Preclinical Development: The Safety Hurdle Prior to Human Trials

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Before any new biopharmaceutical molecules reach the preclinical stage, they have to pass through a series of selections at the discovery stage: target discovery and validation, hits generation and screen, and lead selection and optimization.

Preclinical testing is the final deciding gate prior to clinical studies, and only 12% of the candidates advance to the Phase I clinical trial. From this point, the success rate for the investigational biologics increases at each clinical phase, with 17% at Phase I, 27% at Phase II, 58% at Phase III, and 82% at the registration phase.¹ On average, drug discovery and preclinical development take three to six years and account for 30.8% of costs per approved compound, approximately $788 million.^{2, 3}

Preclinical Testing

During preclinical development, the critical question biopharmaceutical developers seek to answer is whether the novel molecule is safe to be tested in humans — which is also the primary concern of regulatory agencies. The safety assessment starts early, in the stage of screen preparation when bioassays (used to assess biochemical and functional properties such as binding and efficacy assays) of lead molecules are initially developed.

As the candidates advance to the preclinical stage, more extensive tests have to be performed both in vitro and in vivo to gain better understanding of their pharmacodynamics (PD) and pharmacokinetics (PK) behavior and establish their pharmacologic, safety, and toxicity profile. Concomitantly, biopharmaceutical developers need to assess their manufacturability and plan for GMP clinical-scale production since larger quantities of biopharmaceuticals will be needed for clinical trials.

At the end of the preclinical study, the most promising molecules are selected for human testing. Before initiating clinical trials, the sponsor is required to submit an Investigational New Drug application (IND) for any trials conducted in the U.S., which usually goes into effect 30 days after the FDA receives it. A typical IND must contain three categories of information: preclinical data on animal pharmacology and toxicology studies; chemistry, manufacturing, and control (CMC); and clinical protocols and investigator information.⁴ The regulatory landscape is more complex in the EU, where clinical trials are regulated by the National Competent Authorities (NCAs) in each member state (currently 28 member states) instead of one central agency, the European Medicines Agency (EMA). Similar to an IND, a Clinical Trial Authorization (CTA) application must be submitted to the NCAs.⁵ Timelines for review and approval of CTA applications vary among NCAs, ranging from less than 14 days to 90 days_{^{.6, 7}}

Preclinical testing challenges

One significant challenge associated with preclinical testing of biopharmaceuticals is the selection of relevant animal species. In general, the regulation requires toxicology studies to be conducted in two relevant species. The animal toxicity data is essential to determine the safe starting dose and dose range for the first-in-human (FIH) study and identify potential adverse effects relevant to humans. However, for many biologics, there are limited choices of relevant species due to their high tissue- and/or species-specific activity. Sometimes, nonhuman primates may be the only relevant species. When relevant animal species are not available, alternate approaches are considered such as using homologous molecules or transgenic animal models.¹⁰

To date, protein-based biologics (i.e., monoclonal antibodies (mAbs), fusion proteins, and recombinant proteins) account for most development-stage and marketed biopharmaceuticals. One specific challenge with therapeutic proteins is immunogenicity, the generation of antidrug antibodies (ADAs). The undesired immunogenicity may affect biologic’s PK and PD and induce immune reactions. The ICH S6 addendum provides specific instructions on when ADAs level should be measured. On the other hand, ICH S6 recognizes the limitation of nonclinical studies in predicting potential immunogenicity of human or humanized proteins in humans. In other words, immunogenic responses observed in animals are not indicative for humans.¹⁰ Based on the perspective of Dr. Andrew J. McDougal, a FDA/CDER nonclinical reviewer, specific safety concerns for mAbs include cross-reactivity, slow elimination, exaggerated pharmacology, and slow recovery from toxicity. Safety concerns for cytokines and growth factors are species-specificity, interaction with host endogenous cascade, and tumor-promoting potential.¹¹

Collaborations with CROs for preclinical testing

Bringing a novel biopharmaceutical from bench to bedside takes a broad range of collaborations across biopharmaceutical industry, academia, patient and disease groups, government, and contract research organizations (CROs). Groundbreaking discovery (i.e. a novel drug target) flourishes in academia. However, it is the industry that leads the efforts in translating the discovery into meaningful therapeutics. To improve the R&D efficiency and accelerate development, engaging with CROs has become a widely adopted strategy by the biopharmaceutical industry. According to the 2016 Nice Insight CRO Outsourcing Survey, 80% of the respondents acquire or plan to acquire preclinical trial services while 53% of them currently engage with cros for preclinical (includes discovery phase) research. Among a cluster of 16 preclinical trial services, bio-analytical testing (53%), research models (animal models) (50%), analytical testing (49%), chemistry and stability testing (48%), and biostatistics, surgical services (for animal models), and general toxicology (45% respectively) are the top 5 most needed services.¹² Midsized pharma/ biotech companies demonstrate a slightly higher than average demand for all of the surveyed preclinical services while the service demand from small pharma/biotech is lower than average.

In selecting CROs for biopharmaceutical preclinical development, a CRO’s development experience weighs heavily in a sponsor’s decision-making process. A CRO’s experience and expertise in bioanalytics, pharmacology, toxicology, and PK and PD is critical in designing appropriate studies so that valuable safety information of the molecule of interest can be collected and evaluated. Vertical integration is another desired feature often sought by biopharmaceutical clients when selecting a CRO. Drug discovery and development is a continuous coordinated process of research, production, and regulation. In the preclinical phase, CROs with expanded expertise in manufacturing, regulation, and clinical studies are more capable of synchronizing preclinical testing, production and regulatory compliance in a holistic manner, and are thus poised for a long-term partnership with biopharmaceutical manufacturers.

References

1. 1. Philippidis, A., “Studies Suggest that When It Comes to Drug Development Success, Size Matters,” GEN Exclusives. Apr 09, 2012. http://www.genengnews.com/insight-andintelligence/studies-suggest-that-when-it-comes-to-drugdevelopment-success-size-matters/77899586/.
2. Gaffney, A., Mezher, M., “Regulatory Explainer: Everything You Need to Know About FDA’s Priority Review Vouchers,” RAPS. Jul 02, 2015. http://www.raps.org/Regulatory-Focus/ News/2015/07/02/21722/Regulatory-Explainer-Everything-YouNeed-to-Know-About-FDA%E2%80%99s-Priority-ReviewVouchers/.
3. DiMarsi, J.A., “Cost of Developing a New Drug Briefing,” Tufts Center for the Study of Drug Development. Nov 18, 2014. https://www.sla.org/wp-content/uploads/2015/06/1546_ ProductivityBiopharmaIndustry-DiMasi.pdf.
4. FDA, “Investigational New Drug (IND) Application.” http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ HowDrugsareDevelopedandApproved/ApprovalApplications/ InvestigationalNewDrugINDApplication/default.htm.
5. European Medicines Agency, “Clinical trials in human medicines.” http://www.ema.europa.eu/ema/ index.jsp?curl=pages/special_topics/general/general_ content_000489.jsp&mid=WC0b01ac058060676f.
6. Charnas, R., “EU Perspective on Regulatory Issues for Biologics.” Feb 29, 2008. https://www.sitcancer.org/ meetings/am08/primer08_oncology/presentations/16_ charnas.pdf.
7. NHS Health Research Authority, “MHRA-Clinical Trial Authorisation.” http://www.hra.nhs.uk/research-community/ the-review-process/mhra-clinical-trial-authorisation
8. ICH Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals S6(R1). http://www.ich.org/fileadmin/ Public_Web_Site/ICH_Products/Guidelines/Safety/S6_R1/ Step4/S6_R1_Guideline.pdf.
9. McVean, M., “Preclinical Development to IND: Drugs, Biologics, Cellular/Gene Therapies and Vaccines,” PreClinical Research Services, Inc. Apr 18, 2014. http://www. cobioscience.com/biobootcamp/McVean_BioBootCamp_ Preclinical%20Dev%20to%20IND_2014.pdf.
10. Kingham, R., Klasa, G., Carver H.K., “Key Regulatory Guidelines for the Development of Biologics in the United States and Europe,” John Wiley & Sons, Inc. 2014. https:// www.cov.com//media/files/corporate/publications/2013/10/ chapter4_key_regulatory_guidlines_for_the_development_of_ biologics_in_the_united_states_and_europe.pdf. 
11. McDougal, A.J., “Preclinical Development [CDER]: Biological Therapeutics for Cancer Treatment,” iSBTc Oncology Biologics Development Primer. Feb 28, 2008. https://www.sitcancer.org/meetings/am08/primer08_ oncology/presentations/3_mcdougal.pdf. 
12. The 2016 Nice Insight Contract Research — Preclinical and Clinical Survey.