Patrick Stone, President, TradeStone QA

In 1999 the FDA released guidance for industry on the electronic records requirements for human clinical trials involving drugs, devices & biological entities (including the manufacturing of the approved products previously listed). In 2002 the FDA started training the field investigators how to review electronic records during routine inspections of human bioresearch and manufacturing for drugs, devices & biological entities. The catch was FDA investigators were not able to actually cite violations for 21 CFR Part 11 (code of Federal regulations) until approximately 2006.

The FDA instructed field investigators to only write up 21 CFR Part 11 violations if there were other non-Part 11 violations as well. One of the reasons it took so long to enforce the 21 CFR Part 11 violations was that fact that TurboEIR (FDAs report writing template system) did not have 21 CFR Part 11 483 cites. TurboEIR 483 citations became standardized because of the inconsistencies of 483s issued throughout the nation.

Fast forward to 2009 and the FDA starts to ramp up electronic record review for every firm that uses electronic records.

As an FDA investigator I have conducted many electronic record reviews and discussed many 483 cited observations with the Center for Drug Evaluation & Research and the Center for Devices and Radiological Health.

The most recent inspection I conducted for electronic records was a molecular diagnostic laboratory conducting testing for human clinical trials. This was a very special case in which I observed the clinical trial data did not match the data-listing provided by the sponsor. Long story short, the firm was using a data-stick to transfer original data-output and transferring it to an Excel data-set. Microsoft Excel® is not 21 CFR Part 11 compliant and the Excel® program cut off too many digits after the decimal place. The solution was an easy fix in that I suggested the molecular lab simply print out the original data and use that instead of the data-stick transferred data.

The Center put a short hold on the project until the reems of paper could be submitted in proper fashion.

The moral of the story is that as a sponsor or health care manufacturer you have to ensure that any projects slated for all electronic record submissions must be qualified and verified to comply with the electronic record regulation.

I will also give you one more example of a scenario where a project was held up by the agency for electronic record issues. I was inspecting a human clinical drug trial and I observed that source data did not match the sponsor provided data-listing because when the study was closed out and the data-lock was put in place it changed the audit trials and greyed out many data-points.

When choosing an electronic records vendor make sure that the data is never obscured or unreadable when the clinical trial is completed and data-lock is in place. You have to go from cradle to grave with your data and validate every step.

The FDA has made numerous electronic records exemptions for the Department of Defense and other U.S. Government agencies under the following exemption law (device products). A Compilation of Exemptions for Electronic Products Found in 21 CFR Chapter I, Sub-Chapter J — Radiological Health Parts 1000 – 1050.

However, the FDA does not currently abide by the electronic records regulation it enforces, for another case of do what I say, not what I do.

You can follow Patrick on Twitter: http://twitter.com/BIMOQA

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Government officials sure like stats. In a new report, the Center for Devices and Radiological health says it accomplished 86 percent, or 92 of 107 actions it pledged to complete in Fiscal Year 2010.

Among the highlights, the Center notes it completed and released for public comment two preliminary reports recommending concrete steps it could take to strengthen the 510(k) program and increase the predictability of its use of science in regulatory decision making by fostering medical device innovation, enhancing regulatory predictability, and improving patient safety. As we’ve blogged elsewhere, AdvaMed and some others are wary that the agency will stifle medical device innovation if it acts with too heavy a hand here.

CDRH also launched the CDRH Transparency Website; a website which it says will eventually serve as a one-stop-shop for publicly released information about its decisions, as part of the Center’s efforts to increase transparency in its decision making.

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Remember that old expression “you get what you pay for”? Well, it’s a cliché, but most of the time these oft-used phrases are oft-used because they have an underpinning of truth. This brings us to the FDA’s free eMDR options for low and high-volume submissions.

In the past few days we’ve connected with a number of folks who either tried it and liked it, tried it and hated it, and/or were afraid to try it because of all the horror stories they heard.

None wanted to speak on the record, but if you are considering going the free route, their comments are, to use another cliché, food for thought.

“We talked to people from several companies and they found creating the files was still considerably more challenging than it should have been,” a medical device QA official told us. Her bottom-line: “We evaluated eMDR in 2009 and were strongly encouraged by others NOT to utilize” it.

On the other side of the ledger (there’s another cliché, for those keeping score), we heard from at least some medical device companies that said the experience was fine. Example: One told us they’d recently filed their first eMDR, and the report was posted on the FDA’s MAUDE database just under a month later.

And it appears the FDA is at least working to improve its eMDR offerings. Earlier this week, for example, the agency issued a bulletin aimed at high volume submitters in its eMDR user group . The agency told those using a gateway to gateway connection using AS2 or thinking of using a high volume solution in the future that the Implementation Specification found in the Health Level Seven (HL7) Individual Case Safety Reporting (ICSR) files has been updated with some important information.

They boiled down to this:

1) Under the section titled “How do I know my submission reached CDRH?” where the 3 acknowledgments sent via the ESG are discussed, they added the following: “For those reporters using a B2B account (i.e. a gateway to gateway connection) using AS2, you should not rely on the “Content-Type” header for determining how the acknowledgments are processed.  Acknowledgments should be processed based on the file extension and actual content, and your systems should be programmed accordingly.”

This was added to address the issue where the content type sent by the Electronic Submissions Gateway (ESG) in test and production differ, the agency explained.

2) Under the section titled “Can I submit attachments?”  the FDA added an instruction:  “Please limit each attachment to 50 MB in size.”

Worth noting: The FDA said anything larger might cause its loading programs to stall.

3) The FDA also added a new question/answer in the FAQ section:
Q:“Electronically submitted adverse event reports do not have all the fields found in the 3500A form able to be mapped. How should we send information that is not able to be mapped to a 3500A field?”

A: “Correct. Some fields such as G5’s check boxes for combination product, pre-1938, and OTC product are not available for mapping. If you would like to indicate this information or any information that is not mapped, please use section H10 (manufacture narrative) to indicate this information.”

Apparently many reporters already have noticed this, but the agency felt it was helpful to have it noted in the implementation file.

The FDA also tried to deal with some other eMDR issues, too, for WebTrader users.

“The FDA Electronic Submissions Gateway (ESG) has heard from trading partners, industry submitters, and ESG account holders about difficulties logging in to the WebTrader portal. The ESG team has been troubleshooting the issue and has found that the large size of some WebTrader inboxes has been causing login difficulties,” the FDA said.

Because many users have left large numbers of old messages in the WebTrader inbox, the FDA ESG staff announced it would delete all messages other than the most recent 20 messages on Monday, June 14th, 2010 at 1PM EDT.

If you haven’t read your messages or if you might want to save them because they have important information from the FDA, you need to open your WebTrader inbox this week and save them to your own computer or a network location your company defines, the agency said. Otherwise, if you don’t read and save your messages before the deadline, all messages beyond the last 20 will be deleted.

The FDA’s other helpful hint: In order to ensure good WebTrader performance in the future, please save a copy of the receipt and acknowledgment files immediately upon receipt and delete copies from your WebTrader inbox or ensure that the WebTrader inbox has a reasonable number of past messages (i.e. <20).

Direct questions/concerns to the FDA ESG staff at esgreg@gnsi.com.

And if you’ve got any great or horrific eMDR experiences to share with us (off the record, if you prefer) please contact me at mcausey@edataintegrityreport.com

Mark Mansour, Partner, Bryan Cave, LLP

The past several months have brought forth numerous bits of news, pronouncements, expressions of concern and general uncertainty about the device regulatory regime, but also about FDA’s regulatory paradigm in general.  The recent piece in the New York Times regarding disagreement about the diabetes drug Avandia and the controversy involving accusations of conflict of interest by CDER head Janet Woodcock in the consideration of competing applications for enoxaperin, in the wake of last year’s resignation of Dan Schultz at CDER has led many to wonder where FDA is going under Dr. Margaret Hamburg.

Clearly, the new leadership at FDA is now acutely aware of the number and scale of the issues confronting FDA.  In their overwhelming majority, the scientists and technical specialists at FDA are dedicated and committed individuals.  At the higher levels, however, FDA has suffered from a series of problems, none more troubling in its long-term implications for the future of the industries it regulates, than its absence of imagination.

The FDA’s approach to science is rooted in statistical models, and those models and the people who analyze their results are wholly unwilling (as a matter of culture) to do finely tuned, meaningful risk-benefit analysis.  Several years ago, FDA’s own internal assessment cautioned that this blind reliance on statistical analysis will render it entirely incapable of assessing a new generation of complex devices, medications and combinations. The FDA is earning a reputation for inability to approve a product either safely or accurately, because it evaluates products in a statistical vacuum, without regard to societal benefit, need or even real-world safety variables.

There is some hope to be found in the fact that CDRH recently admitted that it needed new methods and new thinking, precisely along these lines.  That represents a refreshing start, but it will only make a difference if it is inculcated in FDA’s culture as a whole. Dr. Hamburg has quite a challenge ahead of her.

Mark Mansour is a partner in the firm, Bryan Cave, LLP