Pushing forward with his commitment to accessibility, Commissioner Gottlieb recently announced further efforts to encourage generic approval. In another FDA Voice Blog Post, Dr. Gottlieb reiterated the agency’s renewed focus on drug pricing and competition and announced new measures to aid in the development of generic versions of “complex drugs.”

Complex drugs, like drug-device combinations or injectable drugs or other forms of complex active ingredients or sites of action, are generally high-cost medicines that are not frequent targets of generic development regardless of patent or exclusivity status. These drugs are often difficult to replicate and have murkier pathways to approval; demonstrating bioequivalence may be challenging when the active ingredient cannot be easily measured in the blood or the therapeutic effect is not delivered systemically. This complexity delays and deters generic development, allowing NDA holders to charge a premium for the brand version.

In an effort to assist potential ANDA applicants for complex products, FDA issued a new draft guidance this week providing information to help sponsors request and conduct product development meetings, pre-submission meetings, and mid-cycle review meetings – all of these are commitments that FDA agreed to in the GDUFA II negotiations. These tools are similar to those available for NDAs under PDUFA, and the initiative is intended to enhance communication between generic drug applicants and FDA early in the development process to allow for more efficient development, review, and approval.

FDA issued an additional draft guidance this week to assist applicants submitting an ANDA for synthetic peptide drug product referring to an rDNA peptide – specifically glucagon, liraglutide, nesiritide, teriparatide, and teduglutide. According to this guidance, FDA believes that peptide synthesis and characterization technology now allows an ANDA applicant to demonstrate that the active ingredient in a generic synthetic peptide drug product is the “same” as the active ingredient in an rDNA peptide based largely on impurity profile comparisons. Because there are quite a few branded medicines without exclusivity that are peptides (compounds made up of 40 or fewer amino acids), this guidance could allow new competition where previously no generic development existed.

FDA is taking advantage of scientific development to expedite drug access and competition. As part of this initiative, Dr. Gottlieb states that FDA’s generic drug regulatory science program will work to develop more tools, methods, and efficient alternatives to clinical endpoint testing in the next year to further enable competition. FDA will continue to hold scientific workshops identifying opportunities for development for both product-specific guidance documents and new analytical tools.

This FDA Voice post is yet another in a series emphasizing FDA’s push towards affordable access to medicines. The enthusiasm with which this administration is addressing drug pricing and competition is not surprising, given Dr. Gottlieb’s extensive economic and health policy background, but it is certainly untraditional with respect to the role FDA has traditionally played in drug pricing. It’s certainly interesting to watch the agency’s “public health” mission expanding in front of our eyes, and we’re looking forward to seeing what else is in the pipeline!

Occasionally we peruse FDA’s inventory of food and color additive petitions under review as a reminder of what might lie on the horizon.  The current list includes some that have gotten considerable attention, and others that have largely flown below radar.  Among the latter, one stands out for its potential to offer a reminder of the nettlesome nature of the Delaney Clause.

By way of background, the Delaney Clause is a provision in the FFDCA that prohibits FDA from approving a food additive if it is found to induce cancer in man or animal, and is so named after the legislator who insisted on its inclusion in amendments to the FFDCA (there actually is more than one such provision in the FFDCA, but that’s beyond the scope of this posting.)  Attacked from the beginning as an unscientific approach to the complex challenge of assessing potential carcinogenicity, the Clause has spawned literally decades of litigation as the agency worked to administer it in light of our advancing scientific understanding of the disease – or rather suite of diseases – that it was intended to address.

One of the food additive petitions under review invokes the Delaney Clause to ask that FDA amend its food additive regulations to disallow the use of seven synthetic flavoring substances, and to prohibit their use.  The petition contends that the substances have been found to induce cancer in man or animal by the National Toxicology Program of the U.S. Department of Health and Human Services, as well as the California Environmental Protection Agency’s Office of Environmental Health Assessment (the office that administers Proposition 65).  Submitted by a coalition of consumer advocates and filed on January 4, 2016, the petition is getting long in the tooth.  The FFDCA establishes a 6-month timeframe for the review of food additive petitions.  Although extensions are the norm, recent history has shown that consumer advocates are disinclined to wait indefinitely for agency action.  Thus, as the 2-year anniversary approaches for this petition, it’s reasonable to expect movement either in the form of a substantive response by the agency, or a lawsuit to compel action.

If indeed the substances in question are found to induce cancer in man or animal within the meaning of the Delaney Clause, then FDA’s hands may be tied – regardless of whether the currently approved uses of the substances meet the safety standard otherwise applicable to food additives (reasonable certainty of no harm).  The resulting revocation of food additive approval could call into question the regulatory status of any foods to which those substances have been added.  Further, it could prompt additional petitions seeking similar action with respect to other substances for which there is evidence of human or animal carcinogenicity.  Ultimately, the only fix might lie in a statutory amendment that would – once and for all – bring the FFDCA’s approach to potential carcinogens in line with contemporary scientific understanding.  Anyone want to take odds on that outcome?

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks an attorney to work with our drug development team. The attorney will assist our clients secure FDA approval for new drugs by leveraging our legal expertise of the approval standards in the FDC Act and implementing regulations to overcome potential regulatory or scientific impediments. The position affords the opportunity to participate in product development strategy at the initiation stage and to navigate the drug through the FDA regulatory process.   

Strong verbal and writing skills are required, as well as a detailed understanding of FDA and the regulatory process.  Ideal candidates will possess a scientific background, such as a masters degree or higher in a hard science.  

Late last month, Judge Wolf, in the federal district court for the district of Massachusetts, dismissed a putative class action against a number of defendants based on impossibility preemption.  The plaintiffs’ basic allegations were that the defendants, all of which manufactured or distributed prescription eye drops, had dispensers that “were intentionally designed to dispense more liquid than the human eye is capable of absorbing.” Plaintiffs further alleged that the purpose of this unfair practice was to cause consumers to purchase more of their product than necessary thereby increasing defendants’ profits.  Before getting to its analysis, the court’s opinion summarized recent Supreme Court decisions – Wyeth v. Levine (failure to warn claims against brand manufacturer not preempted under impossibility preemption because of FDA’s changes being effected (CBE) regulation); Pliva v. Mensing (failure to warn claims preempted because generic manufacturers cannot use CBE regulation); and Mutual Pharm. v. Bartlett (option to stop selling product does not avoid impossibility preemption).

Against that backdrop, the court reasoned that plaintiffs’ claims were preempted because “defendants here could not have marketed droppers that complied with state consumer protection and unjust enrichment laws in the manner plaintiffs advocate without the FDA’s prior approval.”  Central to the court’s analysis were two FDA guidance documents that classified as major changes—and therefore changes that could not be made under the CBE regulation—any changes to the size and shape of the container for sterile drug products such as eye drops.  Based on these guidance documents, the court reasoned that it was impossible under federal law for the defendants to make the changes that plaintiffs alleged were necessary under state law.

The court, while recognizing a split in authority, was unpersuaded by the argument that plaintiffs’ claims were not preempted because defendants could have designed their products differently prior to FDA approval.  The court did not reach several arguments raised by the defendants, including but not limited to a separate motion by generic defendants based on the Supreme Court’s analysis of the availability of CBE to generic manufacturers

Earlier this year, a front page story in the Washington Post spotlighted several cases of fraudulent organic certificates, raising questions about organic certification practices overseas. Now, a new report by USDA’s Inspector General (IG) report confirms those doubts.

The IG reviewed the process used by the National Organic Program (NOP) of the Agricultural Marketing Service (AMS) to determine equivalence of organic standards used by countries exporting to the United States and compliance of imported products with NOP organic standard. Based on its audit, the IG makes a total of nine recommendations for improvements in four different areas.  In summary, the IG found 1) A lack of transparency of the equivalency determination; 2) A lack of verification of documents of imported organic products from countries that have been determined to have an equivalent system (certificates have been required since 2012 but are not verified); 3) Inadequate control over fumigation of imported organic products at the port (fumigation is inconsistent with organic standards); and 4) Infrequent (not timely) audits of foreign countries’ procedures.

AMS responded to the IG report with agreement and a commitment to carry out the IG’s recommendations. AMS already executed a memorandum of understanding with the Animal Plant Health Inspection Service (APHIS) earlier this year to address communication and notification procedures between the two about fumigation of imported shipments.  For the remaining recommendations, AMS committed to addressing them by July 2018.

The IG report makes no mention of the Washington Post article, or Cornucopia’s subsequent petition to the National Organic Standard Board (NOSB) requesting several actions to strengthen NOP’s control of import of organic product.

We have witnessed this past week some noteworthy activity in the drug compounding space. Where will this lead traditional compounders and outsourcing facilities? What will it mean for compounders in the months ahead?  We will just have to wait until FDA releases anticipated draft guidance on changes in outsourcing facility compounding in the coming months. FDA’s announcement about draft outsourcing guidance is somewhat of a headscratcher, especially considering that a number of anticipated compounding guidance documents and regulations were recently moved to CDER’s regulatory agenda inactive list (here; search “drug”).

Curiosity notwithstanding, Commissioner Gottlieb published a statement on September 26, 2017, addressing FDA’s “new efforts to encourage compounding of better quality drugs” under the Drug Quality and Security Act (DQSA), and provide increased access to compounded medications from outsourcing facilities.  First discussing the need for compounded medications, the Commissioner states,  “Supporting access to compounded drugs made under high production standards involves helping new outsourcing facilities as they strive to develop expertise in compounding medicines under [cGMP] standards.”  Dr. Gottlieb further notes the Agency is committed to “realizing” DQSA’s framework for facilities that register as outsourcing facilities;” thus, FDA is working on a number of efforts “specific to this growing sector as to works to meet these regulatory standards and fulfill its intended role.”

Interestingly, the “growing sector” (based on FDA’s website listing of such facilities) shows that, notwithstanding the four years since the DQSA’s enactment, there are only about 72 outsourcing facilities:  FDA has issued Form 483s to all but a few of them, Warning Letters to dozens of them, and engaged in recall activities and shutdowns of many.   Around 40 outsourcing facilities have closed their doors since their much anticipated opening after the enactment of the DQSA four years ago.

Nevertheless, Commissioner Gottlieb’s statement shares a Guide, titled “Outsourcing Facility Information,” which he claims may “assist compounders in deciding whether to become outsourcing facilities.,”  FDA’s Outsourcing Facility Information Guide is a very  general and well-organized  primer on Section 503B compounding.  It describes in chart form the various requirements in Section 503B, and informs the reader whether there is draft or final guidance, or anticipated guidance or regulations concerning each requirement.  The Guide  also provides handy links to the various guidance documents that FDA has promulgated addressing compounding under Section 503B over the last four years.

In its attempt to make the outsourcing registration decision as “efficient as possible, FDA’s Guide is “one step in [FDA’s] efforts help more pharmacies become outsourcing facilities.  Although we don’t yet know what else FDA intends to do to create these “efficiencies,” Dr. Gottlieb states that FDA will “continue to streamline” the process and “appropriately calibrate the regulatory burden” of operating as an outsourcing facility.  The Commissioner concludes: “Our ultimate  goal is to make it more feasible”  for compounding pharmacies to register to become outsourcing facilities, enabling them to grow their business under a legally approved framework, and increase access to better quality compounded drugs….”

Although not once referenced in the Commissioner’s statement, compounds prepared under the statutory rubric set forth in Section 503A (for individually identified patients pursuant to a prescription or order) are indeed another “legally approved framework” for compounded medications, and there are thousands of such compliant pharmacies operating throughout the United States.

As further demonstration to FDA’s commitment to safe compounding, FDA also met with state partners as part of is sixth intergovernmental meeting on drug compounding. This is part of the Agency’s continuing  effort to provide more seamless coordination between states and FDA in the regulation of compounding.   The press release about the meeting addresses targeting oversight by both FDA and states due to limited resources.  Noting the varied types of pharmacies across the country – from “mom and pop” pharmacies to those that ship nationwide like conventional drug manufacturers-  FDA and states will collaborate to determine which ones should be overseen primarily by states, and the small number of larger pharmacies deserving of FDA oversight.  Along these lines, FDA states that it intends to “further enhance our risk-based inspection model to prioritize inspections of compounding pharmacies that operate on a larger scale and ship compounded drugs across multiple state lines.”  Thus large volume traditional compounders should consider themselves warned: FDA is paying attention to compounders that ship a lot of product at high volumes across state lines.  There is nothing in the press release, however, that discusses the efforts, if any (and unlike reported from other meetings ) to ease the confusing and disparate licensing requirements facing FDA- registered outsourcing facilities .  Hopefully creating this “efficiency” is on FDA’s immediate “to do” list

Lastly, FDA published a report, available for your perusal via a link in Dr. Gottlieb’s statement above, setting forth a list of drugs that outsourcing facilities have produced.  Note that outsourcing facilities, unlike traditional Section503A compounders, must report to FDA drugs compounded in June and December of each year.  The list is a spreadsheet 500 pages long that only includes drugs produced (for those facilities that reported) for the time period between December 2016 and May 2017, including the name of the facility, active ingredient information, package description (and dosage amount), and dosage form.

We will keep you posted on outsourcing facility and compounding developments.

On September 26, 2017, FDA combined and finalized two Draft Guidance documents first issued in 2011 that set forth the Agency’s approach to classifying products as “drugs” or “devices” under the FDC Act § 201. In doing so, FDA trimmed significant portions of both Draft Guidance documents ostensibly “for clarity and ease of reference.” See Classification of Products as Drugs and Devices and Additional Product Classification Issues; Guidance for Industry and Food and Drug Administration Staff; Availability, 82 Fed. Reg. 44,802, 44,803 (Sept. 26, 2017).  However, while the Final Guidance does provide helpful clarification and examples, some of the most significant issues with the Draft Guidance documents persist.

The Draft Guidance documents issued in 2011 (which can be found here and here) were titled “Classification of Products as Drugs and Devices & Additional Product Classification Issues,” and “Interpretation of the Term ‘Chemical Action’ in the Definition of Device under Section 201(h) of the Federal Food, Drug, and Cosmetic Act” (hereinafter “Draft Classification Guidance” and “Draft Chemical Action Guidance,” respectively).  These documents were met in 2011 with numerous objections from the medical device industry, because the Agency’s position significantly diminished the scope of the “device” definition.

Specifically, FDA’s Draft Classification Guidance stated that (1) any therapeutic effect by a product would be considered a “primary intended purpose” pursuant to FDC Act § 201(h), and (2) if a product that depends “even in part” on chemical action within or on the body to achieve a primary intended purpose, it is excluded from the device definition. See Draft Classification Guidance at 5.  The Agency further clarified that no chemical action with therapeutic effect would be permitted in a device, noting that “a product that exhibits chemical action within or on the body of man” could remain within the device definition only if its chemical action contributes to something other than a primary intended purpose (i.e., therapeutic effect). Id. at 4-5.

Moreover, the Draft Classification Guidance acknowledged that the new positions set out in both Draft Guidance documents may result in the FDA Office of Combination Products (OCP) changing its view of products that the Agency had already classified, stating that OCP “may determine that, in light of current scientific understanding, the means by which such a [previously classified product] or constituent part achieves an intended use may warrant a different classification for that product or constituent part in the pending RFD than the Agency previously provided.” Id. at 6.

FDA was challenged in litigation over the Agency’s reliance on the extra-statutory “even in part” standard not found in the FDC Act’s definition of “device,” its seeming prohibition of even de minimus chemical action contributing to a therapeutic effect, and its unexplained departure from prior precedents.  The Agency lost at least two lawsuits over its new interpretation of “device.”

In concession to industry concerns, the Final Guidance’s discussion of “chemical action” makes clear that chemical action occurring within the body, but which does not interact “at the molecular level with bodily components . . . to mediate (including promoting or inhibiting) a bodily response, or with foreign entities (e.g. organisms or chemicals) so as to alter that entity’s interaction with the body,” is not sufficient to render a product a drug for purposes of FDA regulation. Final Guidance at 7.  FDA further clarifies that while “interaction at the molecular level” could include chemical reaction, intermolecular forces (e.g. electrostatic interactions), or both, “[t]he mere exchange of non-chemical energy (e.g., electromagnetic or thermal energy) between a product and the body would not constitute ‘chemical action.’” Id. at 7 n. 12.

For example, FDA notes that a polymethlymethacrylate (PMMA) bone spacer would still be considered a device, even though “the molecules [within the product] interact with each other to create a solid mass to fill a bone void physically,” because that “process does not require an interaction between the PMMA and the bone at the molecular level . . . .” Id. at 9 (emphasis supplied).  And topical surgical adhesives, despite bonding to a cut/incision, do not exhibit chemical action “because that binding does not mediate a bodily response.” Id.

At the same time, FDA continues to take the position that the FDC Act’s “drug” definition subsumes the more restrictive “device” definition (Id. at 5), and that product sponsors bear the burden of proving that their product is correctly classified as a device (or drug, as the case may be) (Id. at 6).  Given the difficulty of proving the absence of biological and chemical effect, this burden shifting gives FDA ample room to make mischief.  Moreover, while the Final Guidance no longer states outright that the Agency considers every therapeutic effect to be a primary intended purpose, the examples it cites of products that exhibit chemical action in or on the body, but that remain “devices,” include only products whose chemical action otherwise meets FDA’s definition, but does not contribute at all to a therapeutic purpose of the device.  There is no indication in the Final Guidance that FDA would accept as a device a product exhibiting even minimal chemical action that contributes to a therapeutic effect.  Finally, while FDA states that it has “reconsidered inclusion of content on the status of prior Agency classification decisions” in the Final Guidance, the Agency makes clear that product sponsors should not rely on classification precedents without confirmation by OCP that those precedents remain valid.  82 Fed. Reg. at 44,803.

In sum, while FDA has taken steps toward providing greater certainty to product sponsors by clarifying its stance on the meaning of “chemical action” in this Final Guidance, the Agency’s positions on the remainder of the statutory “device” definition, and on the sponsor’s burden of proof to establish product classification, continue to heavily favor a “drug” designation for hard-to-classify products. This result is arguably contrary to the statutory text, and – in light of the significantly higher cost associated with seeking premarket approval for a drug product – is very likely to result in fewer beneficial therapeutic products reaching the U.S. market.

On September 29, 2017, the Health Resources and Services Administration (“HRSA”) published, in the Federal Register, the Final Rule delaying the effective date regarding the methodology for calculating the 340B ceiling price (including the so-called penny pricing policy) and civil monetary penalties (“CMPs”) for knowing and intentional overcharges of 340B covered entities until July 1, 2018 (“Effective Date Final Rule”). The Final Rule that established the 340B ceiling price calculation methodology and CMPs was originally published on January 5, 2017 (“Substantive Final Rule”; see our original post regarding the Substantive Final Rule here) but subsequently encountered several delays (see our posts here, here, and here).

HRSA reiterated the points it made in the Notice of Proposed Rulemaking (“NPRM”) it published on August 21, 2017. After considering the comments it received to the NPRM, HRSA decided to finalize the delay to implementation of the Substantive Final Rule to July 1, 2018, as initially proposed. The agency stated that it “continue[d] to believe that the delay of the effective date provides regulated entities sufficient time to implement the requirements of the [Substantive Final Rule], as well as allowing a more deliberate process of considering alternative and supplementary regulatory provisions, and to allow sufficient time for additional rulemaking.” 82 Fed. Reg. 45512.

Similar to the NPRM, the Effective Date Final Rule provided no clarity as to what additional rulemaking would be forthcoming. Should HRSA advance “alternative and supplementary regulatory provisions” that would alter the rulemaking described in the Substantive Final Rule, an additional notice and comment period would be required. Therefore, it is unclear whether the 340B Substantive Final Rule will be implemented as finalized in January or whether a July 1, 2018 date for implementation of a 340B final rule can be relied upon, despite HRSA’s statement that a further delay does not appear necessary. What we do know is that entities participating in the 340B program would do well to carefully consider their timelines for implementation of new systems and processes designed to comply with the Substantive Final Rule.

We will continue to track and report on further developments regarding implementation of the Substantive Final Rule or other updates concerning the 340B Drug Pricing Program.

In what may appear to the uninitiated as a step to cooperate with industry on FDA development of a rational policy for new dietary ingredients (NDIs), FDA is holding a public meeting on October 3 with the goal of developing an authoritative list of old dietary ingredients (ODIs), dietary ingredients on the market before the enactment of the Dietary Supplement Health and Education Act of 1994 (DSHEA). ODIs are dietary ingredients that may be included in dietary supplements, assuming the ingredients are safe, without premarket notification to FDA.  In reality, FDA’s October 3 meeting is at best an exercise in futility and a waste of both FDA’s and industry’s time.

FDA’s new leadership should step in to end FDA’s repeated efforts to irrationally and illegally restrict the dietary supplement market, which go back to the 1960s. Instead of holding meetings, FDA should withdraw its August 2016 “Draft Guidance for Industry; Dietary Supplements: New Dietary Ingredient Notifications and Related Issues” to permit the development of a guidance that is consistent with the plain meaning of DSHEA and congressional intent. FDA should also work with industry to create a list of any dietary ingredients that raise safety concerns in order to remove these ingredients from the market, or to resolve these concerns by requiring that notifications be filed.

We have written extensively in blogposts and comments to FDA about the 30-year history of FDA’s bungling of policies for dietary supplements (see our previous posts here, here, here, and here; and comment here).  A brief recap:

• In the 1980s FDA attempted to keep dietary supplements, other than traditional vitamins and minerals, off the market through misapplication of the Federal Food, Drug, and Cosmetic Act (FDC Act) “food additive” provisions. When FDA brought seizure actions arguing that even single ingredient dietary supplement products were food additives, two appellate courts rejected FDA’s legal theories, one court stating that they “pervert[ed] the statutory text, undermine[d] legislative intent, and defenestrate[d] common sense,” while the other described FDA’s theory as an “Alice-in-Wonderland approach,” and “an end-run around the statutory scheme.” FDA’s irrational and restrictive approach to supplement regulation led to a popular uprising and the enactment of DSHEA.
• DSHEA amended the FDC Act in 1994 to prevent further FDA misuse of the food additive provisions and to create separate and less onerous requirements for dietary supplements in recognition of the important role these products play in public health, and that, unlike conventional foods, they are consumed in limited quantities requiring a different safety analysis.
• DSHEA amended the FDC Act to, among other things, (1) make clear that dietary ingredients are not subject to regulation as food additives; (2) exempt dietary ingredients in food marketed before October 15, 1994 from regulation as NDIs; (3) subject NDIs to a premarket notification process (as opposed to a premarket approval process); and (4) exempt from the premarket notification requirement any NDI that is present in the food supply and has not been chemically altered.
• FDA issued draft guidance on DSHEA’s NDI requirements in July 2011, which made it clear that FDA intended to apply the provisions of DSHEA in a way that, instead of providing more opportunities for the development and marketing of safe dietary supplements, exerted more control over the market than FDA had asserted by its misuse of the food additive authorities prior to DSHEA.
• FDA’s draft guidance caused a firestorm of protest from industry as well as Congress. FDA received over 140,000 pages of comments, mostly critical, among them a strongly worded letter to FDA Commissioner Hamburg from the principal authors of the Dietary Supplement Health and Education Act of 1994 (“DSHEA”), Senators Orrin Hatch and Tom Harkin, requesting that FDA immediately withdraw the draft NDI guidance because it undermined DSHEA in unacceptable ways.
• In a June 2012 meeting between FDA and Senators Hatch and Harkin, Commissioner Hamburg committed to issuing a revised draft in order to address the concerns of Congress and industry.
• Four years later, in August 2016, FDA published its revised draft, but instead of revising the 2011 draft to fix the policies that were in direct conflict with DSHEA and congressional intent, FDA doubled down on its prior mistakes. FDA significantly lengthened the guidance “to clarify and better explain [its] thinking on some critical issues” and to address “gaps and unclear statements that were subject to confusion and misinterpretation.”

In short, FDA has once again ignored the plain language of the FDC Act as amended by DSHEA, and is seeking to impose requirements on dietary supplements that have no basis in law. Ironically, as a result of FDA’s restrictive NDI policies, companies now wishing to introduce NDIs to the market are first introducing them as conventional food ingredients using the very procedures that DSHEA was intended to replace.

To appreciate the pointlessness of the October 3 meeting, the announced purpose of which is to develop an authoritative list of pre-DSHEA or ODI ingredients, consider the following:

• Recognizing the initial importance of ODIs to the implementation of DSHEA, in order to clarify for industry and FDA which ingredients were exempt from notification as ODIs, industry trade associations created, published, and revised lists of ODIs, culminating in a joint list from four trade associations published on September 17, 1999. Rather than use these contemporaneous lists as a guide, FDA has repeatedly dismissed them as unreliable and unsubstantiated.
• FDA through its guidance has created irrational barriers to ODI status that are contrary to the wording and intent of DSHEA, including limiting ODIs only to pre-DSHEA dietary ingredients in dietary supplements, a category that of course did not exist prior to DSHEA, and requiring that ODI status not only be established by pre-1994 documentation, but that manufacturers also prove that, in the intervening 23 years, the manufacturing process has not changed, even if the ingredient remains the same.
• In addition to ODIs, DSHEA created an exemption from the requirement of NDI notification for any “dietary ingredient present in the food supply.” This provision sensibly exempts food ingredients, which pursuant to DSHEA includes ingredients in dietary supplements, from notification, therefore exempting not just ingredients marketed in food both pre- and post-DSHEA, but also NDIs for which FDA has already been notified.
• Now, 23 years after the enactment of DSHEA, if FDA were to challenge any dietary ingredient as an NDI for which notification is required, FDA would not only bear the burden of proving that the ingredient lacks ODI status, but also that the ingredient had not been in the food supply in the intervening 23 years anywhere in the world, a difficult if not impossible burden to meet for those dietary ingredients that have been marketed for substantial periods of time with no safety concerns.

As FDA’s focus should be ingredient safety, the obvious conclusion is that FDA should turn its attention from ODIs and instead work with industry to identify any ingredients for which safety concerns exist, and then, using the existing adulteration provisions of the FDC Act as well as an appropriate interpretation of the NDI provision, either remove these ingredients from the market or require NDI notifications. As this change in focus will require an abandonment of FDA’s long held but ill-conceived views of DSHEA, the necessary change will not likely occur without guidance from FDA’s new leadership, under the watchful eye of Congress.

As readers of this blog know, in 2016 FDA published a final rule amending the nutrition labeling regulations. Although the industry requested more time to come into compliance with that final rule (which requires revision of virtually every food label), FDA set the compliance date for all but small companies (with annual sales of less than 10 million dollars) at two years after the effective date, i.e., July 26, 2018.

Then, on June 13, 2017, FDA announced its intent to extend the compliance date.  According to the June 13, 2017 announcement, FDA recognized that it needed more time to issue guidance to industry, and that industry also needed more time to revise labels, reformulate products, and take other actions to be able to comply with the new nutrition labeling requirements. In June, however, FDA only announced its intent to extend the compliance date, without actually setting a new compliance date.

On September 29, 2017, FDA announced (here and here) its proposed new compliance date of Jan. 1, 2020.  In the proposal, FDA asserts that it is “taking this action because, after careful consideration, we have tentatively determined that additional time would help ensure that all manufacturers covered by the final rules have guidance from FDA to address, for example, certain technical questions we received after publication of the final rules, and that they are able to complete and print updated Nutrition Facts labels for their products before they are expected to be in compliance with the final rules.” FDA does not mention the pending citizen petitions requesting a revision of certain aspects of the rule, e.g., the dietary fiber definition and requirement to declare added sugars.

FDA’s proposal to extend the compliance date evaluates the costs and benefits of the extension, and concludes that extending the date by approximately 1.5 years reduces the cost to industry by about 1 billion dollars, while it reduces the benefits to the consumer by 0.9 billion dollars. FDA acknowledges that the methodology to calculate the costs and benefit analysis has flaws. However, it is the same methodology as it used previously in the calculation of the costs and benefits of the final rule and, thus far, no party has suggested better alternatives.

Comments to the proposed rule must be submitted by Nov. 1, 2017. FDA emphasizes that comments should pertain to the extension of the compliance dates only, and not to the substance of the nutrition labeling rule itself.

The American Conference Institute’s (“ACI’s”) Food Law Regulation Boot Camp is slated to take place at the Wyndham Grand Chicago Riverfront in Chicago, Illinois from November 13-15, 2017.  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.”

The  faculty 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 “A Practical Guide to the New Nutrition Facts Label.”  ACI has extended its early bird rate until next Friday, October 6th for friends and colleagues of speakers.  We look forward to seeing you at the conference.

Hyman, Phelps & McNamara, P.C.’s Riëtte van Laack will be presenting on “Food Safety: Ingredient Preclearance/Intentional Components of Food” and on “Food Labeling: General Requirements” at the Introduction to U.S. Food Law and Regulation course, sponsored by the Food and Drug Law Institute on October 11-12, in Washington DC.  A copy of the conference brochure is available here. 

The course is designed for new legal and regulatory professionals as well as seasoned professionals new to the topic or wanting a refresher.

The program explores the essentials of food law and regulation and offers a comprehensive understanding of the various administrative agencies that impact these industries. Attendees will learn about pending regulations, food safety, food labeling, enforcement, and related issues. Case studies, hypotheticals, and ample time for discussion are provided.

To learn more and to register for the conference, visit www.fdli.org/programs. Use discount code “save15”  to save 15% off your registration fee.

Puerto Rico has been a hub of pharmaceutical manufacturing for some time, but in the aftermath of hurricane Maria (and Irma), that has changed – at least for now. Without power in most of the island, but more importantly, without employees who can get to work on a regular schedule, much of Puerto Rico’s pharmaceutical manufacturing has been idled, and is likely to continue that way for some time.

According to the Bureau of Labor Statistics, pharmaceutical manufacturing represented 72% of Puerto Rico’s exports in 2016 ($14.5 billion), and the sector accounted for 25% of the total of U.S. pharmaceutical exports to the rest of the world. By comparison, California was next in line, but had only half as much in the way of pharmaceutical exports.

Puerto Rico has more than 50 registered pharmaceutical facilities on the island, producing sixteen of the top twenty selling drugs in United States, and seven of the top ten selling drugs globally.

Its status as hub of pharmaceutical and biotech manufacturing has its origins in its tax favored status under the Internal Revenue Code, which, for decades, incentivized U.S. based manufacturers to send profits from the island’s plants to their stateside parent companies without having to pay federal taxes. In 1996, President Clinton signed into law an amendment to the Internal Revenue Code, phasing it out over ten years.  Several plants have shuttered since the phase out of this tax favored status, and with the devastation caused by hurricane Maria, analysts worry that several more will never reopen for business.

Recognizing the impact that the shut-down of a large segment of the U.S. pharmaceutical industry can have on the supply of drugs to consumers (and hence on public health), FDA Commissioner Gottlieb has issued two statements (here and here) in recent days, emphasizing the importance of Puerto Rico to the continued success of the U.S. pharmaceutical industry (as well as on the importance of the pharmaceutical industry to Puerto Rico’s economic health), and on the efforts that are being made by FDA to identify and bring the island’s pharmaceutical resources back into operation.

Leading up to the storm, our team of shortage experts worked to identify and coordinate with companies that have manufacturing facilities in Puerto Rico to assess the potential impacts on their facilities to avoid—whenever possible—shortages of critical medical products. During and following the storm, we have worked with pharmaceutical and medical device firms to figure out whether manufacturing facilities were damaged, or if they were still operational and could continue to function on generator power. Since Friday, we have undertaken swift and extensive efforts to prevent or limit the loss or shortage of multiple drugs critical to American patients due to the challenges related to refrigeration, storage and transportation. The agency has been working closely – throughout the weekend and into today – to relocate products in coordination with our federal and local government colleagues and pharmaceutical companies.

The Commissioner also stated that he has directed the creation of a hurricane shortages task force that will be asked to identify potential issues and creative solutions to impending drug shortages, as the agency is aware of several other situations where there may be critical shortages “…if we don’t find a path for removal [of the drug products from Puerto Rico] or ways to get production back up and running.”

For all these reasons, we all hope that Puerto Rico’s recovery is swift and comprehensive.

Hyman, Phelps & McNamara, P.C.’s Mark I. Schwartz will be presenting on the Regulation of Biological Manufacturing at the Food and Drug Law Institute's (“FDLI’s”) Introduction to U.S. Biologics and Biosimilars Law and Regulation course, which is scheduled to take place from October 4-5, 2017 in Washington, DC.  A copy of the conference agenda is available here.

FDLI’s course is designed for new legal and regulatory professionals as well as seasoned professionals new to the topic or wanting a refresher.  The program explores the regulation of biological products, including biotechnology–derived therapeutic proteins, human tissue, gene, and cell products. Attendees will learn about the abbreviated pathway to market for biosimilar biological products and associated intellectual property issues, including exclusivity and biologics patent litigation. Case studies, hypotheticals, and ample time for Q&A are provided.

To learn more and to register for the conference, visit www.fdli.org/programs. Use discount code “save15”  to save 15% off your registration fee.

Earlier this week, FDA published another in its series of guidance documents devoted to implementing the Biologics Price Competition and Innovation Act (“BPCIA”). The objective of the new guidance, entitled Statistical Approaches to Evaluate Analytical Similarity Guidance for Industry, is to assist sponsors in demonstrating analytical similarity to support licensure under section 351(k) of the PHS Act. This guidance is intended to serve as a companion document for Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to Reference Product (we blogged about this guidance here).

According to the guidance, analytical similarity involves the comparison of structural or physicochemical and functional attributes using multiple lots of the proposed biosimilar product and the reference product. Under PHS Act § 351(i), “biosimilar” means that the biological product is “highly similar” to the reference product licensed under PHS § 351(a) – even if there are minor differences in clinically inactive components, as long as there are no clinically meaningful differences between biosimilar and reference product safety, purity, and potency. This must be demonstrated based on “analytical studies.”  In this guidance, FDA details its current thinking on these analytical studies, including challenges a sponsor may encounter.

FDA first addresses the challenges that may arise in attempting to demonstrate analytical similarity. These include a limited number of appropriate or representative reference product or biosimilar lots and the large number of attributes that can be compared to evaluate quality but may not actually be meaningful.

Thus, FDA recommends a risk-based approach in analytical similarity assessment of quality attributes. This approach involves an Analytical Similarity Assessment Plan.  A successful Analytical Similarity Plan will be based on testing with a minimum of 10 reference product lots, 10 biosimilar lots, representative samples of reference product variability (including expiry), U.S.-licensed reference lots only, and lots manufactured with different processes or scales.

The Analytical Similarity Assessment Plan itself should be based on a several step approach:

• Step 1: Determine the quality attributes that characterize the reference product in terms of structural/physicochemical and functional properties.
• Step 2: Rank these quality attributes according to risk of potential clinical impact.
• Step 3: Evaluate these attributes based on three tiers of statistical approaches.

The intent of the analysis is to examine the potential impact on clinical performance and the degree of uncertainty around a clinical attribute in terms of risk to product similarity. Beyond risk, the level of impact of the attribute, the assays used for the attribute, and the types of attributes evaluated should all be carefully considered.

Once the attributes are identified and ranked, the sponsor should determine the appropriate statistical methods to be used based on risk ranking. Tier 1 testing, or formal statistical equivalence testing, should be used for those quality attributes determined to have the highest potential clinical impact.  Tier 2 (called the Quality Metric approach), involves setting ranges of acceptable quality attributes and is best used for medium-impact attributes.  Finally, Tier 3, Visual Displays, involves subjective assessment through observation and should be used for those attributes with either the lowest risk of potential clinical impact or those attributes that are important but not amenable to formal tests or quantitative evaluation.

FDA notes that final assessment of “highly similar” is made upon the totality of evidence rather than the passing or failing of the analytical similarity criteria of any one tier or any attribute. This demonstrates FDA’s willingness to show flexibility in applying a complex concept, which is necessary given the range of sizes and types of molecules eligible as biologic reference products.  Further, establishing biosimilarity is not a one-size fits all process, and this guidance is indicative of FDA’s case-by-case approach.  As with all drug development, both small and large molecule, FDA will be involved in the development program from the start – but this guidance gives industry the broad strokes to allow more productive planning conversations.