FDA U.S. Agent Services

My firm regularly acts as the U.S. Agent for our international clients, so we have lots of experience with that.  In general, the foreign firm in its own FURLS registration records must first designate the U.S. Agent.  Then the prospective U.S. Agent receives a notification to either accept or decline that designation.  To accept or decline, the prospective U.S. Agent does so using the corresponding selection from within either the foreign firm’s FURLS record, or from within the prospective U.S. Agent’s own FURLS record.  My firm uses the latter approach as we have our own FURLS record separate from those of our clients.  Here’s an FDA page that might help you with more specific details.

Don’t Claim Device MR Compatibility Until You’ve Earned It

For the United States, if a device doesn’t yet have FDA-cleared/approved MR labeling, then it would constitute misbranding (illegal labeling) if a letter or other promotional or instructional information is sent to customers stating that the device is MR safe.  In short, this is because a) such a customer letter meets FDA’s statutory definition of labeling; b) if a letter (or other labeling) promotes a device as being MR safe when in fact the sponsor hasn’t actually yet completed and vetted the required MR compatibility testing, then that constitutes an unsubstantiated claim thereby violating FDA’s labeling law, and c) MR labeling is an attribute that needs FDA premarket authorization [e.g., 510(k)-clearance, PMA approval, etc.] before being used for marketed devices.

Nonconforming Expiration Date

In short, if erroneous / outdated / violative / incorrect expiry date (or other related data on the label) are within reasonable risk acceptance criteria (safety, performance, regulatory), then such product can be accepted as-is and left alone.  But if the risk acceptance criteria are exceeded, then corrective measures are needed to eliminate the nonconformity.  Such corrective measures would typically include relabeling and/or removal/recall.

FDA 21 CFR Part 7 vs. Part 806: What’s the Difference?

And as you deliberate on the nature of your proposed field gesture, remember first that 21 CFR Part 806 is not the regulation for categorization, evaluation, or initiation of any recall.  Instead, FDA intends Part 806 to be for assuring proper reporting to FDA of certain recalls; specifically, class I and II recalls. FDA directly clarified this when it promulgated Part 806 after the agency received stakeholder confusion about the relationship between Part 806 corrections and removals vs. 21 CFR Part 7 recalls.

Indeed, 21 CFR Part 806 isn’t triggered or invoked by sending a letter to your customers.  Instead and ultimately, 21 CFR Part 7 governs firm-initiated recalls and FDA-“requested” recalls along with the associated customer notifications (while similarly, 21 CFR Part 810 governs FDA-mandated recalls).  Again, Part 806 is not for initiation of any recall, nor for the related recall or other customer communication.  Accordingly, be sure you first apply the appropriate event-triaging and planning (including customer notification) paradigms from Part 7 as a first step before tackling the separate task of deciding if a recall or safety alert is reportable to FDA under Part 806.

Remember also that firm-initiated recalls may not actually be reportable to FDA, in which cases the firm is responsible to decide whether the action is a recall.  FDA may later scrutinize that decision (e.g., during routine GMP inspections), but nonetheless still leaves the onus on the firm to make the appropriate categorization in real-time.

Another important point to consider is that “safety alerts” as defined by FDA may or may not be a recall, and thus may or may not be reportable to FDA under Part 806.  For example, FDA’s internal operating procedure for this is that some safety alerts might just be safety alerts and/or market withdrawals (i.e., not necessarily reportable to the FDA).  Accordingly, you should certainly NOT invoke Part 806 just because you’ve issued a safety alert.  Instead, invoke Part 806 when Part 806 says to invoke Part 806.

FDA 510(k) Predicate Strategy Tip

If your chosen predicate is a prior 510(k)-cleared version of the subject device, then such predicate is generally the best option.

FDA 510(k) Change Strategy: Reprocessing-Focused

If the only thing that has changed is the reprocessing process, then the substance of the new 510(k) can just be focused on the aspects that changed.  In other words, no need to restate the device description, software contents, etc., etc., that aren’t affected by the change.  However, each of those various unaffected elements still DOES need to be attended to in their respective sections of the 510(k); yet only by referring FDA to the corresponding details in the prior 510(k) and stating that those elements are unchanged and unaffected for the current subject device.

Real-Time or Accelerated Aging?

As a general rule in the medical device sector, accelerated aging data is expected to be ultimately backed up with real-time data.  Consequently, we still generally need to have real-time data to support whatever (let’s say, a 6-year) shelf life we are targeting.  If for example we have a 4-year real-time aging study but 6 years worth of accelerated aging, then we can label with a 6-year expiration date in the interim until 6 years of real-time data are completed.

FDA MDUFMA Small Business Determination (SBD) at the Pre-Revenue Stage

Before addressing FDA’s MDUFMA fees and SBD program for a firm’s premarket submission when at a pre-revenue / premarket stage, my suggestion is to first remember that if a product clearance or approval [510(k) clearance, PMA approval, etc.] hasn’t happened yet, and assuming that the Sponsor is not engaged in other activities triggering the FDA establishment registration requirement, then the Sponsor should be sure it hasn’t unnecessarily registered its establishment.  This is because FDA instructs establishments not to register at the pre-approval stage.  Avoiding unnecessary establishment registration will save $5,546 / year (in today’s MDUFMA dollars) which could really add up to a lot of savings given that product development and FDA market authorization campaigns can often be multi-year efforts.

Regarding a firm’s lack of having yet submitted its first Federal U.S. income tax return, remember that section 738(d)(2)(B)(iii) of the Act is, as far as I know, still in effect and includes a bridging provision for firms that haven’t yet submitted their first Federal income tax return.  That provision says that, in the case of an applicant that has not previously submitted a Federal income tax return, then the applicant and each of its affiliates shall instead demonstrate the “small business” evidence via submission of a signed certification in the English language from the national taxing authority of the country in which the applicant or, if applicable, affiliate is headquartered, certifying that the applicant or affiliate meets the criteria for a “small business”.  Firms need to be sure to give due consideration to this bridging provision when at a pre-revenue / pre-taxation stage.

However, the Act’s section 738(d)(2)(B)(iii) bridging provision may not need to be used at all even though seemingly so at first glance.  Indeed, many corporations must submit periodic Federal income tax returns (e.g., Form 941 QUARTERLY Federal Tax Return) during the year leading up to the annual tax return.  Such periodic returns are in fact official Federal income tax returns.  Accordingly, leveraging such periodic Federal tax returns may also be a viable strategy, specifically, by submitting some or all of the year’s periodic Federal income tax returns in order to officially and statutorily demonstrate that year’s current Federal income status.  Some discussion with the Agency may be needed for that strategy in order to determine if the Agency interprets the Act’s phrase “most recent Federal income tax return for a taxable year” to only mean an annual tax return, or if that could also be interpreted to mean the current year’s Federal income tax returns to date.  If needed, I wouldn’t hesitate to assert with the Agency that a compilation of the year’s periodic Federal income tax returns would meet the statutory criterion “most recent Federal income tax return for a taxable year” called for by the Act.  And it seems that FDA would be amenable to that in light of its webpage guidance stating that if the firm has been in business for less than a year, it can provide the FDA with a copy its U.S. income tax return for a period of time that’s less than 1 year.  FDA says that the dates encompassed by the partial-year return need to be identified on the tax return.  For that scenario, FDA also asks that the firm provide documentation (such as Articles of Incorporation) identifying the business’s formation date in order to further justify the lack of a full year’s tax return.  FDA also says the firm may submit a personal income tax return if needed, where the personal return must identify the submitter’s business and gross receipts or sales under Schedule C of the Form 1040.

Finally, don’t forget that there is a one-time waiver of the MDUFMA PMA fee for a Sponsor’s inaugural PMA pursuant to section 738(d)(1) of the Act.

Showing Conformity to Standards

Regardless of the source of a request for evidence showing conformity with applicable standards, a pivotal underlying fundamental remains the same and drives the answer:  Conformance with standards is generally a design/development verification and/or validation activity.  Therefore, the general rule of thumb is that there needs to be a verification and/or validation protocol (explaining, among other things, how the verification/validation will be done), and a report to document the results and conclusions.  Stick to the principles embodied for example in ISO 13485 clauses 7.3.6 and 7.3.7 and you should be on track.  Failure to do this regarding conformity with applicable standards can lead to compliance (and maybe even safety) problems.

It has been said that design verification may involve inspections, tests, examination, demonstration, or other analyses.  And although various verification methods may be employed, any verification approach which establishes conformance with a design input requirement is an acceptable means of verifying the design with respect to that requirement.  Sometimes we must get creative for this (e.g., via basic visual inspections, document/content review/confirmations, etc.) when the nature of the verification doesn’t warrant actual testing.

Here are some design validation principles I’ve collected from various resources to help determine what may be appropriate validation techniques for a given scenario:  Design validation follows successful verification and may occur in stages. Certain aspects of design validation can be accomplished during the design verification, but design verification is not a substitute for design validation.  State targeted user needs / intended uses in objective, measurable terms, including acceptance criteria.  Specify the collection of discrete, quantified results that can be objectively measured.  Assure that validation studies include actual or simulated use of the product.  Specify defined operating conditions (i.e., temperature, humidity, shock and vibration, corrosive atmospheres, etc.) where appropriate. Include statistically meaningful sample sizes that are justified.  Validation studies must be performed on initial / pilot production units or their equivalents.

EU MDR Scope and Applicability of GSPR 10.4.1

I think there is a good possibility that GSPR clause 10.4.1’s reference both to “invasive” and to “come into direct contact with the human body” may just be an ambiguous redundancy in describing invasive devices, as I have a hard time imagining an invasive device that doesn’t somehow directly contact the human body.  In an explanation from BSI, they seem to have interpreted devices that phrase (“invasive and come into direct contact with the human body”) to simply mean invasive devices.

I’ve also noted that the second two sub-bullets of 10.4.1 are aimed at the indirect contact route (specifically, certain permutations of indirect contact), whereas the first sub-bullet is reserved for the direct contact route (based on its mention of “direct contact” with the human body).  Indeed, the European EU MDR authors seem to distinguish between direct contact and indirect contact (as evidenced by the separate dedication to indirect contact in the second two sub-bullets).  I would be surprised if the EU MDR authors were lumping indirectly-invasive or indirect-contacting devices into the first sub-bullet; this is because if they were, then it would seem there would be no need for the second two sub-bullets.

Because it seems that CMR and ED substances could reasonably be of concern regarding any device that directly contacts the human body, I’ve been recommending that non-invasive direct contacting device manufacturers go ahead and complete the chemical review just to be safe unless more definitive direction is available for a particular case.

I’m also sensitive to GSPR 23.4(s) which calls for IFU precautions where appropriate related to the presence of CMR and ED substances and the potential for device materials to cause sensitization or allergic reaction by the patient or user.  Europe’s liberal stance on toxicants such as CMR and ED doesn’t seem to leave room for excluding users from considerations about the risks of CMR and ED substances.  This would seem to further push the GSPR 10.4.1 interpretation toward including non-invasive direct contacting devices.

In any event, I recommend consulting the responsible notified body (if any is involved) to understand its particular interpretation.