An IND is an Investigational New Drug Application that is required by a clinical study sponsor to obtain authorization from the Food and Drug Administration (FDA) to perform human clinical studies for investigational drug or biological product. This is federally mandated, and the requirements are set forth in 21 CFR Part 312.
Why are INDs needed?
The clinical study sponsor needs to file the IND application to obtain permission to conduct a clinical study. The FDA has two primary objectives to 1) assure the safety and rights of subjects and patients, and 2) to help assure that the quality of the scientific evaluation of the drug during Phase II and Phase III trials.
When are INDs needed?
The IND must be submitted by the study sponsor prior to initiating human clinical studies. The FDA has 30 days to place a clinical hold on the study if the agency believes the information provided in the IND does not satisfy the requirements to demonstrate that the study can be safely completed. As the drug is continuously studied, subsequently IND amendments are submitted. This ensures FDA input as the drug progresses to commercialization.
When are INDs needed?
Not all clinical studies require an IND. The FDA allows exemptions to INDs in specific cases:
Certain investigations using marketed drugs: The FDA allows for clinical investigators studying drugs that are lawfully marketed in the US to perform investigational studies as long as the data is not required as part of a NDA or for labeling changes to the existing drug. In addition, there must be no significant change in the strength, patient population, route of administration, or risk profile for the drug.
Bioavailability or Bioequivalence studies (BA/BE): The FDA allows BA/BE studies utilizing drugs lawfully marketed in the US as long as the strength does not exceed the maximum marketed strength, the study is overseen by an IRB, and standard test article sample retention criteria are met.
Is an IND needed for clinical studies performed in Australia?
There’s been a recent trend amongst pharmaceutical companies to perform early-phase clinical studies in Australia. The Australian government provides significant cash benefits to companies performing clinical research in Australia by providing a 43.5% rebate on such studies. An IND is not required for performing such studies since they are outside the jurisdiction of the FDA. Nevertheless, many companies still opt to use the IND pathway in conjunction with studies, especially if the drug will ultimately be filed for US market authorization. It is important to note that Australian authorities and clinical investigators still require sponsors to meet published ICH (International Conference on Harmonization) criteria for clinical studies and many of the same criteria needed for an IND still apply.
Does the IND process apply for the development of ANDA drugs (generic drugs)?
No, the IND process generally does not apply for the development of generic drugs. Unless specifically required within the product specific guidance, an IND is not required prior to performing BE studies for generic drug development and ANDA filing.
What information is needed to submit an IND?
The four primary sections of the IND are:
- Drug substance – information on the studied molecule, including the synthesis pathway, stability data and known degradants
- Nonclinical – animal pharmacology and toxicology studies
- Chemistry and Manufacturing – relevant chemistry, manufacturing, and controls (CMC) information including stability data on the formulated investigational product
- Clinical – detailed clinical protocol, qualifications of the clinical investigators, and commitments related to informed consent and use of an appropriate institutional review board (IRB)
What is the Process for a Pre-Investigational New Drug (pre-IND) Application?
The Pre-IND program is designed to facilitate and foster early communications between clinical investigators and the FDA. The pre-IND meeting (or written communication) can be used by pharmaceutical companies and clinical investigators to ask the FDA questions about the data needed for IND submission related to nonclinical pharmacology and toxicology studies, CMC, and the clinical program. It is typical to provide details related to the target formulation, route of administration, a summary of nonclinical (animal) studies proposed, and a synopsis of the proposed clinical study as part of the briefing book for FDA review.
Upon submitting a pre-IND meeting request, the FDA responds within 21 days providing a meeting date (or date for written response). The meeting date is usually within 60 days of the FDA receiving the meeting request. The sponsor must be ready to submit the pre-IND package (otherwise known as the briefing book) at least 30 days before the assigned meeting date. The briefing book is a relatively simple document that is not written in the eCTD (electronic common technical document).
At Vici, we strongly recommend all sponsors to initiate the pre-IND meeting request as early as possible during preclinical development prior to start of lab work and major spending. A properly implemented pre-IND strategy can save pharmaceutical companies a significant amount of time and money.
How much does it cost to file an IND?
The FDA does not charge an application fee for filing an IND. Likewise, the pre-IND process is free as well. However, the FDA does charge an application fee for NDA filing.
All the cost associated with the pre-IND and IND process are associated with the R&D process itself and paying for nonclinical toxicology studies, formulation development, supply manufacturing and stability studies, the CRO fees and clinical study costs.
Typical development process and timeline for first-in-human IND studies
At Vici, we recommend the following general plan for our clients seeking to perform first-in-human studies through the IND pathway:
- Assemble a cross functional pharmaceutical drug development team including experts in toxicology, CMC (including formulation development and analytical testing), medicinal/synthetic chemistry, medical writing and protocol development, clinical practice related to the indication and drug under consideration, FDA regulatory strategy and writing.
- Create a regulatory, nonclinical, and manufacturing roadmap including costs and timeline. At this stage, this remains a paper exercise with minimal expenditure on R&D. This includes creating a target formulation (on paper) and writing a clinical synopsis with the help of a CRO.
- Undertake the FDA pre-IND process and receive FDA feedback through a pre-IND meeting or written response.
- Initiate nonclinical (animal) IND enabling toxicology studies
- Initiate and complete formulation development.
- Select and contract with the CRO and complete clinical protocol development .
- Manufacture cGMP clinical trial material and perform stability studies.
- Write the IND in the eCTD format. Note that at least one month stability data on the clinical trail material or investigational product must be part of the IND.
- Wait 30 calendar days and then start the study if there are no clinical holds. If there are FDA clinical holds, they must be addressed and fully resolved before proceeding with clinical studies.
For 505(b)(2) products, this process will take a minimum of eight months. However, this timeline is likely to increase for NCE (new chemical entity) development and based on the overall complexity of the formulation and required time required to complete all the IND enabling nonclinical studies.
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