By Ricardo Carvajal –

DHHS and USDA announced the inaugural meeting of the 2015 Dietary Guidelines Advisory Committee (DGAC), scheduled for June 13-14.  At the inaugural meeting, the DGAC will be provided with an orientation to the process for revising the Dietary Guidelines (revisions take place every five years) and will begin its deliberations.  The agenda for the meeting is available here.  Summary descriptions of the members of the DGAC are available here.  The meeting announcement describes the DGAC’s task as follows:

The work of the DGAC will be solely advisory in nature and time-limited. The Committee will develop recommendations based on the preponderance of current scientific and medical knowledge using a systematic review approach. The DGAC will examine the current Dietary Guidelines for Americans, take into consideration new scientific evidence and current resource documents, and develop a report to the Secretaries of HHS and USDA that outlines its science-based recommendations and rationale which will serve as the basis for developing the eighth edition of the Dietary Guidelines for Americans.

It is difficult to overstate the importance of the DGAC’s deliberations, given the influence of the Dietary Guidelines on food formulation and marketing.  The DGAC will hold several meetings into next year, with the goal of issuing a report to DHHS and USDA in late 2014.  The agencies will consider the DGAC’s report in developing the next iteration of the Dietary Guidelines policy document, which is expected to publish in Fall 2015.

By JP Ellison –

You may not recall our prior April 2009 blog post about the FTC’s settlement with Kellogg over its marketing campaign for Frosted Mini-Wheats.  To briefly recap, Kellogg had claimed that “its cereal was “clinically shown to improve kids’ attentiveness by nearly 20%.”  The FTC disagreed, and claimed that “[i]n fact, the study showed that the children who ate the cereal for breakfast averaged just under 11 percent better in attentiveness.”   The 2009 FTC settlement prohibited Kellogg from making comparable claims unless they were substantiated.  The FTC settlement did not include any consumer redress.

A few weeks after the FTC settlement was announced, plaintiff class action attorneys sent a proposed complaint to Kellogg and shortly thereafter the class action case was filed.  The class action case involved the same advertising, and at least with respect to equitable/injunctive relief regarding advertising claims, sought nothing that was not already covered by the FTC settlement   A proposed settlement of the Mini-Wheats class action was recently announced.  The more than four years between the FTC resolution and the class action settlement can be explained, at least in part, by challenges to the original Frosted Mini-Wheats class action settlement.

In the years between the FTC Frosted Mini-Wheats settlement and the class action Mini Wheats settlement, the FTC again investigated Kellogg over health benefit claims for a cereal – specifically, antioxidant and immune support claims for Rice Krispies.  In that case the FTC seems to have followed in the footsteps of state and local authorities who first challenged the same claims.   The Rice Krispies FTC settlement expanded the existing (Frosted Mini-Wheats) FTC order against Kellogg to cover a wider scope of claims, but again, did not include monetary relief.  As with the earlier FTC settlement, there was a follow-on class action that the company settled in 2011.

The Kellogg experience is not unusual.  FTC investigations and settlements are often followed by class action suits, and state attorney general inquiries can result in federal enforcement actions.  In other instances, private litigation leads to governmental enforcement actions, and sometimes, governmental and private actions proceed simultaneously.  It is not uncommon for these plaintiffs to coordinate with one another. 

Given the myriad of potential investigations and litigations that can arise when advertising claims are challenged, companies facing actual or potential litigation over such claims must be mindful of the effects that one investigation or litigation may have on another.

By Kurt R. Karst –      

For the third time this year, FDA has been asked to recognize 5-year New Chemical Entity (“NCE”) exclusivity for a fixed-dose combination drug product containing both a never-before-approved active moiety and a previously approved active moiety.  In a Citizen Petition (Docket No. FDA-2013-P-0471) submitted to FDA last month on behalf of Bayer HealthCare Pharmaceuticals Inc. (“Bayer”), the company asks the Agency to effectively erase the award of 3-year new clinical investigation exclusivity for the oral contraceptive NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets and instead award a period of NCE exclusivity.  Similar requests for NCE exclusivity recognition were made in petitions submitted to FDA earlier this year concerning STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058) and PREPOPIK (sodium picosulfate, magnesium oxide and citric acid) for Oral Solution (Docket No. FDA-2013-P-0119).  Indeed, the STRIBILD petition called out NATAZIA as one example for which NCE exclusivity would be ongoing if FDA had awarded such exclusivity in the first place. 

As we previously reported, FDA’s long-standing position has been that in order for a fixed-dose combination drug to be eligible for 5-year NCE exclusivity, each of the active moieties in the drug product must be new (i.e., not previously approved).  This interpretation is based on FDA’s reading of the statutory language at FDC Act § 505(j)(5)(F)(ii) (concerning ANDAs) and FDC Act § 505(c)(3)(E)(ii) (concerning 505(b)(2) applications) and application of the Agency’s implementing regulation at 21 C.F.R. § 314.108(b)(2), which precludes FDA from accepting ANDAs and 505(b)(2) applications for drugs that contain the same active moiety as in a previously approved NCE for five years (absent a Paragraph IV certification).

FDA approved NATAZIA on May 6, 2010 under NDA No. 022252 and awarded a period of 3-year exclusivity that expired earlier this month.  NATAZIA contains both the previously approved drug estradiol valerate and the new molecular entity dienogest.  Because of the award of 3-year exclusivity instead of NCE exclusivity, FDA was free to accept ANDAs seeking aproval for generic NATAZIA as of the date of approval of the drug.  Indeed, according to FDA’s ANDA Paragraph IV Certification List, the Agency received an ANDA as of October 22, 2010.  FDA has not yet approved or tentatively approved any ANDA for generic NATAZIA, and at least one generic applcant is involved in patent infringement litigation with Bayer over a patent on NATAZIA (see here).

Like the STRIBILD and PREPOPIK petitions, Bayer argues in its NATAZIA petition that FDA’s historical approach of denying NCE exclusivity for a fixed-dose combination drug containing a new and previously approved moiety is contrary to the statute, congressional intent and FDA’s exclusivity regulations, and produces arbitrary outcomes that disfavor fixed-dose combinations.  Thus, Bayer fully endorses the arguments set forth in the STRIBILD and PREPOPIK petitions.  According to Bayer:

There is no plausible reason why FDA should incentivize sponsors to obtain approval for a drug product that contains a single new active moiety prior to obtaining approval for an [fixed-dose combination] that incorporates that active moiety in combination with other active moieties.  There is also no reason why FDA should encourage sponsors to seek separate approvals for each active ingredient of a combination product rather than to seek approval of a [fixed-dose combination].  But these outcomes are precisely what FDA’s interpretation of the 5-year exclusivity provision with respect to FDCs promotes. . . . .  Regardless of whether the [NCE] is first approved as part of a [fixed-dose combination] with a previously approved chemical entity, significant time and effort was undoubtedly invested in developing that [NCE].  Due to the substantial investment required, a 5-year exclusivity period is appropriate.

The NATAZIA petition, like the STRIBILD petition, also argues that FDA need not undergo notice-and-comment rulemaking prior to adopting a new interpretaion resulting in an award of NCE exclusivity for fixed-dose combination containing a new moiety.  “FDA has not given its relevant regulation a ‘definitive interpretation,’” says Bayer.  “Furthermore, even if FDA’s interpretation were considered definitive, there has not been substantial or justifiable reliance on that interpretation.  Accordingly, notice and comment rulemaking is not required prior to FDA’s adoption of the interpretation of 5-year exclusivity proposed in this petition.”

Given the age of the NATAZIA approval and the status of pending ANDAs relative to the STRIBILD and PREPOPIK approvals, FDA may be forced to address the NCE exclusivity issue raised by Bayer and others sooner than the Agency might want to.  A denial of any of the petitions could very well lead to a lawsuit against FDA.  In the meantime, it is possile that other manufacturers may join the petitioning club.  A quick look at products in the drug development pipeline and in the NDA review queue at FDA shows that there are other membership candidates.

By Paul M. Hyman – 

As we have discussed previously, the Park doctrine allows the government to seek a misdemeanor conviction against a company official for alleged violations of the Federal Food, Drug, and Cosmetic Act ("FDCA") without having to prove that the official participated in or was even aware of the violations.  The government need only demonstrate that the official was in a position of authority to prevent or correct the alleged violation.  The Park doctrine, in effect, renders FDCA violations strict liability crimes for corporate officials in positions of responsibility or authority. 

Several FDA Warning Letters, issued last month and this month, appear to be the first letters in recent memory in which FDA has cited United States v. Park and its predecessor, United States v. Dotterweich.  On closer reading, however, the recent letters do not cite the Park doctrine for the usual theory of strict liability for company officials or even as a clear threat to prosecute individuals.  The letters, instead, appear to cite Park and Dotterweich to make a point about vicarious liability. 

Each letter was addressed to a dietary supplement distributor.  The letters cite Park and Dotterweich to support the legal theory that a distributor that uses contract manufacturers or labelers may be liable (or convictable) for Current Good Manufacturing Practice ("CGMP") violations by its contractors.  The letters state as follows:

Although your firm may contract out certain dietary supplement manufacturing operations, it cannot . . . contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements (see United States v. Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can be committed under the Act by anyone who has “a responsible share in the furtherance of the transaction which the statute outlaws”); United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal liability under the Act does not turn on awareness of wrongdoing, and that “agents vested with the responsibility, and power commensurate with that responsibility, to devise whatever measures are necessary to ensure compliance with the Act” can be held accountable for violations of the Act)[)]. . . .The Act prohibits a person from introducing or delivering for introduction, or causing the delivery or introduction, into interstate commerce a dietary supplement that is adulterated under section 402(g) for failure to comply with dietary supplement CGMP requirements. . . . Thus, a firm that contracts with other firms to conduct certain dietary supplement manufacturing, packaging, and labeling operations for it is responsible for ensuring that the product is not adulterated for failure to comply with dietary supplement CGMP requirements, regardless of who actually performs the dietary supplement CGMP operations.

The idea that a distributor might be responsible for CGMP violations by its contract manufacturers or labelers is, of course, nothing new.  The letters include, almost verbatim, statements about distributor liability from the 2007 FDA notice announcing the final dietary supplement CGMPs.  The citations to the Park doctrine simply appear to add teeth to the prior guidance and possibly suggest (or hint) – without any overt discussion – that a distributor and its officers might be held liable. 

That a company official could be convicted of a misdemeanor based on the acts of a third party contractor appears possible under the Park doctrine.  While Park involved an officer’s vicarious liability for his own company’s acts, Dotterweich involved an officer’s vicarious liability for the acts of third party manufacturers.  Despite the facts of the 70 year-old Dotterweich decision, however, the conviction of an officer for third party acts is not a foregone conclusion – especially at this point. 

Both Park and Dotterweich were split decisions with strong dissents.  Moreover, as we have pointed out previously, what is a misdemeanor now is much more serious than what it was even 20 years ago in terms of potential monetary penalties and prison sentences.  If the penalty sought against a corporate official appears particularly severe – or the alleged FDCA violation appears more technical than dangerous – juries and courts may be wary of finding guilt based on strict liability.  By the same token, the more tenuous the connection appears between an official and those who actually violated the FDCA, the more juries and courts may be willing to cut off vicarious liability.

By Jessica A. Ritsick –

The Fifth Circuit earlier this month, in Elgin Nursing and Rehab Ctr. v. U.S. Dep’t of Health and Human Servs., No. 12-60086, 2013 WL 2149873 (5th Cir. May 17, 2013), struck down a decision by the Department of Health and Human Services (“HHS”) relating to the Centers for Medicare & Medicaid Services’ (“CMS”) interpretation of a regulation concerning serving food safely in a nursing facility.  As a result, the court vacated a fine issued to the nursing facility.

The case arose out of purported violations of sanitary food regulations by Elgin Nursing and Rehabilitation Center in Texas.  The Texas Department of Aging and Disability inspected Elgin, and found smeared egg yolk on some patients’ breakfast plates.  The inspectors concluded that the smeared egg yolks, from unpasteurized shell eggs, were “unsanitary,” and that the nursing home had violated the law.

HHS regulates nursing facilities under 42 U.S.C. § 1320a-7j.  HHS regulations require long-term care facilities to “[s]tore, prepare, distribute, and serve food under sanitary conditions.”  42 C.F.R. § 483.35(i)(2).  “Sanitary conditions” is an ambiguous term, and CMS sought to clarify that term in CMS’ State Operations Manual (“SOM”) Appendix PP, which specifies sanitary cooking conditions for food.  Under CMS’ SOM, unpasteurized shell eggs are required to be cooked to “-145 degrees F for 15 seconds; until the white is completely set and the yolk is congealed.”  CMS argued that this interpretation was conjunctive, and that both the time and temperature, and the consistency requirement, must be met to avoid violation of the regulations.  CMS averred that its conjunctive interpretation of the SOM was entitled to “great deference” by the court.  The court disagreed.

The Fifth Circuit stated that not only would adopting such a policy encourage agencies to write ambiguous requirements, as well as to create and enforce ambiguous interpretations of those requirements, but also that such policy would foreclose agency interpretations from judicial review.  Perhaps most importantly, though, the court stated that such policy would allow agencies to “punish ‘wrongdoers’ without first giving fair notice of the wrong to be avoided.”  Elgin, 2013 WL 2149873, at *4.

“Allowing an agency to apply its own interpretation to an otherwise vague regulation in the context of an enforcement proceeding would unfairly surprise the sanctioned party and ‘seriously undermine the principle that agencies should provide regulated parties ‘fair warning of the conduct [a regulation] prohibits or requires.’”  Id. at *5 (citations omitted) (alteration in original).  Thus, Elgin serves as a cautionary tale to agencies:  where agencies “issue ambiguous interpretive documents and then interpret those in enforcement actions,” id. at *7, courts may not grant the interpretation of the interpretation any deference, and will vacate sanctions that the agency imposes based on such ambiguous interpretive documents.

The court ultimately found that the SOM was disjunctive, that CMS had not adduced any evidence that the eggs served to residents were not cooked to the proper temperature for the proper period of time, and set aside HHS’ decision that Elgin had violated safety requirements related to the cooking of eggs.  As a result, the court vacated the penalty HHS had imposed on Elgin.

By Ricardo Carvajal –

A fight that started as a citizen petition asking FDA to permit the interstate sale of raw milk under limited circumstances is now being waged in federal court.  In 2008, raw milk advocates and the Organic Pastures Dairy Company ("OPDC") petitioned FDA to amend the regulatory ban on interstate sale of raw milk to incorporate the following exception:

Raw milk that is tested, state inspected, state regulated, carries a “government warning statement” and labeled for retail sale in one state may be transported to another state if that other state allows the sale of raw un-pasteurized milk and or dairy products.

Last December, OPDC sued FDA to compel a response to the citizen petition.  On February 26, 2013, FDA denied the citizen petition in emphatic terms, and subsequently filed a motion for judgment on the pleadings based on a number of affirmative defenses (lack of standing, ripeness, and failure to state a claim upon which relief can be granted).  OPDC responded by filing a motion to amend its complaint to address those issues.  The court granted that motion, and dismissed FDA’s motion for judgment on the pleadings as moot.  OPDC recently filed an amended complaint alleging that FDA’s denial of its citizen petition is arbitrary and capricious in part because FDA has taken no action to ban the interstate sale of other foods, including pasteurized milk and produce, associated with outbreaks that have sickened or killed many consumers. 

In the interim, FDA has deployed other tools to advocate its position, including a consumer advisory on the dangers of raw milk.  FDA’s campaign received support from the CDC, which issued its own consumer advisory.  CDC staff also partnered with state health agency staff to publish a report on a recent outbreak of foodborne illness linked to raw milk produced by a dairy with a state-issued unpasteurized milk permit and “minimal deficiencies identified during inspection” – illustrating, in the words of the authors, “the ongoing hazards of unpasteurized dairy products.”  Some states have been clamping down on efforts to circumvent their restrictions on the sale of raw milk (see here).  Not surprisingly, outbreaks linked to raw milk have also drawn the interest of the plaintiffs’ bar (see here).

By Carmelina G. Allis –

FDA has issued an “It Has Come to Our Attention Letter” to Biosense Technologies Private Limited for failure to have a 510(k) clearance for its mobile app, the uChek Urine Analyzer.  The app can be downloaded for 99 cents through the iTunes Apps Store, and uses the phone’s camera to read urine dipsticks.  The app is intended for use with the 510(k)-cleared Siemens and Bayer reagent strips for the qualitative and semi-quantitative determination of urine analytes, including glucose, urobilinogen, pH, ketone, blood, protein, bilirubin, nitrite, leukocyte, and specific gravity.

FDA’s letter explains that because the app allows a mobile phone to analyze the dipsticks, “the phone and device as a whole functions as an automated strip reader” that require clearance as a “urinalysis test system.”

The company is being asked to either identify an FDA clearance for the app, or provide an explanation for why Biosense does not believe that the company needs to obtain 510(k) clearance.

This letter is very unusual.  Although the FTC has publicly stated that it believes that there is a need for more aggressive enforcement action against medical apps (see here), enforcement actions against mobile medical app developers have not been at the top of FDA’s agenda.  In fact, according to press reports, FDA has recently said that the agency is being cautious about which kind of enforcement action it takes because there is no clear agency guidance on the regulation of mobile apps.

As we previously blogged, FDA has proposed to exert regulatory authority over select mobile medical apps that meet the “device” definition in the Federal Food, Drug, and Cosmetic Act, and that are either used as an accessory to a regulated medical device, or transform a mobile platform into a regulated medical device.  In this case, it appears that the Biosense app falls in the category of apps for which FDA will apply regulatory oversight.  The Biosense app appears to transform the mobile platform into a medical device by including functionalities similar to those of currently regulated medical devices, such as Acon Laboratories, Inc.’s Mission U500 Urine Analyzer, K111221, which has the same intended use as Biosense’s app.

It is unclear whether this unusual letter is an indicator of a coming increase in FDA’s enforcement action against medical apps.  FDA may have felt the need to issue this letter because of the intense media coverage that the app and the company have received in the past few weeks.

The letter shows that there will continue to be  case-by-case enforcement even as FDA mulls general guidance for mobile apps.  The letter suggests that mobile apps are particularly at risk of enforcement if their functionality is similar to those of currently regulated devices already subject to FDA regulatory oversight.

By Kurt R. Karst –      

A Citizen Petition (Docket No. FDA-2013-P-0203) submitted to FDA earlier this year raises an issue that comes up from time to time – although not typically in a public forum – about the Agency’s so-called “exception excipient” regulations applicable to sponsors of ANDAs for generic versions of brand-name drugs that differ from the Reference Listed Drug (“RLD”) formulation in certain ways.  Ever since FDA finalized its ANDA regulations in the early 1990s and drafted its Interim Inactive Ingredients Policy in 1994 (which is not specifically cited in FDA decisions, and, while apparently abandoned, still reflects general Agency policy), the Agency has been rather inflexible in applying the regulations.  We previously authored an article for the Washington Legal Foundation – “The Drug User Fee Catch-22” – arguing that FDA should be more flexible in receiving and approving ANDAs for drug products whose formulations differ from that of the RLD.  And now FDA is being asked to do so more formally in the context of a generic version of VFEND IV (voriconazole) for Injection 200 mg/vial.  Unfortunately, history shows that FDA is unlikely to grant the petitioner’s request: that FDA refrain from enforcing its “exception excipient” regulations to permit a “non-exception excipient” change from the RLD.

By way of background, FDA’s regulations implementing FDC Act § 505(j)(4)(H), which concerns ANDA approval and inactive ingredient composition and safety, provide that, for certain types of drug products, generic drug formulations may deviate from the RLD formulation only in certain respects.  For example, FDA’s regulations for parenteral drug products at 21 C.F.R. § 314.94(a)(9)(iii) state:

Generally, a drug product intended for parenteral use shall contain the same inactive ingredients and in the same concentration as the [RLD] identified by the applicant under paragraph (a)(3) of this section.  However, an applicant may seek approval of a drug product that differs from the [RLD] in preservative, buffer, or antioxidant provided that the applicant identifies and characterizes the differences and provides information demonstrating that the differences do not affect the safety or efficacy of the proposed drug product. [(Emphasis added)]

Preservative, buffer, and antioxidant changes in generic parenteral drug products are referred to as “exception excipients,” which may qualitatively or quantatively differ from the RLD formulation.  Other regulations at 21 C.F.R. § 314.94(a)(9)(iv) identify exception excipients for generic ophthalmic and otic drug products (i.e., preservative, buffer, substance to adjust tonicity, and thickening agent).  Excipients not identified in these regulations are referred to as “non-exception excipients.”

FDA’s exception excipient regulations at 21 C.F.R. § 314.94(a)(9) find their parallel in 21 C.F.R. § 314.127(a)(8)(ii), which addresses the grounds for an FDA refusal to approve an ANDA for a parenteral, ophthalmic, or otic drug product.  For example, 21 C.F.R. § 314.127(a)(8)(ii)(B) states: “FDA will consider an inactive ingredient in, or the composition of, a drug product intended for parenteral use to be unsafe and will refuse to approve the [ANDA] unless it contains the same inactive ingredients, other than preservatives, buffers, and antioxidants, in the same concentration as the listed drug. . .” (emphasis added).

FDA has not provided a thorough explanation as to the basis for its exception excipient regulations.  In a recent citizen petition decision (Docket No. FDA-2006-P-0007, at pages 57-58) concerning vancomycin, FDA commented that the Agency “has more stringent limitations on inactive ingredients to account for the fact that each of these drug products represents an individual pharmaceutical system with its own characteristics and requirements, and that inactive ingredients are added to maintain these systems.”

Notwithstanding FDA’s exception excipient regulations, the Agency has, on occasion, but only in very limited circumstances, waived these regulations pursuant to 21 C.F.R. § 314.99(b) to permit the receipt and approval of an ANDA for a drug product containing a non-exception excipient change from the RLD.  Historically, FDA policy limits granting such waivers to cases in which an ANDA applicant seeks approval to market a drug product containing a non-exception excipient used in a discontinued, brand-name RLD formulation that is not used in the currently-marketed RLD formulation.  For example, FDA has granted waivers in the cases of generic ZOSYN (piperacillin sodium; tazobactam sodium) Injection (Docket Nos. FDA-2005-P-0003, FDA-2006-P-0019, FDA-2006-P-0331, and FDA-2006-P-0391), generic SANDOSTATIN (octreotide acetate) Injection (Docket Nos. FDA-2001-P-0121 and FDA-2005-P-0370), and generic ACETADOTE (acetylcysteine) Injection (Docket No. FDA-2012-P-0507).  FDA’s approval of generic ZOSYN was challenged in court and upheld (see our previous posts here and here).  Late last year, FDA’s approval of generic ACETADOTE was challenged in court (see our previous post here).  The case has been briefed (copies of the briefs are available here, here, here, and here) and a decision is pending.  This is the only situation in which FDA will entertain a waiver of the Agency’s excipient regulations.  Indeed, a few years ago, FDA stated just that in correspondence to one ANDA sponsor: “The only situation in which the FDA will entertain a waiver of the requirement under 21 CFR 314.94(a)(9)(iii) . . . is when the [RLD] has changed its formulation and has discontinued the previous formulation for reasons other than safety and/or effectiveness.” (Emphasis added).

Manufacturers unable to obtain a waiver for a non-exception excipient change are effectively forced to submit a 505(b)(2) NDA.  While such products may be A-rated in the Orange Book once approved, and, therefore, are considered substitutable for the brand-name listed drug relied on for approval (e.g., Nicardpine HCl, NDA No. 022276; Oxaliplatin, NDA No. 022160; Docetaxel, NDA Nos. 201195, 022312, 022234, 201525; and Pamidronate Dosodium, NDA No. 021113), 505(b)(2) applications are subject to significantly higher user fees under PDUFA compared to ANDAs under GDUFA.  We also note that two pending Citizen Petitions (Docket Nos. FDA-2011-P-0610 and FDA-2013-P-0371; see our previous post here) request that FDA create a rulemaking process for 505(b)(2) NDA therapeutic equivalence rating decisions.

The recent Citizen Petition requesting that FDA refrain from enforcing its exception excipient regulations for generic parenteral drug product formulations to permit a non-exception excipient change vis-à-vis the formulation of VFEND – i.e., a change in solubilizing agent from SBEβCD to HPβCD – argues that compliance with the non-exception excipient requirements is unnecessary, and that a wealth of scientific information justifies a waiver of the regulations.  Referring to FDA’s petition decisions on generic ZOSYN and SANDOSTATIN formulatins, the petitioner states:

The petitioner recognizes that [FDA’s previous] decisions were based on petitions in which the petitioners sought approval to submit ANDAs based on discontinued formulations of previously-approved RLDs . . . .  Nonetheless, the agency’s decision in those petitions demonstrates that the agency can consider an ANDA drug product to be safe even though it contains a different inactive ingredient (other than preservatives, buffers, or antioxidants) from the current RLD.  The petitioner believes that, even though the inactive ingredient in its proposed formulation of Voriconazole for Injection 200 mg/vial was not part of a previously-approved voriconazole formulation, there is sufficient data to prove the safety of its proposed formulation and its eligibility for ANDA submission relying on Vfend I.V. as the RLD.

Furthermore, the petitioner believes that its proposed formulation is as effective as the RLD, and would meet requirements for ANDA approval pursuant to FDA’s grant of this petition for ANDA submission. . . .

In an interesting twist, the petition also argues that “publicly-available information in the Vfend I.V. NDA shows that in Pfizer’s early development program (starting in 1991) its intravenous voriconazole was formulated with HPβCD,” and that “SBEβCD as a solubilizing excipient began to be used in Pfizer’s intravenous formulation in clinical trials beginning in 1994, and the FDA apparently permitted Pfizer to change the inactive ingredient in its formulation from HPβCD to SBEβCD without requiring bioequivalence studies between those two formulations.”  According to the petitioner, “[t]his implies that the data available within the Vfend NDA submission support the petitioner’s claim that efficacy of the drug will not be affected by changing the solubilizing agents.”

While all of the information provided in the petition to support a waiver of FDA’s exception excipient regulations is quite interesting, we’re reminded of FDA’s statement to an ANDA sponsor that, to our understanding, still reflects Agency policy: “The only situation in which the FDA will entertain a waiver of the requirement under 21 CFR 314.94(a)(9)(iii) . . . is when the [RLD] has changed its formulation and has discontinued the previous formulation for reasons other than safety and/or effectiveness.”

By Jeffrey K. Shapiro & Jennifer D. Newberger –

As discussed in our prior posts (here, here, and here), the Center for Devices and Radiological Health (“CDRH”) has taken much needed steps to improve the most commonly used appeal process, request for supervisory review, available under 21 C.F.R. § 10.75. 

The first major activity was the issuance of a draft guidance in December 2011.  The draft guidance explained the supervisory review process in greater detail than ever before, established voluntarily target timelines that would substantially shorten a process known for its unbearably lengthy timeframe, and introduced what we referred to at the time as new “wrinkles.”  These included, for example, “telescoping” the review process and allowing the submitter to request review by an advisory panel or other experts. 

While the draft guidance was pending, Congress passed the Food and Drug Administration Safety and Innovation Act (“FDASIA”), which included provisions related to the medical device appeals process.  Specifically, FDASIA section 603 (codified at section 517A of the Federal Food, Drug, and Cosmetic Act (“FDC Act”)) imposed timeframes for appeal decisions that were shorter than those proposed in the draft guidance, and required CDRH to provide a “substantive summary” of the rationale for any “significant decision” being appealed.

On May 17, CDRH finalized its guidance on the appeals process and issued a separate draft guidance with a short Q&A on FDA’s interpretation of the “significant decision” provision in section 517A (referred to herein as “Appeals Guidance” and “Draft Guidance,” respectively).  Once finalized, the draft guidance will be included as an appendix to the appeals guidance. 

The draft guidance on section 517A states proposes that “significant decision” will include the following: 

• not substantially equivalent (“NSE”) or substantially equivalent (“SE”) decisions on 510(k) submissions;
• not approvable, approvable with conditions, or approval decisions for premarket approval applications (“PMAs”) or humanitarian device exemptions (“HDEs”);
• disapproval or approval of an investigational device exemption (“IDE”); and
• failure to reach an agreement on a protocol under section 520(g)(7) of the FDC Act, which allows for discussion with FDA of a protocol for the study of a Class III device or an implantable device. 

FDA does not believe that actions earlier in the review process, such as refusals to accept/file, requests for additional information, and deficiency letters, are “significant decisions” subject to section 517A.  

As to the “substantive summary,” the draft guidance explains that it “may be the final version of the review memorandum by the lead reviewer or another summary document that includes the following elements:  an explanation of the rationale for the regulatory decision; documentation of significant controversies or differences of opinion, i.e., ones the resolution of which had a direct bearing on the regulatory decision; and, references to published literature and consensus standards upon which the decision-maker relied.”  Draft Guidance, at 4.

It is not clear whether the entity requesting the summary can specify whether it would like the final version of the review memorandum or the separate document with the specified elements, or whether that decision is left to the review team.  If the latter, it is likely that the summary will more likely be the final version of the review memorandum, so the reviewers will not need to prepare a separate document. 

There had been some question about whether the summary would be redacted.  The draft guidance states that because the memorandum will be provided only to the owner of the proprietary information therein, there should not be any need to redact trade secret and/or confidential commercial information “or any other information in the summary.”  Draft Guidance, at 4.  However, the memorandum will also be available to anyone who asks under the Freedom of Information Act (FOIA).  The version produced under FOIA will be redacted as to trade secret and/or confidential commercial information. 

Unfortunately, the draft guidance fails to answer perhaps the most critical question:  when will the substantive summary be provided to the requester?  Presumably, the entity appealing a decision would like access to the substantive summary prior to preparing the appeal.  Under section 517A, the appeal must be filed within 30 days of the significant decision.  If the substantive summary is provided beyond the 30 day timeframe, or even late in the timeframe, it will be of little to no use in preparation of the appeal, contrary to the apparent statutory intent. 

Certainly, if the review team provides the final review memorandum as the substantive summary, there is no reason why it could not be provided as soon as it is requested.  If an alternative document is prepared, it may take longer.  There is no excuse, however, for FDA to countenance a system that allows reviewers to withhold the substantive summary for any length of time, given that the applicant has only 30 days to prepare an appeal.  The final guidance should address the timing of the substantive summary. 

As for the final appeals guidance, apart from inclusion of information related to section 517A, it does not appear to be significantly changed from the draft guidance issued in December 2011.  Unfortunately, the final guidance followed the draft guidance in failing to retain the tables found in the 1998 guidance that contained the essentials and helpful “pros” and “cons” of each procedure. 

The final guidance states that, while a meeting or teleconference must be granted for a significant decision if requested by the submitter, it is up to the review authority to determine whether one is necessary for a non-significant decision.  In fact, “FDA believes that most appeals of actions other than significant decisions can be decided without an in-person meeting or teleconference.”  Appeals Guidance, at 6.

The guidance also interprets section 517A to require a request for supervisory review within 30 days, and states that there “is no provision in the statute for extensions or waivers, or for partial submissions or ‘placeholders.’”  Appeals Guidance, at 6.  If an appeal of a significant decision is submitted later than 30 days after the date of the decision, it will not be eligible for review under section 10.75.  Thus, the FDASIA imposed timelines are a two edged sword.  On the one hand, they help ensure a speedier supervisory review.  But if the appeal of a significant decision is not filed within 30 days, the right to supervisory review is lost.  The guidance allows more than 30 days for non significant decisions, but suggests that, as an administrative matter, an appeal past 60 days would be considered untimely.  This latter position is legally questionable, since the issue is not addressed in FDASIA and the proposed time limitation has no support in the language of section 10.75. 

The guidance reflects section 517A in providing that a decision respecting a significant decision must be made within 30 days of an appeal meeting or teleconference, or, if none is held, within 45 days of the request for supervisory review. 

While the proposals in the guidance and the shortened timeframes may help resolve certain frustrations, the real test will be whether supervisors at FDA continue to routinely uphold the decisions of their subordinates, or are interested in considering the issues and making difficult decisions when needed.

By Kurt R. Karst –      

As folks in the generic drug industry patiently await the U.S. Supreme Court’s decision in Mutual Pharmaceutical Co. v. Bartlett (Docket No. 12-142), a design defect generic drug preemption case (see our previous post here), we thought we would whet the preemption appetite with two new petitions to the Supreme Court and an interesting state court decision.

Novartis Pharmaceuticals Corp. v. Fussman (Docket No. 12-1339).  In a petition for a writ of certiorari filed earlier this month, Novartis Pharmaceuticals Corporation (“NPC”) is appealing a February 2013 decision (unpublished) from the U.S. Court of Appeals for the Fourth Circuit involving NPS drugs AREDIA (pamidronate disodium) and ZOMETA (zoledronic acid). 

The Fourth Circuit, in affirming a district court’s denial of NPC’s motion for judgment as a matter of law on preemption theory, rejected NPS’s attempt to “carve out a niche in existing precedent” by arguing that Wyeth v. Levine, 555 U.S. 555 (2009), in which the Supreme Court held that a state-law tort action against a brand-name drug manufacturer for failure-to-warn is not preempted, “is inapplicable because it does not expressly reference punitive damages.”  NPS had argued that the FDC Act preempts the recovery of punitive damages because “(1) the purpose of punitive damages is to punish and deter, something the FDA has ‘ample power’ to accomplish through enforcement of labeling requirements and (2) allowing the punishment of FDA-approved conduct is improper.”  According to NPS, Wyeth concerned only compensatory damages.

The questions NPS presents in the case are:

1. Whether the FDA’s exclusive authority to punish violations of federal law governing the lawful marketing of prescription drugs preempts state tort law which allows the imposition of punitive damages to punish the same activity.

2. Whether a punitive damages award imposed in connection with the marketing of an FDA-approved drug impermissibly penalizes a drug manufacturer under state law for the exercise of its federal right to market the prescription drug.

3. Whether the Fourth Circuit below erred in basing its holding solely on [Wyeth], which does not address punitive damages.

NPS argues in its petition, among other things, that:

There was no award of punitive damages in [Wyeth] and, accordingly, no occasion for the Court to consider the separate preemption issue arising from such an award.  In its holding, however, the Court noted that state tort law claims “serve a distinct compensatory function.”  The Court also explained that in enacting the FDCA “Congress did not provide a federal remedy for consumers harmed by unsafe or ineffective drugs.”  By sharp contrast, the FDCA provides a wide variety of federal remedies by which the FDA may punish drug companies for alleged misconduct, and it provides a means for private individuals to raise such allegations through pubic citizen’s petitions. [(Internal citation omitted)]

That last sentence and some other related discussion in the petition about petitioning FDA caught our attention.  Although private individuals can certainly raise allegations in a citizen petition, just last year, FDA denied a citizen petition (Docket No. FDA-2012-P-0431) requesting that the Agency take enforcement action against a particular company.  According to FDA, “[r]equests for the Agency to initiate enforcement actions are not within the scope of FDA’s citizen petition procedures.”  Indeed, FDA’s regulation at 21 C.F.R. § 10.30(k) concerning citizen petitions states the regulation “does not apply to the referral of a matter to a United States attorney for the initiation of court enforcement action and related correspondence, or to requests, suggestions, and recommendations made informally in routine correspondence received by FDA. . . .”

Medtronic, Inc. v. Stengel (Docket No. 12-1351).  In a petition for a writ of certiorari that came out last week, Medtronic, Inc. (“Medtronic”) is appealing a January 2013 en banc decision from the U.S. Court of Appeals for the Ninth Circuit involving Medtronic’s Class III medical device, SynchroMed Pump & Infusion System and claims that the company was negligent under Arizona law because it allegedly violated requirements under the FDC Act to report adverse event information.

The Ninth Circuit held that respondents’ negligence claim was not impliedly preempted under the Supreme Court’s decision in Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341 (2001), “because it was based on duties imposed by Arizona common law and was not brought exclusively under federal law.”  The Ninth Circuit further held that respondents’ negligence claim was not expressly preempted under the Supreme Court’s decision in Riegel v. Medtronic, Inc., 552 U.S. 312 (2008) and under the FDC Act, “because the court deemed the state-law duties of reasonable care on which respondents relied to be “parallel[ ]” to the federal duty to report information to the FDA.”  In Buckman, the Supreme Court ruled that federal law impliedly preempted state “fraud-on-the-FDA” claims.  In Riegel, the Court found express preemption for devices subject to premarket approval based on express statutory language.

According to Medtronic:

The Ninth Circuit’s decision in this case deepens two direct and acknowledged circuit splits concerning the preemptive effect of the Medical Device Amendments (“MDA”) to the [FDC Act].  It also directly contravenes, and effectively nullifies, this Court’s holdings in [Buckman] and [Riegel]. . . .  Congress granted exclusive enforcement authority to the FDA so that it could establish a uniform federal regulatory framework and strike a balance that both promotes safety and ensures that the development of innovative devices is not “stifled by unnecessary restrictions.”  Private enforcement, in contrast, would jeopardize the public health by permitting lay juries to second-guess the FDA’s expert regulatory judgment.  Those jury trials would enmesh federal regulators in litigation as fact witnesses needed to prove what the agency would have done differently in the absence of alleged MDA violations, and interfere with the FDA’s carefully calibrated enforcement decisions. 

The question presented by Medtronic in its petition is “whether the MDA preempts a state-law claim alleging that a medical device manufacturer violated a duty under federal law to report adverse-event information to the FDA.”

Krelic v. Mutual Pharmaceuticals Co., Case No. GD-08-024513 (Pa. C.P. Allegheny Co. Apr.11, 2013).  Our friends over at Drug and Device Law Blog recently posted on an interesting from Pennsylvania (Allegheny County) Judge R. Stanton Wettick, Jr. rejecting a novel argment raised by the plaintiffs against preemption under the Supreme Court’s decision in PLIVA Inc. v. Mensing, 131 S.Ct. 2567 (2011).  In Mensing, the Court ruled that FDA’s regulations preventing generic drug manufacturers from changing their labeling except to mirror the label of the brand-name manufacturer preempt state-law failure-to-warn claims against generic drug manufacturers, because it is impossible for generic drug manufacturers to comply with both federal and state duties to warn.

The argument raised by plaintiffs in this case concerning prednisone is that the “different manufacturers exception” at FDC Act 505(j)(2)(A)(v) (and further discussed in FDA’s regulations at 21 C.F.R. §314.94(a)(8)(iv)) to the requirement that ANDA sponsors have the same labeling as the Reference Listed Drug (“RLD”) relied on for approval was somehow not covered by the Court’s Mensing decision.  (You can access the briefs in the case here by entering the case number above.)  Our friends at Drug and Device Law Blog characterized the exception as applying to “mundane things, such as corporate name, and inactive ingredients.”  We take some exception to that characterization.  Indeed, the statutory and regulatory exception from the same labeling requirement is the basis for our popular Labeling Carve-Out Citizen Petition Scorecard.  In any case, the court refused to accept the argument, saying that the exception “does not permit different labeling as to safety and efficacy.”

This is not the first time a Pennsylvania state court has rejected an attempt to avoid Mensing.  As we previously reported (here and here), several courts, including the Philadelphia Court of Common Pleas, have rejected the so-called “RLD Theory of Liability.”  Under that theory, FDA’s regulations impose new or additional responsibilities on an ANDA sponsor whose drug product is unilaterally designated by FDA as an RLD in the Orange Book when the brand-name NDA RLD is no longer marketed.

By Riëtte van Laack –

On May 9, 2013, the U.S. Court of Appeals for the Third Circuit affirmed a District Court’s decision that a state law class action concerning claims regarding the absence of trans fat and cholesterol lowering effect was preempted.

The case, Young v. Johnson & Johnson (“J&J”), involved J&J’s Benecol Spreads.  Plaintiff asserted various state law causes of action based on allegedly false and misleading labeling of Benecol.  Specifically, plaintiff alleged that the claim that the product contained no trans fat was misleading because, although the amount of trans fat per serving was sufficiently low to require declaration as zero g per serving in the Nutrition Facts box, the products do contain a small amount trans fat.  In addition, plaintiff alleged that the claim that Benecol spreads reduced cholesterol was false and misleading because the claim did not specify that the cholesterol reduction was due to the presence of plant stanol esters in the Benecol spreads, and the presence of trans fat in the spreads invalidated the claim.

Defendant argued that the claims were expressly preempted by the FDC Act § 403A(a) barring state nutritional labeling requirements that are not identical to the FDC Act and FDA’s implementing regulations.

The Court interpreted the preemption provision broadly.  It held that although the FDA regulations did not expressly permit the claim “No Trans Fat,” the regulations do allow claims about the amount of a nutrient if it is not false and misleading.  The Court reasoned that the claim “No Trans Fat” was not misleading because an amount of less than 0.5 g trans fat per serving must be identified as 0 g in the Nutrition Facts box, and because the regulations specifically allow a “no [nutrient]” claim for other nutrients (such as fat) if the product contains less than 0.5 g of the nutrient.  The Court concluded that plaintiff was attempting to enforce a state law requirement that was not identical to the federal requirement.

Similarly, according to the Court, the cholesterol reduction claim for Benecol spreads appeared to comply with the applicable FDA regulations.  In fact, the regulations specifically authorize a cholesterol reduction claim for foods containing stanols, and an insignificant amount of trans fat does not disqualify a product for the claim.  Thus, plaintiff sought to impose a standard that is not identical to the standard set forth in FDA regulations and therefore plaintiff’s claim was expressly preempted.

By Ricardo Carvajal & Wes Siegner –

A year ago, FDA issued a warning letter to USPlabs alleging that certain products containing dimethylamylamine ("DMAA") that were marketed as dietary supplements were adulterated because (1) DMAA is a new dietary ingredient ("NDI") for which no notification had been submitted as required under FDCA section 413, and (2) the products contain an NDI for which there is inadequate information to provide reasonable assurance that the NDI does not present a significant or unreasonable risk of illness or injury.  FDA further contended that synthetically produced DMAA does not qualify as a dietary ingredient.

USPlabs disagreed with FDA’s allegations, and FDA has now posted a follow-up letter in which FDA elaborates on its position.  In that letter, FDA disagrees that DMAA qualifies as a dietary ingredient by virtue of being a constituent of a botanical, namely the geranium P. graveolens.  FDA also disagrees that DMAA is a dietary substance, absent evidence of its presence in geraniums or evidence of common use as a food or drink.  FDA therefore concludes that DMAA is an unsafe food additive that renders the products in question adulterated.  However, perhaps of greatest interest is FDA’s application of 301(ll)’s prohibition against the introduction into interstate commerce of any food to which an approved drug has been added.  FDA states:

DMAA was approved as a drug in 1948… and… was not marketed in food prior to such approval, either on its own or based on its alleged presence as a component of P. graveolens.  You have not presented any evidence of such marketing.  In the absence of such evidence, your. . .products are in violation of section 301(ll) of the Act.

Thus, FDA appears to conclude without explanation that section 301(ll) applies to prohibit the introduction or delivery for introduction into interstate commerce of the products in question because they are “food” to which an approved drug (DMAA) has been added.  This implies one of two additional conclusions: (1) the products are not dietary supplements, but are instead conventional foods to which 301(ll) applies, or (2) the products are dietary supplements, but 301(ll) nonetheless applies.  The basis for either of these conclusions is not readily apparent.  Arguably, the second conclusion would be a more interesting regulatory development than the first, as we are not aware of any prior instance in which FDA has applied section 301(ll) to prohibit the marketing of a dietary supplement. 

One of the more significant questions raised by the addition of section 301(ll) to the FDCA is whether that section applies to dietary supplements, given the fact that the language of the provision does not explicitly mention dietary supplements, and that there already exists a similar provision that explicitly applies to dietary supplements – namely section 201(ff)(3)(B).  In fact, FDA raised this very question in its request for comment on the implementation of section 301(ll) (see our prior post here).  Unfortunately, the cursory reference to section 301(ll) in FDA’s follow-up letter to USPlabs raises more questions than it answers. 

Earlier this week, the National Organization for Rare Disorders (“NORD”) held its annual gala here in Washington, D.C. recognizing achievements and advances in the area of rare (orphan) diseases.  Of course, this year is extra special; it’s the 30th anniversary of the enactment of the Orphan Drug Act (see our previous anniversary post here) and the 30th anniversary of the founding of NORD.

With 30 years having gone by, you can imagine that NORD had a long list of folks to thank for what some have called the most successful piece of food and drug legislation ever enacted.  Leadership in public policy awards were handed out to Deputy Secretary of the Department of Health and Human Services William V. Corr, Senator Nancy Kassebaum (KS-Retired), and Representative Henry Waxman (CA).  Awards for vision and pioneering guidance were given to NIH Office of Rare Diseases Research Director Stephen C. Groft, former FDA Office of Orphan Products Development Director Marlene E. Haffner, Swedish Orphan International AB founder Lars-Uno Larsson, NORD founder Abbey S. Meyers, and Jess G. Thoene, who served as Chairman of the NORD Board of Directors and edited two editions of the Physician’s Guide to Rare Diseases.  Then NORD announced the recipient of the award for lifetime achievement . . . . Hyman, Phelps & McNamara, P.C. Director Frank J. Sasinowski.

Frank played a major role in implementing the Orphan Drug Act during his tenure at FDA between 1983 and 1987, and was instrumental in two amendments to the law – in 1984 and 1985 – that strengthened the Orphan Drug Act.  Since 2000, Frank has served on the NORD Board of Directors, first as vice chair and later as chair.  More recently, Frank served as the principal analyst and author of a seminal report, titled “Quantum of Effectiveness Evidence in FDA’s Approval of Orphan Drugs,” on the ways in which FDA has exercised flexibility in the review and approval of non-oncologic orphan drug products (see our previous post here).  Congratulations Frank (“Mr. Orphan Drug”)!

By Jennifer D. Newberger –

In the Federal Register of May 8, 2013, FDA announced a public meeting titled “510(k) Device Modifications:  Deciding When to Submit a 510(k) for a Change to an Existing Device.”  The notice states that the focus of the meeting will be “FDA's interpretation of its regulations concerning when a modification made to a 510(k)-cleared device requires a new 510(k) submission.”  The meeting is to be held on June 13, 2013, from 9am to 5pm.  The registration deadline is May 30, 2013.

As discussed in our previous blog post, in July 2011 FDA issued a guidance document intended to update the 1997 guidance of the same name as the meeting.  The guidance was met with strong resistance from industry, insisting that the interpretations applied in the guidance would result in the requirement to submit a new 510(k) for numerous device modifications.  In response to the feedback from industry, Congress, in enacting the Food and Drug Administration Safety and Innovation Act ("FDASIA") in July 2012, required FDA to withdraw the guidance and prohibited FDA from implementing a new guidance until it submits a report to Congress describing when a new 510(k) should submitted.  The report must include FDA’s interpretation of several key phrases in 21 C.F.R. 807.81(a)(3), the regulation governing submission of a new 510(k) for a modification to an existing product.  In addition, the report must include “possible processes for industry to use to determine whether a new 510(k) is required, and how to leverage existing quality system requirements to reduce premarket burden, facilitate continual device improvement, and provide reasonable assurance of safety and effectiveness of modified devices.”  The public meeting is intended to solicit stakeholder feedback on these issues.  On a related note, FDA recently issued a draft guidance on when modifications must be reported to FDA, which also received substantial negative feedback from industry (see our previous post here).  Perhaps issues discussed at the 510(k) meeting will shed light on those concerns as well.

In the notice, FDA provides a number of specific policy options on which it is seeking feedback, but notes that “implementation of some of these options may require regulatory changes beyond a guidance document.”  These options appear to be new ideas that have not previously been presented by FDA, and ones that industry would likely agree require changes beyond a guidance document.  In some cases, the changes may require statutory, rather than merely regulatory, changes.

The notice sets forth five policy options, and also asks for ideas of additional policy proposals and examples of device changes that industry believes should not trigger the requirement for a new 510(k).  Under each of the five policy options, FDA poses questions on which it is seeking comment prior to the public meeting and will be discussed at the meeting.

The five policy options and examples of the questions for feedback include:

A. Risk Management

FDA says it is primarily concerned with identifying a way to incorporate risk management to ensure “appropriate and consistent modification decisions by industry and FDA staff.”  Such decisions are those “that allow for both medical device innovation and effective FDA oversight of device changes.”  FDA recognizes the importance of ensuring a process to ensure consistent results, since decisions will be made by a variety of different manufacturers and FDA reviewers.  To address these concerns, FDA seeks input on the following:

1. How can FDA tie risk management to the decision that a change or modification to a device could significantly affect the safety or effectiveness of the device?
2. Given the variability in risk management processes and guides, how can a single risk management process be chosen that leads to consistent and appropriate decisions on whether a 510(k) is required for a device modification?
3. How can the inherent subjectivity of risk management be controlled to ensure consistent and appropriate decisions on whether a 510(k) is required?
4. How can FDA assure that a company’s risk management process is comprehensive and appropriately implemented?

B. Reliance on Design Control Activities

The notice expresses FDA’s desire for effective oversight of the design control process, including the opportunity to review design control activities.  FDA states that “improper application of these activities may lead to incomplete or inaccurate evaluations of design changes and the marketing of unsafe or ineffective devices.”  In considering how FDA can affect oversight of design controls, FDA seeks input on the following:

1. Since FDA does not typically review design control information prior to clearance, how can FDA ensure that design control activities will limit the potential for marketing modified devices that may be unsafe or ineffective?
2. Manufacturers comply with design control requirements in a variety of different manners.  How can FDA ensure consistency in use of design controls to ensure that only safe and effective modified devices are marketed?

C. Critical Specifications

FDA states in the notice that critical specifications could be one way that FDA could link use of design activities to 510(k) modification decisions.  This would involve industry and FDA identifying “essential” or “critical” specifications and agreeing on limits and testing protocols for those specifications.  So long as the modified device remains within those limits, no new 510(k) would be required.  FDA indicates that it would like to discuss the feasibility of this approach with industry, and how it might be implemented.  It also states that this approach would not apply to changes to intended use or labeling, “as those aspects of a device are not associated with specifications.”

Based on information provided in the notice, it appears that this approach may be quite burdensome for manufacturers and reviewers.  FDA states that, in an initial 510(k) submission, manufacturers would have to identify the following information:  a list of potential changes that might be made; critical specifications for each change, i.e., those specifications “that are essential to safe and effective use of the device (e.g., tensile strength)”; bounds for those specifications within which a modified device must remain; and the verification and validation test protocols that will be used to examine the specifications pre- and post-modification.  Providing this information would require a significant amount of work by sponsors, and raise new issues for FDA reviewers.

Given the above, FDA is seeking input on the following questions:

1. How could critical specifications be incorporated into the review process?  For example, if FDA and the sponsor cannot agree on the critical specifications, but FDA is otherwise prepared to proceed with a substantial equivalence decision, how should that be handled?
2. How could critical specification agreements be documented?
3. Should use of critical specifications be limited to certain types of changes?  If so, which ones?
4. Are there certain specifications that could be deemed critical for all devices?  If so, which ones?
5. Could critical specifications be implemented as an optional paradigm, meaning that manufacturers could elect to use it where convenient, and if not elected, the change would remain subject to the 510(k) modifications decision-making paradigm?

D. Risk-Based Stratification of Medical devices for 510(k) Modifications Purposes

Under this framework, FDA would expect 510(k)s for modifications of higher risk devices that meet the standard in 21 C.F.R. § 807.81(a)(3), whereas for lower risk devices, not all modifications would require a 510(k) even if they meet the regulatory standard.  Certain modifications, such as a change in intended use, would always require a 510(k), regardless of the level of risk of the device.  FDA has the following questions about this approach:

1. How should FDA designate higher or lower risk devices?  Are higher risk devices only those designated as life sustaining, life supporting, or implants?
2. Should FDA require some other measure, such as periodic reports, in lieu of 510(k) submissions for lower risk devices?
3. How should FDA determine which modifications to lower risk devices require 510(k) submissions and which do not?

E. Periodic Reporting

FDA is seeking feedback on the submission of periodic reports for modifications to 510(k)-cleared devices that did not require a new 510(k) submission.  FDA acknowledges that this would “be similar to annual reporting of device changes for approved class III devices.”  It also states that FDA would review these changes to “ensure that decisions were made appropriately.”

FDA would like feedback regarding:

1. How often FDA should require periodic reports?
2. Should FDA require periodic reports for all 510(k) devices or only certain devices?  If only certain devices, which ones?
3. What information should be included in a periodic report?

This seems like an option that probably would not appeal to industry as crafted, as it would be imposing an additional obligation not currently required by the regulations.  Moreover, it would almost certainly lead to second-guessing “no-file” decisions.  If FDA and industry can work to clearly delineate when a new 510(k) is required for a modified device, there should be no need for FDA to review information about modifications that do not fit that paradigm.

Given the negative industry response to the July 2011 draft guidance, industry should take advantage of this opportunity to work with FDA to design a modifications paradigm that will meet the regulatory requirements without imposing burdens unnecessary to assure the development and marketing of safe and effective medical devices and enable further product improvements.

The issue of 510(k) modifications is both recurring and important.  This public meeting will not be the final word.  Still, it provides an important forum for responding to some novel ideas that have been broached by FDA.

On May 4, 2013, Hyman, Phelps & McNamara, P.C. Director Jeffrey K. Shapiro presented a draft paper and slides on the 510(k) medical device substantial equivalence program during a conference on FDA in the 21st Century.  The conference was held at the Harvard Law School’s Petrie-Flom Center for Health Law Policy, Biotechnology, and Bioethics (see our previous post here).  The draft paper argues that the 510(k) program is an excellent approach to the premarket review of medium risk medical devices, and has strengths that critics have overlooked.

The draft paper can be found here.  The slides presented on May 4 are available here.