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.
We recently held a roadshow in Cambridge and London, UK, to discuss the challenges in designing and executing a non-clinical development program, as well as how to effectively overcome these challenges. At 'Modern Drug Development - keeping your non-clinical program on track', delegates heard from:
- Dr. Robert Turcan, Head of Regulatory Affairs and Program Management, Envigo, on: "Drug Development - expect the best, plan for the worst, and prepare to be surprised!", which focused on the development of small molecules
- Dr. Kirsty Harper, Head of Biologics, Envigo, on: "Identifying, addressing and smoothing the bumps in the road to successful non-clinical development", relating to the development of biologics.
There was also a panel of experts who co-presented and answered questions from delegates.
In this post, you'll discover the six main take home messages from the roadshow.
Based on the speakers' experience with non-clinical development of many novel drugs, they identified the main factors that can cause delays or issues in planning, design and execution of a development program.
- test item availability
- using an acceptable dose vehicle
- ensuring regulatory compliance of third party PI laboratories
And in design and execution:
- toxicology study design considerations
- analytical method development and validations
- DDI strategy
1. Test item availability is the number one cause of delay in drug development
It's crucial to have enough test item for your non-clinical studies. Estimating this however, can be challenging if you do not have much information on your test article and you don't know the likely dose levels or which toxicology species will be used.
In his presentation, Dr. Turcan gave clear advice on quantity. “It’s better to over-estimate,” he said, “than to find you don’t have enough.”
Dr. Turcan also looked at how much test item is required for a Clinical Trial Application (CTA) enabling non-clinical program to support a First in Human study. "This varies with dose, dose route and type of molecule," he said.
"An 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, plan your test item’s manufacture and delivery well ahead. For example, 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 keep in mind any specific import/export requirements. In our experience most delays in importing are due to requests from Customs officials for appropriate documentation on the material being imported.
When undertaking your clinical trial you will need Good Manufacturing Practice (GMP) material, which will ensure your test item's quality and reproducibility. “For non-clinical trials, it’s fine to use GMP material,” Dr. Turcan said. “but it’s not essential. Non-GMP material should be well characterized according to Good Laboratory Practice (GLP) based on identity, composition, strength/purity, and stability.” And should be representative of the clinical grade material.
2. Don't underestimate the analytical challenges you will need to overcome
Dr. Turcan then introduced from the panel of experts present, Graeme Smith, Principal Scientist, Bioanalysis, who outlined some of the challenges associated with bioanalytical method development and validation. The four main challenges were:
1. What is the bioanalytical data going to be used for? - Namely, to support drug discovery or subsequent regulatory submission
2. What is going to be measured? - For example, you may need to consider both parent drug and metabolites, prodrugs and racemates
3. Starting materials for assay development
4. The lead time to establish methods
“The availability of starting materials for assay development is another challenge,” Graeme said. “For LC-MS/MS methods this will involve reference standards with Certificates of Analysis, isotopically labelled IS for regulatory methods, and specialised reagents and biological matrices.” Graeme stressed the importance of having your sampling, method and validation in place before life phases starts. “Always plan ahead of in life phases,” he recommended. “And remember that your method development defines sample collection and handling conditions.
One of the delegates asked: “Should analytical methods be transferable between non-clinical and clinical phases?” “They can be transferred,” Graeme said, but your testing requirements are different. You will have to consider GLP vs Good Clinical Practice (GCP) requirements and your clinical testing will be more sensitive, so you may need to further optimize the assay.”
3. Drug-drug interactions: be aware of the changing regulatory landscape
Co-presenters Guy Webber and Shaun Johnson, DDI experts, explained that regulators are becoming more concerned about drug-drug interactions (DDIs). Why? Because we are living longer and taking more medication 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 these studies before FIH/ Phase 1 trials. Understanding any DDI liability of your NCE is an important part of the overall risk/benefit profile.
4. Understanding pharmacology is a must
Dr. Harper's presentation focused on the typical non-clinical development pathway of a biologic product using a theoretical novel mAb for the treatment of chronic bronchitis as a case study to illustrate this.
As you will probably be aware, chronic bronchitis is a serious condition that affects millions of people worldwide and developing drugs that cure or prevent it could have a huge impact on the health of the world’s population. But doing so raises many challenges for scientists. 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 should be 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.
5. Species selection is critical, especially for biologics
“Biopharmaceuticals do not have an effect if they do not bind,” Dr Harper reminded delegates. “And binding does not always mean they have an effect.” There are two key questions you must ask when selecting species for use in safety assessment studies, she said:
1. Is your drug pharmacologically active in the test species?
2. Is your drug immunogenic in the test species?
The regulators will expect that all biologics products are assessed in pharmacologically relevant species, and as described in ICH S6(R1), assessment in non-clinical species is actually discouraged.
A delegate then asked Dr. Harper “what happens if you don’t have an appropriate animal model that can be used?”. “In that case,” Dr. Harper said, “you’ll have to find an alternative as you still need to understand the safety of your product. The use of surrogate products or transgenic animal models may need to be considered.
6. Assess the safety of your biologic
Your goals in this area, Dr. Harper said, should be to identify:
- An initial safe dose and subsequent dose escalation schemes in humans
- Potential target organs for toxicity and whether such toxicity is reversible
- Safety parameters for clinical monitoring
“Goals are similar to traditional NCE products,” Dr. Harper said. “But the approach is generally very different for biologics. For biopharmaceuticals, ICH S6(R1) details the over-arching approach to non-clinical safety assessment and the importance placed on understanding and replicating the intended biology of the product in your study. This will drive all aspects of your non-clinical development programme, from selection of relevant species, to identification of appropriate biomarkers, to the specific design required for your safety assessment studies.”
These were just some of the challenges and issues that cause delays to development. Download Dr. Turcan and Dr. Harper's presentations to explore case histories showing how novel approaches in design and management of unexpected outcomes can help keep your non-clinical program on track.