Standardized study data will be required in commercial IND application submissions for clinical and nonclinical studies that start on or after December 17, 2017. On CDER's website you can find Study Data Standards Resources that provides specifications for sponsors regarding implementation and submission of clinical and nonclinical study data in standardized format.
CDER Standardized Study Data
The Electronic Common Technical Document (eCTD) is CDER and CBER's standard format for electronic regulatory submissions. Beginning May 5, 2017, the following submission types: NDA, ANDA, BLA, and Master Files must be submitted in eCTD format. Commercial IND submissions must be submitted in eCTD format beginning May 5, 2018. Submissions that do not adhere to the requirements stated in the eCTD guidance will be subject to rejection.
Today FDA released the DRAFT FDA guidance "Unique Device Identification System: Form and Content of the Unique Device Identifier." While FDA's final rule was passed September 24, 2014, this is their first guidance on the subject.
Part 1: Observations from the US House Passed 21st Century Cures Act – Required Guidance Documents and Projected Timelines for Completion
The U.S. House of Representative passed the 21st Century Cures Act in July of 2015. It was then sent over to the U.S. Senate and has since been referred to the Senate Committee on Health, Education, Labor, and Pensions.
Within this bill there are references to 22 (from my count) guidance documents FDA is required to author if the bill is passed.
Below is the list guidance documents I identified that the FDA will be required to create or update and complete once the 21st Century Cures Act is signed into law. I have also included the House of Representatives projected timelines for completion, which may change in the Senate. Because the Senate has yet to take up and pass this legislation, allowing the President to sign it into law, some of the projected completion dates for certain guidance’s are unlikely to be met. I will update this list with any changes based on a Senate passed bill.
A case for open dialog with your lead FDA reviewer
By John Van Hoven
A number of years ago I inherited a 510(k) submission from a colleague leaving my organization just a few weeks before the submission was planned to go to the third-party reviewing organization. I was anxious to start “my own” 510(k) and I jumped at the opportunity to show my regulatory chops on a high exposure project. Since this project was so far along, I didn’t think I’d have that much to do.
My previous experience with third-party 510(k)’s was not positive, and I had since heard former FDA personnel disparaging the program’s use, clouding my initial perspective of the project.
Shortly after I picked up the project, I identified a significant risk with the submission strategy - the planned inclusion of a formal meta-analysis utilizing existing clinical literature as clinical evidence supporting the safety and efficacy for the new labeling claim being pursued.
FDA’s third party guidance outlines the exclusions from the Third-Party Review Program, one being the inclusion of clinical data to determine substantial equivalence, which this meta-analysis fell within.
These concerns were heard and understood within the organization, but since our plans and strategy had previously been formalized with upper management, the decision was made to stay the course.
So the application was assembled and submitted to the accredited third-party reviewing organization, and then onto the FDA as originally planned. My role was minimal at best, akin to admin.
In spite of these efforts, and as many seasoned regulators might guess, the FDA rejected our submission citing the inclusion of meta-analysis as clinical data making it ineligible for the third-party reviewing program. As FDA does, they referred to FDA guidance stating as much.
Again as FDA does, they took this opportunity to make substantial comments on our attempted formal meta-analysis. The feedback they provided cited every issue they identified with the study design, execution, reporting, and particularly the study bias. They referenced the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA Guidelines for us to follow next time. They also recommended we submit a pre-IDE prior to conducting any future systematic literature review.
This type of feedback and the organizations resistance to it presented unique challenges. Further adding fuel to the fire, the organizations reaction to FDA feedback regarding previous strategy decisions by current regulatory management was accusatory at best, with questions like:
If there is an FDA guidance that explicitly outlined this was something not to do, why did we do it?
How could the Third-Party Reviewer agree to this when their own policies say not to? [Consistent with what I heard from FDA about their dissatisfaction with the program]
Who chose to use an organization that doesn’t have policies consistent with regulation and guidance [referring to the accredited third-party reviewing organization]?
The entire regulatory department was on edge to say the least.
After a number of these discussions between the organization and FDA, we were eventually convinced FDA’s original data request was resolvable, and formal conversations with FDA resumed.
First on the list of change was a complete reworking of our meta-analysis with an outside expert as the primary investigator to alleviate bias. Then we needed independent statistical analysis while also following standards set out in the Cochrane Handbook or PRISMA Guidelines. Finally, FDA requested our protocol be reviewed though the pre-IDE program before beginning the evaluation.
Because this would be the first attempt the organization would make at conducting an investigation with a completely new methodology, the organization considered this to be a high risk project. In fact, I would later discover executive management estimated our success to be just 5%.
Once discussions between the organization and FDA management had ended, I reached out to the lead reviewer to discuss some thoughts on how to proceed in a less formal manner, given it took months to get this far and we needed to work more efficiently to meet our goals. Instead of including my boss, my boss’s boss, the lead marketing manager, and other engineers, I requested one-on-one time with only the lead reviewer, where we could speak more freely and direct without management involvement.
Luckily, this reviewer shared this desire to more openly discuss the submission and our plan to move forward.
During our first conversation, I explained my history with the project, how decisions were made at the organization regarding regulatory submissions, and most importantly though, I shared my desire to work with her, as team members, towards a common goal.
I also took this opportunity to tell her that we understood what they said, took the requests seriously, and wanted a positive working relationship with FDA. This was a shift from how the organization had historically worked with FDA and something that my reviewer admitted wasn’t taken away from previous conversations.
As my team worked on the problems over the next few months, the lead reviewer and I had numerous phone conversations and email exchanges discussing FDA’s reasoning for different feedback. This was particularly helpful when discussing solutions with the project team and helped us craft appropriate responses; through this open exchange we were better able to tailor each response to address the precise concern of the reviewer asking the question. Additionally, it helped me better understand the type of data FDA would accept for new product indications and how that information needed to be presented and justified.
Over time, as the reviewer and I became more familiar with one another, she was willing to hear and discuss our reservations without feeling as though we were saying ‘no’ to their request. This helped us leave no concern or caveat unaddressed and the FDA review team knew what to expect in our response.
The New Submission
It took us two months to hire the Contract Research Organization and complete the protocol for our pre-IDE submission. Considering this was the first time we undertook such a task there was quite a bit of learning, which slowed the process.
We received FDAs response to our pre-IDE questions within a month. Even though FDAs response was non-binding, and thus we didn’t have to incorporate everything they suggested, we chose to fully adopt all of FDAs suggested revisions to our protocol and subsequent report.
It took another 2 months to complete the study and write the new report. We structured the report exactly as outlined in the Cochrane Handbook and included a written description of our actions and the discussion of data relevance in a separate 510(k) application amendment, all submitted together as a response to FDA’s additional information request. This document explicitly addressed each question, with discussion directly related to the data in the new meta-analysis.
A few weeks after our response was received at FDA, we were granted clearance for the 510(k), just a number of days before FDAs official 90 day review clock would end. In the end, the organization received the clearance they wanted, further expanding the product’s indication for use beyond our original intent, and my reviewer beat his review goal. Our common goal was met.
Shortly after we received clearance, I got a phone call from the lead reviewer and his branch chief to thank me for putting together a complete submission that incorporated all the information they requested. The branch chief pointed out that their job was much easier to do, which results in faster review times that are more likely to meet their review goals.
My Take Away
I view this success, which was given a very high likelihood of failure, as a reflection of the benefit of the time the reviewer and I spent in direct conversation. I felt confident my submission response included necessary information to address each specific reviewer’s concerns. I knew everything wasn’t perfect, but I was willing to stand by and defend our actions and the work that came from them. I could defend that we put every effort into answering their questions.
FDAs acknowledgement of the completeness and thoroughness of the response was a proud moment for a regulator who spent an awful lot of time defending the strategy. Now knowing the organization put success at 5% and then exceeding their original goals by gaining clearance for more than we originally wanted helps me rationalize the benefit of open dialogue with FDA reviewers.
I highly recommend reaching out to your FDA reviewer to discuss your shared goal and how you can work together to meet (and possibly exceed) this goal. Do your best to understand the motivations behind each reviewer questioning your submission and make sure your submission directly addresses their concern.
And finally, if you’re able to have a successful working relationship, let your reviewer know you appreciate their effort. Let their boss know you appreciate their effort. Write a blog post about your positive experience. The more we show we are willing to work as team members with FDA, the more our common goals will be met.
John Van Hoven, MS
I started this blog to document my thoughts on working in the medical product regulatory field, in particular my experiences working with the FDA. I hope you find it somewhat helpful.