The two primary application types for the approval of new drugs: The Investigational New Drug (IND) application and the New Drug Application (NDA).
Investigational New Drug (IND) Application
Purpose: The IND application is submitted to the FDA before conducting clinical trials on an investigational drug in humans.
IND Phases: The IND application goes through three phases: Phase 1 (safety and dosing studies in a small number of healthy volunteers), Phase 2 (efficacy and side effects in a larger group of patients), and Phase 3 (larger-scale studies to further evaluate safety and efficacy).
From the FDA’s perspective, the primary purpose of an initial IND submission is to ensure, as much as possible, the safety and rights of clinical trial participants. Besides allowing clinical investigations, the IND also performs an additional legal function. Because federal law states that only marketed drugs are permitted to be transported across states lines, the IND provides a legal framework that allows Sponsors to transport their investigational products to clinical investigators in different states.
Types of INDs
INDs may be categorized as either commercial or research.
Commercial INDs: These are submitted by the companies to obtain marketing approval of new product.
Research INDs: These INDs involve therapies that are not intended for commercialization but are being investigated strictly for research purposes.
In addition to these two primary types, there are emergency INDs and treatment INDs
Emergency use INDs: These INDs allow use of experimental drug in an emergency situation which doesn’t allow submission of IND in accordance with 21 CFR. Emergency INDs act upon a different timeline than other types of INDs.
Treatment INDs: These are also called Expanded Access INDs. These may be submitted for experimental drugs showing effect in clinical testing of serious and life threatening conditions
The first step of any drug’s review process starts with filing an Investigational New Drug (IND) application. The application is submitted to the United States Food and Drug Administration (US FDA) for obtaining exemption to ship the product to investigators across the state. In order to obtain this exemption, the company must provide all the necessary information through the IND.
An IND application contains information in these three areas:
- Animal Pharmacology and Toxicological Studies: This data is obtained from preclinical studies to allow the FDA reviewer to assess the safety of the product for the initial testing in humans.
- Manufacturing Information: This information pertains to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product. This information allows the FDA reviewer to assess quality of the product.
- Clinical Protocols and Investigator Information: These are detailed protocols for the proposed clinical studies to allow the FDA reviewer to assess whether the initial-phase trials will expose subjects to unnecessary risks. In addition, qualification of the clinical investigators is also being assessed to ensure they are qualified to fulfill their clinical trial duties.
When an IND is submitted, the sponsor must wait 30 calendar days before initiating the clinical trial, unless an early notification is sent out by the FDA permitting the investigation to start. During the 30 calendar days, the FDA may order the sponsor to delay the clinical investigation by placing it on a “Clinical Hold” if the FDA concludes that a deficiency exists in a clinical investigation. If the FDA determines that the proposed clinical trials are acceptable, it grants IND activation, allowing the sponsor to proceed with conducting the studies.
New Drug Application (NDA)
Purpose: The NDA is submitted to the FDA after the completion of clinical trials to request approval for marketing a new drug in the United States.
The NDA is a formal request made by a Sponsor to market a new drug in the United States. NDAs are typically regulated by FDA’s Center for Drug Evaluation and Research (CDER). The goals of the NDA are to provide enough evidence to support the safety and effectiveness of the drug and to show that the benefits of its use outweigh the risks. In addition, the FDA will review the proposed labeling for the drug and determine if the manufacturing methods maintain the drug’s identity, strength, quality, and purity. Data collected during the IND phase of the development program will become part of the NDA. However, the NDA is much more comprehensive than the IND and is expected to provide very detailed information about the drug. This includes primary data, reports, and summaries of the results of the nonclinical and clinical studies, analyses related to the body’s effect on the drug and the drug’s effect on the body (PK/PD), characterization of the drug’s ingredients and impurities (including any potential toxicities), and a description of all manufacturing processes and quality control parameters. For any drug to obtain approval for sales and marketing in the U.S., the manufacturer must submit a New Drug Application (NDA). It is a comprehensive document with 15 sections that provides data on animal and human studies, pharmacology of the drug, toxicology, and dosage, and contains information about the drug’s manufacturing process. The purpose of an NDA is to provide the FDA reviewer adequate data to ensure the safety and efficacy of the drug, labeling, and manufacturing process.
The ultimate goal of an NDA is to provide enough information to permit the FDA reviewer to determine the following questions:
- Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh the risks.
- Whether the drug’s proposed labelling (package insert) is appropriate, and what it should contain.
- Whether the methods used in manufacturing the drug and the controls used to maintain the drug’s qualify are adequate to preserve the drug’s identity, strength, quality, and purity.
All of the documents in NDA are required to be organized into five modules in an eCTD (electronic Common Technical Document) format.
Once the FDA receives the NDA application, the reviewing team first reviews it for completeness. FDA takes 60 days to decide whether to review the application or reject it, due to missing information. Completed applications will be reviewed and a decision on whether to approve the drug will be made within 6 to 10 months. Uncompleted applications are subject to refusal.
If the FDA determines that the drug’s benefits outweigh its risks and that it meets the necessary standards for safety and efficacy, it approves the NDA. The approval allows the drug to be marketed and sold in the United States. After NDA approval, the FDA continues to monitor the drug’s safety and effectiveness through post-marketing surveillance and may take regulatory actions if any safety concerns arise.
Comparison of IND and NDA
| IND | NDA |
|---|---|
| IND is required when a sponsor intends to initiate a clinical trial in humans | NDA is required for marketing a new drug |
| Investigational new drug (IND) application is the first step for any pharmaceutical company to a new drug to market | NDA application is the final step in a pharmaceutical company’s journey to getting their drug to market |
| When an IND is submitted, FDA takes 30 calendar days to review | Once the FDA receives the NDA application, FDA takes 60 days to decide whether to review the application or reject it, due to missing information. Completed applications will be reviewed and a decision on whether to approve the drug will be made within 6 to 10 months. |
| Application - Form FDA 1571 | Application - FDA form 356h |
| Content of IND: • Table of contents • Introductory statement and general investigational plan • Investigator brochure • Chemistry, manufacturing and control information • Pharmacology and toxicology information • Previous human experience with investigational product • Additional information | Content of NDA: • User fee cover sheet • Cover letter • Summary chemistry • Manufacturing and control samples • Method • Validation package and labelling • Non clinical pharmacology and toxicology • Human pharmacokinetics and bioavailability • Microbiology • Statistical methods and analysis of clinical data safety update report • Statement of compliance to IRB and Informed consent requirements • Case report forms • Patent information and certification • Other information |