Boyds’ chief development officer, Dr Nick Meyers, and director of regulatory affairs, Dr Eric Hardter, provide advice and guidance to drug developers and sponsors on de-risking the Investigational New Drug (IND) process.
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Transitioning from the preclinical stages to the clinic can be a nuanced process, especially for drug developers working in new and evolving areas like cell and gene therapy. In the US, understanding the expectations and product-specific complexities of the FDA’s Investigational New Drug (IND) application process is crucial to best prevent an adverse regulatory response.
To meet the FDA’s stringent regulatory requirements, a well-structured clinical study design, supported by robust non-clinical and manufacturing packages, is essential. Failing to provide compliant IND documentation supportive of the investigational product’s risk/benefit profile may introduce delays in a sponsor’s development programme. A key step in de-risking this process may be the pre-IND meeting, which allows for dynamic discussion with FDA stakeholders to facilitate transition into a clinical trial. This meeting offers an opportunity for sponsors to align with the Agency’s current thinking, and – importantly – identify and address any potential concerns at an early stage.
Six top tips to de-risk the IND process
There are various de-risking activities sponsors can undertake to potentially save time and minimise unnecessary cost, thereby advancing an investigational product into the clinic without undue delay.
1. Ensure an integrated approach across disciplines
Adopting a multidisciplinary approach to regulatory affairs is vital, as no one discipline is a vertical which stands alone. As such, ensuring consistency of messaging across clinical, nonclinical pharmacology/toxicology, and Chemistry, Manufacturing, and Controls (CMC) disciplines will help generate a cohesive IND that clearly describes the totality of the iterative investigational product development leading to the proposed clinical trial. A regulatory affairs professional should ensure all stakeholders are apprised of development status and may effectively serve as the programme lead and overarching subject matter expert.
2. Engage with regulators early on
Engaging with regulatory agencies early in the development process is crucial. A pre-IND meeting prior to a GLP toxicity study will best de-risk this pivotal study, along with supportive CMC activities. Where a novel, proposed regulatory approach is not defined in regulation, guidance or predicate approvals, an FDA INTERACT meeting may be utilised to clarify early expectations. Additional meetings (e.g., Type C, Type D) may be held if further discussion is needed, and the formal Request for Clarification pathway may be utilised to ensure FDA commentary is understood. Establishment of a good working relationship with the FDA Regulatory Project Manager may also yield informal (e.g., outside of a meeting setting) advice. Regardless of the setting, it is important to ask specific questions and present data clearly when communicating with the FDA.
3. Plan timelines for meetings and submissions
Understanding the varying timelines and distinct deliverables for different types of meetings and submissions is essential for effective planning and resource allocation. On average, sponsors may look to plan INTERACT meetings for complex biologics several years before an IND submission. Pre-IND meetings may be anticipated around a year in advance of the submission date, pending the proposed duration of the GLP toxicity study and finalisation of data. The regulatory affairs professional should guarantee stakeholder availability to ensure all necessary data and documentation are ready for submission.
4. Follow documentation and submission best practices
Avoid making the FDA "hunt" for information within the submission. Clear and organised documentation is crucial for a successful IND application, and as such the submission should be provided with the anticipated granularity of information as described in regulation and guidance. Where FDA meetings were held, sponsors should include a response matrix which contains sponsor responses to FDA commentary, along with hyperlinks to relevant sections of the application.
5. Understand publishing requirements
Sponsors of commercial applications must transmit submissions through the FDA’s Electronic Submissions Gateway in the electronic common technical document (eCTD) format. Identification of a publisher should be performed well before the date of anticipated submission, and documentation must be provided to the FDA to authorise the publisher to submit on the sponsor’s behalf. For submission documents, ensure connectivity (i.e., external hyperlinks) where appropriate, and that the submission meets all electronic publishing standards. This may be an arduous and time-consuming process for larger submissions like INDs, so ensure enough lead time for publishing, and provide documents to the publisher on a rolling basis where possible.
6. Respond to FDA feedback appropriately
FDA commentary, whether received in a formal meeting or during an IND review, is not inherently binding. Where sponsors agree with FDA thinking, this should be noted, and changes should be made to the application accordingly. However, where there is disagreement, then succinct, direct, and data-driven responses should be provided, with submission documents amended as needed. It is important for sponsors to remember that they are the subject matter experts of their development programme, and that FDA stakeholders are invested in getting safe and effective investigational products approved. As such, a respectful, continued dialogue may yield concurrence not initially received.
Progressing the investigational development programme
Navigating the complexities of the IND application process requires strategic planning and informed decision-making. By focusing on integrated planning and early regulatory engagement, and producing clear documentation, sponsors can de-risk their application and best ensure study clearance.
External drug development consultancies like Boyds are well-versed in developing timelines and plans for drug development and can provide the guidance you need to keep your project firmly on track.