By Ricardo Carvajal –

FDA’s issuance of a draft guidance for industry titled Substantiation for Structure/Function Claims Made in Infant Formula Labels and Labeling marks the first issuance of a guidance that addresses structure/function (SF) claim substantiation for a conventional food.  As FDA explains in the guidance, the agency regards SF claims for conventional foods to be narrower in scope than SF claims for dietary supplements because the former derive from the FDCA’s definition of “drug” and case law interpreting that definition – and should therefore “derive from the product’s character as a food.”  Notwithstanding that narrower scope, the agency “intends to apply the ‘competent and reliable evidence’ standard for the substantiation of infant formula claims in a manner that is consistent with FTC’s and FDA’s approach for the substantiation of dietary supplement claims.”  As flagged by the title of the guidance, FDA can be expected to apply the competent and reliable evidence standard not just to claims featured on a label, but also those featured on other materials that the agency views as falling under the broad umbrella of labeling.

Although the guidance is directed to infant formula – a product category subject to especially close regulatory scrutiny – the guidance should be reviewed by any marketer of conventional food. The guidance sets forth an analytical framework that will be familiar to those who track FDA and FTC’s approach to substantiation of other types of health-related claims.  The guidance signals a preference for at least two “independent, well-conducted studies.”  Further, in determining whether a claim is adequately substantiated, the guidance recommends “the use of a systematic evidence-based review process for evaluating the strength of the evidence.”  The guidance describes the steps involved in that type of evaluation, and points to the agency’s approach to evaluating health claims as one of several examples of that approach.

As described in the guidance, an evidence-based review gives preference to well-conducted feeding intervention studies as the “most direct evidence for a cause-and-effect relationship.” Other types of studies “can provide supportive evidence.”  Seriously flawed studies should be weeded out (e.g., those that don’t comply with subject protection requirements, target a different population, fail to use “recognized and accepted” endpoints, and/or lack adequate statistical power).  Also deserving of exclusion are studies that fail to meet certain quality criteria.  Then, the totality of evidence should be evaluated, with sensitivity to the fact that statistically significant differences “may not be clinically significant,” and with an eye toward whether there exist conflicting results that demand a plausible explanation.  In the end, the question of “whether the totality of the evidence reaches the substantiation standard of competent and reliable scientific evidence” should turn on the following factors listed in the guidance:

• What are the individual study’s strengths and weaknesses? For example, consider the quality of the study and the peer review.
• If multiple studies exist, do the studies that have the highest quality suggest a particular outcome?
• If multiple studies exist, what do most studies suggest or find? Does the totality of the evidence agree with the claim(s)?
• Do other study designs that are limited in their usefulness to substantiate a structure/function claim in infant formula labeling provide additional supportive evidence for a claim?

Comments on the guidance should be submitted by November 8.

FDA issued another guidance (this one in final form) directed to labeling of infant formula generally.  That guidance appears to have been motivated in part by the agency’s concern over different products bearing “the same or similar statements of identity,” and “increased use of nutrient content claims that render a product misbranded.”  The guidance discusses why a statement of identity such as “Infant Formula” might not be adequate for a “Soy-Based Infant Formula Powder,” or a “High Protein (3.5g protein per 100 calories) Milk-Based Infant Formula Powder for Premature and Low Birth Weight Infants.”  The guidance also reminds industry that the range of nutrient content claims permitted for infant formula is limited, and that health claims and qualified health claims must conform to conditions established by the agency.

By JP Ellison & Wes Siegner –

There are 12 pages of FDA forms on the FDA website covering everything from product topics (foods, drugs, cosmetics, etc.) to safety forms and FDA field operations forms.  Unless we missed it, one of FDA’s newest forms isn’t on its website.  It’s a form that FDA’s Office of Criminal Investigation (OCI) has apparently begun using in connection with investigations of  drug sales and distribution in the U.S.  As we understand it, OCI’s new “Acknowledgment” form is presented by OCI special agents who personally visit establishments, advise the operators to immediately stop allegedly illegal conduct and request that a responsible person sign the form, which is then co-signed by the special agent.

It is not clear how or why FDA OCI agents are using this form; and to date, our attempts to learn more have not been successful. Nor do we have any sense of how this form relates to FDA’s Regulatory Procedures Manual, Investigations Operations Manual, or its unapproved drug guidance.  We speculate that OCI may be using this form in an attempt to quickly shut down distribution of allegedly  illegal drug sales by drug establishments in situations where OCI does not believe that the persons or entities at the establishment are distributing the products with knowledge that they are “illegal.” Our advice to anyone presented with this form, or any other FDA form; such as “FDA Affidavits,” which are routinely presented in the context of FDA inspections, is to consult with counsel.  By way of example only, the Acknowledgment form asserts that entities and individuals that received adulterated and misbranded drugs, or delivered such drugs violate the laws, can face criminal penalties.  The form omits any discussion of Section 303(c) of the Act (21 U.S.C. 333(c)), which specifically states that the penalties of section 303(a)(1) of the Act (21 U.S.C. 333(a)(1)) do not apply in certain circumstances. While one can understand why OCI might want to utilize such a form to achieve “voluntary” compliance, regulated persons and entities should think carefully about the consequences of signing this form.

By Serra J. Schlanger & Alan M. Kirschenbaum –

For 25 years, drug and device manufacturers and their customers have relied on the discount safe harbor under the Federal health care program antikickback statute (“AKS”) to protect procompetitive discount arrangements that save money for purchasers, patients, and payors, including government programs like Medicare and Medicaid. Unfortunately, a recent opinion from the Federal District Court for the District of Massachusetts eviscerates the safe harbor, rendering it virtually useless – at least in that jurisdiction.

On August 23, 2016, Judge Rya Zobel denied Omnicare, Inc.’s motion for summary judgment in the ongoing qui tam case, United States ex rel. Banigan v. Organon USA, Inc., et al. (Case 1:07-cv-12153-RWZ).  In their complaint, filed on September 13, 2007, the relators allege that Omnicare, a long-term care pharmacy chain, violated the Federal False Claims Act by soliciting and/or receiving kickbacks from drug manufacturer Organon for Remeron prescriptions and by submitting kickback tainted claims to Medicaid.  According to the relators, Omnicare purchased Remeron through membership in several group purchasing organizations (“GPOs”).  Organon offered various GPOs market share rebates on Remeron in exchange for the GPOs promoting the potential benefits of the agreement to their member pharmacies in order to increase Remeron’s market share.  The relators also allege that Omnicare entered into a direct purchasing agreement with Organon that followed the same pattern: the pharmacy accepted a volume-based discount in exchange for a promise to promote the agreement’s potential financial benefits to its clients.  Although the United States and 28 states declined to intervene in the case, the litigation is continuing towards trial.

In a motion for summary judgment, Omnicare argued, among other things, that the discounts were protected by the AKS’ statutory discount exemption and the regulatory safe harbor for discounts promulgated by the Office of the Inspector General (“OIG”) of the Department of Health and Human Services (“HHS”). Pursuant to the statutory exemption, the AKS’ prohibition against unlawful remuneration shall not apply to “a discount or other reduction in price . . . if the reduction in price is properly disclosed and appropriately reflected in the costs claimed or charges made by the provider or entity under a Federal health care program.”  42 U.S.C. § 1320a-7b(b)(3()A).  The regulatory safe harbor protects discounts received by charge-based providers if the discounts are “made at the time of the sale,” are “fixed and disclosed in writing . . . at the time of the initial sale,” and if the provider furnishes documentation of both the discount and the provider’s awareness of its obligation to report the discount “upon request by the Secretary or a State agency”.  42 C.F.R. § 1001.952(h)(1)(iii).

Judge Zobel found that Omnicare was able to satisfy the first requirement of both the statutory exemption and the regulatory safe harbor because the GPO and direct purchase contracts contained and disclosed all of the terms of the agreements between Omnicare and Organon. However, Judge Zobel determined that Omnicare could not satisfy the second element of either the statutory exemption or the regulatory safe harbor.  With regards to the statutory exemption, Judge Zobel stated “Omnicare has offered not an iota of evidence that the discounts were reflected at all, much less ‘appropriately,’ in its charges to Medicaid.”  Judge Zobel’s conclusion ignores the fact that there is no established mechanism for charge-based providers, including long-term care pharmacies, to identify their costs or the discounts they receive in the claims they submit to Medicaid for pharmaceuticals.  The OIG long ago removed a requirement that charge-based providers disclose the amount of discounts on claims submitted to Federal programs.  64 Fed. Reg. 63518, 63529 (Nov. 19, 1999).

Even more puzzling and of more concern, Judge Zobel found that Omnicare could not satisfy the second element of the regulatory safe harbor because Omnicare had not “made the relevant disclosures pursuant to a governmental investigation, as . . . no such investigation took place during the relevant time period.” Although Omnicare testified that the company would have provided the requisite information had a governmental agency requested it, Judge Zobel concluded that “government action [is] a necessary condition” for the regulatory safe harbor.

Judge Zobel’s interpretation is inconsistent with the OIG’s intent in establishing this disclosure requirement. In the 1991 Final Rule setting forth the regulatory safe harbor for discounts, the OIG stated that “if the Secretary or a State Medicaid agency requests information, the buyer must provide the appropriate invoices from the seller.” 56 Fed. Reg. 35,952, 35,979 (July 29, 1991) (emphasis added).  The OIG does not suggest that the government must request information in order for the safe harbor to apply.

Judge Zobel’s Opinion illogically concludes that buyers receiving discounts must meet a condition that is out of their control in order to qualify for protection under the regulatory safe harbor: they must first be asked by the government for discount information, and then they must provide the information.  Under Judge Zobel’s interpretation, the safe harbor is of negligible utility.  Buyers do not have control over whether HHS or state Medicaid agencies may initiate an investigation or other request for documentation that Judge Zobel indicates is a “necessary condition” of the safe harbor, and an infinitesimal proportion of all buyers receive such requests.  Based on the OIG’s 1991 explanation, the regulation clearly was intended to require buyers to provide discount documentation only if it is requested by the government.

Omnicare has filed a motion requesting that the Court reconsider Judge Zobel’s Order or alternatively certify the matter for immediate review by the First Circuit.  We are hoping for a more reasoned decision upon reconsideration or appeal.  We will keep our readers informed about this litigation.

By Allyson B. Mullen –

As our blog readers know, the 510(k) Third Party Review Program has been a bit of a flop in terms of utilization and clearance times (see our previous post here). In Fiscal Years 2013, 2014, and 2015, only 3.2%, 2.2%, and 2.3% of 510(k)s were reviewed by third parties, respectively. See FDA, MDUFA III (FY 2013-2017) Performance, 189, 191, 193 (May 2, 2016).  Needless to say, when we saw FDA published a new draft guidance on the third party review program, we were cautiously optimistic that FDA proposed changes to make the program more useful. Our excitement was short-lived. 

The draft guidance is a combination of the 2013 draft guidance entitled “Accreditation and Reaccreditation Process for Firms under the Third Party Review Program: Part I” and the 2004 final guidance “Third Party Review of Premarket Notifications.” The draft guidance is organized in two parts: content regarding the third party review process; and content regarding the authorization and reauthorization of third party reviewers.  The draft guidance also states that it is consistent with the International Medical Device Regulators Forum’s (IMDRF) guidance, to the extent the IMDRF’s guidance is consistent with the FDCA.

The draft guidance outlines the mechanics of the third party review process (previously found in the 2004 final guidance). This content has been updated to reflect recent FDA 510(k) processes, including suggesting that third party reviewers perform an administrative review of 510(k)s utilizing the 510(k) Refuse-to-Accept Checklist, and requiring third party reviewers to comply with FDA’s eCopy Guidance.  The draft guidance also references the Pre-Submission Program stating that the third party reviewer need not be involved in Pre-Submission discussions prior to the 510(k) submission, but the third party reviewer should request that 510(k) applicants inform the third party reviewer of all prior communication with FDA regarding the subject device.  The draft guidance also recommends that the third party reviewer attend Submission Issue Meetings with FDA and the submitted for third party reviewed 510(k)s.  The sections of the draft guidance regarding the program and review process are, however, otherwise the same as in the 2004 guidance.  With no procedural changes, it is doubtful that this guidance will have much (if any) effect on the usefulness of the third party review program. 

The draft guidance proposes significant changes to the accreditation and reaccreditation requirements previously contained in the 2013 draft guidance. Interestingly, there were zero comments to the 2013 draft guidance, however, FDA still considered this major overhaul three years later.  Most notably, the initial accreditation process requires applicants to provide information regarding prevention of conflicts of interest and personnel qualifications.  It is possible that FDA has been requiring this information from applicants during the accreditation process, but it was not mentioned in the 2013 draft guidance.  With these seemingly new requirements for accreditation, we wonder if even fewer new organizations will be able to meet—or try to meet—the standards to become third party reviewers.  The reaccreditation process will utilize the new accreditation information requirements.  Therefore, it is also possible that some third party reviewers may not be able to retain their certification under the apparently more arduous accreditation requirements. 

In short, although we had hoped that the new draft guidance would signal improvements to the 510(k) third party review program, it appears not much has changed, and in fact, it may be more difficult to bring new third party reviewers into the program.

By Kurt R. Karst –

What a difference a few precedents can make! In a rather surprising turn of events, Judge Rudolph Contreras of the U.S. District Court for the District of Columbia issued a Memorandum Opinion last Friday granting a Motion for Reconsideration filed by Ferring Pharmaceuticals Inc. (“Ferring”) requesting reconsideration of the DC District Court’s March 15, 2016 ruling that FDA’s pre-October 10, 2014 interpretation of the FDC Act’s five-year New Chemical Entity (“NCE”) exclusivity provisions as applied to a newly approved Fixed-Dose Combination (“FDC”) drug product containing an NCE and a previously approved drug – and specifically, to Ferring’s PREPOPIK (sodium picosulfate, magnesium oxide, and citric acid) for Oral Solution (NDA 202535; approved on July 16, 2012) – was not arbitrary and capricious.  Judge Contreras also denied as moot Renewed Motions for Summary Judgment filed by Ferring and FDA (here and here) and a Motion to Intervene and Motion for Summary Judgment filed by proposed intervenor (and ANDA applicant) Par Pharmaceutical, Inc. (“Par”).

As we previously reported (here and here), a lot of events led up to FDA’s denial of NCE exclusivity for PREPOPIK, and to Ferring’s June 2015 lawsuit against FDA. In fact, like a lot of recent controversies involving NCE exclusivity (see, e.g., here), the seeds for Ferring’s lawsuit were sown in the early years after the enactment of the Hatch-Waxman Amendments in the Agency’s proposed and final regulations and in cases like Abbott Labs. v. Young, 920 F.2d 984 (D.C. Cir. 1990) (here). 

If a drug product contains any previously approved active moiety (i.e., if it is not composed of all NCEs), then FDA historically denied NCE exclusivity and granted 3-year exclusivity, provided the statutory requirements were met.  Up until October 2014, this meant that order counted, and that to obtain NCE exclusivity for a FDC drug product containing new and old actives, the NCE component must have been approved first, followed by the combination drug.  In that case, NCE exclusivity granted with respect to the single entity approval applied to the combination drug under FDA’s so-called “umbrella policy,” as FDA articulated in the preamble to the Agency 1989 proposed rule implementing the Hatch-Waxman Amendments.  See 54 Fed. Reg. 28,872, 28,898-99 (July 10, 1989) (“[T]he agency interprets [5-year NCE exclusivity] to cover any subsequent approval of an application or supplemental application for a different ester, salt, or other noncovalent derivative, or a different dosage form, strength, route of administration, or new use of a drug with the same active moiety. Any modification to the product will be protected for the period of exclusivity remaining on the original application, unless the change occurs after or toward the end of the initial 5 years of exclusivity and independently qualifies for exclusivity under another exclusivity provision.”).

On October 10, 2014, after the Agency had received several citizen petitions challenging the Agency’s interpretation of the FDC Act’s NCE exclusivity provisions with respect to certain FDCs (including PREPOPIK), FDA released on the Agency’s website a final guidance document (see our previous post here) reinterpreting the statutory NCE exclusivity provisions to award NCE exclusivity for a newly approved FDC drug product containing an NCE and a previously approved drug.  As summarized by Judge Contreras in his March 2016 Memorandum Opinion:

[P]rior to 2014, the FDA interpreted the five-year exclusivity provision to provide that only drug products containing no previously approved drug substances were eligible for exclusivity.  Once eligible, however, the FDA interpreted the bar clause to bar all ANDAs and 505(b)(2) applications referencing that drug product or any later-approved products containing the product’s drug substances, in order to preserve the innovator’s exclusivity to the greatest extent possible. [(Emphasis in original)]

But, as emphasized above, and as explained in FDA’s guidance document and in various Citizen Petition Responses (see, e.g., here), FDA refused to apply the Agency’s new interpretation to NDAs for FDCs approved prior to October 2014.  Sponsors of NDAs for pre-October 2014 FDC drug products were out of luck – or so it seemed – and would be subject to the “old rules” on NCE exclusivity eligibility, according to FDA.

Enter Ferring’s June 2015 lawsuit against FDA, in which Ferring alleged that FDA’s actions violated the Administrative Procedure Act (“APA”), the FDC Act, and the Agency’s regulations. Specifically:

First, Ferring contends that the FDA’s prior interpretation, under which PREPOPIK was denied five-year exclusivity, contravened the plain language of the FDCA. Second, Ferring argues that, even if the language of the FDCA is ambiguous, the FDA’s interpretive choice to read “drug” in the eligibility clause to mean “drug product” was an unreasonable reading of the statute or was arbitrary and capricious because it treated similarly situated parties differently. Finally, Ferring claims that, even if the FDA’s prior interpretation was permissible, its decision not to apply the new interpretation retroactively was arbitrary and capricious.

Reviewing the case under the familiar Chevron analysis, Judge Contreras considered the term “drug” in the FDC Act’s NCE exclusivity provisions to be ambiguous, thus requiring an evaluation of FDA’s pre-October 2014 interpretation of the statute under Step Two of the Chevron inquiry.  The bottom line, said Judge Contreras in his March 2016 Memorandum Opinion, is that FDA’s interpretation is reasonable:

As a result of the statute’s ambiguity, the FDA was left to determine at what level of specificity to define “drug”: at the “drug product” level, and in reference to all of the product’s “drug substances,” or at the “drug substance” level. Although scientific and policy considerations may have now persuaded the FDA to modify its interpretation, given the statutory ambiguity and the considerations discussed above, it was neither unreasonable nor arbitrary and capricious for the FDA to define “drug,” in the “eligibility clause” as “drug product,” and to thereafter ensure the greatest benefit for pharmaceutical manufacturers who are provided with exclusivity by interpreting “drug” in the “bar clause” as “drug substance.” Therefore, Ferring’s Chevron Step Two argument fails.

That decision left remaining Ferring’s argument that FDA acted arbitrarily and capriciously when the Agency decided not to apply the Agency’s October 2014 reinterpretation retroactively, and only prospectively, thereby denying NCE exclusivity for PREPOPIK. On that issue, Judge Contreras said that he needed more from the parties, and directed FDA and Ferring to file renewed Motions for Summary Judgment “that more fully address the retroactivity issue. . . .” Meanwhile, Par, which submitted an ANDA to FDA on May 21, 2014 containing a Paragraph IV certification to a patent listed in the Orange Book for PREPOPIK, sought to intervene in the case. 

Ferring, in the company’s Motion for Reconsideration, latched on to one “out” offered up by Judge Contreras in his March 2016 ruling. Judge Contreras conceded that “[i]f there were, in fact, situations in which a drug was eligible for five-year [NCE] exclusivity under the FDA’s prevailing interpretation but failed to receive it because of the order in which it was approved, those circumstances might render the FDA’s policy arbitrary and capricious.”  According to Ferring, “there were indeed drug products that were denied NCE exclusivity precisely because of the order in which they were approved” . . . . and some those drug products, like PREPOPIK, were also the subject of Citizen Petitions submitted to and ruled on by FDA.   In addition to PREPOPIK, Ferring points to STRIBILD (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) Tablets (Docket No. FDA-2013-P-0058), NATAZIA (estradiol valerate and estradiol valerate/dienogest) Tablets (Docket No. FDA-2013-P-0471) (see our previous posts here and here), ANORO ELLIPTA (umeclidinium bromide; vilanterol trifenatate), and NUVARING (ethinyl estradiol; etonogestrel) as examples that “demonstrate that a single-entity drug substance’s ability to receive five-year exclusivity can turn arbitrarily on the order in which NDAs including that drug substance are approved.”  STRIBILD in particular, says Ferring, “exemplifies the arbitrariness of FDA’s NCE exclusivity policy.”

With these precedents in hand, Judge Contreras now had the ammunition necessary to find FDA’s pre-October 2014 interpretation of NCE exclusivity, as applied to PREPOPIK, to be arbitrary and capricious and in violation of the APA.

In its prior Memorandum Opinion, the Court believed that the sequence Ferring identified was simply a necessary outgrowth of the FDA’s umbrella policy: that is, manufacturers generally developed a new, novel drug substance, obtained approval of that drug substance in a single-entity version, and then sought protection under the umbrella policy for any later drug products which incorporated that novel drug substance with other, previously approved drug substances. . . . it appeared to the Court that the FDA was not treating similarly situated drug substances differently and that there did not exist examples in which the temporal sequence of drug product approvals was outcome determinative. . . .

In its motion for reconsideration, however, Ferring now provides three examples that lead the Court to doubt the factual basis for its prior conclusion. In each instance, a drug substance that had never been previously approved was included as part of a fixed-combination drug product (a fixed-combination drug product that did not receive five-year exclusivity because it contained other, previously approved drug substances).  And, in each case, a single-entity version of the drug substance was later approved, but did not receive the benefit of a five-year exclusivity period, because the drug substance had been previously approved as part of the fixed-combination product. . . .

These newly highlighted examples now show that, even if the FDA’s prior interpretation is reasonable under Chevron Step Two from a conceptual standpoint, that interpretation produces circumstances that fail to treat “similar cases in a similar manner.” [(Internal citations omitted)]

Thus, ruled Judge Contreras, “FDA’s prior interpretation was arbitrary and capricious,” and Ferring’s initial Motion for Summary Judgment should have been granted. Accordingly, Judge Contreras remanded the action to FDA for further proceedings consistent with his Memorandum Opinion. 

Where do we go from here?  We’ll see . . .  eventually.  After surveying the landscape of affected drugs (as well as ANDA submissions), FDA (or Par) could appeal the decision to the U.S. Court of Appeals for the District of Columbia Circuit, or render a new decision on remand denying NCE exclusivity but that somehow still adheres to Judge Contreras’s decision.   Alternatively, FDA could accept the District Court’s decision, grant NCE exclusivity to PREPOPIK and similarly situated NDA sponsors, and deal with the ANDA fallout.

By Riëtte van Laack –

Last week, FDA announced its final rule regarding over-the-counter (OTC) consumer antiseptic wash products.  As we reported in 2013, FDA issued a proposal to declare all antimicrobial consumer hand wash products as not generally recognized as safe and effective but invited comments to prove that they were.  Notably, the Agency questioned whether there was any benefit of using these products as compared to soap and water. 

Not surprisingly, FDA has concluded that antimicrobial hand wash products containing any one of 19 active ingredients are not generally recognized as safe and effective; “manufacturers did not demonstrate that the ingredients are both safe for long-term daily use and more effective than plain soap and water in preventing illness and the spread of certain infections.”  Therefore, they may no longer be marketed.

FDA deferred action for three active ingredients, i.e., benzalkonium chloride, benzethonium chloride, and chloroxylenol (see FDA letters here, here, and here). In response to comments, FDA decided to “allow for the development and submission of new safety and effectiveness data to the record for these [three] ingredients”

In the final rule as well as in the press release, FDA clarifies that its determination applies only to consumer antiseptic wash products comprising a variety of personal care products intended to be used with water, which may be used by consumers for personal use in the home and in certain public settings on a frequent, even daily, basis.  This final rule does not apply to “leave-on” consumer hand sanitizers (rubs), health care antiseptics, first aid antiseptics, and antiseptics for food industry use.

Based on the comments, it appears that the proposed rule had created uncertainty as to the inclusion of antiseptic for use by the food industry. In the final rule, FDA in no uncertain terms confirms that it considers such products as a separate category:  “A separate category is warranted because of additional issues raised by the public health consequences of foodborne illness, differences in frequency and type of use, and contamination of the hands by grease and other oils.”  FDA will address these products in future rulemaking.

The final rule is effective 1 year after it was issued, i.e., September 6, 2017.

By John A. Gilbert, Jr. & Larry K. Houck –

This is third in a series of in-depth reviews of the Drug Enforcement Administration’s (“DEA’s”) and other federal agencies’ recent decisions/notices on marijuana and industrial hemp issued on August 12, 2016. Previously, we reviewed DEA’s policy expanding the number of marijuana cultivators for research and the agency’s denial of petitions to reschedule marijuana from schedule I in depth (see our previous posts here and here). This analysis focuses on the joint statement by the United States Department of Agriculture (“USDA”)/DEA/Food and Drug Administration (“FDA”) on industrial hemp principles under the Agricultural Act of 2014.

The USDA, in consultation with DEA and FDA, issued a Statement of Principles on how individuals, universities and states can participate in industrial hemp pilot programs in compliance with the Agricultural Act of 2014. Statement of Principles on Industrial Hemp, 81 Fed. Reg. 53,395 (Aug. 12, 2016). The notice acknowledged that while the states were authorized to conduct pilot programs under the law, the Act failed to provide a “specific delegation to the [USDA] or any other [federal] agency to implement the program.” Id. The notice also conceded that the Act “left open many questions” on the continued application of the federal Controlled Substances Act (“CSA”) to industrial hemp particularly related to private parties’ cultivation and sale of such products. Id. The Statement of Principles, while not establishing any binding legal requirements, is intended to “inform the public” on how Federal law applies to industrial hemp under state agricultural pilot programs. Id.

It is worth reviewing the current federal definitions relevant to industrial hemp. Under the 2014 Act, industrial hemp is the Cannabis sativa L. plant and any part of the plant, with a delta-9 tetrahydrocannabinol (“THC”) concentration of not more than 0.3% on a dry weight basis. 7 U.S.C. § 5940(b)(2). Under the CSA, THC is controlled as a schedule I substance. 21 U.S.C. § 812(c)(a)(c)(17). Thus, products containing any quantity of THC, including hemp, are schedule I substances. However, regulations promulgated by DEA exempt certain products that contain THC from control if (1) they are made from certain parts of the Cannabis plant (including the mature stalks, fiber from such stalks, oil or cake made from the seeds of the plant, and sterilized seeds incapable of germination and (2) if they are not intended for human consumption. 21 C.F.R. § 1308.35(a). Industrial hemp containing THC can be used in a wide range of paper, rope, clothing, textiles, shampoo, soap, body lotion and animal feed products.

The USDA emphasized that the 2014 Act did not amend the Food, Drug, and Cosmetic Act related to approval of new drug applications nor did it alter the requirements of the CSA related to the manufacture, distribution or dispensing of substances derived from the Cannabis plant. Statement of Principles at 53,396. So, what is authorized under the 2014 Act?

According to the USDA/DEA/FDA Statement of Principles, the 2014 Act limits the cultivation of industrial hemp to agricultural pilot programs for research meaning “to study the growth, cultivation, or marketing of industrial hemp established by a State department of agriculture or State agency responsible for agriculture” where industrial hemp production is legal under state law. Id. at 53,395. State pilot programs must register and certify industrial hemp cultivation sites, with registrations to include the manufacturer’s name, licensure period that the state authorizes the activity, and the location. Id. The Statement of Principles restricts industrial hemp cultivation to state departments of agriculture and persons authorized by them to conduct research under a pilot program, as well as universities, or persons employed by or under contract or lease with universities to conduct research. Id. Over 30 states have established industrial hemp research or pilot programs that authorize hemp industry studies or commercial industrial hemp programs. State Industrial Hemp Statutes, National Conference of State Legislatures.

The Statement of Principles state that the sale of industrial hemp products is restricted within states or among states with pilot programs for marketing research by universities or state departments of agriculture. Id. Industrial hemp products cannot be sold for “general commercial activity” and cannot be sold in states that prohibit such sales. Id. Industrial hemp plants and seeds cannot be transported across state lines. Id. The Statement of Principles further note that although the law authorizes certain entities to cultivate industrial hemp, only DEA-registered importers can import viable cannabis seeds and USDA phytosanitary requirements that apply to plant material also apply to the importation of industrial hemp seed. Id. at 53,395-96.

So, in looking at the three recent notices related to marijuana, it is clear that the federal government is clarifying and removing previous obstacles related to research involving marijuana. The government’s actions encourage responsible research of hemp as an agricultural commodity and industrial product in states where it is allowed. Registration with a state department of agriculture (for industrial hemp under pilot programs) and DEA (marijuana for research) are critical components of the government’s regulatory scheme. Interestingly the Statement of Principles requires registration of industrial hemp cultivation sites by a state’s department of agriculture rather than a controlled substance authority or law enforcement agency. We anticipate the federal government incorporating registration as well as recordkeeping, reporting, inspections and plant testing into its regulatory regimen to closely regulate marijuana and industrial hemp as private entities outside the states become involved in research, cultivation, manufacturing and distribution activities with those substances.

One cannot help concluding, when considering the recent marijuana and industrial hemp decisions together, that the federal government is trying to find a way to maintain its authority in the face of a growing majority of less restrictive state laws. These measures may help minimize some aspect of the federal/state conflict in the short run, especially in encouraging research. However, there will be no reconciliation of state and federal law until the ultimate question is resolved: whether marijuana has a legitimate medical use.

By Wes Siegner –

After 20 years of marketing vinpocetine, and accepting without objection the filing of 5 new dietary ingredient notifications (NDINs), FDA has “tentatively concluded” that vinpocetine is an illegal dietary ingredient for two reasons: 1) it does not fit within the statutory list of dietary ingredient types in FDC Act § 201(ff)(1)(A)-(F); and 2) it is excluded from legal dietary ingredient status as a result of drug studies in the mid 1980s pursuant to FDC Act § 201(ff)(3). From any perspective, this is an important development for the dietary supplement industry.

Coming on the heels of several rounds of warning letters over the past 18 months to remove BMPEA, picamilon, and oxilofrine from the market, as well as FDA’s attempted rewrite of the draft NDI guidance (see our previous post here), FDA’s approach to vinpocetine reflects an as yet uncharted path for ingredient removal – notice to industry and a request for comments on an FDA “tentative conclusion.” It is not clear what initiated FDA’s action — FDA may have received information from a drug company wishing to pursue marketing of vinpocetine in the U.S.  What is clear is that, without a strong response, FDA intends to remove vipocetine from the dietary supplement market.

FDA’s first reason for its tentative conclusion of illegality is based on FDA’s narrow reading of the list of types of dietary ingredients in FDC Act § 201(ff)(1)(A)-(F) asexclusive, rather than inclusive. This theory has been presented in warning letters as well as FDA’s first draft of the NDI guidance in July 2011.  As this firm and others have stated in comments (see our previous post here), FDA has interpreted the list of types to exclude synthetic copies of botanical ingredients, and more important from a limiting standpoint, to exclude any ingredient that is not already marketed as an ingredient in food.  This turns on its head the flexibility Congress intended to provide to dietary supplement marketing through the Dietary Supplement Health and Education Act of 1994 (DSHEA), effectively precluding the marketing of any truly “new” dietary ingredients. 

FDA’s second basis rests on the statutory prohibition of the marketing of ingredients first studied as drug ingredients “where substantial clinical investigations have been instituted and for which the existence of such investigations has been made public” (FDC Act § 201(ff)(3)). This theory will require further research to determine whether the facts as FDA presents them trigger the so-called “exclusionary clause.”  All we can ask now is, if these facts are so clear and so easily known, then how have they escaped FDA’s and industry’s notice for 20 years?

Recall that DSHEA passed with unanimous consent in both houses of Congress as a result of FDA’s having exceeded its statutory authority to limit the dietary supplement market through the rules for conventional food ingredients in ways that the courts, Congress and consumers found unacceptable. FDA’s move on vinpocetine should help wake industry up to the danger that FDA’s new (but not much revised) NDI draft guidance presents. If FDA’s narrow construction of DSHEA as illustrated in the 2011 and 2016 drafts of the NDI guidance and the vinpocetine notice prevails, FDA will succeed in relegating many dietary ingredients in dietary supplements to a more limited market than for conventional foods. 

Vinpocetine is but a symptom of a bigger struggle, but a symptom that nonetheless deserves the best defense that the industry can offer.

By Kurt R. Karst –      

Last week, Elliott Associates, L.P., Elliott International, L.P. and Knollwood Investments, L.P. (collectively “Elliott”), a hedge fund with investment interests in Takeda Pharmaceuticals U.S.A., Inc.’s (“Takeda’s”) gout flare drug COLCRYS (colchicine) Tablets, 0.6 mg (NDA 022352), filed a Petition for Rehearing and/or Rehearing en banc with the U.S. Court of Appeals for the District of Columbia Circuit seeking reconsideration of a July 2016 Per Curiam Judgment from a panel of DC Circuit Judges (Judges Kavanaugh, Wilkins, and Silberman) affirming a January 2015 ruling from DC District Court Judge Ketanji Brown Jackson. Judge Jackson upheld FDA’s September 26, 2014 approval of a 505(b)(2) application (NDA 204820) submitted by Hikma Pharmaceuticals LLC (“Hikma”) and its U.S. partner West-Ward Pharmaceutical Corp. (“West-Ward”) for MITIGARE (colchicine) Capsules, 0.6 mg, for prophylaxis of gout flares, which 505(b)(2) NDA did not cite COLCRYS as a listed drug (and thus did not include patent certifications to patents listed in the Orange Book for COLCRYS). 

As we previously posted (, here, , and ), Takeda and Elliott unsuccessfully sued FDA in October 2014 alleging that the Agency’s approval of MITIGARE violates the FDC Act and the Administrative Procedure Act (“APA”) in several respects, including that “FDA’s failure to require Hikma to reference Takeda’s own colchicine drug, Colcrys®, in its application interfered with Takeda’s rights to participate in the administrative process, including the Paragraph IV certification process under the Hatch-Waxman Act and the Citizen Petition process.”  On appeal, the DC Circuit panel concluded that as to the issue of whether or not Hikma should have certified to the COLCRYS patents listed in the Orange Book, the issue is moot because of the Delaware District Court’s decision, rendered outside of the Hatch-Waxman context, resolving the issue of patent infringement in favor of Hikma (see our previous post here).

Elliott contends in its Rehearing Petition that the case involves a question of “exceptional importance,” and that rehearing is warranted because “[t]he panel’s decision dismissing this appeal as moot conflicts with precedent from the Supreme Court and several courts of appeals regarding the proper application of the Hatch-Waxman Amendments . . . and the 30-month stay provision.” “After the District Court for the District of Delaware dismissed Takeda’s patent-infringement suit against Hikma, the panel dismissed this appeal as moot, citing the provision of the Hatch-Waxman Amendments that terminates the 30-month stay upon entry of a judgment of non-infringement only ‘[i]f the applicant made a certification’ to the innovator’s patents and the innovator subsequently sued ‘for infringement of the patent that is the subject of the certification,’” writes Elliott (emphasis in original).  “But here, Hikma never made the required certification and Takeda was precluded from bringing a Hatch-Waxman infringement suit.  The panel’s unprecedented decision departs from a uniform body of case law distinguishing between post-certification patent-infringement cases subject to the limitations of [FDC Act § 505](c)(3)(C), and non-certification patent-infringement cases like the Delaware Proceeding to which that provision does not apply” (emphasis in original).

For its part, Takeda filed a Partial Joinder in Elliott’s Rehearing Petition. “This Court has not expressly addressed the possibility that the judgment in the Delaware proceedings could be reopened,” writes Takeda.  “And the parties have not fully briefed the statutory question that would follow: whether an approval under 21 U.S.C. § 355(c)(3)(C)(i)(I) remains in effect if the district court itself withdraws an initial erroneous judgment of non-infringement” (emphasis in original). 

The American Conference Institute’s (“ACI’s”) Food Law Regulation Boot Camp is slated to take place at the InterContinental Chicago Magnificent Mile in Chicago, Illinois from November 15-16, 2016. The conference is billed as a way to “[c]onnect the dots of food regulatory law and gain a clear understanding of how the FDA, USDA and FTC work together to regulate the food industry.”

A stellar cast of presenters will share their knowledge and provide critical insights on a host of topics, including:

• Food ingredients and additives
• GRAS
• Labeling regulations
• Product labels including the new Nutrition Facts Label
• Marketing and advertising
• Food safety essentials and FSMA
• cGMPs
• Food imports
• Inspections
• Recalls

Hyman, Phelps & McNamara, P.C.’s Riëtte van Laack will be speaking at the conference in a session titled “An Overview of Food Labeling Laws, Regulations, and the Components of a Compliant Label.”

FDA Law Blog is a conference media partner. As such, we can offer our readers a special 10% discount. The discount code is: P10-999-FDAB17. You can access the conference brochure and register for the event here.  We look forward to seeing you at the conference.

Over the course of roughly the last year, gene editing has gone from being a topic limited to scientific conferences to being featured in the New York Times and on the cover of TIME magazine.  Most of the attention has been due to a molecular tool with an opaque name but simple acronym: clustered, regularly interspaced, short palindromic repeat (CRISPR) technology.  Despite all the attention that has come to CRISPR and gene editing in general, many legal questions linger; it is not immediately clear how the FDA and USDA will approach the regulation of various applications of this powerful technology.

In the feature article in FDLI’s July/August issue of Update magazine, titled “Ready or Not, CRISPR and Gene Editing Have Arrived and Are Here to Stay,” Hyman, Phelps & McNamara, P.C., attorneys Jay W. Cormier and Ricardo Carvajal provide a common understanding about gene editing and CRISPR and discuss potential applications of the technology as well as regulatory issues in the FDA and USDA arenas.

In recent years, the level of scrutiny on foreign pharmaceutical manufacturing facilities in countries like China and India has skyrocketed—along with the demand and dependence of western countries on the supply of goods coming from those facilities. Furthermore, increased enforcement aimed at the medical device industry and the safety and effectiveness of medical device production have become a key focus of global regulators.

With the latest updates to the global standard for medical device quality management systems and the proposed new EU Medical Device Regulations, device manufacturers, service providers, and supply chain partners will need to closely assess their product lifecycle risk management systems to ensure they are complying with requirements.

This webinar will discuss these recent pharmaceutical and medical device supply chain developments and what steps companies need to take to prevent and remediate compliance issues in the context of:

• The uptick in investigations in China and India.
• Speed vs. Safety: the approval process differences between the EU and U.S.
• Increased scrutiny of non-EU-based manufactures and requirements for importers and distributors.
• The potential impact of adverse regulatory actions against nonconforming facilities.
• Threats posed by bribery and corruption.
• Anti-corruption compliance issues from U.S. and Asian perspectives.
• “War stories” from recent investigations.

When

Wednesday, September 14, 2016
1:30 p.m. – 2:30 p.m. BST (8:30 a.m. – 9:30 a.m. EDT)

A recording of the webinar will be available to all registrants after the live event.

Where

This presentation will be simulcast via Webex as a webinar.  Please click here to register. 

Speakers

Douglas B. Farquhar
Director
Hyman, Phelps & McNamara PC
Washington, D.C.

Mark I. Schwartz
Of Counsel
Hyman, Phelps & McNamara PC
Washington, D.C.

Jeremy B. Zucker
Partner
Dechert LLP
Washington, D.C.

Lewis Ho
Partner
Dechert LLP
Hong Kong

Kareena Teh
Partner
Dechert LLP
Hong Kong

Sophie Pelé
Associate
Dechert LLP
Paris

Application for accreditation of this program for Continuing Professional Development (CPD) in the United Kingdom is currently pending.  Application for accreditation of this program for Continuing Legal Education (CLE) in California, Massachusetts, New Jersey, and New York is currently pending. 

For questions, please contact Reiko Tate (reiko.tate@dechert.com).

By Anne K. Walsh & Andrew J. Hull –

FDA announced in an August 31, 2016 notification (“Notification”) that it will convene a public hearing to address its authority to regulate communications regarding unapproved uses of approved or cleared drugs and medical devices. The public hearing will take place on November 9 and 10, 2016, and FDA will take written comments from those unable to attend the hearing until January 9, 2017.

This public hearing comes in the midst of an ongoing debate between FDA and industry surrounding FDA’s authority to restrict the speech of drug or medical device manufacturers related to the unapproved or “off-label” use of their otherwise approved or cleared products. We have posted regularly on these developments, particularly in light of FDA’s significant losses in cases where it has attempted to regulate companies that promote their products for off-label uses (see our previous posts here, here, and here; but see our post discussing the government’s recent prosecution of Acclarent, Inc.’s executives). Those cases have demonstrated the power of the First Amendment, and have held that companies may distribute truthful, non-misleading information about off-label uses of their products without running afoul of the Federal Food, Drug, and Cosmetic Act.

This public hearing appears to be another step in FDA’s long review of these issues:

As we announced in 2014, FDA is currently engaged in a comprehensive review of the regulatory framework related to firms’ communications about unapproved uses of approved/cleared medical products—medical products that may be legally introduced into interstate commerce for at least one other intended use. The purpose of this review is to help ensure that our implementation of FDA Authorities (including promulgating and amending regulations, issuing guidance, developing policies, and taking enforcement action) best protects and promotes the public health in view of ongoing developments in science and technology, medicine, health care delivery, and constitutional law.

Notification at 5. At this rate, it seems unlikely there will be any final pronouncements made until well into 2017.

In the Notification, FDA repeats its oft-stated acknowledgment that the dissemination of information regarding off-label use of an approved or cleared drug or medical device can play an important role in promoting the public health. FDA notes that “relevant, truthful, and non-misleading scientific or medical information regarding unapproved uses of approved medical products may help health care professionals make better individual patient decisions.” Id. at 8.  FDA notes, however, that “[n]ot all communications of information about unapproved uses help support public health.” Id. at 9.  For example, FDA realizes that some communications may emphasize a manufacturer’s claims about the benefits of using its product without disclosing potential consequences:

For example, communications that emphasize a medical product’s claimed benefits, while minimizing the limitations of the supporting evidence, or minimizing the product’s known or potential adverse effects, may inappropriately influence prescribing or use decisions in a manner that is not in a patient’s best interest.

Id. Accordingly, FDA seeks comments on both the pros and cons of communications regarding unapproved uses, and is specifically requesting empirical evidence demonstrating the impact of these types of communications. Id.

FDA lays out nine categories of issues, posing about thirty questions that it hopes will be addressed through the public hearing and comment process. FDA requests feedback from a broad group of stakeholders, including “health care professionals and professional societies, patients and their caregivers, patient advocates, representatives from regulated industry, health care organizations, payors and insurers, academic institutions, public interest groups, and the general public.” Id. at 10.

Notable questions include the following:

• What are the drawbacks and risks of making more information related to unapproved uses of drugs and medical devices available to practitioners, payors, and patients? What safeguards can be put in place to mitigate these drawbacks and risks?
• What effect will increased communications have on patient incentives to enroll in clinical trials?
• How do these changes affect incentives for firms to seek FDA approval or clearance of new uses?
• What criteria should FDA consider in determining whether a study or analysis that is the basis of a firm’s communication is scientifically appropriate to support the presentations or conclusions in the communication?
• What information is most important to health care professionals and other entities in allowing them to judge the validity and utility of firms’ communications about unapproved uses, and why?
• What information should firms communicate to make audiences aware that the product is unapproved for the use discussed?
• What information should firms disclose in order to make sure audiences are not misled (e.g., product risks, nature and weight of evidence supporting unapproved use, regulatory history relating to unapproved use, and financial involvement of firms in described research)?
• How should FDA monitor firms’ communications about unapproved uses, and what actions should FDA take with respect to communications it determines are false or misleading or otherwise raise public health issues?

Some of these questions are similar to those FDA raised in its 2011 request (“2011 Request”) for comments on communications and activities related to off-label uses of marketed products. See Communications and Activities Related to Off-Label Uses of Marketed Products and Use of Products Not Yet Legally Marketed; Request for Information and Comments, 76 Fed. Reg. 81508 (Dec. 28, 2011). Similar to FDA’s recent Notification, its 2011 Request sought comments on the types and quality of data that should be considered part of the scientific exchange of information, as well as on how FDA should treat these types of exchanges.  A noticeable difference between these two sets of requests for comments is that the 2011 Request specifically asked for industry opinions on the “distinctions” and “boundaries” between “scientific exchange and promotion.”  The current Notification, on the other hand, does not address the issue of promotion, but instead focuses on the dissemination of truthful and non-misleading information—a shift in terminology and approach that is likely the byproduct of the recent litigation regarding alleged off-label promotion and the First Amendment.

Another difference from the 2011 Request is that the Notification explicitly identifies a concern that a less-stringent regulatory control of off-label communications would have a negative impact on the development of high-quality scientific studies of these uses.

The types of questions that FDA is opening up for public comment suggest that FDA is significantly reshaping its approach on regulating a company’s off-label communications. Given congressional scrutiny (see our post here) and recent litigation, it is not a surprise that FDA is soliciting additional comments.

Attendance at the public hearing is free and open to the public. More information on the meeting registration and/or submitting a comment can be found here.

By Riëtte van Laack –

On August 17, FDA published in the Federal Register the long awaited final rule, “Substances Generally Recognized as Safe.” The final rule is based on the proposed rule from 1997, and a reopening of the comment period with supplemental questions in 2010. . The final rule includes a number of tables that provide an overview of the differences between the proposed rule and the final rule. 

The final rule does two main things: 1) it clarifies the criteria for determining when the use of a substance in a food for humans or animals is “generally recognized as safe” (GRAS) for its intended use and therefore exempt from the food additive definition in the Federal Food, Drug, and Cosmetic Act (FDC Act), and 2) officially replaces the voluntary GRAS affirmation petition (GRASP) process with a voluntary GRAS notification (GRN) procedure.  FDA’s Center for Food Safety and Applied Nutrition (CFSAN) implemented the GRN process soon after publication of the 1997 GRN proposed rule, operating it successfully for nearly two decades, whereas FDA’s Center for Veterinary Medicine (CVM) did not establish a pilot process for GRAS notices for animal feed ingredients (AGRNs) until 2010 (see our previous post here).  As of Dec. 31, 2015, CFSAN had filed 614 GRNs for use of human food ingredients and CVM had filed a mere 18 AGRNs for use of animal food ingredients. 

A major driver for FDA’s shift from GRASPs which involve notice-and comment rulemaking to GRNs and AGRNs is the ability to respond in a timely manner. Under the final rule, FDA commits to respond to the notifier within 180 days of the date of filing the GRN or AGRN, with a possible extension by another 90 days.  Thus, the notifier may not receive a substantive response until 270 days after filing.  For purposes of comparison: during the 10-year period from 1990 through 1999, CFSAN completed the rulemaking process for 24 GRASPs, with an average elapsed time of approximately 7.9 years (median elapsed time of approximately 6.9 years).

In recent years, the integrity of GRAS determinations and FDA’s reliance on the voluntary GRN process has been under attack.  Critics allege that, among other things, GRAS determinations employ outdated science, are rife with conflicts of interest, and the data supporting GRAS determinations are secret.  As we previously reported, in October, 2014 the International Society for Regulatory Toxicology and Pharmacology (ISRTP) held a Workshop on GRAS determinations. The ISRTP Workshop provided a forum for experts in the food safety scientific community to respond to criticisms of the FDA’s GRAS processes.  The manuscripts from the Workshop are now available in a special GRAS Supplement of Regulatory Toxicology and Pharmacology Journal (2016), including an Overview of the Workshop co-authored by Diane McColl, Past President of ISRTP.  FDA’s 97-page final rule also addresses many of these critiques and explains the law and public nature of GRAS conclusions.

A main thread through the preamble is FDA’s emphasis on the public availability of information supporting GRAS status. With respect to GRAS status based on scientific procedures – the principal basis for GRAS conclusions in the modern era – the critical difference between a GRAS use and an approved food additive use is that the conclusion of GRAS status (FDA’s new terminology for what used to a GRAS determination)  must be based on safety information that are generally available and accepted.  As explained in the preamble, “[a]lthough general recognition of safety through scientific procedures may be corroborated by the application of unpublished scientific data, information, or methods, . . . to satisfy GRAS criteria, qualified experts must be able to conclude the substance is not harmful under the conditions of intended use without access to 'corroborative' information.”  As FDA further explains, there can be no basis for a conclusion of GRAS status if trade secret information (or other non-public information) is necessary for qualified experts to reach a conclusion that the notified substance is safe under the conditions of its intended use.  Also, if the public description of the method of manufacture that a notifier includes in a GRAS notice does not provide sufficient detail to evaluate the safety of the notified substance as manufactured, there would be inadequate basis to support a conclusion of GRAS status.

FDA acknowledges that there are differences between the “evaluation” of a GRAS notice and the “review” of a GRASP. Among other things, the data and information in a GRN are summary data and information whereas GRASPs would include the underlying data from studies described in the petition.  This does not mean, however, that FDA’s evaluation of a GRAS notice does not constitute a substantive evaluation, or that the safety standard for a GRAS notice is different from that of a GRAS affirmation.  Because of questions and potential confusion resulting from FDA’s standard language in a “no questions letter” (i.e.,“The Agency has not . . .  made its own determination regarding the GRAS status of the subject use of the notified substance”), FDA will use different language in the future, i.e., “the Agency has not affirmed the GRAS status of the notified substance under the conditions of its intended use in accordance with 21 CFR 170.35.”

In terms of data quality and quantity to support a conclusion of GRAS status, the final GRN rule does not impose any substantially different data requirements than did the GRN process operated under the proposed rule. However, the final regulations include more specific descriptions of what must be included in a GRAS notice. 

A GRN must include seven parts. For parts that may not be applicable (e.g., self-limiting levels of use (part 4), experience based on common use in food (part 5)), the GRN must include an explanation for the “omission.”  Under the new regulation, a GRN must include a certification that the GRN is “complete” in addition to “representative” and “balanced.”  FDA clarifies that it is the notifier’s responsibility to identify, discuss, and place in context, data and information that are, or may appear to be, inconsistent with a conclusion of GRAS status.  Such data need not be publicly available. 

Although the decision to submit a GRN is voluntary, the information included in a GRN is mandatory. The final rule stipulates that the data and information in a GRN are considered a mandatory, rather than voluntary, submission for purposes of its status under the FOIA and 21 C.F.R. Part 20.

FDA will make a GRN available for public disclosure immediately upon receipt, and will make certain information pertaining to filed GRAS notices readily accessible to the public so as to provide an opportunity for outside parties to make FDA aware of dissenting views about whether the available data and information support a conclusion that the notified substance is GRAS under the conditions of its intended use.

FDA’s final regulations do not specify the data and information that the Food Safety and Inspection Service (FSIS) of the U.S. Department of Agriculture will need to evaluate whether the intended use of the notified substance complies with applicable statutes and regulations enforced by FSIS.

A change from the past is that FDA no longer requires that a GRN provide the common or usual name for the notified substance. Instead, the GRN must provide an appropriately descriptive term.  What constitutes a common or usual name of the substance is not considered in the evaluation of the GRN.  

FDA’s final rule does not address potential conflicts of interest of an expert panel. FDA explains that an expert panel, often called a GRAS panel, is not mandatory.  “Convening a GRAS panel has historically been a way to provide evidence that generally available data and information are generally accepted by the expert scientific community, but convening a GRAS panel is not the only way to provide such evidence.”  Therefore, the issues of potential conflict of interest and ways to avoid a conflict of interest are not addressed by the final rule.  FDA plans to address these issues in guidance.

The regulations concerning AGRNs for animal food ingredients largely track the regulations for human food ingredients.

The final rule becomes effective on October 17, 2016.  As of the effective date of the final rule, FDA will close the docket for any pending GRASPs. There are 45 pending GRASPs.  The Agency plans to contact the affected petitioners and provide them with the option to submit a GRN that incorporates the GRASP.

As we previously reported, in 2014, FDA and the Center for Food Safety (CFS) entered into a consent decree that required FDA to issue the final rule by August 31, 2016. CFS reserved the right to “challenge . . . the merits of the final rule.”  As we indicated at that time, CFS’s posture suggests that FDA’s issuance of a final rule could beget additional litigation.  Litigation remains likely (see here). 

By Jennifer D. Newberger –

Perhaps the most interesting thing about the recently released draft guidance, Deciding When to Submit a 510(k) for a Software Change to an Existing Device, is its mere existence. Historically, all changes to 510(k)-cleared devices were analyzed under the same guidance, regardless of whether the change related to software, labeling, materials, or anything else. That FDA has now carved out software changes indicates the importance that software has come to play in a wide variety of medical devices, and the complexities associated with software modifications.

Much of the draft software guidance mirrors a companion guidance issued the same day, Deciding When to Submit a 510(k) for a Change to an Existing Device, which addresses non-software modifications, and on which we previously blogged here. For example, the emphasis on whether a change is “intended” to significantly affect the safety or effectiveness of a device, and the use of risk management to identify potential hazards associated with the proposed modification, feature prominently in both documents.

In order to encourage the security of medical devices, the draft guidance begins by explicitly stating that if the change is done solely to strengthen cybersecurity without otherwise impacting the software or device, then no 510(k) is needed. Given the recent allegations involving pacemakers and defibrillators, this text may be reviewed more closely than it would have been just a few weeks ago.

The draft also addresses the issue of “bug fixes.” Though the draft states that such fixes are to be considered design changes under 21 C.F.R. Part 820, it also states that “[w]hen a change to the software only restores the device to the specifications of the most recently cleared device, then a new 510(k) is likely not required.”

The draft also separates out whether the software modification creates a new cause of a hazardous situation versus creates a hazardous situation itself, or alters an existing hazardous situation. It is not clear how a software modification could create a hazardous situation without creating a cause of a hazardous situation, or vice versa.

As with the companion draft guidance, this draft guidance regarding software modifications includes a number of detailed examples regarding when a new 510(k) would be needed, and should be helpful to industry in assessing software modifications. As is the case with the other draft guidance, companies should review carefully, since seemingly subtle changes could have major impacts (see our previous post here).