Healthcare regulatory submissions: A primer

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A regulatory submission for a healthcare product includes any documentation or information submitted to a regulatory agency for review, for notification or in response to a request for additional information related to a healthcare product. The format can be paper or electronic, or both. The amount of information involved and its required complexity can vary significantly. A licensing application for a drug or biological product may contain hundreds of paper volumes whereas a response to an agency’s question for a clarification may involve a single page.^1,2

Due to the enormous amount of information presented in a marketing application, agencies are encouraging applicants to submit applications electronically in required formats that can facilitate their regulatory review (for example, eCTDⁱ for drugs and biologics).^1,2 In Canada, for example, all premarket review documents for class III and class IV medical device licence applications and licence amendment applications are expected to be submitted in both paper and electronic formats, and the applicant must structure the format of the  electronic submission to meet the agency’s specifications.^2,3 Be sure to monitor the regulations concerning electronic submissions as this format may soon become mandatory for your regulatory submission.ⁱⁱ

Types of regulatory submissions

Types of regulatory submissions can include:

• Licensing applications for drug, biologics or devices
• Clinical trial applications
• Requests for orphan drug or fast-track designations
• Requests for protocol assistance
• Responses to agency questions that arise during the review; for example, clarifaxes, deficiency letter, requests for additional information
• Post-approval studies or commitments
• Amendment/variation applications or notification submissions

Planning for and preparing your regulatory submission

Before preparing any regulatory submission, identify the relevant regulatory requirements so that you can ensure your submission will comply. Note that the requirements for drug and medical device submissions are quite different.

Consider the following:

• Who is the regulatory agency and what is the review division for my healthcare product?
• What are the regulatory requirements that govern my submission?
• What kind of information should be included? Is there a guidance document available that details the format and content requirements of the submission?
• Where do I send the submission?
• How many copies should I submit?
• Should I submit the submission in an electronic format? Is that mandatory?
• For hard-copy submissions, are there requirements regarding binding?
• For electronic submissions, what is the acceptable data format, file size and means for submission (CD-ROM, secure gateway, others)?

Develop a standard format or style guide for managing submissions. Submission templates should have built-in styles for headers and footers, headings, table and figure titles, and so forth. Such templates should also identify the paper size as well as the margins (both portrait and landscape) for printing and binding purposes. This is particularly important if you plan to generate global submissions, as the information can then be printed on both letter size and A4 paper and permit proper binding.

As the submission should facilitate the regulatory review, organize the information so that it is easy to read and properly sectioned. Have it support navigation so the reviewer can quickly find what they need. Where applicable, consider using these elements:

• Cover letter
• Table of contents
• Volume and page numbers
• Clear headings and subheadings
• Table and figure numbers, with accurate references to them from within the text
• Tabs that aid quick finding of the submission sections
• Reader-friendly font sizes, types and colours

Ensure that content is clearly legible and that submissions are properly bound using binders acceptable to the regulatory agency. Lastly, if any source document is in another language, ensure you provide an appropriate translation.

Generate electronic submissions in accordance with regulatory requirements.

Once you have prepared your regulatory submission, examine it thoroughly to ensure it is accurate and complete (for example, no missing pages within a hard copy, no broken links within an electronic submission) before you submit it to the regulatory agency.

Remember:

Your submission should make it easy for the reviewer to understand the objective of your application and how your data contribute to it. As different regulatory reviewers have different backgrounds, experience and training and may be handling multiple submissions at once, it is useful to always provide a concise summary at the start to “set the stage” for the submission. Such information may highlight a very brief product description, the proposed indication, the intended patient population, the purpose of the submission (for example, a modification to an existing device design) or any key information that could assist the reviewer’s understanding prior to the review.⁴ⁱ eCTD = electronic Common Technical Document

ⁱⁱ On October 17, 2012, the U.S. Food and Drug Administration (FDA) distributed for public comment draft guidance document entitled, eCopy Program for Medical Device Submissions. It states, “[Medical device] submissions submitted without an eCopy and eCopy submissions that do not meet the standards provided in this guidance will be placed on hold until a valid eCopy is submitted to FDA and verified to meet the standards, unless a waiver or exemption has been granted.”

Disclaimer

The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.

Published: October 17, 2012

Summary: Regulatory submissions for healthcare products vary in complexity—ensure you comply with all relevant regulatory requirements and that your submission is accurate, clear, organized and complete.

References

1. Babiarz, J.C.  (2008). Chapter 3. The new drug application. In D.J. Pisano & D.S. Mantus (Eds.) FDA Regulatory affairs. A guide for prescription drugs, medical devices, and biologics (2^nd ed). New York: Informa Healthcare.
2. Kumar, S. & Hall, Y.  (2008). Chapter 10. Electronic submissions – A guide for electronic regulatory submissions to the FDA. In D.J. Pisano & D.S. Mantus (Eds.) FDA Regulatory affairs. A guide for prescription drugs, medical devices, and biologics (2^nd ed). New York: Informa Healthcare.
3. Health Canada. (2011, October 19). Guidance for Industry: Preparation of a Premarket Review Document in Electronic Format for a Class III and Class IV Medical Device Licence Application. Retrieved October 3, 2012, from http://www.hc-sc.gc.ca/dhp-mps/md-im/activit/announce-annonce/notice_e-form_class_iii_iv_avis-eng.php.
4. Silverstein. B. (2011, October). Tell me a story: Writing a Persuasive Regulatory Document. Regulatory Focus, 35-7. Retrieved May 30, 2012, from  http://www.raps.org/Portals/0/DigArticle/65/focus_Oct11_35-37.pdf.