by Rajeswara Rao Pannem
The aim of an investigational new drug application (IND) is to obtain approval from FDA to perform clinical trials of an investigational medicinal product (IMP) in humans in the US. The IND follows the CTD structure developed by ICH and requires very detailed product and development data such as information of manufacture, data from nonclinical studies, previous clinical studies if any related to the IMP (Figure 1). It is also required to provide comprehensive source documentation including study reports. It is mandatory to submit an IND in the eCTD format starting from May 2018.
When a sponsor from the EU intends to initiate a clinical trial in the US, the relevant documents of the EU Clinical Trial Application (CTA) such as investigator’s brochure (IB), investigational medicinal product dossier (IMPD), study reports, study plans, and study plan amendments are key elements to start the preparation of an IND. The IMPD is the main document of the CTA in the EU used for obtaining the authorization to conduct a clinical trial with an IMP. For the IMPD preparation, a concise high-level summary of quality, manufacture, control of the IMP, data from nonclinical studies and data from its clinical use, and the overall risk and benefit assessment of IMP in proposed clinical trials are the prerequisites. In some cases, for nonclinical data and clinical use of the IMP, the IMPD cross refers to the IB. Moreover, upon submission of the IMPD the inclusion of study reports is not mandatory, but the sponsor should make them available on request of health authorities.
Comparing the EU with US, there are two main differences between the IMPD and IND structures:
- In the beginning of the clinical development program of an IMP, some information in the IMPD is summarized high-level whereas the IND requires extensive details.
- As the product advances in clinical development, new data are added to the IND whereas a new or updated IMPD is submitted with each CTA.
Therefore, preparing an IND on the basis of an IMPD – and vice versa – is not a copy and paste exercise.
There are various questions that typically arise when writing of an intricate IND is planned. Most of them are answered in the relevant ICH guidelines that provide the basic information about structural elements and about the content required by the CTD format (ICH M4 The Common Technical Document. These guidelines allow a certain level of flexibility to represent the content in a meaningful way. From our experience, the following aspects need to be considered when writing an IND:
- Create a template with all parameters mandatory according to FDA and ICH guidelines in CTD format with low level granulation
- Understand the background of product development before initiating writing
- Have all the information about the compound avaiable
- Understand if studies are missing, data gaps or discrepancies in data are present within the source documents and study reports
- Maintain an IND tracker of all elements requested by FDA for internal purpose to follow up with documentation during the compilation, publishing and e-submission or during NDA/BLA application later
- Involve a service provider specialized in eCTD compilation early on
Addressing these initial questions facilitates the IND writing process. In case uncertainties or discrepancies are found in the source documents, those issues need to be discussed first with the sponsor or CRO. In addition, the sponsor often provides source documents in PDF format rather than word files. Therefore, the writing process is laborious and time consuming especially when it comes to summarizing data of study results in a tabulated format.
Thus, writing an IND requires skilled and experienced people with relevant background who understand the regulatory requirements, can interprete the scientific data and identify gaps and discrepancies and who have the regulatory writing style expected by agencies. For example, to work on the nonclinical IND parts, the writer must have a strong biological science background to understand various experimental setups and wide range of topics covered during the drug development program.
Biopharma Excellence is experienced in writing INDs and IMPDs and in overcoming the challenges when submitting INDs and CTAs. If you seek support in preparation of regulatory submissions, please do not hesitate to contact us.