Drug sponsors looking to initiate clinical trials for new products must first secure approval from regulators. This authorization can only be granted following an Investigational New Drug (IND) submission, and the entire development process is on hold until approval is granted. In the U.S., regulators have 30 days to respond to an IND submission. They can either approve the submission or ask for additional information. If additional information is sought, the submission is put on clinical hold until the sponsor corrects the deficiencies found. The ultimate goal of an IND submission is to provide data to regulators assuring them the product is safe for human use.
What do regulators look for?
A regulator’s review process focuses on protecting study participants from any “unreasonable risk of significant illness or injury” during early clinical trials. INDs lacking sufficient safety evidence may face a “clinical hold” until the completion of a thorough review.
While only 9% of applications are placed on clinical hold1, such a designation can swiftly derail a program. For drug sponsors addressing rare diseases or responding to widespread emergencies, delays due to clinical holds can have costly consequences.
What goes into an IND submission?
There are three sections of IND applications that regulators need: preclinical testing data; chemistry, manufacturing, and controls; and clinical protocol or investigator information. These are some of the key elements of a submission.
- Nonclinical testing data: IND-enabling tests are conducted both in vitro and in vivo, with the aim of addressing any therapeutic safety concerns.
- in vitro and in vivo: In vitro data helps researchers refine a drug candidate’s chemical structure, analyzing in vivo PK properties, and assessing its potential drug interactions in humans. In vivo studies involve test articles with PK properties closely mirroring those of humans. Studies used for metabolite identification, quantitative whole-body autoradiography (QWBA), and radiolabeled/non-radiolabeled mass balance yield the most valuable ADME data. Metabolite identification is needed for small molecules, selecting species for the toxicology program based on which animals metabolize the drug similarly to humans.
- Toxicology: For small molecules, toxicology data are required from two species— rodent and non-rodent—in addition to genotoxicity data. Small molecules can form metabolites in the body, posing additional risks, and requiring identification through validated bioanalysis of blood, plasma, or other biological matrices. Large molecules require data from pharmacologically relevant species (rodent and/or non-rodent), with non-human primates (NHPs) often being the pertinent species. Large molecules do not require genotoxicity data or metabolite identification.
- Dosing: Both single-dose and repeated-dose testing is completed, and when necessary, includes information on immunotoxicity and local tolerance. Regulatory bodies expect to receive data on reproductive and developmental toxicity, along with carcinogenicity assessments, after the conclusion of first-in-human (FIH) studies.
- CMC: Chemistry, Manufacturing, and Controls (CMC) data, an integral part of IND applications, ensures pharmaceuticals’ safety, efficacy, and uniformity across batches. It encompasses several components like active pharmaceutical ingredients, solvents, and inactive ingredients. For instance, sterile products must have a validated sterilization protocol. CMC data assure regulators of consistent manufacturing and demonstrate the developer’s ability to optimize production from small to large scales.
- Clinical Protocol: This includes essential details about each investigator working on a study and its parameters. It outlines investigator qualifications, financial disclosures, trial design, patient selection criteria, procedures, and monitoring measures. Any deviations from the protocol, including adverse effects, must be documented.
- Timeline: Nonclinical testing and gathering investigator data for an IND application can take as little as nine months or as long as several years. It’s important to start with CMC data due to its impact on toxicity, followed by in vivo toxicity testing. Submission delays often stem from unforeseen toxicity and insufficient sample sizes for tests.
IND applications for new versus existing drugs
Applications for IND vary across new and existing drugs, with specific FDA pathways for each category.
- 505(b)(1) Pathway is the most comprehensive route for new drug development, commonly utilized for innovative drug candidates whose Active Pharmaceutical Ingredient (API) has not been previously studied or approved. The original drug sponsor is accountable for generating all necessary data and retains the right of reference for all information gathered during the investigation.
- 505(b)(2) Pathway, introduced in 1984, streamlines drug development for rare diseases and prevents study duplication. It’s used when modifying a previously approved drug. “Modifications” encompass reformulating the drug or altering its route of administration, dosage, strength, or indication. This approach is only available if developers or sponsors demonstrate advancements to a previously approved drug, relying on published data or peer-reviewed articles, highlighting the drug’s similarities to established molecules.
- 505(j) Pathway is used for generic versions of existing drugs and requires drug candidates to be nearly identical in API, dosage, strength, administration route, labeling, quality, and intended use. Minor differences are acceptable if they do not necessitate additional data to support their use.
Scheduling a pre-IND meeting
Pre-IND meetings allow questions related to the initial first-in-human (FIH) study for new drugs and biologics. To initiate this process, a formal request should be directed to the relevant Review Division overseeing products in the therapeutic area of the IND application.
The Office of New Drugs (OND) oversees pre-IND consultations, determining whether the benefits of a new drug outweigh its known risks. The OND offers guidance on various aspects, including:
- Data requirements to support testing a drug in humans.
- Designing nonclinical pharmacology, toxicology, and drug activity studies.
- Initial drug development plans and regulatory requirements for safety and efficacy.
- Additional data requirements for IND applications.
Pre-IND interactions begin with written comments and may progress to teleconferencing or in-person meetings. Sponsors should prepare a briefing package, including Chemistry, Manufacturing, and Controls (CMC) data, preliminary pharmacology and toxicology data, Drug Metabolism and Pharmacokinetics (DMPK) data, and a clinical protocol with investigator information.
When to Schedule:
A pre-IND meeting offers a unique opportunity to engage with regulators and ensure a comprehensive IND application. A successful outcome helps minimize errors and clinical holds. Typically, regulators respond within 21 days, and meetings are scheduled within 60 days of the request. Thus, sponsors should aim to submit their request approximately two months before the desired meeting date. However, compiling the required information demands extra time and resources, underscoring the complexity of the IND submission process.
1 Lapteva L, Pariser AR. Investigational New Drug applications: a 1-year pilot study on rates and reasons for clinical hold. J Investig Med. 2016 Feb;64(2):376-82. doi: 10.1136/jim-2015-000010. PMID: 26911627.
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