As the nation’s principal authority overseeing the safety of food, drugs and cosmetics, the US Food and Drug Administration (FDA) requires manufacturers to provide proof of the safety and efficacy of their drugs before bringing them to market. This has been the case since 1962. That year, in response to the thalidomide tragedy, the US government enacted the Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act.
The amendment requires drug developers (also called “sponsors”) to file Investigational New Drug (IND) applications, providing evidence that these drugs would be safe to use in human trials. The IND authorization must be secured prior to interstate shipment and administration of any new drug that is not the subject of an approved new drug application.
When is an IND Needed?
The FDA requires an IND application for clinical investigation of a new drug or biologic in the US. Sponsors should also submit an IND when the company wants to study an approved product for a new indication, patient population (e.g., pediatric, gender), route of administration, or dose.
What are the Contents of an IND application?
An IND application typically contains the following information at a minimum –
- Clinical Protocol, Informed Consent Form, Investigator’s Brochure
- Animal data-Pharmacology and Toxicology
- Chemistry, Manufacturing and Controls
- Administrative Documents
By Day 30, post submission of the IND application the FDA will notify the sponsor if they may proceed with the study or the study is placed on clinical “hold”. All IND applications will only be accepted in the eCTD format.
When is an IND submission exempted?
Some studies are exempted from the requirement to submit an IND only if they meet the following five criteria:
- The study is not intended to support new use or a significant labeling change
- The study is not intended to support a significant change in advertising for the product
- The study does not significantly increase the risks associated with the use of drug
- The study is conducted in compliance with institutional review board (IRB) and informed consent regulations
- The study is conducted in compliance with appropriate regulations with regards to promotion and charging of investigational drugs
The FDA publishes a complete checklist of criteria that must be met in order to exempt an IND submission.
Importance of Pre-IND Meetings
The FDA strongly recommends a Pre-IND consultation meeting with the FDA staff, typically held three-to-nine months before submission of an IND application. These meetings give sponsors the opportunity to ask questions about the planned IND and to receive valuable feedback. Sponsors can learn, for example, how to squeeze the most useful information out of the necessary studies and can also obtain the FDA’s initial feedback on the design of their planned clinical study. Conversely, they can learn which studies may be unnecessary. This information may accelerate the drug development timeline: the FDA tracking studies show that Pre-IND meetings can shave an average of two years off drug development.
Sixty days prior to the meeting a sponsor is required to submit a Pre-IND meeting request, which essentially contains questions for the FDA, along with the context of the development, and brief information about their program. Thirty days prior to the meeting, a sponsor is required to submit a Pre-IND meeting package to the Agency. The meeting package should provide information relevant to the discussion topics and enable the FDA to prepare adequately for the meeting. The package should include information on:
- Purpose of meeting
- Characteristics of the new drug
- Chemistry, manufacturing and controls information of the new drug
- Planned or completed pre-clinical studies
- Development plan
- Design of the planned investigation in humans
- Questions for the FDA
The most effective pre-IND meetings focus on a specific regulatory or scientific issue (e.g., questions about clinical trial design, toxicology studies, or pharmacology studies). It is critical for sponsors to remember that complete transparency is necessary to obtain the maximum value from the meeting, and to prevent potential clinical hold issues. Sponsors should preface their questions with supportable information, and end them with a request for confirmation, such as, “Does the FDA agree?”. Approximately 30 days after the meeting, the FDA sends official meeting minutes back to the sponsor.
The FDA’s Guidance Documents for IND submission
The FDA has published guidance to help sponsors prepare IND applications, including documents that cover the Agency’s current thinking on subjects related to the processing, content, evaluation and approval of IND applications, as well as to the design, production, manufacturing and testing of regulated products.
Most recently, in December 2017, the FDA issued a new guidance describing best practices and procedures for timely, transparent, and effective communications between IND sponsors and the FDA staff at significant junctures in drug development. “By collaborating with IND sponsors early in the application process, the FDA believes its science-based feedback can make the drug development process more efficient, enabling patients to get timelier access to safe and effective new medicines,” said the FDA in announcing the release of the guidance.
Clinical Considerations in an IND Review
The Good Review Practices addition to the FDA’s Manual of Policies and Procedures highlights the FDA’s key considerations in reviewing IND applications. This document lists considerations for each stage of drug development – including pre-IND meetings, Phase I clinical trial protocol and Phase II/III planning. It presents detailed discussions on critical aspects of overall development and trial design, and lists questions for sponsors to consider. Good Review Practices also provides specific instructions on planning dosing schemes, assessing dose-response, setting up controls and truth standards, randomizing and blinding, planning statistical analysis, reporting adverse experiences and adopting good clinical practices.
To have a successful IND submission and outcome, it is essential that a sponsor learn the grounds for imposition of clinical hold and considerations of the Agency in an IND review process. The IND will be placed on hold if the FDA suspects participants in the study may be exposed to significant risk of illness or injury. For maximum success Novella recommends the following:
- Consider the Pre-IND communication and the FDA feedback prior to IND submission
- Include details of safety monitoring plan in the protocol
- Provide a clear scientific rationale for dose selection
- Include previous human experience and known safety data, if available
- Include sufficient animal and manufacturing data to assess the risks to trial participants