By Kurt R. Karst –      

Earlier this week, Public Citizen announced the release of a report, titled “House Orphan Drug Proposal: A Windfall for Pharma, False ‘Cure’ for Patients,” that takes aim at a particular provision in the 21st Century Cures Act (H.R. 6) that the U.S. House of Representatives passed in July 2015.  The report comes out at a time when the debate over drug pricing in Congress has reached fever pitch, and shortly after the publication of an article in the American Journal of Clinical Oncology alleging that companies are exploiting the Orphan Drug Act, which President Ronald Reagan signed into law on January 4, 1983 (and that some have referred to as one of the most successful pieces of FDA legislation in the history of food and drug law).  

Section 2151 of the Cures Act, titled “Extension of Exclusivity Periods For A Drug Approved For A New Indication For A Rare Disease Or Condition,” but known more popularly as the “Orphan Product Extensions Now Act,” or “OPEN Act,” would amend the FDC Act to provide a 6-month extension of exclusivity periods – what we’ve referred to as “exclusivity stacking” – for a drug approved for a new indication for a rare disease or condition (i.e., so-called “repurposed” drugs).  The OPEN Act is intended to increase the number of rare disease therapies and to address off-label reimbursement problems faced by rare disease patients.  We previously discussed the OPEN Act in posts here and here.

According to Public Citizen, “the current orphan drug approval system is hardly in need of a stimulus, as companies are pursuing, and achieving, orphan drug approvals at record rates.”  Moreover, says Public Citizen, the OPEN Act “is emblematic of the false hope offered more broadly by the 21st Century Cures legislation.”  Specifically, the OPEN Act would, according to Pubic Citizen:

result in higher drug prices for both orphan and non-orphan diseases: Conservatively, the provision would cost the public close to $4 billion, but given the structure of the financial incentive, the cost could easily approach $12 billion.  The new incentive would further distort existing incentives by encouraging pharmaceutical companies to spend money repurposing old drugs, rather than investing in truly innovative new drug development.  And it encourages more investment in a flawed system that effectively lowers FDA standards for approval and allows for considerable abuse.  Worst of all, the costs of the new incentive would fall not only on taxpayers but also on the backs of patients with common, non-orphan diseases, who will be denied potentially life-saving, affordable generic medicines for six additional months.

Just last month, several folks from the Johns Hopkins University School of Medicine penned a piece for the American Journal of Clinical Oncology, titled “The Orphan Drug Act: Restoring the Mission to Rare Diseases,” alleging that companies are “gaming” the orphan drug system established by the Orphan Drug Act “to use the law for mainstream drugs.”  According to the authors, although the Orphan Drug Act has been successful in getting therapies approved for otherwise overlooked populations, “evidence demonstrated that the [Orphan Drug Act] is often abused.”  The authors point to drugs and biologics approved for a rare disease, but that are used more broadly (for prevalent conditions and diseases) as evidence of this alleged abuse.  (We’ve seen these and other criticisms of the Orphan Drug Act before, which led to the introduction of legislation that was not ultimately enacted – see, e.g., here.) 

In the end, the authors of the article say that the Orphan Drug Act needs to be reformed . . . and they make some suggestions: “(1) increased submission scrutiny to ensure that benefits are allocated to drugs truly intended to treat orphan disease; (2) stratified benefit systems; (3) decreased exclusivity periods when benchmark profits are achieved; (4) decrease benefits to drugs that reach a much larger target populations [sic]; and (5) increased price transparency.” 

So it seems that orphan drugs are under attack from both ends of the spectrum: on the one hand, drugs approved for prevalent uses repurposed for rare conditions, and, on the other hand, approved orphan drugs repurposed for prevalent conditions.   

By Josephine M. Torrente & Etan J. Yeshua –

In September, FDA proposed a significant limitation on the way drug sponsors can appeal FDA decisions, and yesterday Hyman, Phelps & McNamara, P.C. (HP&M) formally requested that the Agency reverse course. In a draft guidance document issued in September, FDA stated that advice from review divisions to drug sponsors as formalized in meeting minutes and in advice letters would no longer be appealable to officials above the review division. Until now, the Agency routinely accepted requests for such appeals through its “formal dispute resolution” (FDR) procedures.

Requests for formal dispute resolution – which involve critical drug development issues ranging from Phase 3 study endpoint selection, to the need for carcinogenicity studies, to the adequacy of impurity characterization – make it possible for a sponsor to ensure that advice it receives from a review division (particularly advice with which the sponsor disagrees) has been vetted and approved by senior officials at the Agency. But FDA’s proposed new practice (as demonstrated by one example in the comment we submitted yesterday) would require that a review division repeat the same advice no fewer than five times over multiple years before that advice would be appealable. This is an untenable position for the Agency to take.

As we stated in our comment to the draft guidance document:

[O]ur firm has drafted dozens of FDR requests for clients and has also advised numerous other clients that pursuing FDR was not advisable based on the facts or circumstances of their cases . . . [A] failure to resolve such disputes efficiently and effectively has the palpable potential to hinder the availability of promising drugs and biologics and, ultimately, public access to them – sometimes for many years and sometimes forever.

Just last week, the Agency stated in a separate draft guidance document that, “It is critical to efficient drug development for sponsors to ascertain FDA’s views on the applicable statutory and evidentiary requirements well in advance of submission of an application.” We couldn’t agree more: timely use of the dispute resolution process can give a sponsor confidence that a review division’s advice is “FDA’s view” and is not merely an initial determination liable to be overturned later in the development process.

However, unless the Agency reverses its new position on the reviewability of a division’s advice, a sponsor who questions or disagrees with the scientific or regulatory feedback it receives from a review division would be faced with two risky and untenable options: either stake its development plan on the division’s controversial advice, or reject the division’s advice and pursue the path that the sponsor believes is scientifically and legally warranted. In either case, the sponsor would be taking on significant and preventable risk. Rather than allowing scientific and regulatory disputes to be appealed in a timely manner, the new FDA practice would require the sponsor to wait until FDA rejects or refuses to file the IND, NDA, or BLA in order to determine that the division’s advice had been vetted and approved by more senior officials at the Agency. By then, much may have been wasted: large numbers of patients participated in unnecessary placebo-controlled trials; years of patent life on the product were lost; and millions of dollars were spent on trials that could have been avoided had the dispute resolution process been available earlier.

To prevent wasted efforts by patients, investigators, sponsors, and the Agency itself, HP&M’s comment, which you can read here, requests that FDA revise its guidance document and continue its long-standing practice of accepting requests for formal dispute resolution when the dispute arises. We hope the Agency will do so.

By Riëtte van Laack –

On December 4, 2015, the California Office of Environmental Health Hazard Assessment (OEHHA) added Aloe vera, non-decolorized whole leaf extract and Goldenseal root powder to the list of “chemicals known to the State of California to cause cancer for purposes of the Safe Drinking Water and Toxic Enforcement Act of 1986” commonly known as the Proposition 65 (or Prop. 65) list. On the same day, OEHHA published a document with its responses to the comments.

OEHHA’s responses clarify various aspects. The basis for the addition of these substances to the Prop. 65 list is their identification as “possibly carcinogenic to humans” with sufficient evidence of carcinogenicity in experimental animals by the International Agency for Research on Cancer (IARC). OEHAA claims, that as a result, the science is not open for discussion; OEHHA must add these substances to the Prop. 65 list. The listing of these chemicals is not “route-specific,” i.e., it applies to all routes of exposure including oral ingestion and topical application. The original notice of intent to list the aloe vera did not include the qualification that only non-decolorized whole leaf extract is a potential carcinogen.

Businesses now have 12 months to either reformulate their products or provide a “clear and reasonable” warning before knowingly and intentionally exposing anyone to these substances. If the past is any indication, plaintiff attorneys will be ready with notices of violation when the 12 month period expires.

The Food and Drug Law Institute (FDLI) is holding a two day conference, titled “Enforcement, Litigation, and Compliance conference.”  The workshop is this week, on December 9 and 10.  Within the conference, Jeff Shapiro will participate in a medical device breakout panel focused on mHealth and cybersecurity.  A copy of the FDLI workshop agenda and information on registration is available here.  FDA Law Blog readers can get a 15% discount by using speaker referral code ENFORCE15.

By Kurt R. Karst –    

Here’s something you don’t often see: FDA initiating procedures to suspend the approval of an ANDA because of an Agency determination that the Reference Listed Drug (“RLD”) was withdrawn for what the Agency determined were safety or effectiveness reasons. But on December 3, 2015, that’s exactly what FDA did when the Agency sent a letter to Armenpharm, Ltd. (“Armenpharm”) for the company’s Chloramphenicol Capsules, 250 mg (previously marketed under the brand name MYCHEL) approved under ANDA 060851 on June 20, 1967. The story here dovetails nicely with two posts we put up over the past six months providing an analysis of FDA determinations that a drug was withdrawn from sale for reasons of safety or effectiveness (here) and how to bring a drug out of discontinued status (here).

Although there’s a lot of food and drug history here, including the old antibiotic drug approval procedures under Form 5 and Form 6 applications, we’ll begin with a February 7, 2011 Citizen Petition (Docket No. FDA-2011-P-0081) Armenpharm submitted to FDA requesting that the Agency determine that the RLD for ANDA 060851, Parkdale Pharmaceutical’s (“Parkdale’s”) CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, approved on December 8, 1950 under ANDA 060591, was not discontinued for reasons of safety or effectiveness. You see, MYCHEL (ANDA 060851) had not been marketed for a while and Armenpharm wanted to submit a Prior Approval Supplement to FDA for an alternate manufacturing site as part of an effort to remarket the drug. The RLD, however, had been discontinued back in October 2007, and FDA withdrew approval of the application in early 2009, but continued to identify the ANDA in the Discontinued Drug Product List section of the Orange Book. To remarket MYCHEL in light of the discontinuance of ANDA 060591, FDA had to make a determination as to whether or not Parkdale discontinued CHLOROMYCETIN 250 mg for safety or effectiveness reasons.

In July 2012, FDA responded to Armenpharm’s discontinuation petition and issued a notice in the Federal Register providing FDA’s conclusion that Parkdale’s CHLOROMYCETIN 250 mg approved under ANDA 060851 was discontinued for safety or effectiveness reasons. (For an analysis of FDA’s recent track record on responding to discontinuation petitions, see our previous post here.)  According to FDA:

After considering the citizen petition, and based on the information we have at this time, FDA has determined under § 314.161 that CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, were withdrawn for reasons of safety or effectiveness. We have carefully reviewed Agency records concerning the withdrawal of CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, from sale. We have also independently evaluated relevant literature and data for possible postmarketing adverse events. At the time of the approval of CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, there was significant unmet medical need. With the approval of additional therapies with less severe adverse drug effects, FDA has determined that the risks associated with CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, as currently labeled, outweigh the benefits. Most importantly, CHLOROMYCETIN (chloramphenicol) Capsules, 250 mg, may cause a number of adverse reactions, the most serious being bone marrow depression (anemia, thrombocytopenia, and granulocytopenia temporally associated with treatment).

FDA also determined that the latest labeling for CHLOROMYCETIN is deficient, that a Risk Evaluation and Mitigation Strategy would be necessary to ensure that the benefits of the drug outweigh its risks, and that additional nonclinical and possibly clinical studies of safety and efficacy would be necessary before the drug product could be remarketed. Given FDA’s determination, FDA removed CHLOROMYCETIN 250 mg from the Orange Book pursuant to FDC Act § 505(j)(7)(C). (Both the 100 mg and 50 mg strengths of CHLOROMYCETIN remain listed in the discontinued section of the Orange Book.)

Under the FDC Act, FDA may refuse to approve an ANDA if the Agency determines that the RLD was withdrawn from sale for reasons of safety or effectiveness. In addition, FDA can withdraw or suspend approval of an ANDA if the RLD is withdrawn from sale for reasons of safety or effectiveness (FDC Act § 505(j)(6)). With respect to an ANDA suspension under FDC Act § 505(j)(6), FDA’s regulation at 21 C.F.R. § 314.161(d) provides that the Agency will initiate a proceeding in accordance with 21 C.F.R. § 314.153(b). That regulation lays out the procedures for suspension of an ANDA when the RLD is voluntarily withdrawn for safety or effectiveness reasons. Specifically, the regulation states, in relevant part:

(1) If a listed drug is voluntarily withdrawn from sale, and the agency determines that the withdrawal from sale was for reasons of safety or effectiveness, the agency will send each holder of an [ANDA] that is subject to suspension as a result of this determination a copy of the agency’s initial decision setting forth the reasons for the determination. . . .

(2) Each [ANDA] holder will have 30 days from the issuance of the initial decision to present, in writing, comments and information bearing on the initial decision. If no comments or information is received, the initial decision will become final at the expiration of 30 days.

(3) Comments and information received within 30 days of the issuance of the initial decision will be considered by the agency and responded to in a final decision.

(4) The agency may, in its discretion, hold a limited oral hearing to resolve dispositive factual issues that cannot be resolved on the basis of written submissions.

(5) If the final decision affirms the agency’s initial decision that the listed drug was withdrawn for reasons of safety or effectiveness, the decision will be published in the Federal Register in compliance with § 314.152, and will, except as provided in paragraph (b)(6) of this section, suspend approval of all [ANDAs] identified under paragraph (b)(1) of this section and remove from the list the listed drug and any drug whose approval was suspended under this paragraph. The notice will satisfy the requirement of § 314.162(b). . . .

(6) If the agency determines in its final decision that the listed drug was withdrawn for reasons of safety or effectiveness but, based upon information submitted by the holder of an [ANDA], also determines that the reasons for the withdrawal of the listed drug are not relevant to the safety and effectiveness of the drug subject to such [ANDA], the final decision will state that the approval of such [ANDA] is not suspended.

FDA’s December 3, 2015 letter to Armenpharm kicks off the ANDA suspension process by satisfying the first requirement under 21 C.F.R. § 314.153(b), and the letter also explains the remainder of the process. Will Armenpharm respond within 30 days?  Perhaps so. According to FDA’s December 3rd letter, the company previously corresponded with FDA in May 2013 and January 2014, apparently challenging the Agency’s determination on the withdrawal of CHLOROMYCETIN 250 mg.

We’ll keep an eye on this brewing battle. As noted above, an FDA decision to initiate procedures to suspend ANDA approval is pretty rare. (The topic was raised several years ago in the context of Midodrine HCl Tablets [Docket No. FDA-2007-N-0475], but nothing ever came of that.) Also rare is pushback on an FDA proposal to withdraw ANDA approval, but we have that too right now in the context of applications for the prescription laxative Polyethylene Glycol 3350 (see our previous post here).

In November 2013, the Drug Quality and Security Act (“DQSA”) was signed into law in an effort to increase the quality of the United States drug supply. The law contains two separate acts: the Compounding Quality Act (Title I), and the Drug Supply Chain Security Act (Title II). As industry implements new requirements, questions on office use, traceability, serialization, preemption, and licensing persist.

On January 26, 2016, the Food and Drug Law Institute (“FDLI”) will hold a one-day conference in Washington, D.C., titled “Drug Quality and Security in 2016,” to discuss the ongoing implementation of both DQSA titles and recent FDA guidance. Hyman, Phelps & McNamara, P.C.’s Karla L. Palmer will lead a breakout session on the DQSA’s Compounding Quality Act, during which she will review recently released guidance for compounders under FDC Act § 503A and § 503B and related topics (see our previous post here).

A copy of the FDLI conference agenda and information on registration is available here.  FDA Law Blog readers can get a 15% discount off the registration fee by using the following discount code: 16DQSA.

By Riëtte van Laack - 

On November 23, an updated version of the Food Labeling Modernization Act (FLMA) of 2013 was introduced.  Representatives Frank Pallone and Rosa DeLauro introduced the House bill (H.R. 4061) and a Senate version (S. 2301) was introduced by Senators Richard Blumenthal and Ed Markey.  

The FLMA of 2015 proposes to amend the FDC Act to “strengthen requirements related to nutrient information on food labels, and for other purposes.”  Similar to the 2013 version (see our previous post here), the FLMA of 2015 addresses various labeling issues for conventional foods only, and not dietary supplements.  The FLMA of 2015 includes many of the same provisions as the 2013 version requiring front-of-packaging labeling, issuance of a regulation defining “natural,” an update to the definition of “healthy,” updates to the Nutrition Facts box (NFB) information and format, a regulation specifying the format of the ingredient statement, and the disclosure of caffeine content above 10 mg caffeine per serving.  So what is “new?”  

Possibly, the two most significant updates are the new provision adding sesame to the list of the major food allergens and the new provision requiring submission of food label information for imported foods.  

The FLMA adds sesame as a major food allergen and requires that FDA issue a regulation regarding the disclosure for sesame only.  These new provisions seem to mirror a 2014 Citizen Petition by CSPI.  The FLMA further includes a new requirement for an allergen declaration for non-packaged food at the retail level.  

The FLMA also includes a new provision requiring that the manufacturer or importer of any imported food submit to FDA information that must be included in the labeling of food (the NFB; ingredient statement, and any natural or artificial flavoring; any applicable allergy statements; nutrient content claims; health claims; a copy of the principal display panel; and whatever else FDA might request).  This information would be used to create a public database. 

Other new provisions concern a requirement that FDA perform consumer studies to assess consumers’ understanding of “natural” in its rulemaking defining this term, and a requirement that the NFB declare the amount of sugars and added sugars in teaspoons, in addition to grams.  The 2013 provision requiring grouping of all sources of sugar, non-caloric sweeteners, and sugar alcohols in the ingredient statement has been removed.  The FLMA of 2015 also includes new definitions of “synthetic” and “artificial” and states that high-fructose corn syrup is an example of a synthetic substance. 

By Ricardo Carvajal –

FDA’s Food Advisory Committee (FAC) will meet on December 7-8 to discuss a number of issues related to Listeria monocytogenes (L. mono) in ready-to-eat (RTE) foods.  As summarized in the supporting background document, the public health and regulatory challenges posed by L. mono have bedeviled FDA and industry since at least 1996, when the agency established a zero tolerance for the presence of L. mono in cooked, RTE foods.  Subsequently FDA issued draft guidance documents in which it signaled that it was considering softening that stance for RTE foods that do not support the growth of L. mono, based on a risk assessment and follow-on analysis suggesting that such foods presented a lower risk of listeriosis.  A move away from zero tolerance certainly would have been welcome by affected segments of industry.  However, recent developments – including a dose-response model developed by the agency, and an outbreak of listeriosis associated with ice cream – now have FDA rethinking whether a move away from zero tolerance would be adequately protective of “the most vulnerable individuals in at-risk subpopulations.”  

The FAC meeting would be noteworthy even if the above issue were the only one on the agenda.  However, FDA has teed up a number of other significant issues, including:

• Whether frozen vegetables and foods that appears to be cooked should be considered RTE, even if they bear cooking instructions;
• Whether FDA should soften its stance on steps manufacturers should take when they detect Listeriaspp. on a food-contact surface, so as not to discourage the implementation of “robust Listeria control programs”;
• The need to generate data to help FDA distinguish between contamination of produce with L. monothat could occur in packinghouses versus contamination originating in a growing area – an issue of interest to produce packers regardless of whether they are subject to the new produce safety rule or the preventive controls rule issued under the authority of FSMA; and 
• Whether FDA should change its sampling priorities, which are currently biased toward increased sampling of foods that support the growth of L. mono.

Additional information on the meeting – including access to all background materials – is available here.

By Kurt R. Karst –       

On November 18, 2015, Representative Peter Sessions (R-TX) introduced H.R. 4075, the Cosmetic Modernization Amendments of 2015, to little fanfare. The bill continues a recent trend among legislators (both federal and state) to attempt to legislate in the personal care products space. In addition to the Cosmetic Modernization Amendments of 2015, there’s the Microbead-Free Waters Act of 2015 (S.1424 and H.R.1321) that would begin a phase-out of synthetic microbeads used as exfoliants in some personal care products, and the Humane Cosmetics Act (H.R. 4148) that would phase out animal-based testing for cosmetic products in the United States. There have also been other bills in recent years that, like H.R. 4075, are broad in scope insofar as FDA regulation is concerned. There’s the Safe Cosmetics and Personal Care Products Act of 2013 (H.R. 1385), the Cosmetic Safety Amendments Act of 2012 (H.R. 4395) (see our previous post here), the Safe Cosmetics Act of 2010 (H.R. 5786) (see our previous post here) and the more recent Personal Care Products Safety Act of 2015 (S. 1014) (see our previous post here).

The Cosmetic Modernization Amendments of 2015 is a pared down version of some of the “Safe Cosmetics” bills mentioned above. H.R. 4075 would amend the FDC Act to add several new sections and would redefine cosmetics as we know them under the FDC Act.

Proposed Section 605 would require FDA to promulgate regulations requiring that every domestic and foreign establishment engaged in the manufacture of a cosmetic intended to be sold in the United States, and that is not otherwise exempt under another section of the bill (e.g., beauty shops, spas, and cosmetic retailers), be registered with FDA within 60 business days after the first commercial sale of a cosmetic in the United States. FDA would provide each registrant with a unique “cosmetic establishment registration number” and would create a publicly available list of registered establishments.

Proposed Section 606 would require FDA to promulgate regulations requiring that every domestic establishment and foreign establishment engaged in the manufacture of a cosmetic intended to be sold in the United States to submit to the Agency a “cosmetic and ingredient statement” for each cosmetic manufactured in the establishment (except for cosmetics manufactured by establishments exempt from registration) within 60 business days after the first commercial sale of the cosmetic. The statement would include the unique establishment registration number of each manufacturing establishment where the cosmetic is manufactured, the brand name(s) for the cosmetic, the applicable cosmetic category or categories for the cosmetic, the ingredients in the cosmetic, and establishment contact information.   FDA would be required to use the statement information to compile and maintain an up-to-date and publicly available electronic list of cosmetics and ingredients.

Proposed Section 607 would require FDA to promulgate regulations requiring that a domestic or foreign manufacturer, packer, or distributor whose name appears on a cosmetic label to submit to FDA 15-day adverse event reports. Specifically, such reports would include “information received concerning any serious and unexpected adverse event in the United States allegedly associated with the use of the cosmetic for which it is reasonably likely that the adverse event was caused by the cosmetic when used as recommended or suggested in the labeling,” and “a copy of the label for the cosmetic.” The bill states specifically that such adverse event reports “shall not be construed as an admission that the cosmetic involved caused or contributed to the adverse event,” and that they “may be accompanied by a statement that denies that the report constitutes an admission that the cosmetic involved caused or contributed to the adverse event.”

Proposed Section 608 would permit FDA to establish by regulation “principles and standards for good manufacturing practice for the manufacture of cosmetics” in accordance with FDC Act §§ 601(a) and (d), which sections specify when cosmetics are adulterated.

Proposed Section 609 would provide what ingredient and nonfunctional constituent categories are “deemed to be adequately substantiated for safe use in cosmetics subject to the requirements of good manufacturing practice.” Safe ingredients include:

• Color additives approved by [FDA] for use in cosmetics, within any limits established in such approval;
• Food additives approved by [FDA] for direct addition to food for human consumption, within any limits established in such approval;
• Food ingredients that have been determined by [FDA] to be generally recognized as safe for direct addition to food for human consumption, within any limits established in such determination;
• Food ingredients for which monographs have been included in the Food Chemicals Codex for direct addition to food for human consumption, within any limits established in such monographs;
• Pharmaceutical excipients and inactive ingredients approved or permitted by the Secretary, listed on a [FDA] website for use in drugs for human consumption or for which monographs have been included in the Handbook of Pharmaceutical Excipients, within any limits established in such lists or monographs;
• Cosmetic ingredients that have been reviewed for safety by a qualified nongovernmental or governmental expert scientific body, including the Cosmetic Ingredient Review Expert Panel, and that are the subject of a monograph published in a peer-reviewed scientific journal, within any limits established in such monographs;
• Fragrance ingredients that have been reviewed for safety by a qualified nongovernmental or governmental expert scientific body, including the Research Institute of Fragrance Materials Expert Panel, and that are the subject of a monograph published in a peer-reviewed scientific journal, within any limits established in such monographs; and
• Cosmetic ingredients approved or permitted for use in cosmetics by any of the countries listed in section 802(b)(1)(A) as having an adequate regulatory authority, within any limits established by such regulatory authority.

Safe nonfunctional constituents are those that fall within certain levels specified in the bill. For example, “[t]he levels approved or permitted for nonfunctional constituents by [FDA] for color additives for cosmetic use and for food additives and generally recognized as safe food ingredients for direct human consumption,” and “[t]he levels approved or permitted for nonfunctional constituents by [FDA] or the United States Pharmacopeia for oral nonprescription drugs.”

FDA would also be required to establish within the Center for Food Safety and Applied Nutrition a program “to evaluate and make determinations, by regulation, on the safe use of cosmetics and ingredients and nonfunctional constituents thereof.”

The Cosmetic Modernization Amendments of 2015 includes several smaller provisions – at least in length (but not in effect) – concerning myriad topics, including requiring the establishment of a “National Cosmetic Regulatory Databank” containing various pieces of information required to be submitted to FDA under the bill, providing when the importation of a cosmetic may be denied, and, importantly, revising FDC Act § 752 to rename it “National Uniformity for Cosmetics” and to make modifications concerning the scope of the preemption provision (think preemption of California Proposition 65). Also tucked away in a section of the bill titled “Special Rules” is an attempt to redefine the term “cosmetic.”

Currently the statute defines the term “cosmetic” at FDC Act § 201(i) to mean:

(1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.

The Cosmetic Modernization Amendments of 2015 would amend that definition as follows:

(b) Cosmetic definition.— Section 201(i) (21 U.S.C. 321(i)) is amended by adding at the end the following: “An article described in subparagraph (1) that is intended only for topical external use to alter the appearance by temporarily affecting the structure or any function of the human skin, and that is not the subject of an approved new drug application under section 505, shall, for purposes of this Act, be treated only as a cosmetic and not a drug.”

If this definition is enacted, it would significantly change the historical line defining the boundary between drug claims and cosmetic claims for topical products, pushing some claims that are now drug claims over into cosmetic territory.

By Kurt R. Karst –

Last Wednesday, November 25, 2015, after a long slog through the legislative process (see our previous post here), President Obama signed into law the Improving Regulatory Transparency for New Medical Therapies Act (H.R.639). (Unlike other bills, H.R.639 doesn’t have a sexy acronym, so we’ll just refer to it as “the Act.” “IRTNMTA” – the Improving Regulatory Transparency for New Medical Therapies Act – rolls off the tongue about as easily as “FLDSMDFR” – the “Flint Lockwood Diatonic Super Mutating Dynamic Food Replicator” – for those of you with children or who are fans of the movie “Cloudy with a Chance of Meatballs.” And here’s the obligatory You Tube clip explaining the FLDSMDFR.)

The Act amends the FDC Act to add Sections 505(x) (human drugs) and 512(q) (animal drugs), and the PHS Act to add Section 351(n) – in each case titled “Date of approval in the case of recommended controls under the CSA” (where “CSA” is the Controlled Substances Act) – to provide, in general, that:

with respect to a [human or animal] drug [or biological product] for which the Secretary provides notice to the sponsor that the Secretary intends to issue a scientific and medical evaluation and recommend controls under the [CSA], approval of such application shall not take effect until the interim final rule controlling the drug is issued in accordance with [CSA § 201(j)].

Specifcally, the Act provides that the “date of approval” of an NDA, NADA, or Section 351(a) BLA for a controlled substance awaiting a scheduling determination by the DEA is the the later of the date of NDA, NADA, or Section 351(a) BLA approval, or “the date of issuance of the interim final rule controlling the drug.” A similar change is made to the Patent Term Extension (“PTE”) statute at 35 U.S.C. § 156(d)(1) to provide that the 60-day deadline for filing a PTE application with the PTO for a patent on a covered drug subject to CSA scheduling is the later of application approval or “the date of issuance of the interim final rule controlling the drug under [CSA § 201(j)].” (There are some additional provisions under the Act applicable to animal drugs for minor use and minor species – FDC Act § 571 – and to marketed unapproved new animal drugs for minor species – FDC Act § 572 – but we won’t get into those provisions here.) Further, the Act amends the CSA to add Section 201(j) concerning issuance of an interim final rule scheduling a drug under the CSA. (The Act also makes other changes to the CSA concerning enhancing new drug development and re-exportation among members of the European Economic Area.)

Putting aside for a moment all of the legal citation and what not, what’s the bottom line of the Act? Well, as explained in so many words in the House Report accompanying the Act, the Act would remedy an unfairness created by bureaucratic red tape. Drug products containing controlled substances can be approved, but, until the enactment of the Act, were unable to be marketed until the DEA issued a final determination scheduling the controlled substance under the CSA (and appropriate labeling changes were made reflecting the scheduling determination). In some relatively recent instances, that has meant that a company has been unable to market its drug product after FDA approval – sometimes for more than a year – while the 5-year period of New Chemical Entity (“NCE”) exclusivity has ticked away. By resetting the date of approval of a drug product containing a controlled substance requiring scheduling to be the later of the date of application approval or the date of issuance of the interim final rule scheduling drug, a company will not be punished by a scheduling delay.

Eisai Inc. (“Eisai”) led the charge to change the law. The company initially sued DEA to force the issuance of a Notice of Proposed Rulemaking to schedule FYCOMPA (perampanel) Tablets (NDA 202834) (see our previous post here), and petitioned FDA alleging that the Agency erroneously triggered the 5-year NCE exclusivity periods for FYCOMPA and BELVIQ (lorcaserin HCl) Tablets (NDA 022529) before the drugs were scheduled by the DEA under the CSA (see our previous post here).  After FDA denied Eisai’s Citizen Petition (Docket No. FDA-2013-P-0884), the company sued FDA (see our previous post here).  In September 2015, the U.S. District Court for the District of Columbia granted FDA’s Motion for Summary Judgment and denied Eisai's Motion for Summary Judgment. Judge Randolph D. Moss concluded that despite some good arguments put forth by Eisai, FDA’s interpretation of the Agency’s own controlling regulation defining the term “date of approval” is not plainly erroneous or inconsistent with that regulation (see our previous post here).

While the Act clearly applies to future instances in which DEA delays cut into a company’s period of NCE exclusivity, it’s unclear to us whether or not the Act will have any retroactive effect to apply to cases such as FYCOMPA and BELVIQ. The Act does not include an “effective date” provision, perhaps leaving open the door for some argument for retroactive effect. This is not a new debate in the context of newly enacted legialtion. As former FDA Chief Counsel Daniel E. Troy noted in his treatise on retroactive legislation, “[t]he problem of defining when laws are and are not retroactive, and when they should and should not be permitted, is of ancient origin.”

By Riëtte van Laack –

In 2002, FDA issued regulations providing for a process, the Time and Extent Application (TEA), to create a new Over-the-Counter (OTC) drug monograph or amend an existing monograph to recognize that an active ingredient or condition (e.g., dosage form) is Generally Recognized as Safe and Effective (GRASE).  The TEA review is a two-step process: first, the drug must be determined eligible, in which case FDA will publish a notice of eligibility (NOE); and, second, the drug must be determined GRASE.

The Sunscreen Innovation Act (SIA), enacted in 2014 (see our previous post here), amended the FDC Act to provide specific deadlines for FDA’s review of TEAs for sunscreen active ingredients.  Among other things, the SIA sets deadlines for FDA’s determination of eligibility, review of safety and efficacy data, publication of a proposed order, and publication of a final order.  The SIA applies to sunscreen TEAs that were pending before its enactment and to new sunscreen TEAs. (The SIA also applies to non-sunscreen ingredients with separate but similar procedures).

The SIA also required that FDA, within one year of the enactment of the SIA, publish draft guidance on the implementation of, and compliance with, the requirements of the SIA with respect to sunscreens.  A few days before this one-year deadline, FDA issued the required draft guidance, in the form of four draft guidance documents on:

1. format of submissions by the sponsor to support GRASE status;
2. withdrawal of a sunscreen TEA;
3. requesting an advisory committee review; and
4. safety and effectiveness data to determine whether a sunscreen active ingredient is GRASE.

In light of FDA’s determination that all pending sunscreen TEAs were lacking sufficient information to determine that the active ingredients are GRASE, the draft guidance on required data to support GRASE status of the sunscreen ingredient undoubtedly will get the most attention.  Nevertheless, the other draft guidance’s should not be ignored as they provide information relevant to pending as well as new TEAs as well.

For example, FDA’s draft guidance on content and format of the sponsor’s submission in support of the GRASE status of the sunscreen active ingredient reminds sponsors that they “should not submit . . . evidence of safety and efficacy that the sponsor has marked as confidential.”  Not surprisingly, the data to support a GRASE determination must be publicly available.  

The draft guidance on withdrawal of sunscreen TEAs describes the consequences of withdrawal at various stages in the SIA process.  Notably, FDA intends to consider a sunscreen TEA withdrawn if a sponsor fails to respond within 90 days for a request for data or update by FDA. Although, FDA generally will stop the review process upon receipt of a request for withdrawal, the request for withdrawal may not affect the process if the withdrawal occurs after a proposed order has been published.  In that case, FDA may proceed and issue a final order. 

The draft guidance on requesting advisory committee review clarifies what conditions, according to FDA, may merit an advisory committee review and the process that FDA will use when it determines an advisory committee meeting is warranted.  The SIA limits the number of advisory committee meetings FDA must convene per sunscreen TEA and per year.   The combination of FDA’s limits on what conditions merit a committee review, the costs of organizing an advisory committee meeting and FDA’s limited resources, suggests that the likelihood of FDA's granting an advisory meeting request is low.

Safety and effectiveness data for GRASE sunscreens

As mentioned above, what data are required to support a determination that a sunscreen active ingredient is GRASE has been an issue of discussion.  In 2014, FDA held a 2-day meeting of the Nonprescription Drugs Advisory Committee to discuss the data requirement.  Thus far, FDA has determined that the data for the eight pre-SIA sunscreen TEAs were insufficient to support that any of these ingredients are GRASE. 

FDA's draft guidance describes the various studies that may be needed.  According to FDA, “the proposed studies are not novel and are consistent with [FDA’s] standard data requirements for approved topical drug products for chronic use.” 

Safety issues that FDA wants addressed include: dermal tests to determine irritation, rashes, reaction to exposure to the sun (photo safety studies), available adverse event data, and absorption through the skin (maximal usage trial).  If the ingredient is absorbed, additional data (in animals) regarding carcinogenicity, reproductive harm, and possible endocrine effects due to systemic exposure (in addition to dermal exposure studies) may be required.  Whether pediatric studies are required will depend on the characteristic of the ingredient.

Efficacy testing on the ingredient should be done in accordance with the procedures described in FDA’s regulation for SPF testing of monograph products, 21 C.F.R. 201.327(i). 

One novel issue is FDA’s discussion on possible requirement for final formulation testing.  Apparently, “FDA has not yet determined whether final formulation testing as described in [its draft guidance]” will be required.  FDA “is particularly interested in . . . a scientifically persuasive rationale as to why” such testing would not be necessary or alternative approaches to the one described in the draft guidance.

FDA opened separate dockets for the four draft guidances.  Comments must be submitted by January 22, 2016. 

Earlier this week we received an email from the editors of the American Bar Association (“ABA”) Journal announcing that Hyman, Phelps & McNamara, P.C.’s FDA Law Blog was selected to the 2015 (and 9th annual) ABA Blawg 100.  The Blawg 100 is a list of the top 100 legal blogs in the blogosphere, as selected by the ABA from a list of more than 4,000 blogs.  This is the fifth time we have made the list (we were previously given the honor in 2009, 2010, 2013, and 2014).  Thank you to our loyal readers who nominated us!  We’ll promptly add the coveted badge handed out by the ABA to the “Awards & Honors” section of the FDA Law Blog.  

In addition to the Blawg 100, the December issue of the ABA Journal includes an interesting piece, titled “What is the state of the legal blogosphere?”  It traces the evolving nature of law blogs and discusses some of the effects of law blogs on the broader legal community.  The article also notes how difficult legal blogging can be.  “Law blogging is not for the faint of heart,” says one legal blogger.  Yeah, we know!  It’s hard work.  We’ve spend more nights at work putting together posts than we care to remember.  After all, we have a deadline to meet.  “But done correctly it is a very powerful tool in this advanced technological age,” notes the same legal blogger.  It is.  And as we finish up our ninth year of blogging, we think (and hope) that we’ve mastered the “secret sauce” of legal blogging.  It’s a pinch of this and a dash of that.  You have to be thoughtful, creative, timely, and, above all, committed (both the dedicated and “strait-jacket” meanings of the word apply).  A successful blog also requires teamwork.  And that’s a hallmark of Hyman, Phelps & McNamara. 

REMINDER: You can follow FDA Law Blog on Twitter @fdalawblog

As combination products continue to increase in number and complexity, FDA has shifted its focus to developing more effective ways to review them.  While FDA has strived to clarify regulatory requirements and coordinate product reviews among the various centers, it is often difficult to know how a product will be classified and, as a result, what center will be tasked with reviewing its application. 

On December 17, 2015, the Food and Drug LawInstitute (“FDLI”) will hold a workshop in Washington, D.C., titled “Combination Products Workshop – A Comprehensive Overview,” that is intended to provide a comprehensive look at how FDA makes its jurisdictional decisions, how a company can file a persuasive, accurate Request for Designation, and how to understand and fulfill the manufacturing practices required.  Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will participate on a panel at the workshop focusing on streamlined cGMP requirements, including the draft guidance issued earlier this year.

A copy of the FDLI workshop agenda and information on registration is available here.  FDA Law Blog readers can get a 15% discount by using speaker referral code COMBO15.

By Ricardo Carvajal –

In tandem with its approval of genetically engineered (GE) salmon (see our previous post here), FDA issued two guidance documents on labeling of GE foods – a final guidance document applicable to foods derived from GE plants, and a draft guidance document specific to GE salmon.  The guidance documents are very similar in content, so it seems fair to speculate that the issuance of the final guidance for GE plant foods was prompted by the need to issue a draft guidance that addressed labeling of the newly approved GE salmon.  The latter is novel in the sense that it accompanies FDA’s first approval of a food derived from a GE animal.  However, the positions articulated in both guidance documents are hardly novel; rather, they echo positions staked out in the draft guidance on labeling of GE foods that FDA issued in 2001. 

In the GE plant foods final guidance, FDA continues to:

• Adhere to the view that bioengineered foods do not “differ from other foods in any meaningful or uniform way, or that, as a class, foods developed by the new techniques present any different or greater safety concern than foods developed by traditional plant breeding.”  By implication, labeling of GE foods as such cannot be required on those bases. 

• Frown on the use of the terms “genetically modified” and “GMO” on the grounds that the terms are less scientifically accurate than alternate terms such as “genetically engineered” or “bioengineered.”  However, the agency makes clear that it does not intend to take enforcement action when the term “GMO” is used in claims that a food was or was not produced through genetic engineering, provided that the claim is true “and the labeling is not otherwise false or misleading.” 

• Recommend against the use of the claim “GMO-free” due to the difficulties of substantiating that claim – difficulties that are addressed in the guidance in some detail.  Instead, FDA recommends that manufacturers use the process-oriented claims favored by the agency.

• Disfavor the incorporation of descriptors regarding bioengineering into a food’s common or usual name, on the ground that such descriptors constitute impermissible intervening material

FDA also continues to address voluntary labeling of foods that are derived from GE plants.  However, that discussion now follows the discussion of labeling of foods that are not derived from GE plants – perhaps a tacit recognition of greater interest in the latter than may have been anticipated in 2001. 

Not surprisingly, FDA’s guidance is silent on the question of whether GE foods can properly be labeled as “natural” – a question on which FDA recently asked for comment (see our previous post here).  However, coming on the heels of that request for comment, the issuance of the GE labeling guidance documents serves as an additional indication that FDA is ready and willing to engage on labeling issues that fall under its jurisdiction – an important development in and of itself.

By Anne K. Walsh & John R. Fleder –

As we reported in September, DOJ’s Deputy Attorney General Sally Quillian Yates released a seven-page memorandum announcing DOJ’s reinforced efforts to bring cases against individuals. She anticipated that DOJ would revise the U.S. Attorney’s Manual (USAM) to implement these principles. On November 16, 2015, again via a speech by Ms. Yates, this time before a group of bankers, DOJ announced the issuance of the revisions to the USAM.

For those who do not have prosecutor backgrounds, as Ms. Yates explained, the USAM is “one of the most important documents within the Justice Department community.” It sets forth guidance on how decisions are made within DOJ, and is used to detail DOJ policy and principles.

The Yates memorandum is mostly cut and pasted into various sections of the USAM, either revising existing sections (e.g., in the “Principles of Federal Prosecution of Business Organizations”) or creating wholly new sections (e.g., addressing the pursuit of claims against individuals in civil litigation). Highlights include the following:

• Section 1-12.000 has been updated to specifically identify the Yates “policy statement” emphasizing the importance of parallel civil and criminal investigations seeking to hold individuals accountable. It requires that coordination occur unless there are circumstances where the secrecy of an investigation is “paramount to the success of the investigation” or if compliance with the policy is “impractical.” This section cautions government lawyers, however, to avoid allegations of improper release of grand jury material or abuse of civil process.

• Section 4-3.100 is a new section that sets forth the same six factors Ms. Yates outlined in her original memo, that must be considered before resolving a case with a corporation. (Curiously these points are reordered from the original memo.) Like section 1.12.000, this section also advises the use of caution in sharing evidence in parallel proceedings that was obtained via the grand jury process or Civil Investigative Demands.

• Section 9-28.000 includes sections that have been newly drafted, revised, or simply renumbered. The policy underlying the Yates memo is interspersed throughout. The most significant change is the bifurcation of one of the nine factors used to determine whether to charge a corporation, into two separate factors: one focused on the company’s timely and voluntary disclosure, and the second on its cooperation. This change is intended to recognize the significant value of, and encourage, prompt voluntary disclosure by a company.

Ms. Yates announced in her more recent speech that DOJ was adding new “internal reporting and approval requirements” designed to ensure consistency within DOJ and to track how the policies are implemented. Although there may be other requirements, the USAM now prohibits a prosecutor from closing an investigation without bringing civil or criminal charges against individuals without the express approval of the U.S. Attorney or Assistant Attorney General who handled the investigation. Although declination memoranda are not atypical, this mandatory requirement to prepare and obtain approval of declination will almost certainly impact the decision-making and workload of government prosecutors.

Our firm has already seen evidence from conversations with prosecutors that they are taking the Yates memorandum to heart. Government investigations of companies will be getting much more complicated as companies and their counsel will need to carefully weigh the impact of their interactions with prosecutors on potential cases that may be brought against the company’s current and former officials. Whether to get individuals separate counsel will be just one of many thorny issues that companies will need to address when they learn of a government investigation.

The government enforcement world is getting more and more complicated every day.