation for subsequent clinical translation.
3. Time bioanalytical assays carefully
The development of critical bioanalytical reagents and assays is too often deprioritized. However, bioanalytical assay (PK and ADA assays) method development, and qualification to support the nonclinical program, should begin well before any PK and toxicology studies start, including any non-GLP studies. Drug developers need to account for the several months that it can take to develop critical reagents and methods, while also qualifying the methods for use on the PK and dose-range finding studies.
Bioanalytical assays results are essential when designing subsequent toxicology studies and interpreting data. These results are important when selecting the starting dose, dosing regimen, and dose escalation scheme for the FIH clinical trials.
4. Navigate regulatory interactions skillfully
Preparing for an IND submission requires a nuanced understanding of the differences between regulatory bodies, as each has distinct guidelines and pre-IND interaction protocols.
For most protein-based biotherapeutics, including monoclonal antibodies, derivatives, fusion proteins, endogenous replacement therapies, and nanoparticles, the primary regulatory guideline is ICH S6(R1): Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. A pre-IND meeting provides further guidance on the nonclinical, clinical, and CMC aspects before the IND submission.
For bacterial and viral products, blood and blood products, and vaccines, the main guideline is “Preclinical Assessment of Investigational Products.” Numerous regulatory guidelines support the nonclinical development of these diverse products.
Regardless of the regulatory body, pre-IND meetings offer invaluable opportunities for clarification and guidance, ensuring alignment with regulatory expectations and smoothing the path to successful IND submission.
5. Decide how ‘global’ you want to go
Global IND submissions present drug developers with both opportunities and challenges. While a global approach can increase testing and data requirements, it can also be a more cost-efficient approach. To ensure drug developers have an all-encompassing approach, they need to determine which markets they’ll initiative clinical work in. It’s important that this decision takes place before IND-enabling studies to ensure that the study is tailored to the specific agency requirement. The right laboratory testing partner can ensure planning accounts for the timelines and expertise needed to meet regulatory requirements.
A final word
Navigating non-clinical programs for biotherapeutics demands a holistic approach, blending scientific rigor, regulatory acumen, and strategic foresight. With these five considerations, drug developers can pave the way for successful non-clinical programs.
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