Investigational New Drug (IND) approval processes and time-lines involved.

Investigational New Drug Current federal law mandates that a drug must have an approved marketing application before it can be transported or distributed across state lines. When sponsors intend to ship an investigational drug to clinical investigators in multiple states, they must seek an exemption from this legal requirement. The Investigational New Drug (IND) application is the mechanism through which sponsors obtain this exemption from the FDA.

During the early preclinical development of a new drug, sponsors primarily aim to establish its initial safety for human use and demonstrate pharmacological activity that justifies further commercial development. Once a product is identified as a viable candidate, sponsors focus on gathering the necessary data to ensure that its use in limited, early-stage clinical studies does not pose unreasonable risks to humans.

The FDA’s involvement in the new drug development process begins when the drug’s sponsor—typically the manufacturer or potential marketer—wishes to evaluate its diagnostic or therapeutic potential in humans after screening it for pharmacological activity and acute toxicity in animals. At this stage, the molecule’s legal status changes under the Federal Food, Drug, and Cosmetic Act, making it subject to specific regulatory requirements.

An Investigator IND is submitted by a physician who initiates and oversees an investigation, administering or dispensing the investigational drug under their direct supervision. A physician may submit a research IND to propose studying an unapproved drug or an approved product for a new indication or in a different patient population.

An Emergency Use IND allows the FDA to authorize the use of an experimental drug in emergency situations where there is insufficient time to submit a standard IND as per regulations. It is also used for patients who do not qualify for an existing study protocol or when no approved protocol exists.

A Treatment IND is submitted for experimental drugs that show promise in clinical testing for serious or immediately life-threatening conditions while final clinical trials are ongoing and FDA review is underway. Regulatory Approval Process download free PDF

 IND categories Investigational New Drug

Commercial

Research (non-commercial)

The IND application must contain information in three broad areas:

1. Animal Pharmacology and Toxicology Studies: Before testing in humans, preclinical data is necessary to determine the safety of the product. This includes any prior human use experiences, often from international sources.
2. Manufacturing Information: This section covers details about the composition, stability, and manufacturing processes of both the drug substance and product. It ensures that the company can consistently produce and supply the drug.
3. Clinical Protocols and Investigator Information: Detailed protocols for initial clinical studies are reviewed to minimize risks to participants. This section also outlines the qualifications of clinical investigators, typically physicians, to ensure they are capable of fulfilling their trial responsibilities. Additionally, it includes commitments to obtain informed consent, undergo institutional review board (IRB) review, and comply with investigational new drug regulations.

Once the Investigational New Drug (IND) application is submitted, the sponsor must await FDA review for 30 days before commencing any clinical trials. This review period ensures that potential research subjects are not exposed to undue risks.

 Labeling of an Investigational New Drug: The labeling of an investigational new drug must include the statement: “Caution: New Drug-Limited by Federal (or United States) law to investigational use.” This statement must not be false or misleading, and it should not imply that the drug is safe or effective for its investigational purpose.

 Control of an Investigational New Drug: An investigational new drug can only be administered to participants under the supervision of the principal investigator or a sub-investigator, typically a physician. The investigator is prohibited from supplying the drug to unauthorized individuals.

 Use of Controlled Substances: Research involving investigational new drugs classified as controlled substances must adhere to U.S. Drug Enforcement Administration regulations (21 CFR 1300-end). Measures must be taken to prevent theft or diversion of these drugs into illegal channels, including secure storage in locked cabinets or similar secure enclosures.

 Promotion and Distribution: Neither the investigator nor the sponsor may promote or advertise an investigational new drug as safe or effective for its investigational purpose. The drug cannot be commercially distributed or used in a test market. If sufficient data from the investigation indicates the drug is safe and effective, the study should be concluded, and further enrollment halted.

 Charging for Investigational New Drugs: Charging for an investigational new drug in a clinical trial is not allowed without FDA approval, except in cases where the drug is provided for treatments.

Phases of Clinical Trials for Investigational New Drugs

Clinical trials for investigational new drugs typically progress through four main phases, designated as Phase 1 to Phase 4. Additionally, there are Phase 0 trials, also known as “exploratory” trials, which involve minimal dosing typically below therapeutic levels and include only a small number of participants. While less common than Phases 1 to 4, Phase 0 trials serve a specific purpose in early drug development. Each phase aims to gather distinct types of information, although these phases may occasionally overlap.

Eligibility for participation in these trials varies based on factors such as age, overall health, the specific disease and its stage, and any prior treatments received.

1. Phase 1 Trials

Phase 1 trials mark the initial introduction of an investigational new drug into human testing. They typically involve healthy volunteers, though individuals with the targeted disease may also participate. These trials generally include a small group, often between 20 and 80 participants. Phase 1 trials are primarily designed to:

• Assess the safety of the drug in humans.
• Identify early side effects associated with its use.
• Establish a preliminary safe dosage range for therapeutic purposes.

2. Phase 2

Trials Phase 2 trials are conducted with individuals who have the disease targeted by the drug or those at high risk of developing it. These trials are larger in scale than Phase 1, typically involving several hundred participants. Phase 2 trials focus on:

• Evaluating the drug’s effectiveness in treating or preventing the targeted disease.
• Determining the optimal dosage for further studies.
• Identifying common short-term side effects and risks associated with the drug.

3. Phase 3

Trials Phase 3 trials proceed when earlier phases suggest the drug’s safety and potential effectiveness. These trials enroll several hundred to several thousand participants and are crucial for:

• Gathering extensive data on the drug’s safety and effectiveness.
• Comparing its benefits versus risks, often against standard treatments or placebos in blinded studies.
• Investigating interactions with other concurrent therapies.
• Providing sufficient evidence to support the drug’s labeling, specifying approved uses and any restrictions (e.g., age limitations).

These phases collectively form a systematic approach to assessing new drugs, ensuring that only those demonstrating safety and efficacy proceed toward approval and wider clinical use.

Phase 4 Trials

Phase 4 trials occur after a drug or treatment has received marketing approval. These trials are undertaken to achieve several objectives:

• Continued Safety Evaluation: Phase 4 trials continue to monitor the drug’s safety profile, focusing on gathering additional short-term safety data in larger populations.
• Effectiveness in Diverse Populations: These trials aim to assess how the drug performs in various populations, beyond those studied in earlier phases.
• Long-term Side Effects: Phase 4 trials also investigate any potential side effects that may arise with prolonged or widespread use of the drug, providing crucial insights into its long-term safety profile.

Phase 4 trials play a pivotal role in further refining our understanding of a drug’s benefits and risks once it reaches the broader market, ensuring ongoing safety and effectiveness monitoring.

Protocol Amendments for Investigational New Drugs (IND)

When sponsoring an Investigational New Drug (IND), it is mandatory to submit protocol amendments to the FDA under specific circumstances. These include changes to Phase 1 protocols that significantly impact participant safety, or alterations to Phase 2 or Phase 3 protocols that affect participant safety, the scope of the study, or its scientific quality.

 Safety Reporting for INDs

Sponsors are required to promptly review and investigate all relevant safety information concerning the investigational drug, received from any source worldwide. This encompasses clinical and epidemiological studies, animal research, commercial experience, scientific literature, unpublished papers, and reports from foreign regulatory bodies. In the event of an unexpected fatal or life-threatening experience linked to the drug, sponsors must notify the FDA within 7 calendar days of first receiving the information. Additionally, sponsors must inform both the FDA and participating investigators in writing within 15 calendar days of any serious adverse event that is unexpected and likely related to the investigational drug. They must also provide follow-up information as it becomes available. Furthermore, sponsors must promptly notify the FDA, within 15 calendar days of receipt, of any findings from animal studies suggesting significant risks to human participants.

Information Amendments and Annual Reports for INDs Investigational New Drug

Aside from protocol amendments, safety reports, and annual reports, sponsors must file information amendments to report critical IND-related details that do not fall within these categories. Examples include new technical information about the drug’s toxicology or chemistry, and discontinuation of a clinical investigation.

Furthermore, within 60 days of the IND’s first anniversary and annually thereafter, sponsors must submit a concise report on the investigation’s progress. This report should include a summary of each ongoing or completed study’s status, the most frequent and severe adverse experiences observed, all IND safety reports submitted, a list of participant deaths with causes specified, details on participants who discontinued due to adverse experiences regardless of relatedness, an outline of the upcoming year’s investigational plan, an updated Investigator’s Brochure if available, a summary of foreign market developments, and any unresolved matters with the FDA regarding the IND (such as responses to FDA requests for information).

Investigational New Drugs Responsibilities

1. Responsibilities of Sponsors Sponsors, whether individuals or organizations overseeing clinical trials conducted under an FDA-issued Investigational New Drug (IND) application, are obligated to fulfill specific duties:

• Selecting qualified investigators.
• Providing investigators with necessary trial information.
• Ensuring proper trial monitoring.
• Overseeing adherence to the IND’s plan and protocols.
• Promptly notifying the FDA and investigators of significant new adverse effects or risks attributable to the investigational new drug.
• Maintaining accurate records and disposing of unused investigational new drug supplies.
• Except when serving as both sponsor and investigator, sponsors do not conduct the investigation themselves.

In accordance with Good Clinical Practice (GCP) guidelines (ICH GCP E6, 5.12; 5.13; 5.14), additional sponsor responsibilities include:

• Ensuring investigational product manufacturing aligns with Good Manufacturing Practices.
• Packaging investigational products to prevent contamination and deterioration during transport and storage.
• Supplying investigators or institutions with the investigational product.
• Establishing written procedures for investigational product handling and storage.
• Maintaining adequate investigational product quantities for specification verification if necessary.

These responsibilities may be delegated to a Contract Research Organization (CRO), but the sponsor retains ultimate accountability for the investigational product.

2. Responsibilities of Investigators Investigators involved in clinical trials have distinct responsibilities:

• Providing the sponsor with a completed and signed Statement of Investigator (Form FDA 1572).
• Conducting the trial in accordance with the signed investigator statement, protocol, and relevant regulations.
• Safeguarding the rights, safety, and welfare of trial participants.
• Securing informed consent from all participants.
• Maintaining accurate records throughout the trial.
• Submitting required progress reports, safety reports, financial disclosures, and a final report.
• Adhering to Institutional Review Board (IRB) oversight and ensuring proper handling of controlled substances.

Additional investigator responsibilities under GCP guidelines (ICH GCP E6, 4.6) include:

• Ensuring accountability of investigational products.
• Designating a pharmacist or licensed individual for investigational product dispensing.
• Recording the journey of investigational product from delivery, through use by participants, to return or destruction.
• Ensuring investigational product use aligns with approved protocols.
• Educating participants on correct investigational product usage and verifying compliance regularly.