Bringing a drug from discovery to market is an expensive and time- consuming business. Every drug that fails comes with a cost which could be both reputational and financial. Keeping your development program on track is therefore critical to success.
In the planning, key considerations include test item availability, using an acceptable dose vehicle and ensuring regulatory compliance of third-party principal investigator laboratories.
Furthermore, during study design and execution phases, important factors include the specific design of toxicology studies, analytical method development and validation, and drug-drug interaction (DDI) strategy.
Test Item Availability is the Number One Cause of Delay in Drug Development
It is crucial to have enough test item for your non-clinical studies. Estimating this however, can be challenging especially if you don’t have much information on the potential toxicity of your test item and hence the likely dose levels in the toxicology studies or indeed which toxicology species will be used for this work. It is better to over-estimate your test item requirements rather than to find you don’t have enough.
The amount of test item required for a non-clinical program to support a First in Human clinical study varies with dose, dose route and type of molecule. A New Chemical Entity (NCE) administered orally could require up to four-to-five kg if toxicity is low. A biologic often requires a lot less test item.
To prevent delays, you should plan your test item manufacture and delivery well ahead. For example, and depending on the complexity of the synthetic route, it can take six-to-eight months to manufacture a one-to-ten kg batch. If you are manufacturing your test item abroad, you should also keep in mind any specific import/export requirements. In our experience, most delays in receipt of test item are due to requests from Customs officials for appropriate documentation on the material being imported.
When undertaking your clinical trial, you will need test item manufactured according to Good Manufacturing Practice (GMP) which will ensure your test item's quality and reproducibility. For non-clinical trials with an NCE, it’s fine to use GMP material but it is not essential. Non-GMP material should be well characterized according to Good Laboratory Practice (GLP) based on identity, composition, strength/purity, and stability. It should be representative of the clinical grade material and provided with an appropriate Certificate of Analysis. For large molecules (biologics) it is more common to conduct the non-clinical safety assessment work using the same GMP batch of test item that is subsequently used in the First-In-Human clinical study.
Don't Underestimate the Analytical Challenges You Will Need to Overcome
There are four main challenges associated with bioanalytical method development and validation.
First, you should consider what the bioanalytical data is going to be used for. You may need a bioanalytical method to support studies in drug discovery or you may require the analysis be to support subsequent regulatory submissions. The approach taken for method development and validation will depend on what the data is to be used for with wider acceptance criteria generally acceptable to support drug discovery. Second, you must determine what is going to be measured, for example, you may need to consider parent drug and metabolites, or the presence of a prodrug or racemate. The third challenge lies in the starting materials for assay development and whether there is a significant lead time required to obtain these. This can significantly impact the time required to establish the methods.
The availability of starting materials for assay development can also be a challenge. For LC-MS/MS methods this involves reference standards with Certificates of Analysis, isotopically labelled internal standard (IS) for regulatory methods, and specialized reagents and biological matrices. It is important to have your sampling, method and validation in place before toxicology studies start to avoid any risk of samples not meeting acceptable stability criteria while they await analysis. Always plan ahead for the in-life phases and remember that your method development defines sample collection and handling conditions.
Your analytical methods can be transferred between the non-clinical and clinical phases but your testing requirements are different. You will need to consider Good Laboratory Practice (GLP) vs Good Clinical Practice (GCP) requirements and your clinical testing will usually require a more sensitive assay, so you may need to further optimize the method.
Drug-drug Interactions: Be Aware of the Changing Regulatory Landscape
Regulators are becoming more concerned about drug-drug interactions (DDIs). Why? Because we are living longer and taking more medications at the same time, which is increasing the risk of adverse effects from DDIs.
Due to these concerns, the DDI regulatory landscape is changing. In October 2017, the FDA issued new draft guidelines for DDIs. They state that DDI studies should be started at an earlier stage of development and you should now be considering initiating these studies before FIH/ Phase 1 trials. Understanding any DDI liability of your NCE is an important part of the overall risk/benefit profile.
Understanding Pharmacology is a Must
The typical non-clinical development pathways of a biologic product are based on the specific properties of each product and their target biology.
Whatever drug you’re developing, it’s vital that you ensure it is effective and safe at every stage. For biologics in particular, it is critical that wherever possible, the relevant pharmacology should be measured, and appropriate biomarkers or assays included throughout development to support this, whether in initial candidate selection, developing efficacy data, or assessing the safety of a product prior to clinical evaluation.
Species Selection is Critical, Especially for Biologics
Biopharmaceuticals do not have an effect if they do not bind to their target, but binding alone does not always mean they have an effect. There is therefore a key question you must ask when selecting species for use in safety assessment studies:
Is your drug pharmacologically active in the test species?
The regulators will expect that all biopharmaceuticals are assessed in pharmacologically relevant species, and as described in ICH S6 (R1), assessment in non-clinical species is actually discouraged.
What happens if you don’t have an appropriate animal model that can be used? In that case, you’ll have to find an alternative as you still need to understand the safety of your product. In this case, the use of surrogate products or transgenic animal models may need to be considered.
Assess the Safety of Your Biologic
The goals for safety assessment of Biologics are similar to those of traditional NCE products:
- Identify an initial safe dose and subsequent dose escalation scheme in humans
- Identify any potential target organs for toxicity and determine whether such toxicity is reversible
- Identify safety parameters for clinical monitoring
However, the approach used is generally very different for biologics; as described in ICH S6 (R1), which details the over-arching approach to non-clinical safety assessment of biopharmaceuticals, importance is placed on understanding and replicating the intended biology of the product within your safety study. This drives all aspects of your non-clinical development program, from selection of relevant species, to identification of appropriate biomarkers, to the specific design required for your safety assessment studies.
https://blog.envigo.com/6-take-home-messages-from-our-modern-drug-development-roadshow