An Investigational New Drug Application (IND) is like an orchestra - it brings together many players with different specialties that need to work together in harmony to create a synchronous melody (in the case of the orchestra) or message about the compound (in the case of an IND). With one instrument out of tune or with one musician who does not play his or her part there will most certainly be a displeasing sound to the ear and a composition that is thrown off. The same can be said for a section of the IND that does not support the safety of the compound. Keeping the instruments tuned and working together in harmony is comparable to the job of the regulatory group who will, in concert with project management, conduct the IND orchestra. However, keeping everyone in tune, while playing at the same time, and keeping everyone moving toward the same goal of an IND submission can be a challenge with many "sour notes" hit along the way. However, these sour notes can be avoided if everyone is playing the same sheet music and everyone knows how to avoid common INC submission pitfalls.
Broadly, the IND requirements are divided into 11-12 sections, depending on whether or not you are using the traditional IND format described in 21 CRF 312.23 or if you are transferring the requirements to the CTD format. The ultimate goal is to demonstrate safety of the compound through conducting pharmacology, pharmacokinetic and toxicology studies and the judicious use of the compound in initial human studies via a well vetted study protocol.
Many disciplines contribute to the components of the IND. With each discipline there are certain challenges that consistently occur within each department—across all companies—big and small. Table 1 gives an overview of the challenges presented by each department based on their IND contributions while Table 2 goes into depth about the specific IND myths and challenges and the proposed solutions for a more harmonious IND process.
Arming the IND team with the information presented in this article will help each team member understand their personal "blind sides," shed light on common IND myths and help to eliminate discord in the planning stages of an IND. That way, the real focus is on an effective IND, and subsequently, the ability to to initiate human clinical trials and bring therapies to those in need.
Table 1. IND Contributors, What They Contribute to the IND and Typical Pitfalls with the Department
|Research and Development/Translational Medicine|
Table 2: Common IND Mistakes and Their Solutions
|Unfocused Development Plan/Lact of Strategy||The IND looks like buckshot. The proposed clinical plans and/or proposed nonclinical studies do not support each other, it is just a jumble of studies and data, i.e. the nonclinical tests don't support the proposed clinical dose or indication.||Before the IND work is started, put together a Target Product Profile (TPP) (a draft product label in a different format) to align the clinical goals with the nonclinical testing and CMC development. If clinical goals or development changes then the nonclinical testing to support the proposed indication can readily be reviewed to see if it still supports the development. As well, construction of a TPP can help direct the draft investigator brochure and protocols.|
|Expecting the Agency to Understand your Technology; to just "Get" it without Explanation||Sometimes a company does not know how to explain their product, so they amass a lot of data, cross their fingers and hope the Agency will let them proceed with human clinical trials.|
If you don't understand or explain the compound fully, the Agency won't understand it either. This can result in a Clinical Hold until all questions have been addressed.
|Know your compound inside and out. Don't assume the reviewer understands the technology; explain it like you would to a 6th grader all the while avoiding jargon. |
Write your IND sections and then let them sit overnight. After a day or two of "rest" re-review your contributions for:
|Knowing the Reviewing Division's Culture||While each Division within CDER and CBER follows the same laws, regulations and most guidance documents, how they interpret and apply this differs based on the type of indications they have jurisdiction to regulate. If you don't know your Division culture or expectations, you don't know what specific issues need to be addressed in the IND.||Read past filings for drugs approved by your Division (www.accessdata.fda.gov/scripts/cder/drugsatfda/), specifically the Administrative and Correspondence section, to see what questions or issues your Division typically needs addressed.|
|Flowery Language/ Pontification/Meandering/Non-essential langugage||Authors of several sections use language or writing evoking complicated words, thoughts, and tangential paths that are intended to make it seem like the author is more intelligent but only serves to confuse the reviewer.|
|Sections Do Not Support Each Other||Because sections are written by different experts, if they don't consult each other, then they will say or make different claims about the compound resulting in mixed messages and more FDA questions about the IND; possibly resulting in Clinical Hold.||Develop a set of 3-5 key messages to be woven into the document that support the key nonclinical, CMC and clinical (if any available) findings. These messages must be based on fact. Some key message types include: |
|Text Too Dense||Looks do matter, especially for regulatory submissions. Formatting or lack thereof is a common mistake. Dense text is hard to read and makes the reviewer want to look for something else to do or review. You do not want to give the reviewer any reason to put down your submission, you want to keep them interested and continue reviewing.|
|Under-resourcing the IND||QA, Formatting and Publishing the IND takes time and dedicated resources. The belief that "it really shouldn't take that long" needs to be dispelled because this continued belief denies regulatory and operations the time and resources it needs to be a good job.||The IND should put forth as a company's best work; the FDA will remember the quality of your submission. It sets the tone for your interaction with the Agency. Quality takes time; IND publishing takes about a week; this needs to be immutable in the timeline.|
Meredith Brown-Tuttle, RAC is the Chairperson of the RAPS Publication Board. She is a full-time consultant specializing in US and Global Submissions and Regulatory Intelligence. As well she is an instructor for both Barnett and UC-Santa Cruz Regulatory Certificate program and author of the book, "IND Submissions: A Primer," by Barnett. She can be reached at firstname.lastname@example.org.