FDA Law Blog: 510(k) Clearance “Corrected” 19 Years after Original Clearance

FDA Law Blog: 510(k) Clearance “Corrected” 19 Years after Original Clearance

510(k) Clearance “Corrected” 19 Years after Original Clearance Posted: 31 Mar 2016 06:36 AM PDT By Jeffrey N. Gibbs & Allyson B. Mullen – Imagine that you were working at a device company and you received a letter today from FDA saying that FDA was “correcting” the FDA clearance you received nineteen (19 – that is not a typo) years ago.  You would probably think about all the things that have changed in 19 years, your original 510(k) submission not being among them: a second gulf war, 9/11, the Great Recession, our first African-American president, the Red Sox finally winning a world series (and then two more), the Yankees winning five world series, and the Cubs – well not everything changes. Then you might suspect that this was just an April Fool’s prank.   It probably isn’t. Recently, we found a letter from FDA that did precisely that.  According to FDA’s 510(k) database, the Whatman Body Fluid Collection Paper was originally cleared via K932661, on April 17, 1996. On February 6, 2015, FDA sent the company a letter stating “this letter corrects our substantially equivalent letter of April 17, 1996” (a copy of the letter can be found here).  The letter offered no explanation for why the correction was issued, let alone why FDA felt it needed to correct a clearance letter issued during the first term of the Clinton Administration.  It is possible, however, that the nature of the correction may simply not be clear to us because of the limited information available regarding this 510(k) due to its age. A similar device, the Ahlstrom 226 specimen collection paper, was originally cleared on October 19, 2007, and received a nearly identical 510(k) “correction” letter. Both the Whatman and Ahlstrom correction letters were issued on the very same day, February 5, 2015 (a copy of the letter can be found here).  Because the Ahlstrom clearance is more recent, there is a 510(k) Summary available.  The only discernable difference between the information in the 510(k) Summary and the “corrected” clearance letter is the product code.  The Ahlstrom paper was originally cleared under product code JKA (tubes, vials, systems, serum separators, blood collection devices, 21 C.F.R. § 862.1675).  The “corrected” clearance letter cites product code PJC, which is the product code for Newborn Screening Specimen Collection Paper (21 C.F.R. § 862.1675). (The legal significance of product codes is not altogether clear; that is a different topic for a different day). While it is not unusual for FDA to change or obsolete product codes for administrative reasons, this change appears substantive in that it could affect the products’ intended use and their suitability as predicates. The Ahlstrom paper, and presumably the Whatman paper because Ahlstrom cited it as its predicate, were cleared for use “as a medium to collect and transport blood specimen spots to be laboratory.”  There was no specific assay or analyte specified in the intended use.  However, the Ahlstrom 510(k) decision summary prepared by FDA (available here) indicates that the device was tested to Clinical Laboratory Standards Institute (CLSI) standard NCCLS/CLSI LA4-A3: Blood Collection on Filter Paper for Newborn Screening Programs; Approved Standard—Third Edition.  The “corrected” product code is specific to newborn screening.  The definition of product code PJC (the “corrected” code), in FDA’s product classification database, states “newborn screening specimen collection paper is a blood collection device intended to be used as medium to collect and transport whole blood specimens from newborns to the laboratory for in vitro diagnostic analysis.”  This definition uses the nearly identical language as the Ahlstrom clearance, but is limited to newborn screening only. Was FDA attempting to limit the scope of the Ahlstrom clearance ex post facto? Possibly.  The public record does not say.  Anyone trying to obtain clearance for an IVD collection device (e.g., blood, saliva) today certainly knows that FDA will no longer allow a broad indication for use like the original Ahlstrom use without very extensive clinical testing. Seeing these letters made us wonder if this was a unique event.  It turned out that post-clearance corrections of 510(k)s are not all that unusual.  We found nearly 400 letters doing just that. (While a low frequency event, it can still be a disconcerting one for those receiving such a letter).  Based on a sampling of these letters, none of the letters appear to give an explanation for the “correction.”  Many of the letters appear to “correct” the product code originally assigned to the device. Although this issue of changing a product code years after the 510(k) clearance may seem relatively minor, it does raise more profound questions.  What do belated "corrections" mean for the stability and predictability of the regulatory process?  Do the letters truly represent corrections, or changes in policy?  Assuming that the letters are due to changed policy, does FDA have the statutory authority to alter the scope of the clearance?  Can these changes in product code restrict the ability of other companies -- and the 510(k) holder -- to use the cleared device as a predicate for the indications for use for which it was cleared? We do not know. But, in light of the amount of effort that goes into the FDA review process for 510(k)s, it is remarkable how many post-clearance corrections there have been.  Given how long it can take to obtain a 510(k) clearance, many applicants are relieved when the process is over.  The Whatman “correction” letter shows that sometimes it ain’t actually over even when it is over. Reminder: Register now for the May 3, 2016 Virginia Tech and HP&M Conference on Effective Documentation.  Information on the conference is available here.

FDA’s Biosimilar Labeling Guidance Posted: 01 Apr 2016 01:01 AM PDT By James C. Shehan – On March 31, 2016 FDA released its promised guidance on labeling for biosimilar products. A few parts caught our eye, including another change of mind by FDA on the issue of whether a biosimilar’s labeling should identify itself as a biosimilar, The guidance primarily affects prescribing information (a.k.a. the package insert) but a few sections affect patient labeling. FDA lays out a few general principles before proceeding to some specific recommendations. Under general principles, FDA begins with the premise that, because the Biologics Price Competition and Innovation Act ("BPCIA”) requires that biosmilars have “no clinically meaningful differences from the reference product in terms of safety, purity, and potency, and because the labeling of the reference product reflects FDA’s findings of safety and efficacy, that labeling “may be relied upon to provide health care practitioners with the essential scientific information needed to facilitate prescribing decisions” for the biosimilar. Thus, biosimilar labeling should “include a description of the clinical data that supported safety and efficacy of the reference product as described in the FDA-approved product labeling” for that reference product, with appropriate biosimilar-specific modifications. The guidance then makes some detailed recommendations on treatment of clinical study data in biosimilar labeling. These positions seem to coincide with positions advocated by biosimilar applicants. FDA states that clinical studies of biosimilars should not be included in their labeling, unless it is necessary to do so to “inform safe and effective use.” In support, FDA points out that clinical studies of biosimilars are usually designed to detect clinically meaningful differences between the biosimilar and the reference product and not to independently demonstrate safety and effectiveness. As a result, a biosimilar’s clinical studies may use different endpoints and different patient populations than were used in reference product studies. This leads FDA to conclude that information about such clinical studies is “not likely to be relevant to a health care practitioner’s considerations regarding safe and effective use of the biosimilar.” Including it “may cause confusion, resulting in an inaccurate understanding of the risk-benefit profile of the product.” FDA also states that biosimialrs follow the content and format requirements of the physician labeling rule and the pregnancy and lactation labeling rule, regardless of whether the labeling of the reference product does or does not follow those rules. Turning to specific issues, FDA states that those sections of the biosimilar product labeling based on the reference product labeling should be similar but need not be identical. For example, differences in administration, storage or safety information may require different labeling. The guidance devotes several pages to describing when biosimilar sponsors should use their biosimilar’s name, the reference product’s proprietary name and the “core name” of the product, the latter term referring to that portion of the proper name that does not include the four letter suffix proposed in FDA’s draft guidance on biologics naming (see our post here). FDA recommends that: The biosimilar’s name (proprietary or proper) be used in labeling where information is (1) specific to the biosimilar product or refers solely to the biosimilar product, such as in Indications and Usage and Dosage and Administration sections; and (2) for directive statements and recommendations for preventing, monitoring, managing, or mitigating risks, typically included in sections such as black box warnings, Contraindications, Warnings and Precautions, and Drug Interactions. The reference product name be used when clinical studies or data of the reference product are described, e.g. in the Adverse Reactions and Clinical Studies sections. The core name should be used in labeling sections where risks apply to both the biosimilar product and the reference product, such as black box warnings, Contraindications, Warnings and Precautions, and Adverse Reactions. In such sections, the labeling should refer to the core name followed by the word “” More than one name be used where necessary to accurately convey information. While this part of the guidance appears to be logical, it may result in labeling that is confusing to users, considering that the labeling will apparently switch back and forth between three different names to make distinctions whose subtlety may escape a busy or uninformed end user. The guidance briefly addresses labeling for biosimilars that are approved for fewer indications than the reference product, noting that text regarding those indications should not be in the biosimilar labeling, except when necessary to ensure safe use. In those situations, FDA admonishes biosimilar applicants to write labeling “in a manner that does not imply that the biosimilar product is approved for a reference product indication(s) or use(s) that has not been approved for the biosimilar product.” Notably, the guidance does not address AbbVie’s request that the labeling of a biosimilar call out that it is not approved for all the indications of the reference sponsor (see our post here). The section of the guidance that may generate the most discussion is the one calling for the labeling of biosimilar products to identify these products as biosimilars. FDA originally called for this to be done in a 2012 draft guidance, deleted that point in the 2015 final version of that guidance, but now has reinstated it here. FDA “recommends inclusion of a statement, on the line immediately beneath the initial U.S. approval date in Highlights, that the product is biosimilar to the reference product.” This statement should read “[BIOSIMILAR PRODUCT’S PROPRIETARY NAME (biosimilar product’s proper name)] is biosimilar* to [REFERENCE PRODUCT’S PROPRIETARY NAME (reference product’s proper name)] for the indications listed.” FDA provides precise wording and placement for the asterisked statement, essentially a paraphrasing of the BPCIA’s definition of a biosimilar: “Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. the a s