Category Archives: Stay Current

Good Laboratory Practice Q&A

FDA frequently issues guidance documents in the form of Questions and Answers.  The August 28, 2013 draft is still lingering on the FDA website pending comments.  But with the FDA’s Refuse to File Checklist, some companies may be in for a shock if preclinical studies are submitted without a statement of compliance to Good Laboratory Practices.  For many years, device studies have been informally allowed to skim GLP regulations but future studies may be in peril if the sponsors don’t appreciate the risks involved in failure to demonstrate GLP compliance.

The Good Laboratory Practice for Nonclinical Laboratory Studies Regulations, 21 CFR part 58 are NOT a suggestion!  According to the GLP preamble, safety studies must follow GLPs, but “functionality studies” are excluded.  This has been the source of confusion since for many device manufacturers, testing an animal-version of a medical device constitutes a “functional” model.  Unfortunately this draft guidance does nothing to clarify this definition. To understand the meaning of this exemption the device test sponsor must understand that the GLP regulations grew out of the pharmaceutical industry where a “safety” study in animals was quite different from one that evaluated the “function” of a drug. When device manufacturers evaluate a medical device for biocompatibility, bone in-growth or potential wear; particularly when histopathology is an outcome measure, FDA typically views these studies as first and foremost: safety.  For all the trouble to develop this guidance, it might have been nice if FDA had made this clear.

If it is too late and your study is complete and you must submit the data to FDA with a submission, it is important to recognize that the FDA will allow a well-written deviation discussion.  It is important to understand that if a study is a pilot trial, failed to include sufficient specimen and there are no “controls”—even literature, then FDA may still reject the data from the study as inadequate for its purpose.  As the saying goes, “you can’t make a silk purse out of a sow’s ear”—pun intended.  If you believe the study was scientifically sound but the laboratory does not employ a Quality Assurance Unit (QAU), there may be ways to demonstrate how well the study was managed and that the data has integrity.  We employ an itemized checklist and demonstrate section by section how the study quality was maintained.  Post-study data auditing can be useful to demonstrate the data should be considered valid, as well as including the laboratory’s AAALAC and/or USDA inspection results with your report.  The most critical issue may be simplest: can you account that all test specimen and all test articles resulted in reported data?  If animal data is missing, if animals died during the study without an autopsy or vet examination of the cause, don’t expect FDA to jump right into believing the data have integrity.  This is risky business and no medical device study sponsor should go into a preclinical study with the idea the study can be conducted as “GLP-like”.  You don’t want to bet your submission, and maybe your company, on the prospect that FDA will accept your position.

Paladin Medical can assist you in developing a scientifically sound preclinical protocol that will result in data that will support your submission.  We can help you to qualify the laboratory and instruct you on methods to augment GLP-compliance deficiencies if certain sub-contractors are not currently compliant.  Despite the FDA’s Question and Answers guidance, it is still more cost and time effective to do the best study the first time with the best laboratory for your device.  Go to www.paladinmedical.com for additional information.

Device Master File (MAF)

DEVICE MASTER FILE (MAF) Companies that sell materials, components or manufacturing services should consider the benefits of a DEVICE MASTER FILE (MAF) with the Center for Devices and Radiological Health (CDRH).  A MASTER FILE is a service for your customers but also helps you to maintain control on your company’s proprietary information.  Consider the content of a Device Master File, how it is used by the FDA and your customers, and how it provides a shield around your company’s intellectual property, while providing the quality information your customer needs for their medical device application.  Originally conceived as a means for submitting data in support of a PreMarket Approval Application (PMAA), Master Files also serve to support Investigational Device Applications, 510(k) applications and deNovo submissions. The Device Master File owner controls the content and access to the file by way of a letter to the customer and FDA indicating the scope of access to the proprietary information.

CONTENT:  A Device Master File typically provides proprietary data about a material, a component, or a manufacturing process that the holder of the Master File wishes to make available to FDA on behalf of the customer, without relinquishing control of the contents to the customer.  The proprietary information can take many forms, including proprietary test results and manufacturing processes.  A typical material MAF might include proprietary chemical test results, formulations, biocompatibility and toxicology test results, literature articles and comparative analysis to other materials.  Components, such as batteries, may have reliability and compatibility data, including decay curves, explosive and altitude testing results and storage information.  Contract manufacturers may include process validation protocols and reports, cleaning validation reports and other proprietary manufacturing information.  Process flow charts, raw material suppliers and process risk analysis documents are also included in aDevice Master File.  Consider the content of a Device Master File can be any proprietary information that FDA may need in reviewing your customer’s medical device submission.

ACCESS: Only customers that you designate by letter may have access to your Device Master File at the FDA.  You can indicate in the letter the portions of the Device Master File to which you will allow the access and for the specific device submission; so customers have to request access each time it is referenced.  Some suppliers charge their customers for access to the Device Master File, but this has become less common. The value of the access to the Device Master File is only worth the amount of money that your customer saves by having access to your MAF on file with the US FDA.  If you don’t manage the content to keep it fresh and accurate, there is no value to your customer.  The best Device Master Files are organized with a detailed Table of Contents which allows the customer to know whether or not the contents may be of value to their regulatory efforts.  Typically the holder of the MAF will provide a copy of the Table of Contents at no charge to prospective customers to demonstrate the value of the file contents.  Although unusual, a device manufacturer may choose to file their own MAF in order to facilitate review by different divisions to the same corporate quality information.

HOW FDA USES the CONTENT: FDA will only access your Device Master File when your customer makes a submission to the Agency and includes your access letter.  Only at that time, as the FDA reviews the submission and as the customer designates within the submission, the FDA reviewer will open and review the referenced contents.  This is when the customer will need to be specific as to how the content in the Master File supports their requirements for the submission.  As an example, if the applicant contends that the material’s biocompatibility testing is included in the master file, that section of the MAF would be referenced with a justification for why these data are relevant to the device under review.  If the FDA needs more data, the reviewer states that to the applicant.  If the applicant should request of the MAF holder to add more information and the holder agrees, then the existing File may be supplemented as an amendment to the MAF.  Some Master File holders might decide that the additional testing is the responsibility of the customer, or both parties might strike an agreement to share costs and data access.

PROTECTING DATA in the MAF: Your proprietary information is more secure in the DEVICE MASTER FILE than it is under a confidential disclosure to your customers because the only time the information is accessed by the FDA is when a submission is filed.  However, FDA has made it clear that “under the Freedom of Information Act (FOI), information in 510(k)s, IDEs, PMAs and other device-related submissions, such as MAFs, is subject to public disclosure unless determined by FDA to be trade secret or confidential commercial or financial information within the meaning of 21 CFR 20.61 or otherwise prohibited from public disclosure.”   FDA is required to publish a detailed summary of the safety and effectiveness data forming the basis for the FDA decision to approve, or deny a customer’s PMA (other submission types have different disclosure requirements.)  Therefore it is possible that some information included in the publication would be derived from the contents of the MAF.  To ensure the best protection of proprietary data, MAF holders should identify information in their MAFs which are trade secret or confidential commercial/financial information within the meaning of 21 CFR 20.61. Of course, MAF information already in the public domain is subject to disclosure (e.g., any published literature, catalog, or product specification sheets distributed by the MAF holder to potential customers).

HOW TO SUBMIT A MAF: There is no fee to submit a Device Master File to the FDA, nor any charge to make amendments.  There are however, certain requirements in the file submission so that FDA can log-in the MAF in an expedient manner.  Each MAF is given a file number that must be used on the access letters.  Maintaining the data within the Device Master File as current and of value to your customers should be simple if the MAF is laid out initially with a comprehensive outline.  Not all sections of the MAF need be filed at the same time, as some companies find that filing the portions needed by the first customer helps to expedite the process and “break the ice”.  It is important to realize that FDA does not “approve” the data in the Device Master File in advance when it is filed.  It is only reviewed by particular FDA reviewers when the customer submits the access letter, and only for that particular submission.  There is no limit to the number of MAF that a single company may file.

If you think your company would like to know more about creating and filing a Device Master File, you can find additional information at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketApprovalPMA/ucm142714.htm or contact us at Paladin Medical, Inc.   We can help you get started, work with your staff to compile and file the MAF and help you to decide the content that can best help your customers succeed.  We have outline templates and guides to maintaining a current MAF.  www.paladinmedical.com.                

©Paladin Medical, Inc. 2015

Run the FDA RTA & e-COPY 510(k) Gauntlet

Filing a 510(k) according to the current FDA “refuse to accept” policy can be challenging.  The former checklist of a few pages is now more than 26 pages for a traditional 510(k).  The new policy is supposed to help FDA focus its resources on those submissions which are complete.  Unfortunately some of the quirks of the checklist and the UBER-interpretations of guidance documents and regulations have caught some folks with one or more recycles of their 510(k) submission.  At Paladin Medical, Inc. we have the experience to help you avoid the recycling syndrome by working with you early to plan the content of your 510(k).   Working efficiently and effectively with FDA is much more than checking boxes.  But in like token, we understand that the initial Refuse To Accept review is critical to speedy processing.  For example, we use the checklist to annotate and direct the initial reviewers attention to the location in the document that the required elements can be found.  We know where the trip wires are in the checklist that can stall an otherwise complete submission.   We’d like to share these tips and tricks of the trade with you and discuss your next submission project.  Maybe we can help, or maybe just a look at our presentation given to the LifeScience Alley “Smoldering Submission Issues” can give you the help you need.  Please go to the CONTACT PALADIN MEDICAL tab and sign in for the information request.  We can send a copy of the presentation to your email address.

510(k) Review Process Detailed by FDA

FDA has updated the explanation of how the Agency will process the review of a 510(k).

  The most important improvement on the webpage is a color coded chart which provides a time line for each major phase of review.  New in 2013, FDA added the “pre-review” step known as “Refuse to Accept” (RTA).  This first review follows a very detailed checklist based upon the type of submission.  The trip wire in this new review process is the way FDA reviews submissions against any guidance documents and refuses to accept any submission that fails to address ANY item in the guidance document.  The guidance documents often are DRAFT and use terms such as “recommend”, but the RTA review process requires EACH AND EVERY ITEM to be addressed, and an explanation for why it is not, if you are brave enough to think the “guidance” is only a guidance.

  Getting through RTA now means the “real review”, known as Substantive Review, has less to review, so the Reviewers are now hard-pressed to find any deficiencies.  We now see increased scrutiny of minor differences between the candidate device and predicates.  Even when the guidance document has not raised a particular performance question, reviewers now find it is necessary to consider that even cosmetic differences are substantial enough to question.

  When we prepare your submission now, you will find that we do our best to immolate the type of reviews that FDA is now instituting so that your submission is less likely to encounter FDA deficiencies for petty differences.  We will be increasing our written “arguments” in the submission for substantial equivalence and alerting you when you have introduced a potential issue for FDA finding.  FDA has tightened up on labeling requirements, discussion of animal study protocols, details of biocompatibility testing protocols and reports and comparative analysis.  Assume that if there is not a reputable published performance characterization of the predicate(s) you may have to do comparative side-by-side testing.  Early consultation on the verification and validation testing for your devices is now critical to ensure your submission encounters the least amount of FDA resistance to acceptance.

  It is critical to good planning to understand that each submission now only has a total review time of 180 days.  Extensions beyond 180 days are no longer allowed.  If your submission is not cleared in that amount of time, FDA will stop review and withdraw the submission.  You’ll be required to resubmit and pay the additional fee for review.  The new review will not be accepted as a Special 510(k) and the full fee will be required.  The review team may change and the goal post could be moved by the time the resubmission is filed.  It is critical to do all required testing prior to submission to avoid this likelihood.  FDA will not accept an “IOU”.  Call us for details on how to ensure your submission clears!

 

Counterpoint Opinion Exchange: Medical Device Tax Deserves Criticism

The Star Tribune published (October 15, 2013) the editorial submitted by Elaine Duncan in response to a previous op-ed concerning the medical device excise tax.  This counterpoint editorial took exception to cynicism towards the bipartisan support to the repeal of the tax and clarified that the tax was not just a tax on medical device companies but in reality a tax on recipients of medical devices.  Here is Elaine’s editorial and the link to the referenced pro-tax article  .  The blogs on this site certainly support Elaine’s observation that the justification for the tax as a punishment to medical device companies underlies much of the rancor against repealing the tax.  Please continue to write your Congressman and support the repeal of the medical device tax when it comes up again later this year.

Paladin Medical will help you establish systems that ensure compliance as well as improve efficiency and productivity.

A Brief History of the Paladin

The modern meaning of the word “Paladin” is a heroic champion and strong supporter or defender of a cause. It is derived from the Latin “palatines,” meaning “of the palace,” and came to mean a warrior or knight. The twelve knights of Charlemagne were called Paladins; their mission to solve disputes between the king's subjects.

In the late 1950s, a television character on the popular Western "Have Gun Will Travel" was named Paladin. He solved problems with intellect, not gunfire. The knight symbol on his business card conveyed his message of stoic service.