What are Pre-Clinical Data Summaries?
Pre-clinical studies are investigations that test the drug in a non-clinical setting with cells and/or animal models to determine potential adverse/toxic effects before clinical trials
Can I ‘bypass’ some CMC summaries with a ?
Since a platform approach may use similar upstream and downstream processes, cell lines, raw materials, etc., testing related to the vector/capsid specifications for components kept the same across, purification, shipping/compatibility, stability and potentially other CQAs or evidence requirements might be exempt if that data/information already exists. [8]
The pre-clinical data summaries for AAV gene therapies would include information about the AAV vector used, transgene expression, biodistribution, shedding, and reports of any adverse effects and/or immune response. [4]
The goal for all non-clinical studies is to support Phase 1/2 safety and tolerability studies and comply with good laboratory practice (GLP). The GLP regulations can be found in 21 CFR Part 58.1: Good Laboratory Practice for Nonclinical Laboratory Studies.[8]
These regulations can provide you with the minimum requirements needed for your non-clinical investigations, specifically on:
Information regarding studies conducted – including protocols, operating procedures, and study reports
Personnel involved
Facilities and equipment
A system of quality assurance oversight for each study to help assure the safety of the FDA-regulated product
Data about a drug’s activities and effects in animals helps establish boundaries for safe use of the drug in subsequent human testing (clinical trials).
Before testing your product clinically, you must determine its toxicity. Usually, pre-clinical studies will be animal studies foundational to the planned clinical investigations, but will provide detailed information on pharmacology, biodistribution, safety exposure, dosing, and toxicity levels.
Additionally, it is recommended that you provide summarized results of your completed pre-clinical studies along with information on any planned studies. Providing this information will help the FDA with background information and context to be able to answer any pre-clinical questions you may have. To best convey your data, consider categorizing it into the broad sections shown in the figure below.
Below are brief descriptions of what each section entails. For the FDA guidance on specific details that go into each category, refer to the guidance titled Preclinical Assessment of Investigational Cellular and Gene Therapy Products | FDA. [4]
Proof of Concept Studies
In this section your goal is to provide the FDA with the feasibility and efficacy of your product in a pre-clinical setting, such as in vitro models or animals. It is important for you to ensure that the summarized results you provide in this section are well organized and include sections on study design, methods and materials, statistics, etc., for ease of review by the FDA reviewers. Furthermore, you can develop these summaries into study reports for the IND submission.
Toxicology Studies
In this section your goal is to provide the FDA with data sets from your toxicology studies showcasing the safety and risk assessment of your product, prior to advancing to clinical setting.
Pharmacology Studies
Here, your goal is to provide the FDA with the key data sets that highlight the pharmacological properties of your product including its interaction with the target site, absorption, metabolism, elimination, and potential adverse effects. Additionally, if the intended target population or the initial clinical trials are to be conducted in children, it is important that pre-clinical studies demonstrate a prospect of “direct benefit" to the child.
Studies of ROA devices (if applicable)
In this section your goal is to provide the FDA with studies showing the efficacy and biocompatibility of your product’s device component. In addition, you should provide detailed information about your device, the device description and the regulatory status of the device in the US (if device delivery is a critical component of your product delivery, as in intrathecal injection).
Other Non-clinical Studies (if applicable)
In this section you can provide the FDA with any other non-clinical data sets that support the efficacy and feasibility of your product.
What are the consequences or considerations of a platform-based approach for pre-clinical studies?
With a platform-based approach, your product may have similar components as other products – e.g., use the same vector, regulatory elements, route of administration – but use a different transgene. Therefore, there may be opportunities to streamline here as well. Some pre-clinical studies may be waived based on existing data/information for elements that are the same as previously manufactured clinical grade AAV vectors that have been used under INDs approved by the FDA-CBER.
Additional pre-clinical studies may be needed for assessment of toxicity due to the transgene itself, and if different regulatory elements are included (e.g., promoter), then you should still be able to streamline studies to address any residual uncertainty, e.g., impact of different promoters on biodistribution or other attributes. [2] The BGTC is developing a minimal set of animal toxicology studies to reduce use of non-human primates (NHPs) for IND submissions – please refer to the Platform-based approach for AAV gene therapies section for more information on the platform-based approach.