For Pharmaceutical Professionals

How to Avoid Common IND Submission Pitfalls
by Meredith Brown-Tuttle, RAC, Chairperson of the RAPS Publication Board

Apr 12, 2010 | Free Downloads | email | Print

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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.

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.

The Composition

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.

Who Sits on the Orchestra

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.

Avoiding the Sharp Tones

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

  • Don't understand the importance of an overarching strategic document (like a package insert) for the compound to guide the development of the drug or the IND
  • Underestimating the resources and time to pull together and publish an IND
  • Not knowing the Division's culture and the type of issues and question that will be asked
What They Contribute to
IND Challenges
Research and Development/Translational Medicine
  • Nonclinical integrated summaries for Pharmacology, Pharmacokinetics, and Toxicology studies
  • Literature review (for a compound previously used in animal/human trials)
  • Nonclinical sections of the Investigator's Brochure
  • Nonclinical study reports
  • Nonclinical Testing Strategy
  • Text too dense, lack of white space, headers, tables and figures
  • Overwhelming amount of unorganized data
  • Written like a thesis; too many details, not geared for a regulatory document
  • Overwhelmed with regulatory requirements coupled with the amount of data that must be put together
  • Expecting the Agency to understand the technology or study results without really explaining it well
  • Chemistry, manufacturing and control sections (Drug substance, Drug product and placebo)
  • CMC Sections of the Investigator's Brochure
  • Sample label
  • Environmental Analysis
  • Formulation development strategy
  • Overall Clinical Strategy/Development Plan
  • Writing the:
    • Clinical protocol
    • Investigator's Brochure
    • General investigational plan
    • Previous human experience with compound
    • Investigator CV and FDA form 1572
    • Clinical Study Report (If include ex-US data)
    • Lieterature Review (for a compound previously studied)
  • Often overworked and under resourced
  • Flowery writing/over writing their sections
  • Not understanding the importance of other department's contributions
  • Underestimating the amount of time it takes to write and review sections
  • Overall Regulatory Strategy
  • Coordinate the Target Product Profile (TPP) construction
  • IND Introduction
  • Writing, editing and/or review all IND sections
  • Cover Letter
  • FDA Form 1571 and 3674
  • Often this group is underutilized and under resourced even though they are the experts in putting together cohesive submissions and strategy that could greatly benefit the team.
  • Team expects the IND to "magically" be put together in no time; often negotiating away the Regulatory timeline to counteract their tardiness
What They Contribute to IND
IND Challenges
Project Management/Team
  • Project timeline
  • A forum for discussion of group goals, issues and challenges
  • Accoundtability for the project
  • Facilitate drug development
  • Facilitate IND preparation

Table 2: Common IND Mistakes and Their Solutions

  • The submission should be organized in such a way to facilitate review and understanding.
  • The rationale for every point made should be clearly thought out and concisely delineated with supporting data
  • Relevant points should not be diluted with irrelevant information
  • Length does not equate to better understanding, brevity leads to better understanding
  • Use of jargon does not equate to better understanding, use simple terms and explain them
  • Development of key messages is very important
Why it Presents a Problem
The Solution
Unfocused Development Plan/Lact of StrategyThe 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 ExplanationSometimes 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:
  • Consistency of message
  • Accuracy of data
  • Ability to convey inforamtion about the compound effectively and without confusion
  • There are no open-ended questions left in the section; all possible questions the Agency might have about the data are answered or plans to mitigate issues have been presented
Knowing the Reviewing Division's CultureWhile 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 (, specifically the Administrative and Correspondence section, to see what questions or issues your Division typically needs addressed.
Why it Presents a Problem
The Solution
Flowery Language/ Pontification/Meandering/Non-essential langugageAuthors 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 OtherBecause 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:
  • Drug is delivered topically and did not achieve systemic levels.
  • The safety profile of this compound is substantially better than the standard of care.
Text Too DenseLooks 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.
  • Add headers to break text into "units" so it is easy to follow and links to other sections, building on previous information.
  • Utilize white space in the document layout to make the document easier to read.
  • Include graphics to support textual information (such as tables and figures).
  • Utilize an easily readable font (at least 11 points, 12 points is best)
Under-resourcing the INDQA, 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.


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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

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