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The FDA’s Center for Drug Evaluation and Research (CDER) reviews each application within 30 days. CDER looks for evidence that study participants will avoid “unreasonable risk of significant illness or injury” during early clinical trials and that the study is designed to meet its objectives. INDs that fail to support safety claims adequately can be placed on “clinical hold” until a further review is complete.
The FDA receives around 200 new IND applications per quarter—e.g., 777 applications between October 2020 and September 2021—and while only about 9% of applications are placed on clinical hold, the designation can quickly derail a program. As the first significant milestone sponsors face, getting an IND submission right is paramount to protecting the program timeline. And if the drug candidate is being developed to combat a rare disease or respond to a widespread emergency, delays caused by clinical hold can be devastating.
The bottom line is that a successful IND submission requires strategic planning and precise timing. But drug sponsors unfamiliar with the required steps need not fret. Help is available.
What goes into an IND submission?
Regulators expect IND applications to contain three sections: preclinical testing data, chemistry, manufacturing and controls (CMC) data and a clinical protocol or investigator information.
Preclinical “IND-enabling” tests are conducted in vitro and in vivo and are designed to answer specific questions about therapeutic safety. For example, DMPK studies examine a drug’s absorption, distribution, metabolism and excretion (ADME) properties. Assays that assess a drug candidate’s stability, permeability and interaction with other drugs (DDI) comprise the required in vitro data.
In vitro data helps researchers optimize a drug candidate’s chemical structure and analyze in vivo PK properties and drug interaction potential in humans. In vivo studies are typically performed in test articles whose PK properties most closely resemble those of humans. Studies used for metabolite identification, quantitative whole-body autoradiography (QWBA) and radiolabeled/non-radiolabeled mass balance generally derive the most valuable ADME data.
Preclinical toxicology data are also critical to the progression of any IND submission. Toxicology data for small molecules is required from two species — i.e., rodent and non-rodent—in addition to genotoxicity data. Small molecules can also form metabolites in the body, adding additional risk, and must be identified through the bioanalytical method validation of blood, plasma or other biological matrices. Large molecules, on the other hand, require data from pharmacologically relevant species (i.e., rodent and/or non-rodent) and often NHPs are the only relevant species to use. Typically, they do not require genotoxicity data or metabolite identification. Safety pharmacology testing is also conducted to assess a drug’s potential effect on the cardiovascular, pulmonary and central nervous systems.
Preclinical toxicology assessments should include single-dose and repeated-dose testing and, if necessary, immunotoxicity and local tolerance information. Regulators will also expect reproductive and developmental toxicity and carcinogenicity data following first-in-human (FIH) studies.
The second critical section included in an IND application is CMC data. These data help ensure pharmaceuticals are safe, effective and consistent between each batch. Obviously, drugs contain an active ingredient (API), but they also comprise various solvents, chemical starting materials, inactive ingredients, etc., and the quality of those raw materials needs to be assessed and controlled. For example, drugs that require sterile products must have the sterilization protocol documented and validated. Similarly, a molecule’s inherent stability must be consistent with the shelf-life information contained on a pharmaceutical label.
Put simply, CMC data assure regulators that the same product can be produced consistently and with the exact specifications. It also demonstrates a developer’s ability to optimize their manufacturing process and scale from producing milligrams to kilograms and beyond.
The clinical protocol and investigator information is the final section of the IND submission that regulators expect to see. This section contains crucial information about each investigator participating in a clinical study. Among other details, the investigator statement must include information related to each participating investigator’s certifications, qualifications and disclosure of financial arrangements.
A clinical protocol also details the trial design, patient selection criteria, clinical procedures, laboratory tests and any measures that will be taken to monitor the drug’s effects on patients. Any experience investigators have with the proposed primary endpoints should also be disclosed. And any potential deviations from the trial design — including collecting and reporting adverse effects — should also be included in the clinical protocol.
Conducting the necessary preclinical testing and collating the required investigator information for an IND application can take as few as nine months or as long as several years. Starting with CMC data is probably best as it contributes to potential toxicity. In vivo toxicity testing should come next, followed by the clinical protocol. Submission delays occur for various reasons, but unexpected toxicity and failing to create a large enough drug sample to complete the battery of required tests are among the most common.
IND applications for new vs. existing drugs
The FDA designates specific pathways for new (i.e., “innovative”) drug candidates versus those being repositioned or reformulated. The drug candidate’s path will determine the scope of preclinical and clinical data needed to achieve IND approval. These pathways include:
505(b)(1) pathway. This is the most comprehensive pathway for new drug development and the framework by which most drugs have come into being. It is reserved for “innovative” drug candidates whose API has never been studied or approved. The original drug sponsor is responsible for generating all necessary data and retains the right of reference for all data gathered during the investigation.
505(b)(2) pathway. Developed in 1984 to prevent the duplication of studies and to fast-track drugs used to treat rare diseases, this pathway is used when modifying a previously approved drug. “Modifications” include reformulating the drug or changing its route of administration, dosage, strength or indication. The 505(b)(2) pathway is only available if a drug developer or sponsor can demonstrate they have somehow advanced a previously approved drug. Investigators may rely upon published data or peer-reviewed articles in their application and must show the drug’s similarities to established molecules. Drug sponsors do not retain right of reference under this pathway.
505(j) pathway. This pathway is reserved for generic versions of existing drugs. Drug candidates must be identical, or almost identical, in API, dosage, strength, administration route, labeling, quality and intended use. Minor differences from existing drugs are acceptable if they do not require additional data to support their use.
Though seemingly straightforward, choosing the right pathway and generating the appropriate in vitro and in vivo data for a drug candidate can be quite complex. The best way to know what regulators will expect in your IND submission is to schedule a pre-IND meeting.
Scheduling a pre-IND meeting
The pre-IND meeting is intended to address specific questions related to the initial U.S. first-in-human (FIH) study for new drugs and biologics and other questions that could affect the IND application. A pre-IND meeting request should be sent to an appropriate Review Division responsible for overseeing products in the therapeutic area relevant to the IND application. The FDA’s Office of New Drugs (OND) operates pre-IND consultations, ultimately deciding whether the benefits of a new drug outweigh its known risks. To do so, the OND advises drug sponsors on:
- The necessary data to support the rationale for testing a drug in humans.
- Designing nonclinical pharmacology, toxicology and drug activity studies.
- Initial drug development plans and regulatory requirements for demonstrating safety and efficacy.
- Additional data requirements for IND applications.
Pre-IND interaction will occur in written comments, which can evolve into teleconferencing and in-person meetings. Sponsors should also note that pre-IND meetings require submitting a briefing package consisting of CMC, preliminary pharmacology, toxicology and DMPK data, and a clinical protocol that includes investigator information.
Scheduling a pre-IND meeting is one of the most critical steps a drug sponsor can take, but it is not always straightforward. Timing and strategy are key. The pre-IND meeting is a unique opportunity for the sponsor to meet with the FDA to discuss their specific questions and to ensure a complete IND application is submitted. A successful outcome of the pre-IND meeting can help avoid clinical holds and mistakes during program development. The Agency typically responds within 21 days upon receipt of the Pre-IND request, and meetings are generally scheduled within 60 days of the request. As a result, the sponsor should submit their request approximately two months before they would like to have the pre-IND meeting. Also note, it will take extra time and resources to compile and collate the clinical protocol and investigator information. Suffice it to say IND submission includes a lot of moving pieces.
A final word
Any research in which human participants will ingest or apply a product requires IND approval. As demonstrated, there are several regulatory pathways and there can be multiple concerns to mitigate, depending on the drug candidate. The U.S. FDA’s aim is not to convolute or mystify the application process but to ensure new drugs are as safe as they can be for human consumption. Drug sponsors that lack in-house experience with IND-enabling studies—especially those related to toxicology—and the shifting regulatory landscape may want to consider working with a lab testing partner.
About the Author
Joining WuXi AppTec with more than 15 years of preclinical drug development experience, Dr. Xiaoxia Li provides scientific support to our clients and will enhance the quick response rate for technical questions. She began her career at a preclinical Contract Research Organization (CRO), BOZO (Biology and Zoology) in Tokyo, and then spent over 13 years working as a Study Director at ITR Laboratories in Montreal, Canada. Afterwards, she worked as a Scientific Leader in nonclinical development for a pharmaceutical company in Toronto, Canada, before starting her own consulting firm, Sunrise IDD Inc. Dr. Xiaoxia Li is a Diplomate of the American Board of Toxicology (DABT). She completed her Ph.D. in pharmacology in Japan and received her MD and MSc in China.
Filed Under: Drug Discovery, Drug Discovery and Development
