One of the first steps toward obtaining approval to market drug products or biological compounds in the United States is the submission of an Investigational New Drug (IND) application. Your research team is hard at work developing a very promising new drug, and they are naturally anxious to get a product to market. An important part of this process is to have a spot-on IND submission that sails through the FDA’s evaluation program.
New drug products and biological therapies go through a rigorous review process to prove they are safe and effective. So, what role does the IND submission play in this process? Prior to marketing, a New Drug Application (NDA) or Biological License Application (BLA) must be submitted and approved by the FDA’s respective consumer watchdog organizations, the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER). In order to submit an NDA or BLA application, products must first be tested for safety and efficacy in human clinical trials, which is where INDs come into play. Federal Law prohibits transportation of drugs across state lines without an approved marketing application. Approval of an IND allows the drug or biologic to be legally transported and distributed across state lines for use in the clinical trials that support the NDA and BLA applications.
Once the IND is submitted, the clock starts ticking and the FDA has 30 days to comment. Following a review process, the FDA will either approve the IND indicating the product is “safe to proceed”, thus allowing the product to be used as an investigational drug or biologic, or a “clinical hold” will be placed on the IND application to delay or suspend the proposed clinical investigation. The sponsor is given an opportunity to address the issues cited in the clinical hold and the process then starts over again. Even a technical problem in submitting the IND can trigger a clinical hold and cause a significant delay in getting a product to market.
These programs provide an opportunity to set the stage and build a relationship with the FDA. For small companies, the IND submission process is likely their first interaction with FDA and vice versa. First impressions matter! Be prepared and build a solid reputation that can benefit your company for years to come. Listed below is a little more information about how these programs work.
The INTERACT is the newest FDA initiative (announced June 22, 2018) and is designed to enhance early communication amongst sponsors and the FDA; INTERACT replaces the pre-pre-IND meeting and allows sponsors to obtain feedback from CBER before they are ready for a pre-IND meeting. Thus, sponsors can get some initial advice from the FDA regarding “the chemistry, manufacturing and controls, pharmacology/toxicology, and/or clinical aspects of the development program” that is not binding. FDA suggests that each meeting consists of only one issue that needs to be addressed by the sponsor allowing for a focused consultation.
The Pre-IND Consultation Program is highly encouraged by FDA as part of their commitment to help accelerate the approval of innovative medical products.
Here are some of the benefits that can be obtained from a Pre-IND meeting:
Verification that the appropriate animal model is being used to determine product safety
Determine if the toxicology data is sufficient to justify a First-in-Man study
Discuss any data concerns or potential roadblocks
Develop a relationship with the agency team that will be reviewing the submission
Going into the INTERACT and pre-IND meetings prepared and with total transparency will help you get the most out of these meetings, and ultimately will circle back to strengthen point #3 of making sure your plan is ready to drive your product forward. Plus, these are a great opportunity to build a strong relationship with the FDA.
2. Having a poorly written document that frustrates and confuses the reviewers will not help your cause.
One of the biggest reasons’ sponsors receive a clinical hold independent of poor study design is that the IND document lacks organization and clarity.
It is the sponsor’s job to make sure that the IND is well-written and easy to understand. Like me, I’m sure you have read a plethora of manuscripts and documents that leave you wondering what the take-home message is or spent way too much time interpreting findings. All aspects of the IND should be presented in a cohesive manner in an format that is easy to read; also remember, it is much easier to look at the data when you have a big picture concept and know the project’s key message upfront.
In the 2018 fiscal year, the FDA received 675 original INDs and took a total of 1,224 actions against IND submissions. That’s a lot of information to process! Make sure your submission is clear and to the point.
The easier it is for the reviewer to find the pertinent information, the more likely they are to provide a review that is in line with your expectations. Keep these points in mind when generating the IND application.
Create a document that is easy to review.
Include the supporting data and protocols.
Provide rationales for each conclusion.
Do not ignore the comments from the INTERACT and Pre-IND meetings!
Involving regulatory experts, either in-house or contracted from a respected CRO like Criterion Edge, early in the IND application phase may save both time and money.
3. Using nonclinical data or manufacturing information that does not adequately support the clinical protocol ultimately hurts the IND application.
It is critical to ensure that the nonclinical data supports the clinical design and that both provide adequate justification of the desired labeling claims, including basic exposure data. This requires detailed planning among your various teams and a strong knowledge base of the IND regulations.
Most importantly, specify how patient safety will be assured during the study. Include sufficient information to both assure the proper quality, purity, and strength of the drug or biologic, and to assess the adequacy and consistency of production.
4. Leaving out data pertinent for evaluating the procedures makes it difficult to determine the quality of the proposed studies.
Take extra care to make sure there is evidence that supports the robustness of the assay to be used for evaluating the clinical trials. Also, include representative output data such as chromatograms and procedural details in the form of standard operating procedures (SOPs). This can be a big undertaking, especially with complex biological products.
5. Including massive amounts of data and assuming it is self-explanatory slows down the review process.
While this seems to be the opposite of mistake number 4, not having the information presented concisely is a major flaw with many submissions. Being brief and guiding the document with clearly presented points helps the reviewer know what is relevant for the product under consideration.
6. Not clearly stating the potential risk of the drug or biologic in the submission raises red flags.
Potential issues of concern need to be presented in a forthcoming and transparent manner during and after the regulatory review. Failure to do so will impact the sponsor’s credibility. It is the sponsor’s responsibility to provide the FDA with the information in a manner the helps them understand what the safety issues are and how they will be mitigated.
7. Sponsors should note that Study Data Standards are required for commercial INDs as of December 17, 2017, for both nonclinical and clinical studies.
This is a specific requirement to comply with the Clinical Data Interchange Standards Consortium (CDISC). FDA states this very clearly; “FDA will not accept an electronic submission that does not have study data in compliance with the required standards specified in the FDA Data Standards Catalog.”
8.Making inadvertent submission mistakes in the IND submission isthe most common reason for technical rejection of an eCTD filing.
A surprising number of IND applications are rejected for technical issues. Double check the application to make sure that the correct eCTD format is being followed and that all the pre-clinical data and documents are included. It is also worth a second look to ensure the IND submission is sent to the correct center.
9. Underestimating the time required to develop an IND application and complete the submission is easy to do.
It can take 12 to 14 months to complete the IND application package, and this does not include the time commitment for the INTERACT and pre-IND meetings. Do not wait until the last minute to begin the process!
As of May 5th, 2018, Commercial INDs and the Master Files must be submitted using the Electronic Common Technical Document (eCTD) standard format. Ensuring that all files contain the proper information and are in the proper format will require some technical expertise.
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