Patent Docs

A Solution in Search of a Problem

By Kevin E. Noonan --

On March 8th, a canonical "bipartisan of Senators" (a phrase used to signal bills that must be in the public interest because these Senators put aside business as usual to reach across the aisle) introduced S.659, entitled "The Biologic Patent Transparency Act."  These Senators (Collins, R-ME; Kaine, D-VA; Portman, R-OH; Shaheen, D-NH; Braun, R-IN; and Stabenow, D-MI) are purportedly motivated by a desire to reduce prescription drug prices (according to their websites) and have focused on differences between the Biologics Price Competition and Innovation Act (BPCIA) and the Hatch Waxman Act that, in their view, reduces "transparency" to the public's detriment.  But a close look at the provisions of the bill suggest that it solves a problem that doesn't exist and instead focuses on cosmetic changes that have little chance to resolve the issues that have arisen in the implementation of the BPCIA.

The bill provides for improvements to the so-called "Purple Book," established by the U.S. Food and Drug Administration but insufficiently utilized because listing is not tied to any penalty or disadvantage for failure to list.  The provisions of the bill (Section 2) mandate that Biologics License Applications granted under Section 351(a) of the Public Health Service Act (codified at 42 U.S.C. § 262) or abbreviated Biologics License Applications granted under Section 351(k) of the PHSA must submit to the Secretary of Health and Human Services:

[A]ny patent for which the holder of a biological product license approved under subsection (a) or (k), or a biological product application approved under section 505 of the Federal Food, Drug, and Cosmetic Act and deemed to be a license for a biological product under this section on March 23, 2020, believes a claim of patent infringement could reasonably be asserted by the holder, or by a patent owner that has granted an exclusive license to the holder with respect to the biological product that is the subject of such license, if a person not licensed by the holder engaged in the making, using, offering to sell, selling, or importing into the United States of the biological product that is the subject of such license.

In addition, the bill would amend 35 U.S.C. § 271 to include a penalty for non-compliance with this disclosure requirement:

(7) The owner of a patent that should have been included in the list described in section 351(o)(1) of the Public Health Service Act (42 U.S.C. 262(o)(1)), including any updates require under subparagraph (C) of that section, but was not timely included in such list, may not bring an action under this section for infringement of the patent.

The Senators, in introducing this bill, seem to believe that implementation of the BPCIA has been inhibited by non-disclosure by reference product sponsors (RPS) of patents that can be asserted against biosimilar applicants to their detriment.

This sentiment ignores some important facts.  First, the BPCIA already includes a provision, codified at 35 U.S.C. § 271(e)(6)(C), that seriously disincentives a reference product sponsor from failing to notify a biosimilar applicant of relevant patents:

The owner of a patent that should have been included in the list described in [paragraph 3(A), the patent disclosure of the "patent dance"], but was not timely included in such list, may not bring an action under this section for infringement of the patent with respect to the biological product [emphasis added].

Second, if any party has been disadvantaged under the BPCIA, it has been the reference product sponsor, as the result of judicial imprimatur of a strategy first employed by Sandoz to not disclose its aBLA or relevant manufacturing information to the RPS.  Enactment of S.659 will not address these issues, which include judicial interpretation of a Congressional mandate ("A biosimilar applicant shall [disclose its aBLA and relevant manufacturing information]"; emphasis added) to be optional.

Another justification for these changes in the law involves the potential difficulty in a potential biosimilar applicant identifying before the fact (i.e., before a RPS competitor committed to pursuing a biosimilar) multiple patents that might be asserted against the biosimilar applicant.  But these concerns fly in the face of available outlets (for example, www.drugpatentwatch.com) that has this information readily available.

On the other hand S.659 contains provisions that could increase transparency in useful ways, by establishing "a single, easily searchable, list that includes:

(i) the official and proprietary name of each biological product licensed under subsection (a) or (k), and of each biological product application approved under section 505 of the Federal Food, Drug, and Cosmetic Act and deemed to be a license for the biological product under this section on March 23, 2020;

(ii) with respect to each biological product described in clause (i), each patent submitted in accordance with paragraph (1);

(iii) the date of licensure and application number for each such biological product;

(iv) the marketing status, dosage form, route of administration, strength, and, if applicable, reference product, for each such biological product;

(v) the licensure status for each such biological product, including whether the license at the time of listing is approved, withdrawn, or revoked;

(vi) any period of any exclusivity under subsection (k)(7)(A) or subsection (k)(7)(B) of this section or section 527 of the Federal Food, Drug, and Cosmetic Act, and any extension of such period in accordance with subsection (m) of this section with respect to each such biological product, and the date on which such exclusivity expires;

(vii) information regarding any determination related to biosimilarity or interchangeability for each such biological product; and

(viii) information regarding approved indications for each such biological product, in such manner as the Secretary determines appropriate.

Political posturing is in vogue and particularly posturing regarding prescription drug prices.  'Twould be pretty if 'twere so that patents are the problem; bills like this one promote that narrative but at the cost of addressing systemic issues with drug pricing that will be unaffected by any changes or diminution of patent protection that protects biologic drug innovation.

FDA Issues Revised Draft Guidance Regarding Biologic Drug Naming

By Kevin E. Noonan --

More than two years ago, on January 17, 2017, the U.S. Food and Drug Administration released its Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Nonproprietary Naming of Biological Products, extended to both reference biologic drug products and their biosimilar counterparts.  The basis for this naming regime, and its extension to both types of biologic drugs, reflected the agency's rationale for providing a naming convention in the first place and was based on FDA's dual responsibilities to protect the public and at the same time facilitate availability of biosimilar drugs according to Congress's intentions in passing the BPCIA.

On March 8th, the FDA released its updated, revised, draft Guidance on non-proprietary naming of biological products, for comment purposes only.  The draft Guidance announces the update in the Introductory Section, stating that nonproprietary names of products that did not have an FDA-designated suffix would no longer be required to be revised in order to accomplish the objectives of the naming convention described in the January 2017 Guidance.  Similarly, the FDA does not intend to apply this naming convention (wherein the nonproprietary name is the combination of a core name, equivalent to a generic name for small molecule drugs combined with a four-letter suffix to designate its source but that was devoid of any meaning that would indicate its source, a so-called "nonsense" suffix).  Further, the draft Guidance states that this naming convention would not be applied to any biologic drug approved under Section 202 of the Food, Drug, and Cosmetics Act as of March 23, 2020, the sunset date wherein such drugs will be considered to be approved under a biologics license application (BLA) under section 351 of the PHS Act (known as transition biologic products).

New in this draft Guidance is "FDA's current thinking" regarding the naming convention to be applied to interchangeable biosimilar products under Section 351(k) of the PSHA.  Like biosimilar products under the earlier Guidance, the FDA intends to designate a proper name that is a combination of the "core name" and a distinguishable suffix equally devoid of meaning composed of four lowercase letters.  While not decided the draft Guidance indicates that the FDA is considering whether to include vaccines within this naming convention.

As in the earlier Guidance, the FDA justifies this draft Guidance by stating the purported advantages: to facilitate pharmacovigilance, facilitate accurate identification of these products by source and/or manufacture, and help minimize (preferably, prevent) inadvertent substitution of biological products.

The first substantive section, entitled "Scope," sets forth the biological products falling within the scope of this draft Guidance as including "therapeutic protein products, vaccines, allergenic products, and blood derivatives, and do not include in vitro reagents (e.g., antibody to hepatitis B surface antigen, blood grouping reagents, hepatitis C virus encoded antigen), blood donor screening tests (e.g., HIV and hepatitis C), and those reagents used in determining donor/recipient compatibility in transfusion medicine.  Section III provides background, including the earlier naming convention Guidance.

Section IV of the draft Guidance announces that the FDA will no longer impose a modification of previously licensed biological products to contain FDA-designated suffix because the Agency has determined that "the core objectives of the naming convention — pharmacovigilance and safe use — can be accomplished by applying the naming convention to biological products at the time they are licensed under section 351 of the PHS Act, and without applying it to licensed biological products that do not contain a suffix in their proper names."  The change is intended to "minimize the potential burden upon sponsors and the healthcare system and avoid the possibility of confusion regarding previously approved biological products.  The Guidance also espouses the FDA's belief that "applying the naming convention to all biological products at the time they are licensed under 351(a) or 351(k) is expected to mitigate the risk of inaccurate perceptions of the relative safety and effectiveness of biological products based on licensure pathway."

Turning to vaccines, the draft Guidance asserts that vaccines are within the scope of the current Guidance, and notes that it will determine whether currently available identification systems used for vaccine administration are sufficiently robust to provide "optimal pharmacovigilance" and safe dispensing practices without using distinguishable proper names.

Turning to interchangeable products, the draft Guidance states that the FDA considered two approaches: either providing a unique suffix that would distinguish the interchangeable product from other products having the same core name, or using a suffix shared with the reference product.  The Agency has concluded that interchangeable products need their own unique suffix, to permit adequate pharmacovigilance (i.e., providing a means to track which biological product is dispensed to particular patients).  Using a unique suffix will also avoid having to change those products first licensed as a biosimilar and later licensed as an interchangeable product.  The draft Guidance imposes on the applicant for an interchangeable product the requirement to suggest "a suffix composed of four lowercase letters for use as the distinguishing identifier included in the proper name designated by FDA at the time of licensure," for example during the investigational new drug (IND) phase or when a BLA is submitted.  The FDA requires "up to 10 proposed suffixes," in Applicant preference order.  In a supplement to an approved 351(k) application the draft Guidance directs that the applicant would keep the nonproprietary name of the biological product and the FDA-designated suffix and not submit further suffixes; this will be the name used throughout the propose labeling of the interchangeable product.

For the absence of doubt, the draft Guidance closes with a glossary of several of the terms used throughout the Guidance.

And like all such Guidances, this draft Guidance contains an express disclaimer:

The period for comments by the public extends until 60 days after the draft Guidance is published in the Federal Register, or until May 7, 2019.  Comments should be directed to https://www.regulations.gov (if electronic) and written comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.  The draft Guidance directs that all comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.

Finally, questions regarding this draft Guidance should be directed to Sandra Benton, 301-796-1042, or (CBER) Office of Communication, Outreach and Development, 800-835-4709 or 240-402-8010.

Guest Post -- The Final Score: 2018 Drug & Biologic Patent Approvals

By Brittany Knight* and Anthony Sabatelli** --

The past year was a big year for FDA approved new drugs and biologics -- 59 in fact, compared to 46 in 2017 and a mere 22 in 2016.  From the published list of approvals on the FDA website Novel Drug Approvals for 2018, we compiled data on the listed patents associated with these drugs.  As a whole, the 59 drugs included 42 "conventional", i.e., small molecule drugs, of which 35 were new chemical entities (NCEs approved via a New Drug Application or NDA), and 17 were biological molecules (approved via a Biological License Application or BLA).  For background, "conventional" drugs are small (i.e., generally under 1000 molecular weight), synthetically manufactured chemical entities that are chemically and molecularly well-characterized.  Currently, these drugs make up the majority of approved drugs.  Information regarding patents and exclusivity for these "conventional" drugs is referenced in the Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the 'Orange Book'[i].

On the other hand, biological molecules or 'biologics' are a newer class of drugs that are either produced in living organisms or contain biological materials.  Compared to their small molecule chemical counterparts, biologics are not as easily characterized.  Examples of biologics include, vaccines, gene therapies, cellular biologics, and recombinant proteins.  More limited information regarding biologic drug products can be located in the 'Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations', also known as the 'Purple Book'[ii].  However, since this book was established in 2014, information regarding pertinent patent and exclusivity of biologics remains a challenge to access.  Although the Purple book is still relatively new, the FDA should consider including this patent information in the future.  In the table below, each of the 59 approved drugs are listed and for each of the 42 conventional drugs we compiled the listed patents.

In summary, a total of 216 patents are listed for the 42 approved conventional drugs.  Nine of these drugs have no listed patents.  This turns out to average just over 5 patents per drug.  With the most listed patents -- a whopping 21 -- is Alnylam's drug Onpattro (active ingredient - patisiran) for the treatment of hereditary transthyretin-mediated amyloidosis or Familial amyloid polyneuropathy (FAP).  FAP is a fatal neurodegenerative disease that affects approximately 50,000 people worldwide.  Second highest with 18 patents was Vitrakvi (larotrectinib) by Loxo and Bayer to treat TRK fusion-related cancers.  TRK fusion proteins are known to promote tumor formation in a variety of cancers that affect adults and children.  And in third place, with 17 associated patents, is Vertex's Symdeko (tezacaftor; ivacaftor) for the treatment of Cystic fibrosis.

In addition, 2018 was also noteworthy for the approval of GW Pharma's Epidiolex (cannabidiol), a cannabis-related drug (with 8 patents listed).  This was an exciting and perhaps controversial approval considering the stigmas, public policy considerations, and current laws regarding marijuana in the United States.  Late last year, Surgeon General Jerome Adams asked the U.S. government to reconsider the classification of marijuana.  Currently, as it stands marijuana is a schedule I drug with no currently acceptable medical use with high likelihood for abuse.  However, the potential health and economic benefits associated with cannabis have yet to wait upon these impending changes to national policy.  Additionally, it will be interesting to follow future R&D and intellectual property trends as more approvals are likely to follow in the cannabinoid area in the future.  Nevertheless, it was interesting to see the relatively large number of patents listed for Epidiolex.

Summary Table of 2018 Drug Approvals
Note: Drugs are delineated by their approval via New Drug Application (NDA) or Biologics License Application (BLA)

[i] The first print copy of Approved Drug Products with Therapeutic Equivalence Evaluations was published around Halloween in 1980, thus inspiring the orange cover and the nickname.

[ii] Since "Orange" became a single-color nickname for Approved Drug Products with Therapeutic Equivalence Evaluations, the FDA named the book of licensure for biological molecules as the Purple Book.  Ironically, this is not a book of conventional sorts and it does not have a Purple cover.

[iii] Patent information for drugs approved via a Biologics License Application (BLA) is not included in the table.

* Brittany Knight is a Ph.D. Candidate in the Biomedical Sciences Ph.D. Program in the Neuroscience Department at the University of Connecticut.  Prior to attending the University of Connecticut, Brittany obtained her B.S. in Psychology and a minor in Biology with Global Honors with Distinction from Lock Haven University of Pennsylvania.
** Dr. Sabatelli is a Partner with Dilworth IP

Guest Post -- The Priority Review Voucher: An Untapped Asset

By David Puleo* and Anthony D. Sabatelli** --

Typically, we think of patents as the main tool that allows for product exclusivity in the pharmaceutical industry.  However, exclusivity has a regulatory component.  For example, a new drug product cannot be marketed until it has undergone review and approval by the U.S. Food and Drug Administration (FDA) or other foreign counterpart.  Probably the most familiar regulatory exclusivity is the five years given upon approval of a new drug application (NDA) during which no generic drug application can be filed.[1]  This regulatory exclusivity is a valuable asset, so much so in fact that it is often desirable to accelerate the drug approval process.  An untapped asset that has arisen out of this framework is the priority review voucher (PRV).  A helpful summary on PRVs was recently published in a piece from the Regulatory Affairs Professional Society.

PRVs were first proposed in 2006 by faculty at Duke University to incentivize the development of drug therapies, specifically citing the unmet medical need for treatments against tropical diseases.[2]  One year later, the FDA implemented the Priority Review Voucher Program, which allows for expedited review of those drugs treating rare or unmet diseases.  The first program, which was created under the FDA Amendments Act of 2007, encouraged development of treatments for disease on the FDA list of tropical diseases, which includes tuberculosis, malaria, and cholera, to name a few.  The FDA also has PRV programs for Rare Pediatric Diseases (RPD) as well as for Medical Countermeasures.  Interestingly, these vouchers can either be used by the company that originally purchased them or can be re-sold to other companies and, thus, are seen as a valuable asset.  The first PRV re-sold for $67M in 2014; the most expensive was sold by United Therapeutics (UT) to AbbVie for $350M.  These prices are dizzying, considering that the FDA fees for the initial drug application filers are just north of $2M.  Despite this, vouchers have become coveted property.

However, it appears that the value of PRVs has been declining in recent years.  Recently, Kyowa Hakko Kirin and partner Ultragenyx sold an RPD PRV to an undisclosed party for for $80.6 million, 3-4 fold less than the aforementioned UT-AbbVie deal.  However, it is not readily apparent why the value is decreasing.  One reason could be that the FDA has been issuing an increased number of PRVs.  Lawmakers see the added value in how PRVs drive innovation and treatments for unmet diseases; their opinions could have contributed to this trend.  It is uncertain whether this trend will continue.  Nonetheless, PRVs are an important part of a company's portfolio and are still a valuable bargaining chip and exclusivity asset in the tool box of the pharmaceutical company.

[1] See 21 U.S.C. § 355(c)(3)(E)(ii) of this section of the U.S. Code relating to New Drugs.  The situation is more complex and other regulatory provisions apply, but the point being made is that the FDA provides for various exclusivity periods for small molecule drugs.  Analogous periods of exclusivity are provided under provisions for the Regulation of Biological Products at 42 U.S.C. § 262.

[2] See the seminal paper proposing PRVs can be found here.

* David Puleo is Technology Specialist with Dilworth IP
** Dr. Sabatelli is a Partner with Dilworth IP

FDA Issues Plan for Further Facilitating Biosimilar Development

By Kevin E. Noonan --

Earlier this month, the U.S. Food and Drug Administration announced a new initiative, the Biosimilars Action Plan: Balancing Innovation and Competition in furtherance of its efforts "to ensure that this balance between innovation and competition exists across the spectrum of pharmaceutical products."  The hoped-for outcome of the BAP:  that "[a]fter patents or other exclusivities expire on these novel products, prices can fall dramatically once follow-on products are available, potentially lowering costs for patients and payors and expanding access to these innovations."

The Introduction states that:

The agency is taking steps to more efficiently manage our review and licensure pathways to facilitate biosimilar competition.  We are modernizing our policies that govern the development of biosimilar to make it more efficient.  We are also educating clinicians, payors and patients about biosimilar products and the rigorous evaluation they must go through.  And, we are modernizing regulatory policies to accommodate new scientific tools that can better enable comparison between biosimilars and reference products that may reduce the need for clinical studies.

Some of the bureaucratic measures the agency intends to implement in furtherance of these efforts include:

1.  Introducing new FDA tools to improve efficiency of FDA review (e.g., templates "tailored to marketing applications for biosimilar and interchangeable products")
2.  Creating information resources and development tools for biosimilar applicants (in silico models and simulations for correlating PK/PD responses to clinical outcomes)
3.  Enhancing the Purple Book
4.  Looking into data sharing agreements with foreign regulators
5.  Establishing a new Office of Therapeutic Biologics and Biosimilars to improve coordination under the BsURA program
6.  Providing critical education to health care professionals
7.  Finalizing Guidance on labeling
8.  Providing finalized Guidance on interchangeable biosimilars
9.  Improving analytical approaches for structure/function for demonstrating biosimilarity including statistical methods
10.  Implementing standards for manufacturing quality control
11.  Improving public dialog with hearings and requests for public input on FDA actions to evaluate and promote biosimilars

Why now?  The FDA contends that "[t]his is a crucial time in the emergence of the marketplace of biosimilar and interchangeable products."  The agency expects continued expansion in the number of approved biosimilar and interchangeable products in the coming years.  The announcement of this new initiative recognizes "barriers to marketing a biosimilar or interchangeable product that are outside of the FDA's purview," but assert that it is part of the agency's mandate to "advance[e] policies to facilitate the efficient development and approval of these products."  Hence, the enunciation of the BAP.

There are four "key elements" of the BAP:

1.  Improving the efficiency of the biosimilar and interchangeable product development and approval process

How?

• Providing application review templates, formatted for 351(k) BLA requirements
• Transitioning to a Therapeutic Biologics and Biosimilars Staff (TBBS) from the Office of New Drugs under Center for Drug Evaluation and Research (CDER) to the Office of Therapeutic Biologics and Biosimilars (OTBB), intended to "improve coordination and support" of activities under the Biosimilar User Fee Act (BsUFA), increase agency response times, and improve efficiencies in policy development and response to applicants
• Improve coordination with CDER
• Develop information resources for biosimilar applicants, such as an "index of critical quality attributes" for comparing reference products to biosimilars, and comparison metrics that will reduce the size of clinical studies

2.  Maximizing scientific and regulatory clarity for the biosimilar product development community

How?

The FDA has issued six final (see "Nonproprietary Naming of Biological Products"; "Considerations in Demonstrating Interchangeability with a Reference Product"; "Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product"; "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"; "Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product"; and "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009") and four draft (see "Scientific Considerations in Demonstrating Biosimilarity to a Reference Product"; "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product"; "Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009," as discussed in "FDA Publishes Draft Guidelines for Biosimilar Product Development" and "More on FDA Draft Guidelines for "Follow-on" Biologic Drug Approval Pathway") Guidance documents relating to biosimilars.  The FDA expects additional Guidances to be forthcoming that will involve public hearings, prioritizing the following issues:

• Final or Revised Draft Guidance: Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act
• Final or Revised Draft Guidance: Implementation of the "Deemed to be a License" Provision of the Biologics Price Competition and Innovation Act of 2009
• Final or Revised Draft Guidance: Considerations in Demonstrating Interchangeability with a Reference Product
• Final or Revised Draft Guidance: Statistical Approaches to Evaluate Analytical Similarity
• Draft Guidance: Processes and further considerations related to post-approval manufacturing changes for biosimilar biological products

The agency is also developing guidance for biosimilar applicants who will seek approval for fewer than all conditions for which the reference product is licensed, and developing a formal rule for interpreting the definition of "biological product" under the BPCIA, to provide additional "clarity."  FDA is evaluating regulations regarding aBLA submission, and working on an enhanced Purple Book (which will contain "information about newly approved or withdrawn BLAs and about reference product exclusivity determination").

Finally, under this part of the BAP, the agency will be "[s]trengthening its partnerships with regulatory authorities in Europe, Japan and Canada" by "harmonizing requirements for their development as well as sharing regulatory experience across national boundaries," including data sharing agreements to increase the use of non-U.S.-licensed comparator products to support biosimilar application.

3.  Developing effective communications to improve understanding of biosimilars among patients, clinicians, and payors

How?

This portion of the Plan is aimed at increased educational efforts according to the Biosimilar Education and Outreach Campaign released in October 2017; continuing efforts including videos, webinars, information on the webpage, and providing educational materials for patients, pharmacists, and other stakeholders.

4.  Supporting market competition by reducing gaming of FDA requirements or other attempts to unfairly delay competition

How?

In many ways the most provocative part of the Plan, the announcement states that:

The FDA will clarify our position on issues affecting reference product exclusivity to better effectuate balance between innovation and competition.  We will also take action, whenever necessary, to reduce gaming of current FDA requirements, and coordinate with the Federal Trade Commission to address anti-competitive behavior.  Additionally, we will work with legislators, as needed to close any loopholes that may effectively delay biosimilar competition beyond the exclusivity periods envisioned by Congress.

The FDA intends to take steps for biosimilars analogous to the Drug Competition Action Plan (DCAP) the agency has implemented for generic drugs, where it was "a priority to address practices that delay or block competition from entering the market."  For generic drugs, these efforts were aimed at preventing branded drug makers from activities such as "refusal to sell the samples necessary for developing generic drugs [a practice we've seen with products under limited distribution, whether the drug maker limits distribution voluntarily or does so in connection with a Risk Evaluation and Mitigation Strategy (REMS) program]."  Insofar as such practices are being used by reference product sponsors (and the announcement does not provide any examples of such behavior, the agency states that "[w]e will apply the same principles used in DCAP to our BAP to address circumstances in which drug makers refuse to sell samples, or use any other anticompetitive strategies, to delay the entry of biosimilar or interchangeable development and competition."

In conclusion, the FDA says it expects development of biosimilar and interchangeable drugs to "continue to evolve" and thus implementation of the BAP to be "dynamic."  And:

The FDA is committed to transparent, science-based regulation of biosimilar and interchangeable products that maintains the dynamic balance between innovation and timely access, as Congress intended.  Appropriate market exclusivities allow innovators to recoup their investments, and compensate them for the time, risk and uncertainty that make the cost of capital to undertake these endeavors high.  These rewards provide incentives for research and development of new treatment options, as well as help advance medical innovation and improve outcomes.

While a good deal of this announcement is conventional bureaucratic promotion, there are a few nuggets that suggest that the FDA under this Administration may be more confrontational and aggressive towards perceived "bad behavior" by certain of its shareholders.  It is certainly the case that the price of drugs, particularly biologic drugs, is high and poses a significant cost burden on the health care system as a whole (both public and private).  The BAP appropriately addresses these concerns and recognizes that they must be addressed.  But it is also good to try to understand the economic realities that have created the situation (without excessive and unproductive finger-pointing).  It is a truism that everything has increased in price (and many things even adjusted for inflation); after all, it isn't just the elderly that are confronted with prices that seem ridiculously excessive.  But for drugs it also must be recognized, by policy makers as well as the public, that the low-hanging fruit of small molecule drugs and those with (relatively) simple etiologies have been discovered in the first flowering of the modern pharmaceutical intervention in human disease (see, e.g., Epstein, 2006, Overdose: How Excessive Government Regulation Stifles Pharmaceutical Innovation; and Rosen, 2017, Miracle Cure: The Creation of Antibiotics and the Birth of Modern Medicine).  And federal regulation, particularly by the FDA, is more extensive and costly than it was prior to the thalidomide tragedy in 1962.  While it is convenient and politically expedient to castigate the pharmaceutical industry for high prices, it is foolhardy not to recognize these and other factors in producing the current price situation.

The context of the comments in the FDA's BAP also comprises statements by Commissioner Gottleib regarding the possibility of changing U.S. drug importation regulations (but with disclaimers regarding exclusivities and prompted by "supply chain disruptions" to soften the political effects of implied threat) to permit "temporarily" importation of drugs from foreign sources.  The FDA has also created a task force to address drug shortages, either due to supply chain difficulties or source monopolization of unpatented drugs without remaining regulatory exclusivity due to sole sourcing.

But there is another aspect that is typically overlooked.  For many biologic drugs, the diseases they address are ones that a generation ago resulted in significant morbidity and mortality; indeed, some diseases were invariably fatal (many cancers, HIV) or severely debilitating (kidney disease, hepatitis).  Some of these were diseases of the elderly, and the wisdom of expending vast sums to extend few lives for short times is a topic for another day.  But for the overwhelming number of cases where individuals in the prime of life are cured or their diseases managed, these drugs provide significant advantages, both for the afflicted individuals and society as a whole.  In the most hard-hearted, dollars-and-cents analysis, what pundits who bemoan high drug costs appear to forget is that these individuals are returned to the workforce as productive participants, who hold down jobs and pay taxes and participate in the U.S. consumer economy.  Society, whether in the form of local or nationwide businesses or federal, state, and local tax collectors, reaps the benefit of those who have returned to the workforce due to the effects of biologic drugs that did not exist twenty, ten, five, or even one year ago.

And that doesn't take into account the human benefits, which now routinely permit individuals (and their spouses, sons, daughters and grandchildren) to enjoy the benefits of longer life and participation in weddings, births, and other lifetime milestones.  Undue focus on the goal -- obtaining biologic drugs at reduced prices -- raises a risk of not having these drugs, or their benefits, because private investment is frustrated and the government is a generally a poor source of innovation.  It would be well for policymakers, particularly at FDA, to keep such considerations in mind to temper their fiscal zeal.

Status of U.S. Biosimilar Approvals and Pending Applications*

By Kevin E. Noonan --

The Biologics Price Competition and Innovation Act (BPCIA) was enacted as part of the Affordable Care Act (colloquially called "Obamacare," Public Law 111-148) (see "House Passes Health Care Reform Bill -- Biosimilar Regulatory Pathway Makes Cut, Pay-for-Delay Ban Does Not").  It gave the U.S. for the first time a pathway for FDA approval of alternatives to biologic drugs (termed "biosimilars" because the complexity of these molecules precludes the atom-for-atom identity of small molecule generic drugs), codified at 42 U.S.C. § 262(k), as well as provisions for resolving patent disputes between innovator biologic drug companies (termed "reference product sponsors" in the Act) and biosimilar applicants (codified at 42 U.S.C. § 262(l)).

Nine years later, after promulgation of several Guidances by the FDA regarding how it will (and has) implemented the biosimilar pathway, it is reasonable to review what the BPCIA hath wrought.  While the litigation provisions have been the source of some controversy (and arguably have played out in ways not envisioned when the Act was passed), the biosimilar pathway has been somewhat successful in bringing a first generation of biosimilar drugs to market.  For example, as of December 2017 there were 59 biosimilar products enrolled in the FDA's Biosimilar Development Program:

And as of June 2018, 24 biosimilar applications have been filed and eleven biosimilar drugs have received FDA approval.

FDA approval of these drugs has been relatively rapid, typically taking 10-20 months from FDA acceptance to approval.  There have been some outliers; Pfizer/Hospira's Retacrit^® (a biosimilar of Epogen^®/Procrit^®) was under FDA review for 42 months.  Most (but not all) of these FDA-approved biosimilars have also been approved in Europe (some quite a while ago, paradoxically including Retacrit^® which was approved in Europe in 2007).  The FDA decided early in its implementation process that it would accept clinical and other comparative data previously submitted to European regulators, supplemented by so-called "bridging studies," in the FDA approval process. Such studies were submitted for Sandoz's Zarxio^® (filgrastim-sndz) and Erelzi^® (etanercept-szzs) biosimilars, for example.  Several products (Amgen's Amjetiva^® (adalimumab-atto), Pfizer/Celltrion's Inflectra^® (infliximab-dyyb), and Merck/Samsung Bioepsis's Renflexis^® (infliximab-abda)) were supported by double-blind clinical studies comparing the biosimilar to EU-licensed and RPS-sourced biologic drugs.

The prolonged regulatory saga for Retacrit^® illustrates the extent to which the FDA can require a biosimilar applicant to satisfy its purity, safety, and efficacy standards for a biosimilar product:

Mere approval is not sufficient, of course; many but not all of these drugs are on the market in competition with the reference biologic drug.  These include Zarxio^® (filgrastim-sndz) (in competition with Amgen's Neupogen^®), which launched in September 2015, and Inflectra^® (infliximab-dyyb) (in competition with J&J/Janssen's Remicade^®), which launched in November 2016; each of these biosimilars are sold at a 15% discount from the reference biologic drug price.  Renflexis^® (infliximab-abda) (another Remicade^® competitor) launched at risk (i.e., while patent litigation was on-going) at a 35% discount, and Amjetiva^® (adalimumab-atto) is scheduled to enter the market in competition with AbbVie's Humira^® in January 2023 as the result of a settlement agreement between the parties.  Several other approved biosimilars are not yet on the market, however; these include Boehringer Ingelheim's Humira^® biosimilar, Cyltezo^® (adalimumab-abdm); Amgen/Allergan's Avastin^® biosimilar, Mvasi (bevacizumab-awwb) (Amgen/Allergan); and Mylan/Biocon's Herceptin^® biosimilar, Ogivri (trastuzumab-dkst), despite a global licensing agreement with Genentech entered into on March 31, 2017; and Hospira's Epogen^® biosimilar, Retacrit^® (epoetin alfa-epbx).  In addition, Pfixer has decided not to enter the marketplace with its Remicade^® biosimilar, Ixifi, which would also compete with Pfizer's other Remicade^® biosimilar, Inflectra^®.

Fourteen biosimilar (§ 262(k)) applications are currently pending:

These applications have encountered more challenges on their approval pathways; several of them have received Complete Response Letters from the FDA (indicating that the agency will not approve the application under 21 C.F.R. §§ 314.125 or 314.127), and many have been pending longer than the 10-20 month average experienced by the already-approved biosimilars.

Biosimilar litigation is also proceeding and provides a reason that some of the approved biosimilars are not yet on the market (including Erelzi^®, Cyltezo^®, Mvasi, and Mylan/Biocon's Neulasta^® biosimilar, Fulphila™).  Consistent with expectations during passage of the BPCIA, there is also active litigation involving reference product sponsors and biosimilar applicants:

So far, approved biosimilars and pending biosimilar applications have been concentrated amongst the top U.S. biologic drugs, but there are several such drugs that are among these top drugs and have no prospective biosimilar competitors:

Finally, it must be recognized that other considerations can and have arisen, particularly antitrust concerns.  Pfizer filed suit against Johnson & Johnson and Janssen Biotech for antitrust violations related to alleged anticompetitive activities surrounding competition between Remicade^® and Inflectra^®.  Pfizer alleged that the defendants engaged in "improper exclusionary tactics," including exclusionary contracts, coercive rebate policies with insurers, hospitals, clinics ("fail first" restrictions), exclusionary rebates, bundling, and coverage restrictions.  This advertisement hasn't helped:

Pfizer's four-count complaint alleged Sherman Act Section 2 violations for monopolization and attempted monopolization; Clayton Act violations for entering into exclusive contracts; and Sherman Act Section 1 violations for entering into agreements in restraint of trade.  Pfizer has asked the court for $150 million in damages, attorneys' fees, costs, and an injunction.  J&J/Janssen has responded with a motion to dismiss under Fed. R. Civ. Pro. 12(b)(6) based in pleadings deficiencies under Ashcroft v. Iqbal and Bell Atlantic Corp. v. Twombly.  Substantively, defendants allege that Pfizer did not show antitrust injury or anticompetitive behavior, and that their actions were just robust capitalist competition.  The motion has been pending since November 2017, and the court has stayed discovery while considering the motion.

Within the last year, the number of approved biosimilars in the U.S. has more than doubled, and with the number of pending biosimilar applications it is likely that this trend will continue.  One aspect of the BPCIA has not yet come to pass, a designation of any biosimilar as being interchangeable.  The FDA released draft Guidance directed to the standards it is considering for awarding an interchangeability designation in January 2017 (see Considerations in Demonstrating Interchangeability with a Reference Product); a Final Guidance is expected in 2019.

*Adapted from a talk given at the American Conference Institute's 9th Annual Conference on Biosimilars, held in New York, New York on June 25-27, 2018.

GW Pharmaceuticals Wins FDA Approval of First CBD Drug

By Nicole Grimm, George "Trey" Lyons, III, and Brett Scott --

On June 25, 2018, GW Pharmaceuticals plc and its U.S. subsidiary, Greenwich Biosciences, made history in the cannabis industry by winning FDA approval of the drug Epidiolex, a cannabidiol (CBD) oral solution for the treatment of seizures associated with two rare forms of childhood-onset epilepsy (Lennox-Gastaut syndrome and Dravet syndrome).[1]  Both Lennox-Gastaut syndrome and Dravet syndrome are debilitating forms of epilepsy that have been known to be difficult to treat.  Epidiolex is the first FDA-approved drug containing plant-derived CBD, a non-psychoactive cannabinoid naturally produced by cannabis plants.

In approving Epidiolex, the FDA voiced support for further research and studies on medical uses for cannabis through its approval process.  According to FDA Commissioner Scott Gottlieb:

Controlled clinical trials testing the safety and efficacy of a drug, along with careful review through the FDA's drug approval process, is the most appropriate way to bring marijuana-derived treatments to patients . . . .  We'll continue to support rigorous scientific research on the potential medical uses of marijuana-derived products and work with product developers who are interested in bringing patients safe and effective, high quality products.[2]

However, Commissioner Gottlieb cautioned that the FDA is prepared to take action against illegal CBD-products marketed with unproven medical claims.

FDA approval of Epidiolex may also prompt the Drug Enforcement Administration (DEA) to reschedule CBD from a Schedule I drug under the Controlled Substances Act, which would be another historic event for the cannabis industry.  And, in spite of Attorney General Jeff Sessions's continuing war on cannabis, President Trump has indicated support for such a shift.[3]

Rescheduling Epidiolex is necessary for the drug to become available to patients in the U.S.  As part of the approval process, the FDA, through the Department of Health and Human Services, makes recommendations to the DEA regarding scheduling based on scientific and medical studies of scheduled substances such as Epidiolex.  In turn, the DEA is required to make a scheduling determination.  Additionally, in making its determination, the DEA will likely consider the results of clinical and nonclinical studies regarding the abuse potential of CBD that GW Pharmaceuticals conducted as part of its application for Epidiolex.  Although the FDA did not indicate whether it provided a favorable scheduling recommendation for Epidiolex, GW Pharmaceuticals stated in its press release that it expects the DEA to reschedule the drug in the next 90 days.

Rescheduling Epidiolex from a Schedule I drug may have implications for GW Pharmaceuticals' intellectual property surrounding the drug as well.  First, enforcing cannabis patents in federal district courts remains a grey area in the industry since cannabis is currently classified as a Schedule I drug.  By rescheduling Epidiolex, the drug will become legally available by prescription, and GW Pharmaceuticals should be able to enforce the patents covering Epidiolex like any other pharmaceutical patent.  In turn, the company may also experience an increase in inter partes review (IPR) proceedings to challenge patents in its portfolio.  As we have previously discussed, one of GW Pharmaceutical's patents involving treating partial seizure by administering CBD is already involved in an IPR proceeding.

Additionally, while the USPTO has categorically declined to grant trademarks based on the cannabis plant itself (and derivatives thereof), as well as cannabis goods and services that contribute to federally illegal activity (often referred to as those that "touch the plant"), rescheduling cannabis-based pharmaceuticals like Epidiolex may help eliminate any hurdles faced in obtaining federal trademark protection for such pharmaceuticals.  Indeed, unlike Schedule I drugs, scheduled prescription drugs have a legal use in commerce and are therefore routinely granted federal trademark protection.  In fact, the USPTO has already granted a trademark for Epidiolex; but note, in doing so the drug was described broadly, without referring to federally prohibited subject matter (e.g., cannabis), and instead referring to, for example, "medicinal herbs" and "medicinal infusions for the treatment of epilepsy."

Either way, right now the approval and tentative rescheduling of Epidiolex is a step in the right direction and could pave the way for other cannabis-based drugs to gain FDA approval and open up new treatment options for patients suffering from a variety of diseases moving forward.

[1] http://ir.gwpharm.com/news-releases/news-release-details/gw-pharmaceuticals-plc-and-its-us-subsidiary-greenwich

[2] https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm

[3] See, e.g., https://www.wsj.com/articles/jeff-sessions-struggles-to-get-planned-marijuana-crackdown-going-1528628400

FDA Permits Marketing of First AI-based Medical Device; Signals Fast Track Approach to Artificial Intelligence

By Aaron Gin --

"The first and only autonomous AI system authorized by the FDA"

On April 11, 2018, the U.S. Food and Drug Administration (FDA) permitted marketing of a medical device that utilizes artificial intelligence to diagnose eye disease in diabetic adults.  The device, called IDx-DR from the company IDx, screens patients for diabetic retinopathy using deep learning algorithms.  The screening involves standard retinal imaging, takes less than a minute, and can be performed without a clinician's interpretation of the images or results.  Accordingly, IDx-DR may be used in primary care offices for early detection of retinopathy, which can lead to vision impairment and blindness.

IDx founder Michael Abramoff, a retinal specialist at the University of Iowa, told Science News that the medical device is unique because it operates autonomously and there is no specialist "looking over the shoulder of the algorithm."  "It makes the clinical decision on its own."

The FDA based its decision to permit marketing of IDx-DR, in part, on a clinical trial of the system involving the screening recommendations and corresponding retinal images from over 800 diabetic patients at ten different primary care sites.  The study indicated that IDx-DR correctly identified the presence of more than mild diabetic retinopathy 87.4% of the time and correctly identified patients with less than mild diabetic retinopathy 89.5% of the time.  The former group was referred to a specialist and the latter group was scheduled for a checkup in 12 months.

Tweets from FDA Commissioner Indicate AI Push

On the same day as the IDx-DR announcement, FDA Commissioner Scott Gottlieb M.D. unleashed a string of tweets that strongly endorsed AI-based health care solutions.  Based on Dr. Gottlieb's comments, it appears that the FDA may be currently accelerating review of AI-based systems.  Looking ahead, Gottlieb also signaled that AI-specific fast track regulatory pathways are under development.

Despite such relaxed AI regulations at the FDA, however, Dr. Gottlieb tweeted that the agency's approach would maintain consumer safety by establishing "appropriate guardrails."  Based on Dr. Gottlieb's comments, it will be interesting to track the FDA approval rate and timeline of AI-based healthcare solutions.  Additionally, in the case of new AI-specific regulatory pathways, time will tell what "guardrails" the FDA will put in place to maintain adequate safety as future AI innovations are made available to patients and providers.  Data privacy, algorithmic transparency, and "unbiased" learning datasets are just a few broad areas in which the FDA might regulate artificial intelligence as applied to health care.

For additional information regarding this topic, please see:

• In the future, an AI may diagnose eye problems (Science News, March 4, 2018)
• IDx-DR (IDx LLC Website)
• FDA permits marketing of artificial intelligence-based device to detect certain diabetes-related eye problems (FDA News Release, April 11, 2018)
• Scott Gottlieb, M.D. – Commissioner, U.S. Food and Drug Administration (Twitter: @SGottliebFDA)

FDA Approves First Cancer-Treatment Biosimilar -- Amgen's Mvasi

By Andrew Williams --

Earlier today, the U.S. Food and Drug Administration approved Amgen's application to market Mvasi (bevacizumab-awwb), a biosimilar to Genentech's Avastin therapeutic antibody for the treatment of multiple types of cancer.  This marks the first time that a biosimilar for the treatment of cancer has been approved by the FDA.  According to the FDA's press release, Mvasi was approved for the following indications in adult patients:

• Metastatic colorectal cancer, in combination with intravenous 5-fluorouracil-based chemotherapy for first- or second-line treatment.  Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
• Metastatic colorectal cancer, in combination with fluoropyrimidine-irinotecan- or fluoropyrmidine-oxaliplatin-based chemotherapy for the second-line treatment of patients who have progressed on a first-line bevacizumab product-containing regimen.  Mvasi is not indicated for the adjuvant treatment of surgically resected colorectal cancer.
• Non-squamous non-small cell lung cancer, in combination with carboplatin and paclitaxel for first line treatment of unresectable, locally advanced, recurrent or metastatic disease.
• Glioblastoma with progressive disease following prior therapy, based on improvement in objective response rate.  No data is available demonstrating improvement in disease-related symptoms or survival with bevacizumab products.
• Metastatic renal cell carcinoma, in combination with interferon alfa.
• Cervical cancer that is persistent, recurrent, or metastatic, in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

FDA Commissioner Scott Gottlieb, M.D., indicated that the FDA would "continue to work hard to ensure that biosimilar medications are brought to the market quickly, through a process that makes certain that these new medicines meet the FDA's rigorous gold standard for safety and effectiveness."  As apparent evidence of this commitment, Amgen's biosimilar application was filed last November, and accepted by the FDA for review on January 4, 2017 (according to a complaint filed by Genentech in Delaware last February).  This means that the FDA approved this aBLA in less than nine months from the acceptance of the application.

Interestingly, there is currently no litigation pending that could prevent Amgen from launching its new biosimilar drug product.  Even though Amgen had disclosed its aBLA pursuant to the BPCIA, Genentech did file the aforementioned complaint to force Amgen to provide Genentech with manufacturing information allegedly not found in the aBLA.  Genentech had provided Amgen with a written request for information related to, among other things, the host cells used to manufacture the drug, the composition of the cell culture media, the extent and nature of the glycosylation patterns of the drug, the transformation of the culture cells, the sparging of the culture fluid, the Protein A chromatography purification process, any cation or anion exchange chromatography used to purify the drug, any viral inactivation steps, all formulations considered or used, and the filling of vials and/or the use of tangential flow filtration.  Amgen apparently took the position that it had satisfied its obligation under 42 U.S.C. § 262(l)(2)(A) by providing the aBLA.  The Court agreed that Genentech could not obtain relief, granting a 12(b)(1) motion filed by Amgen to dismiss the case for lack of subject matter jurisdiction in light of the Federal Circuit's holding in Amgen v. Sandoz.  No subsequent litigation has yet been filed, so it is unclear whether the Patent Dance has occurred notwithstanding the alleged disclosure deficiency.

Mvasi is the seventh biosimilar application to be approved by the FDA, and the second in less than a month.  In late August, the FDA approved Boehringer Ingelheim's aBLA for Cyltezo (adalimumab-adbm), a biosimilar to Abbvie's Humira^® (see "Boehringer Ingelheim Pharmaceuticals, Inc. receives FDA approval for CyltezoTM (adalimumab-adbm), a biosimilar to Humira®, for the treatment of multiple chronic inflammatory diseases").  This was the second approved biosimilar to this reference product, and the first biosimilar approval obtained by Boehringer Ingelheim.  Nevertheless, just as with Amgen's approved Humira® biosimilar, concurrent litigation will likely keep Cyltezo off the market for the foreseeable future.

We will continue to monitor these situations and report any updates as warranted.

FDA Report: Agency Announces Expedited Review of Certain ANDAs

By Andrew Williams --

On June 27, 2017, the U.S. Food and Drug Administration issued a press release stating how it would begin implementing its plan to increase competition for prescription drugs.  This comes on the heels of FDA Commissioner Scott Gottlieb's blog post last week, in which he indicated that the FDA would begin lifting the barriers to drug competition.  The first of the two new initiatives announced this week was to publish a list of branded drugs that were off patent but nevertheless had no approved generics.  The second initiative was to implement a policy to expedite the review of ANDAs for any drugs until there are three approved generics.  However, even though the press release indicated that these initiatives reflect the Administration's goal of improving access to prescription drugs, it did not address the potential reality that there may be little economic incentive for generic manufactures to seek marketing approval for these drugs.

The FDA press release was accompanied by two documents, each of which was directed to one of the two initiatives.  The first, entitled "List of Off-Patent, Off-Exclusivity Drugs without an Approved Generic," includes two sections: (1) a list of drug products for which the FDA could immediately accept an ANDA; and (2) a list of drug products for which there might be legal, regulatory, or scientific issues.  The FDA suggested that any sponsor wishing to seek approval of a drug product on the second list should first submit an initial inquiry to the Office of Generic Drugs.  Such drug products on this second list can include those that are more appropriate for the 505(b)(2) abbreviated approval pathway, those for which there are "regulatory complexities," and those that are proteins and may be transition products pursuant to the BPCIA.  No NDA drug products that have been approved in the past year have been included, and the FDA suggests that it will update the list every six months.

The second document was an updated "Prioritization of the Review of Original ANDAs, Amendments, and Supplements," as found in the Manual of Policies and Procedures for the Office of Generic Drugs.  The accompanying "Change Control Table" indicates that the revisions found in this version were to "include prioritization of generic products for which there are fewer than three ANDAs approved for the reference listed drug (RLD) and updated certain external references."  Nevertheless, this prioritization appears to be contingent on there being no blocking patents.  For submissions that contain Paragraph IV certifications, additional criteria were provided before expedited review could be received.

These documents related to the expediting of certain ANDAs were released about a week after newly appointed and confirmed Commissioner Gottlieb posted to his blog, the FDA Voice.  In this blog post, Commissioner Gottlieb indicated that the FDA was working on a Drug Competition Action Plan to address "some of the scientific and regulatory obstacles to generic competition across the full range of FDA-approved drugs."  The post, however, explicitly excluded patent and statutory exclusivity periods from these obstacles.  The only example of "gaming" the system provided was the alleged "increasing unavailability of certain branded products for comparative testing," either through restrictions placed on distributors, or the adoption of voluntary Risk Evaluation and Mitigation Strategies (or REMS) by the NDA holder.  The Commissioner also indicated that the FDA would be looking at how best to coordinate with the FTC to identify and publicize anti-competitive practices.  Finally, he announced a July 18 meeting, in which the FDA would seek input from the public about ways in which the current rules were no having their intended effects.  Of course, this post reverses a long-standing principal of the FDA to not get involved in issues of drug pricing.  We will continue to monitor any updates from the FDA or the current administration on any policies related to generic drugs.

Biosimilars Update -- Pfizer's Proposed Epogen®/Procrit® Biosimilar Recommended for Approval

By Andrew Williams --

On May 25, 2017, the FDA's Oncologic Drug Advisory Committee recommended approval of biologics license application ("BLA") 125545 submitted by Hospira Inc., a Pfizer company, for Retacrit, a proposed biosimilar to Amgen Inc.'s Epogen/Procrit (epoetin alfa).  According to a press release from Pfizer, the committee "recommended approval of the Company's proposed epoetin alfa biosimilar across all indications."  Pfizer had sought approval for treatment of anemia due to Chronic Kidney Disease (CKD), for treatment of anemia due to zidovudine in HIV-infective patients, for treatment of anemia in patients with non-myeloid malignancies, and to reduce the need for allogenic RBC transfusions among patients with perioperative hemoglobin.  If ultimately approved, Retacrit would become the sixth biosimilar in the U.S.  And if the experience with the previous five biosimilars is any indication, the FDA should be expected to approve the present application in the next couple of months.  Retacrit would also be the second biosimilar for Pfizer, which began selling Celltrion's biosimilar INFLECTRA^® in late 2016.  As Pfizer's representative Diem Nguyen said in the press release:  "Following the approval and launch of INFLECTRA^® (infliximab-dyyb) in 2016, this positive recommendation -- a first for a proposed ESA [erythropoiesis-stimulating agent] biosimilar -- marks an important milestone for Pfizer's U.S. biosimilars portfolio."

The Retacrit application would also represent the longest delay between submission and approval.  BLA 125545 was originally submitted in December 2014, and according to a Complaint filed by Amgen in September 2015, the application was accepted sometime on or before February 23, 2015.  But on October 27, 2015, Pfizer announced that it had received a complete response letter (CRL) from the FDA that required more evidence to support approval.  According to Pfizer's FDA Advisory Committee Briefing Document, the CRL "requested additional data and sensitivity analysis to align with the most current FDA expectations and to ensure the robustness of the data demonstrating biosimilarity of Epoetin Hospira to the Epogen/Procrit reference product."  This included information in the categories of:  manufacturing process, analytical, clinical pharmacology, clinical efficacy, and clinical immunogenicity.  In response, Pfizer obtained the additional scientific evidence, which it summarized in the following figure that it said "establishes the biosimilarity of Epoetin Hospira to the Epogen/Procrit reference product."

Marketing of the drug will likely be delayed because of the requirement to give the 180-day notice of commercial marketing.  In anticipation, though, Amgen filed a motion for preliminary injunction on May 26, 2017, because (as it alleged in the original underlying Complaint (at paragraph 66)):  "Hospira has indicated that it intends to violate the statute by categorically refusing to provide Amgen with a legally operative notice of commercial marking under 42 U.S.C. § 262(l)(8)(A)."  Of course, according to the Federal Circuit's Amgen v. Sandoz ruling, Hospira cannot give notice until after the FDA has approved the product.  But this requirement may change this month when the Supreme Court issues its decision in the Sandoz v. Amgen case.  The Delaware Court also denied Amgen's request for discovery related to Hospira's manufacturing process that was not supplied during the patent dance.  The appeal from that decision was heard by the Federal Circuit in April 2017, and an opinion is expected within the next few months.

As a reminder, both this author and Kevin Noonan will be attending the American Conference Institute's 8th Annual Summit on Biosimilars next week, June 12-14, 2017 in New York, NY.  Dr. Noonan is co-chair of the conference and will be on a panel reviewing the first 18 months of biosimilars (and looking ahead).  If you are attending, please say hello.  As a reminder, Patent Docs readers are entitled to a 10% discount off of registration using discount code P10-999-PTD17, but hurry because registration is closing soon.

FDA Relents, Grants Premarket Authorization to 23andMe Genetic Diagnostics Test

By Kevin E. Noonan --

On April 6th, the U.S. Food and Drug Administration (FDA) continued to loosen the reins on the genetic diagnostic and DNA analysis company 23andMe with regarding to direct-to-consumer (DTC) genetic testing related to predicting disease risk.  While falling short of permitting the company to provide risk analysis for disease likelihood in individuals per se, the agency granted permission to market its genetic diagnostic kits for a limited number of diseases according to an official announcement.  The agency's actions suggest that it believes there is sufficient evidence that the risks to the public it perceived that motivated its earlier restrictions are not as likely as once thought.

The FDA's actions come on the heels of the agency's approval of DNA diagnostics for Bloom's Syndrome earlier this year (see "23andMe Receives FDA Approval for Genetic Diagnostic Test").  Readers may recall that the FDA effectively stopped 23andMe from selling its genetic analysis kit, which the company marketed as Personal Genomic Services (PGS) in November 2013 by issuing a Warning Letter to the Company (see "FDA Threatens Agency Action Against 23andMe Over Personal Genetic Testing").  According to the FDA, genetic diagnostics assays fall under the agency's purview and authority because they are medical devices (21 U.S.C. § 321(h)).  According to its earlier letter, the testing service offered "is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body."  At that time, the agency professed a desire to work with the company to assist in developing the type and quantity of evidence required for approval, but warned that it had spent "significant time" evaluating the PGS test and providing feedback to 23andMe.  By complying with the agency by submitting the evidence for approval of a much more limited test, 23andMe was able to get the Bloom's Syndrome test approved.

This most recent approval is for ten genetic diseases as detected by 23andMe's at-home health-and-ancestry DNA testing kit (retailing at $199).  The kit detects single nucleotide polymorphisms (SNPs) related to development of these ten diseases having a genetic component:

• Late-onset Alzheimer's – detecting the ε4 variant in the APO-E gene
• Parkinson's  - the G2019S variant in the LRRK2 gene and the N370S variant in the GBA gene
• Celiac disease - a variant in the HLA-DQ2.5 haplotype
• Hereditary thrombophilia - Factor V Leiden variant in the F5 gene, and the Prothrombin G20210A variant in the F2 gene
• Alpha-1 Antitrypsin Deficiency - PI*Z and PI*S variants in the SERPINA1 gene
• Gaucher's disease type 1 - N370S, 84GG, and V394L variants in the GBA gene
• Early-onset primary dystonia - deltaE302/303 variant in the DYT1 gene,
• Factor XI deficiency - F283L, E117X, and IVS14+1G>A variants in the F11 gene,
• Glucose-6-phosphate dehydrogenase deficiency - Val68Met variant in the G6PD gene,
• Hereditary hemochromatosis - C282Y and H63D variants in the HFE gene

The agency did not grant approval for tests related to developing a disease in an individual, in particular for detecting disease-related variants of the BRCA1 or BRCA2 genes related to breast and ovarian cancer.  Rather, the test results are predictive for the risk of inheritance of these genes by offspring, to be used inter alia to identify prospective parental pairs who both carry a disease-related allele and thus are at heightened risk for having a child with the disease.

FDA approval for genetic health risk reports were evaluated through the de novo classification pathway, a regulatory process for low-to-moderate-risk medical devices, the company said.  In its approval, the FDA indicated it will create a class II exemption for 23andMe's substantially equivalent reports for other diseases and risk-predictive genes, provided that the company complies with agency requirements for establishing efficacy and safety.  These actions open a pathway for the company to release additional genetic health risk reports, 23andMe also said in its announcement.  "These special controls, when met along with general controls, provide reasonable assurance of safety and effectiveness for these and similar [genetic health risk] tests," the FDA added.  And the agency announced that it will outline a pathway for similar exemption for other DTC companies in the Federal Register.

These tests are much more limited in scope than 23andMe's original test, which included more than 250 "diseases and conditions" such as BRCA gene mutations, diabetes, coronary artery disease, an sensitivities to drugs such as warfarin, clopidigrel, and 5-fluorouracil.  But the agency's approval, and avowed intention to permit 23andMe, and other companies, to market DTC genetic diagnostic tests suggest that the dawn of the age of personalized medicine has crept ever closer to breaking.

FDA Issues Guidance Regarding Interchangeability of Biosimilar and Biologic Drugs

By Kevin E. Noonan --

On Tuesday, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Considerations in Demonstrating Interchangeability with a Reference Product, Is long-awaited and addresses a important aspect of the biosimilar drug regime.  Interchangeability, which is the standard for conventional, small molecule generic drugs, is challenging for biologic drugs because of their size and complexity, and because the biosimilarity standard encompasses molecules that are not atom-for-atom identical to the reference biologic drug product.  Accordingly, the ease with which conventional generic drugs are substituted for brand name versions is not appropriate for biosimilar drugs, and the statute sets out standards for interchangeability status (Section 351(k)(4) of the PHS Act), wherein FDA must find that:

(A) the biological product—
    (i) is biosimilar to the reference product; and
    (ii) can be expected to produce the same clinical result as the reference product in any given patient; and
(B) for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch.

Interchangeability is important for a variety of reasons, particularly with regard to biosimilar drug acceptance and the ability for the interchangeable biosimilar to be substituted for a reference biologic drug product without intervention or approval of a health care provider.  Accordingly, such drugs are rewarded with additional layers of exclusivity (indeed, the only exclusivity for biosimilar drugs contained in the statute, as set forth in the PHSA under Section 351(k)(6)), wherein FDA shall not grant interchangeability status for any second biosimilar drug until the later of:

(A) 1 year after the first commercial marketing of the first interchangeable biosimilar biological product to be approved as interchangeable for that reference product; [or]
(B) 18 months after –
    (i) a final court decision on all patents in suit in an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
    (ii) the dismissal with or without prejudice of an action instituted under subsection (l)(6) against the applicant that submitted the application for the first approved interchangeable biosimilar biological product; or
(C)(i) 42 months after approval of the first inter- changeable biosimilar biological product if the applicant that submitted such application has been sued under sub- section (l)(6) and such litigation is still ongoing within such 42-month period; or
    (ii) 18 months after approval of the first interchange- able biosimilar biological product if the applicant that sub- mitted such application has not been sued under subsection (l)(6).

The Guidance provides FDA's first attempt to operationalize the statutory requirements and give the biopharmaceutical industry guidance on what the agency will require to grant interchangeability status to a biosimilar drug.

The Guidance is expressly focused on therapeutic protein products with regard to the evidence necessary to establish interchangeability with a reference biologic drug product that is a therapeutic protein.  As with almost all other FDA Guidances on biosimilars, this one recites that interchangeability determinations shall be made after consideration of the totality of the evidence that a biosimilar dug satisfies the statutory requirements.  Thus, the first requirement is that a biosimilar applicant show that its drug is biosimilar to the reference biologic drug product, and envisions that first licensure will be on biosimilarity grounds.  With regard to the requirement that a purportedly interchangeable biosimilar drug would be "expected to produce the same clinical result as the reference product in all of the reference product's licensed conditions of use," the Guidance sets forth a nonlimiting set of data and information:

• The identification and analysis of the critical quality attributes
• The identification of analytical differences between the reference product and the proposed interchangeable product, and, in addition, an analysis of the potential clinical impact of the differences
• An analysis of mechanism(s) of action in each condition of use for which the reference product is licensed, which may include the following:
    -  The target receptor(s) for each relevant activity/function of the product
    -  The binding, dose/concentration response, and pattern of molecular signaling upon engagement of target receptor(s)
    -  The relationship between product structure and target/receptor interactions
    - The location and expression of target receptor(s)
• The pharmacokinetics and biodistribution of the product in different patient populations The immunogenicity risk of the product in different patient populations
• Differences in expected toxicities in each condition of use and patient population (including whether the expected toxicities are related to the pharmacological activity of the product or to off-target activities)
• Any other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed

If there are differences between the reference biologic drug product and the biosimilar with respect to any of these factors, the Guidance asserts that the biosimilar applicant must supply a scientific justification as to why those differences don't preclude a determination of interchangeability.  However, the Guidance does not envision that satisfying this standard will necessarily require additional clinical studies.  Also, an applicant can (but FDA recommends that she does not) seek approval for less than all the indications approved for the reference biologic drug product (and in this regard the Guidance envisions that an applicant may "extrapolate" the data and information supporting interchangeability for one indication to support interchangeability for additional indications).

As for the other statutory requirement, that "for a biological product that is administered more than once to an individual, the risk in terms of safety or diminished efficacy of alternating or switching between use of the biological product and the reference product is not greater than the risk of using the reference product without such alternation or switch," the Guidance expects a biosimilar applicant will need to do one or more "switching studies" (the general requirements being set forth with some specificity in the Guidance) that will be used to assess the risk to safety or efficacy of alternating between the reference biologic drug product and the biosimilar.

The Guidance provides "an overview of important scientific considerations in demonstrating interchangeability with a reference product," including:

• Data and information needed to support a demonstration of interchangeability
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
• Recommendations regarding the use of a U.S.-licensed reference product in a switching study or studies
• Considerations for developing presentations, container closure systems, and delivery device constituent parts for proposed interchangeable products.

And the Guidance then sets forth more detailed explication of these considerations, including product-dependent factors that could influence the data needed to show interchangeability (again urging a "stepwise" approach to establishing interchangeability as FDA has urged for establishing biosimilarity) and showing a high degree of biosimilarity (with reference to biosimilarity Guidances regarding so-called "fingerprint identity" measures of biosimilarity).  The information and data should be aimed at reducing the amount of residual uncertainty, which is expected to depend on the structural and functional complexity of the biosimilar drug.  Particularly called out in this regard is the risk of product-specific immunogenicity, which may be more relevant to some biosimilar drugs than others depending on the nature of the reference biologic drug product.

The Guidance also envisions that interchangeability may require biosimilar product postmarketing data, and that such data would not obviate the need for other, interchangeability-related data (e.g., from switching studies, particularly with regard to comparison of pharmacokinetic or pharmacodynamics parameters).

The Guidance provides detailed discussion of the characteristics of switching studies expected to be required to satisfy interchangeability requirements, for those drugs expected to be administered to a patient more than once (presumably this category encompasses many of not most biologic drugs).  These studies will depend on how the drug will be used in practice, according to the Guidance, and the Guidance sets out considerations regarding study endpoints, design and analysis, sample size and number of switches, sampling for PK, PD and immunogenicity, study population, and study analysis, as well as conditions of use and routes of administration.

There is also a section regarding the conditions under which data can be extrapolated (e.g., from one condition of use to another for which the reference biologic drug product is licensed), supported by scientific justification based on mechanism of action, immunogenicity risk, expected toxicities, or "[a]ny other factor that may affect the safety or efficacy of the product in each condition of use and patient population for which the reference product is licensed."

Unlike the Guidances concerning the grounds for establishing biosimilarity, which permit comparative data with a non-U.S. licensed reference biologic drug products to be submitted, the Guidance states that switching studies must be performed using a U.S. licensed reference biologic drug product.  This is because in these studies the reference biologic drug product is not used just as a control but is also part of the study, administered in both the switching arm and the non-switching arm.  This limitation appears to be based on concerns regarding unpredictable differences in immunogenicity or PK profiles, as well as the existence of several ex-U.S. versions of biosimilar drugs having slight but perhaps clinically relevant differences when used in a switching study that could negatively impact the reliability of study results.

The Guidance ends with a detailed description of presentation designs for the data and information supporting an interchangeability determination (referencing Section VII of FDA's earlier Guidance entitled Scientific Considerations in Demonstrating Biosimilarity to a Reference Product) and a section on postmarketing safety monitoring.  The Guidance also contains an Appendix related to Comparative Use Human Factor Studies.

And like all such Guidances, it contains an express disclaimer:

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

FDA Issues Guidance Regarding Biologic Drug Naming

By Kevin E. Noonan --

Late last week, the U.S. Food and Drug Administration released its latest Guidance for Industry relating to the biosimilar application process set forth in the Biologic Price Competition and Innovation Act of 2009 (BCPCIA).  This Guidance, entitled Nonproprietary Naming of Biological Products, extends to both reference biologic drug products and their biosimilar counterparts.  The basis for this naming regime, and its extension to both types of biologic drugs, reflects the agency's rationale for providing a naming convention in the first place and is based on FDA's dual responsibilities to protect the public and at the same time facilitate availability of biosimilar drugs according to Congress's intentions in passing the BPCIA.

In a nutshell, FDA sets forth a regime for a nonproprietary name that is the combination of a core name (equivalent to a generic name for small molecule drugs) combined with a four-letter suffix to designate its source.  The suffix (both the requirement that each biologic drug have one and the "nonsense" ("devoid of any meaning") nature of it) has been the source of much of the criticism of the naming scheme since the agency published a proposed rule in the Federal Register of August 28, 2015 (80 Fed. Reg. 52224) ("Designation of Official Names and Proper Names for Certain Biological Products").  The Guidance provides its rationale for the proposed rule, stating that the naming scheme, which is required "for each originator biological product, related biological product, and biosimilar product," will "facilitate pharmacovigilance" (for all categories of biologic drugs), by permitting a specific biologic dug product to be tracked from its source particularly in instances where other means of doing so are not readily available.  Also, these names would permit accurate source identification by patients, healthcare providers and payors (one of the features that biosimilar advocates fear might lead to discrimination).  For the agency, using source suffixes also provides a means to "minimize inadvertent substitution" (especially when such biosimilar products, like all current biosimilar products have not been determined to be interchangeable; FDA will develop a naming convention based on the same principles for interchangeable biosimilar products but "is continuing to consider the appropriate format of the suffix for these products").  The benefits envisioned by FDA should be to "(1) encourage routine use of designated suffixes in ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices and (2) avoid inaccurate perceptions of the safety and effectiveness of biological products based on their licensure pathway" according to the Guidance.

One aspect of the Guidance is that the naming convention will be used for all biologic drug products, both newly licensed as well as previously licensed drugs.  For previously licensed biologic drugs (all of which are innovator-produced "reference biologic drug products") the revised proper (nonproprietary) name would comprise the original name as the core name and have a new distinguishing suffix configured consistent with the Guidance.  While the process for implementing this "renaming" of previously licensed biologic drugs is ongoing, FDA will assign distinguishing suffixes to "a limited group" of these drugs as well as accepting submissions (presumably by the drug sponsor) for supplementing approved drug labels with new nonproprietary names include a proposed suffix.  The names will be required for all "biological products licensed under the PHS Act, such as therapeutic protein products, vaccines, allergenic products, and blood derivatives, and [will] not include certain biological products that also meet the definition of a device in section 201(h) of the FD&C Act (21 U.S.C. 321(h)), such as in vitro reagents (e.g., antibody to hepatitis B surface antigen, blood grouping reagents, hepatitis C virus encoded antigen) and blood donor screening tests (e.g., HIV and hepatitis C)."

Returning to the agency's rationale for the proposed naming convention, the Guidance states that it anticipates "a growing number of biological products" to be entering the marketplace.  The nonproprietary name (in contrast with the proprietary (brand) name, "reflects certain scientific characteristics of the product, such as chemical structure and pharmacological properties" and, inter alia, "helps health care providers identify the product's drug substance and distinguish biological products from one another."  The proposed naming scheme was developed based on comments solicited by the agency from the public (as found in "Federal Register, 'Approval Pathway for Biosimilar and Interchangeable Biological Products; Public Hearing; Request for Comments' (75 FR 61497, October 5, 2010); 'Draft Guidances Relating to the Development of Biosimilar Products; Public Hearing; Request for Comments' (77 FR 12853, March 2, 2012); [and] 'Nonproprietary Naming of Biological Products; Draft Guidance for Industry; Availability' (80 FR 52296, August 28, 2015)").  The Guidance specifically recites that the naming convention is intended to "maximize the success of biosimilar products and interchangeable products and to help ensure the safety of patients receiving biological products licensed under the PHS Act."

The Guidance sets forth the "main considerations" used by the agency in arriving at the naming scheme.  These include "enhancing biological product pharmacovigilance"; "ensuring safe use of biological products"; and "advancing appropriate practices and perceptions regarding biological products."  With regard to pharmacovigilance, the Guidance acknowledges that despite agency efforts to "rigorously assess[]" for biologic (and other) drugs for safety and efficacy, issues can arise post-approval that create a need for the agency to be able to "track adverse events to a specific manufacturer" (or even specific lots or manufacturing sites) in a surveillance system that exists throughout the product's lifecycle.  If the source of a biologic product can be readily identified, remedial action can be taken effectively and not implicate products "for which no problem exists."  Such surveillance systems can be active or passive, and can use identifiers including "proprietary name, proper name, manufacturer, national drug code (NDC) number, lot number, and billing codes."  Unfortunately, many systems have "limited ability" to track products by manufacturer, according to the Guidance, and some identifiers are not recorded routinely (for example, in patient and billing records).  The proposed naming convention is intended to "provide another critical tool for accurately identifying and facilitating pharmacovigilance for originator biological products, related biological products, and biosimilar products."

With regard to safety, the Guidance states that inadvertent substitution is a particular risk for biological products due to their complexity and "unique safety concerns related to immunogenicity."  Inadvertent substitution, particularly wherein patients could receive reference biologic drug product and biosimilar versions thereof serendipitously, raises the specter of unapproved interchangeability, which the agency wishes to avoid until such time as it sets out the scope of what constitutes biosimilar drugs that can be considered interchangeable with the reference biologic drug product.  There is also the risk of different versions of a biologic drug or biosimilar versions thereof to be approved for different indications, and the naming convention is believed to be helpful in ensuring that a drug be administered for just those indications for which it has been approved.  There is the further risk that poorly informed healthcare providers or their patients might assume that a biosimilar drug having the same nonproprietary name as the reference biologic drug product had been approved as being interchangeable.  This risk is mitigated not only by using distinguishable names but by providing in such names a ready distinction in the Purple Book (Purple Book: Lists of Licensed Biological Products With Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations).

Finally, the Guidance believes that by requiring routine use of a nonproprietary names comprising source-identifying suffix in "ordering, prescribing, dispensing, recordkeeping, and pharmacovigilance practices" it will provide "a consistent, readily available and recognizable mechanism" for patients and healthcare providers to correctly identify the products (and their source) being administered.  FDA also appreciates that by requiring both newly approved biosimilar drugs and previously approved reference biologic drug products to use the naming convention, "inaccurate perceptions" of the safety and efficacy of biosimilar drugs, compared with reference biologic drug products, can be avoided.

In practice, FDA intends to use the core name of a previously approved originator biologic drug for both the reference biologic drug product and all biosimilar versions.  Source will be identified by a four-letter suffix otherwise "devoid of meaning."  This naming scheme will indicate the relationship between the products (the core name) and identify source by the suffix.  The agency also notes that having the distinguishing code as a suffix (instead of a prefix) will facilitate grouping the drugs together in electronic databases and thus help healthcare providers to locate their alternatives.  Applicants for biologic drug products pending approval should propose to FDA up to 10 suffixes from which the agency could choose (and also submit any "supporting analyses" that could influence the agency's decision on the suffix to be used); current BLA holders for approved drugs and biosimilar applicants should do the same.  Guidelines for suffix selection according to the Guidance should have the following characteristics:

The proposed suffix should:

• Be unique
• Be devoid of meaning
• Be four lowercase letters of which at least three are distinct
• Be nonproprietary
• Be attached to the core name with a hyphen
• Be free of legal barriers that would restrict its usage

The proposed suffix should not:

• Be false or misleading, such as by making misrepresentations with respect to safety or efficacy
• Include numerals and other symbols aside from the hyphen attaching the suffix to the core name
• Include abbreviations commonly used in clinical practice in a manner that may lead the suffix to be misinterpreted as another element on the prescription or order
• Contain or suggest any drug substance name or core name
• Look similar to or be capable of being mistaken for the name of a currently marketed product (e.g., should not increase the risk of confusion or medical errors with the product and/or other products in the clinical setting)
• Look similar to or otherwise connote the name of the license holder
• Be too similar to any other FDA-designated nonproprietary name suffix

The Guidance ends with the following statement of FDA policies regarding naming:

The final determination on the acceptability of a proposed suffix is based on FDA's review of all information and analyses described in this guidance, along with any information submitted by the sponsor.

FDA will evaluate proposed suffixes against the factors described in this section and may consider other factors if they impact the utility of the suffix in meeting the goals of the naming convention articulated in this guidance.  Upon completion of the Agency's evaluation, FDA will notify applicants if a proposed suffix is acceptable or if all of the proposed suffixes are determined to be unacceptable.  If all of the proposed suffixes are determined to be unacceptable, applicants may submit additional proposed suffixes for FDA's consideration.  If an applicant does not submit a suffix that FDA finds acceptable or does not propose suffix candidates within an appropriate time frame to allow sufficient time for FDA review, FDA may elect to assign a four-letter suffix for inclusion in the proper name designated in the license at the time FDA approves the application.

And like all such Guidances, it contains an express disclaimer:

This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.