In this article, Dr. Thuy Tran, a CMC Project Leader at Servier, gives us a quick explanation of what an IND is, what a clinical hold is, and why clinical holds happen for drug discovery scientists.
What is an IND?
Health authorities require drug developers to provide and justify safety and efficacy information for new treatments in humans prior to granting marketing authorization. In the United States, drug developers (or sponsors) must submit an Investigational New Drug Application (IND) to the Food and Drug Administration (FDA) before conducting clinical trials in the US. The investigational drug can be a new vaccine, a new compound, a combination of compounds, or an existing compound tested for a new indication or a new targeted population.
An IND includes:
- preclinical data (i.e. animal pharmacology and toxicology)
- pharmaceutical quality/chemistry, manufacturing, control (CMC)
- clinical protocols
While drug discovery scientists most often think of first-in-human trials when they hear “IND,” INDs are required for Ph. II and Ph. III studies as well for unapproved molecules. The FDA will determine if the study can be conducted based on a benefit-to-risk evaluation.
When is an IND not required for clinical trials?
There are two specific instances when commencing clinical trials do NOT require an IND. First, clinical trials with on-label use of a marketed drug (i.e. same indication, same dose, same route of administration, same patient population, same drug formulation, same drug combinations as in the label) do not require an IND.
Second, a bioavailability or bioequivalence study of an unapproved version of marketed drug can be conducted without an IND, which is favorable for generic drug development. In the case of off-label use of a marketed drug (i.e. any difference from what is approved in the label), an IND may be requested by the FDA if it is determined that there is an increased risk to healthy volunteers or patients.
What is a pre-IND meeting?
Before the submission of an IND, sponsors can request a pre-IND meeting with the FDA to gain its advice on data requirements for IND as well as critical issues that may have occurred during the drug development program. This pre-IND meeting is especially useful before making major decisions and costly investments.
To schedule a pre-IND meeting, sponsors submit a written request to the appropriate division such as the Division of Anti-infectives (DAI) or the Division of Oncology 1 (DO1). Within 21 days after receiving the request, the FDA determines whether to grant or deny the meeting and confirms the meeting format (i.e. face-to-face, teleconference/videoconference or written responses only or WRO) . If granted, the meeting or WRO happens 60 days after the request.
The sponsor must submit a meeting package with questions at least 30 days before the meeting (see Table 1). A preliminary written response from FDA will confirm the meeting 1-2 days before the meeting. Meeting minutes will be sent within 30 days after the meeting.
Table 1. Pre-IND Meeting Package Checklist
The pre-IND meeting package should include:
- Description of the product: including product name, chemical name, established name and structure, regulatory pathway, indications or context of product development, dosage form, route of administration and dosing regimen
- Pediatric study plan (if applicable)
- Human factor engineering plan (e.g. how to deal with human behaviors with devices) (if applicable)
- Combination product information (if applicable)
- List of participants of the pre-IND meeting (e.g. team lead, CMC leader, FDA staff, …)
- Development program summary: including history, previous communication with FDA, changes and current status.
- Meeting purposes and proposed agenda
- List of questions organized by FDA discipline (eg. pre-clinical, clinical pharmacology, clinical, CMC, clinical) with brief summary of the context (e.g. formulation issues, toxicology study design, use of an excipient, adequacy of in-process control or lot-release testing, trial design)
- Summary of relevant data to support discussion (e.g. pre-clinical data, manufacturing flowchart, clinical trial results, trial endpoints)
What goes in an IND filing?
The content of an IND is described in the Code of Federal Regulations (CFR Title 21 Part 312) and easy to find in FDA website (link). Table 2 presents the outline of the list. Commercial INDs must to be submitted in electronic format (electronic Common Technical Document (eCTD)) via the FDAs Electronic Submissions Gateway (ESG), an improvement from when paper documents were shipped by the truckload. Study data needs to be complied within the FDA Data Standards Catalog to avoid eCTD rejection. Using an eCTD can be practical because the same format is used by drug regulatory agencies in other countries. The FDA encourages sponsors of Research Use Only INDs to submit eCTD formatted IND, but it is not mandatory.
Table 2. IND Filing Checklist
The IND must include:
- Cover letter (brief explanation of the intended investigation, proposed formulation, etc.)
- Forms: Form 1571 (IND), Form 1572 (Statement of the Investigator), Form 3674 (Certification of Compliance)
- Table of contents
- Introductory statement and general investigational plan: Summary of drug information, previous human experience and overall clinical development plan (rationale, indication, clinical trial type)
- CMC information:
- Drug substance: physical, chemical and biological characteristics, manufacturer, method of preparation, acceptable limits, analytical methods, stability data
- Drug product: components, manufacturer, manufacturing process, acceptable limits and analytical methods, stability data)
- Placebo: composition, manufacture and control
- Environmental analysis requirements
- Pharmacology and toxicology Information: data on pharmacological effect, mechanism of action, drug disposition, toxicology studies (in vitro or in vivo) to support the use in human
- Investigator’s brochure: brief description of drug substance and drug product, summary of relevant preclinical and clinical data, possible risks and side effects
- Clinical protocols: (clinical studies) Form 1572
- Previous human experience with the investigational new drug
- Additional information (if applicable): drug dependence and abuse, radioactive drugs, pediatric studies,
- Relevant information if requested by FDA
Within 30 days after receiving the IND, FDA will review and decide if the clinical trial is “safe to proceed” (STP) or there are deficiencies to be resolved. In case of deficiencies, FDA will address a “information request (IR)” to the sponsor for additional information or modifications to the IND. If after this 30-day period, the sponsors receive a “safe-to-proceed” letter or no communication from FDA, the clinical trial can begin. The sponsors can withdraw the IND if they decided to abandon the clinical trial for any reason.
What is a clinical hold?
A clinical hold is an order issued by FDA to delay fully or partly a proposed clinical study or to suspend an ongoing one. During or after the 30-day review period after the IND submission, the FDA can request the sponsors to resolve any deficiencies that impact the safety of healthy volunteers and patients participating in the proposed or ongoing clinical trial.
If no satisfactory solution is provided, a clinical hold will be issued. A written explanation of the clinical hold will be sent within 30 days after imposition of the hold, which allows the sponsor to address the deficiencies. The FDA will review the submission within 30 days from when all deficiencies are addressed by the sponsors and determine whether the hold can be lifted.
Why do clinical holds happen?
It is sometimes possible to find information on a clinical hold of a study that’s already been launched, but less likely for a study not yet started. Two papers with interesting statistical data on the rates and reasons for clinical holds can be found here and here.
Table 3. Some examples of reasons for clinical holds.
Product Quality/CMC Information
- Lack or insufficient information of manufacturing process or product description
- Lack or insufficient information of batch analysis
- Presence of impurity profile indicative of a potential health hazard
- Lack of stability data of clinical batches
Pharmacology and Toxicology Information
- Missing animal studies or supporting information to support the anticipated exposure (dose, route of administration, duration)
- Poor quality non-GLP toxicology studies
- Lack of prior clinical safety data
- Insufficient information in safety assessment
- Eligibility criteria
- Insufficient information to support proposed initial dose
- Treatment plan expose healthy volunteers or patients to unreasonable risk
- Safety monitoring does not include all safety issues identified during preclinical studies
Filing an IND marks one of the most important milestones in the drug development timeline as it enables studies in humans for the new treatment. The FDA issues numerous guidances on the IND and review process that are easy to find online. The FDA is also a more interactive agency than many realize – in cases of inquiries, sponsors can directly contact FDA for clarification. While the whole regulatory process may seem intimidating, the central role and critical impact of clinical trials in drug development program make it worth the effort.
We hope this has been helpful in putting INDs and clinical holds in context. Explore drughunter.com/resources for more drug discovery resources.
About Dr. Thuy Tran, PhD, PMP
Thuy Tran is a CMC Project Leader at Servier. She currently focuses on CMC development and global regulatory strategy for lifecycle management of marketed pharmaceutical products with previous experience on development of new molecules for oncology. Before Servier, she worked for Capsugel (currently NextPharma) as Formulation Specialist. Thuy earned her PhD at the University of Copenhagen, Denmark where she studied and optimized the use of lipid-based formulations to enhance the absorption and biodistribution of poorly-water soluble drugs.