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Learning to think with the end in mind will help clients and their selected CRO to design and conduct the right studies.
Well-designed nonclinical studies are foundational to a successful drug development program. Beyond simply meeting regulatory expectations, nonclinical studies provide an understanding of the margin of safety, the nature of drug-related toxicities, and the basis for selecting a starting dose for first-in-human/Phase I trials. Most contract research organizations (CROs) have the technical skills to conduct nonclinical studies in a manner that meets regulatory requirements, which makes it tempting to “bargain shop” based on price alone; however, this approach overlooks the expertise within a CRO that may prove to be an invaluable resource. Partnering with a CRO to optimize the design of investigational new drug (IND)-enabling nonclinical studies (also termed safety assessment studies) has the potential to maximize the information that can be collected in early clinical trials, while being an efficient use of resources. For many smaller biotech or pharmaceutical companies, limited resources mean focusing internal efforts on the chemistry/manufacturing and proof-of-concept pharmacology studies. In such cases, clients often have limited guidance or experience with IND-enabling nonclinical studies.
In selecting a CRO, clients should take into consideration factors other than schedule availability and price. They should look for an organization with extensive and diverse experience and deep scientific expertise that can help with gap analysis and proper staging of their drug candidate. Equally or more important than the organizational level considerations are the individual interactions that occur. Some CROs have dedicated scientists with decades of drug development experience whose primary role is to provide this kind of perspective and guidance. As with any relationship, communication is key, and it is important for a client to openly share information on the company’s research and development focus, capabilities, and the overall development plan including the regulatory pathway (e.g., 505(b)(1), 505(b)(2), etc.).
For virtual/small biotechnology companies, the general business strategy is to minimize internal operational costs and to maximize expenditures toward direct advancement of drug development efforts. In these situations, the regulatory toxicology experience within the company may be limited. Working with a CRO that has drug development experience can mean that the CRO acts as a partner or extension of the company in developing the regulatory strategy for the drug candidate. Thus, in evaluating a potential CRO, factors to consider include: the range of services offered, experience in guiding clients to develop IND-enabling programs, experience with drug class/modality, and experience in the desired therapeutic area.
Books have been written on the process of drug discovery and development (1,2). Nonclinical safety assessment encompasses the evaluations immediately prior to beginning human (i.e., clinical) studies and includes several types of studies: absorption, distribution, metabolism, and excretion (ADME); safety pharmacology; genetic toxicology; and general toxicology. ADME studies investigate how the body handles the drug candidate (i.e., how readily the drug is absorbed, where it distributes within the body, and how it is metabolized and excreted). Safety pharmacology studies (3) assess critical organ systems in the body. The core safety pharmacology battery includes testing for effects on the cardiovascular, respiratory, and central nervous systems. Genetic toxicology studies consist of in-vitro and in-vivo tests designed to detect compounds that induce genetic damage by various mechanisms (4). There are many other types of toxicology studies (e.g., juvenile toxicity, abuse-liability testing, developmental and reproductive toxicity, carcinogenicity, etc.) that may be required for an IND, at later stages of development, or based on the nature of the target and/or specific patient populations.
With the broad variety of studies required for drug development, a client may choose to contract with several CROs to independently conduct select sets of studies. However, this approach requires that each CRO be vetted separately, have separate master services agreements, and have independent monitoring for study progress and report quality; all of which require a significant input of time and logistical capabilities. Partnering with a single CRO capable of performing most or all of the studies can reduce the work and effort, with the added benefit that the CRO develops a growing depth of experience with the drug candidate. However, a client should carefully evaluate the capabilities of a CRO before selecting it to design and conduct their nonclinical safety assessment studies. Depending on the scientific disciplines needed (e.g., juvenile toxicology or abuse-liability experience), CROs have differing levels of expertise. The specific requirements of a drug candidate need to be considered in the decision.
Answers to the questions of how to conduct the nonclinical studies, what studies are needed, and when they should begin are all directly influenced by the nature of the drug candidate, the clinical trial designs, and the therapeutic/commercial objectives. The disease indication and drug target are important, but a CRO also needs to understand the characteristics of the drug candidate to be studied, the intended patient population, and the dosing route, regimen, and planned clinical trial durations. This is where open information sharing and learning to think with the end in mind are critical.
Many companies share proprietary information about their drug candidate only on a “need to know” basis with their CRO. However, when engaging with a CRO that is under a confidential disclosure agreement/contract, this assurance of confidentiality should free the client to share as much information as possible for the benefit of their program.
Clients should also develop the practice of thinking with the end in mind. A disease indication(s) affected by the target for the drug candidate is usually identified early in the drug discovery process, but clients may not consider until much later the essential properties and necessary label claims for a commercial drug product. Working with their CRO, they can develop a target product profile (5) to establish the “desired attributes” and work backwards to determine the studies needed to support the claims in the new drug application/biologics licensing application. If the CRO has extensive experience in the drug class, the client can leverage that knowledge to identify key attributes that are needed for a successful filing.
Timeline management is another area where CROs can benefit a client. A universal goal with IND-enabling studies is to complete them as quickly as possible. The use of multiple CROs for an individual program requires the client to manage many moving parts as well as to serve as the liaison for information-sharing when current study designs depend on previous work performed at different CROs. Due to program complexities and the need to maintain timelines, many CROs offer project/program management services to help clients oversee the progress of their drug development plan. These services can be helpful in managing study milestones (study starts, data sharing, report timelines, etc.) as well has helping in risk mitigation. A program manager can work on solutions to reduce or eliminate delays in the program timeline more effectively than a study director whose focus is on an individual study. When dealing with several CROs, this task can be daunting, as each CRO can only help in the context of their assigned studies. This makes schedule adjustments across different CROs difficult. Working with a single CRO can ameliorate this concern, as the program manager can view and change schedules across an entire program.
CROs can also help a client optimize manufacturing and drug candidate/test article availability. It may seem obvious; adequate amounts of the drug candidate need to be available to conduct the nonclinical studies. However, clients frequently underestimate the amount of drug required to complete all the nonclinical safety studies. For most drug candidates, regulatory guidelines specify that the general toxicology studies identify dose-limiting toxicity and a no observed adverse effect level (NOAEL) (6), which may require high dose levels for well-tolerated drug candidates. Close interactions with the CRO can help accurately predict the amount of drug needed for the IND program, thereby reducing the risk of manufacturing too little compound and delaying study starts. Another factor to consider in drug manufacturing is the value of having the same lot of test article used for both the IND-enabling studies and the initial human trials. By using the same lot of material, the client ensures that all impurities are “qualified” through testing in the nonclinical safety studies. This is particularly important with large molecules, where inherent variability in the manufacturing process may make it difficult to produce multiple identical lots of material. Small-molecule synthesis is somewhat more forgiving because impurities are generally consistent between lots.
Additional topics that should be discussed with the CRO are the clinical route of administration, the clinical dosing regimen, and the clinical trial duration. It is a regulatory expectation that the nonclinical studies will be conducted using the intended clinical route of administration (6). Using the same route of administration will increase the likelihood that the observed kinetic and toxicity profiles are predictive of what will occur in humans. If the dose route in the clinic differs from that used in the nonclinical studies, a bridging study may be required to demonstrate that the kinetic and toxicity profiles are not affected. Likewise, the dose regimen and duration of the toxicology studies should mirror the clinical plan. Dosing more or less frequently than what is planned in the clinic may over or underestimate, respectively, the toxicity of the drug candidate. Additionally, the duration of dosing in the nonclinical studies is designed to support the duration of the clinical trials, with longer duration nonclinical studies being required to support increasing clinical trial durations (6).
As with any relationship, there is significant depth and complexity of the discussions needed for a successful IND-enabling program. Essential to this are open lines of communication and early, goal-driven planning. Trends for smaller companies foregoing internal expertise in nonclinical development and larger companies diversifying into multiple drug classes (e.g., gene therapy, adoptive cell therapies, oncolytic viruses, etc.) have intensified the importance for the relationship between client and CRO to be viewed as a partnership. Drug development has become more complex overall; nonclinical studies and development plans need to reflect this change, and utilizing all available experts and resources is paramount.
1. Benjamin Blass, Basic Principles of Drug Discovery and Development (Academic Press, May 11, 2015).
2. Raymond G Hill, Drug Discovery and Development: Technology in Transition (Churchill Livingstone, Sept. 13, 2012).
3. ICH, S7A and S7B, Pharmacology Studies (ICH, November 2000).
4. ICH S2(R1), Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use (ICH, Nov. 9, 2011).
5. FDA, Guidance for Industry and Review Staff: Target Product Profile - A Strategic Development Process Tool, Draft Guidance (CDER, March 2007).
6. ICH, M3(R2) Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (ICH, June 11, 2009).
Vol. 32, No. 10
When referring to this article, please cite it as N. D. Horton, S. S. Chuang, and M. V. Templin,"Outsourcing of Nonclinical Studies for Drug Development: Tips and Trends," BioPharm International 32 (10) 2019.