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Per Senator Orrin Hatch, the America Invents Act has disrupted the “careful balance” he struck with Senator Waxman in the development of the decades-old Hatch-Waxman Act governing the adjudication of generic drug litigation. On June 13, 2018, Senator Hatch filed an amendment in the Senate Judiciary Committee to remedy the perceived conflict between the “carefully calibrated requirements” of Abbreviated New Drug Application (“ANDA”) litigation under the Hatch-Waxman Act and the “much blunter instrument” of post-grant proceedings before the United States Patent Trial and Appeal (“PTAB”).   According to Senator Hatch, the amendment “will ensure that Hatch-Waxman continues to operate as originally intended by protecting the ability of generic drug companies to develop low-cost drugs while at the same time ensuring brand-name companies have sufficient protections in place to recoup their investments.”  A press release of Senator Hatch’s remarks is available here.

The “Hatch-Waxman Integrity Act” by Senator Hatch is an amendment to the Creating and Restoring Equal Access to Equivalent Samples Act (CREATES Act), legislation designed to help generic drug companies acquire the samples they need to develop generic drugs, particularly for products subject to a risk evaluation and mitigation strategy (“REMS”). The CREATES Act advanced to the Senate from the Judiciary Committee on June 14, 2018, and was been placed on the Senate Legislative Calendar on June 21, 2018.

The Amendment would add to the CREATES Act a section entitled “Preventing the Inter Partes Review Process for Challenging Patents from Diminishing Competition in the Pharmaceutical Industry and with Respect to Drug Innovation; Preventing the Manipulative and Deceptive Use of Inter Partes Review.” The section has three parts and targets both generic drug manufacturers and biosimilar companies.

In the first portion of the Amendment, an ANDA applicant must certify that they have not and will not file an Inter Partes Review (“IPR”) or Post-Grant Review (“PGR”) or forfeit the ability to participate in the Hatch-Waxman litigation procedures.  Additionally, the ANDA applicants must certify that they are not relying in whole or in part on any decision reached by the PTAB in an IPR or PGR proceeding.

Second, the Amendment forces a similar choice for biosimilar applicants.  Those who file an abbreviated Biologics License Application (“aBLA”) must decide, with respect to any patent that is or could be included in the lists of patents that are exchanged as part of the “Patent Dance,” whether to challenge patents in an IPR/PGR or take the path outlined in the Biologics Price Competition and Innovation Act (“BPCIA”).

Third, the Amendment aims to end certain market practices and appears to apply broadly to all parties filing for post grant proceedings. To “prevent[] the Manipulative and Deceptive Use of Inter Partes Review,” the Hatch-Waxman Integrity Act amends the Securities Exchange Act of 1934 to address market manipulation tied to inter partes review petitions, such as that attempted by the Coalition for Affordable Drugs.  Specifically, “a person shall be considered to be using a manipulative or deceptive device” if they file a petition for an IPR and engage in a short sale of any publicly traded security of the owner of the patent at issue in the IPR for the 90 days before and after the filing of the petition.

We will continue to monitor the CREATES Act and the Hatch-Waxman Integrity Act in the future. For more information, please feel free to contact Jamaica Potts Szeliga at any time.

In a few short days, the United States will mark the eight-year anniversary of the Biologics Price Competition and Innovation Act (“BPCIA”). Signed into law on March 23, 2010, the BPCIA creates a regulatory pathway for the approval of biosimilar drugs in the United States and a mechanism, albeit voluntary, for resolving patent right disputes relating to the innovator biologic products.  Continue Reading “Rigged” Pricing, Contracting and Rebate “Schemes,” and Drug Pricing “Shell Games:” FDA Commissioner Scott Gottlieb Lets Loose on the U.S. Biosimilar Market While Offering Peek at New Policies

The Hatch-Waxman Act was enacted in 1984 to address two main congressional goals: (1) to encourage innovation in pharmaceutical research and development; and (2) to help generic drugs reach the market more quickly. Through amendments to both the patent and the food and drug laws, the Act established several practices intended to provide brand-name firms with incentives to innovate while facilitating the marketing of generic pharmaceuticals. Whether or not it was envisioned at the time, the use of generic drugs in the US has seen a tremendous increase since the enactment of the Act. From about 13% (of all prescriptions) in 1984, use of generic drugs grew to 50% by the late 1990s and currently constitute well over 80% of all prescriptions in the US.

Among other things, the Act included elaborate provisions governing the mechanisms through which a potential generic manufacturer may obtain marketing approval for a drug that has been patented by another party. It also put in place an expedited approval processes for generic drugs. In doing so, the Act launched a new type of litigation, “Hatch-Waxman” or “ANDA” litigation. The evolution of the US generic drug industry has been shaped, in part, as a result of such litigation proceedings that unfolded many questions critical to understanding the generic approval process.

Although generic drug usage is over 80% of all prescriptions in the US, as of 2015 the sale of generics were only a quarter as large as those of patented drugs. In the past several years, the number of ANDA litigations has significantly increased. As an active member of the legal community within the ANDA space, we took a look at the latest developments in the field and now share our observations. In the article titled “Hatch-Waxman And Biosimilars Litigation: 2017 Year-in-Review,” we provide a brief overview of the Hatch-Waxman Act, a summary of the recently released FDA Draft Guidance, a general timeline of Hatch-Waxman and Biosimilars litigation, and summaries of some of the related decisions issued by the U.S. Supreme Court and Court of Appeals for the Federal Circuit in the year 2017. If you would like to order a hard copy of the Year in Review, please see our blog post.

This webinar is hosted by The Knowledge Group.

On April 17th at 10 a.m. ET, Dr. Dean Fanelli and Dr. Thomas Haag, along with Jens Viktor Nørgaard of HØIBERG, Niklas Mattsson of Awapatent, Mr. Glyn Truscott of Elkington + Fife LLP and Jennifer O’Farrell of Boult Wade Tennant, will present a live webcast on Bridging the Gap Between EU and U.S. Biotech Inventions Protection.

Biotechnology companies both in the U.S. and Europe rely greatly on patents to protect their biotech inventions, especially during the research and development process. However, with the evolving economic landscape, and the rise of complex developments and innovation, protecting biotech inventions has become more difficult.

In this LIVE Webcast, a team of thought leaders and professionals brought together by The Knowledge Group will provide and present and in-depth analysis of the laws and regulations in the EU and U.S. concerning Biotech Inventions Protection. Speakers will also provide practical tips and strategies to maximize legal protection and to avoid risks and pitfalls while complying with applicable laws.

Key topics include:

  • EU and U.S. Biotech Inventions Protection – Laws and Regulations
  • Similarities and Differences
  • Significant Court Rulings
  • Trends and Legal Updates
  • What Lies Ahead in 2018

For more information and to register for the webinar, click here.

This webinar is hosted by The Knowledge Group.

On March 22nd at 12 p.m. ET, Dean Fanelli and Jamaica Szeliga, along with Timothy Shea of Sterne, Kessler, Goldstein & Fox P.L.L.C., will present a live webcast on Biosimilar Litigation and Your BPCIA Compliance: Key Strategies In Light of AbbVie v. Boehringer.

The previous year saw an increase in biosimilar filings in the U.S., including the recent suit filed by AbbVie in the U.S. District Court for the District of Delaware against Boehringer Ingelheim regarding Boehringer Ingelheim’s adalimumab product, Cyltezo®, a proposed biosimilar to AbbVie’s Humira®. The complaint alleges infringement of 8 patents in the initial phase of litigation, as Boehringer Ingelheim was able to cap the scope of litigation by complying with the procedures of the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This case reflects the benefits of complying with the BPCIA’s patent dispute resolution procedure, also known as patent dance.

In this LIVE webcast, a panel of distinguished professionals and thought leaders will discuss the latest legal and regulatory updates that are continuously changing the biosimilar landscape. They will review the on-goings of the AbbVie v. Boehringer Ingelheim litigation and give insights on the benefits and risks of engaging in the BPCIA’s patent dance. Speakers will also provide considerations in adopting appropriate litigation strategies.

Key issues that will be covered in this course are:

  • Biosimilar Litigation Landscape Post Sandoz v. Amgen
  • Complying with BPCIA: AbbVie v. Boehringer Ingelheim
  • The Benefits and Risks of Patent Dance
  • Recent Legal and Regulatory Updates
  • Strategic Considerations for Biosimilar Litigation
  • Significant Trends and Legal Updates

For more information and to register for the webinar, click here.

Seyfarth Shaw Offers Hatch-Waxman And Biosimilars Litigation: 2017 Year-in-Review

Today’s rapid scientific and technological advances demand not only a thorough understanding of the complex technology, but also a meticulous application of intellectual property law to protect the technology.

Seyfarth’s Intellectual Property and Hatch-Waxman Litigation practitioners are pleased to announce the release of Hatch-Waxman And Biosimilars Litigation: 2017 Year-in-Review which provides a brief overview of the Hatch-Waxman Act, a summary of the recently released FDA Draft Guidance, a general timeline of Hatch-Waxman and Biosimilars litigation and summaries of some of the related decisions issued by the U.S. Supreme Court and Court of Appeals for the Federal Circuit in the year 2017.

How to Get Your Desktop Guide:

To request the Hatch-Waxman And Biosimilars Litigation: 2017 Year-in-Review as a pdf or hard copy, please click the button below:

 

 

For updates and insight on Hatch-Waxman related issues, we invite you to subscribe to our BioLoquitur Blog.

Continue Reading Now Available! Seyfarth Shaw’s Hatch-Waxman and Biosimilars Litigation: 2017 Year-in-Review

BioLoquitur has reported on legislative developments in the past, but never did we expect to discuss a tax bill. Last week, however, the U.S. House of Representatives passed the “Tax Cut and Jobs Act” Bill (H.R. 1) and H.R. 1 deserves a spotlight. After all, one of our goals is to provide the life science industry with the latest news that could affect the industry.

Below are a few provisions that could affect U.S. pharma and biotechnology companies and others investing in those companies.[1]

  • Section 3001 reduces the U.S. corporate tax rate from 35% to 20%. If the bill goes into law, the reduction will be the largest corporate tax cut in over 100 years.
  • Under Title IV, the U.S. will only tax the U.S. income of a corporation and exempt most or all foreign income. Currently, a corporation headquartered in the U.S. pays corporate income tax on all income, both U.S. and foreign income that has been brought back into the U.S.
  • Section 3401 eliminates the Orphan Drug Tax Credit (“ODTC”). Currently, the U.S. provides an orphan drug manufacturer a tax credit of 50% of qualified clinical research costs incurred between the date of approval for the drug and the date that the U.S. Food and Drug Administration (“FDA”) designates the drug as an orphan drug. According to the U.S. Department of the Treasury, the tax expenditures attributable to the ODTC credit are expected to be $2.3 billion in 2017 and would grow substantially over the next ten years; eliminating the credit would thus generate billions in revenue for the United States.
  • After December 31, 2022, Section 3315 provides that research and experimental expenditures are not deductible unless they are charged to a capital account, where they must be amortized over a five year period. Currently, the tax code allows such research and experimental expenses as a deduction without requiring amortization under 26 U.S.C. § 174(a).
  • Section 3312 changes the tax treatment for self-created patents, taxing the gains from sales of such patents as ordinary income rather than capital gains.
  • Section 3307 narrows the ability to deduct certain business expense, eliminating deductions for membership dues, any payments relating to “entertainment, amusement, or recreation,” and on-premises athletic facilities, among others.
  • Section 1308 repeals the deduction for medical expenses. The tax code provides for the deduction of medical expenses that exceed 10% of an individual’s adjusted gross income. H.R. 1 eliminates this deduction. Critics suggest the elimination may potentially leading to reduced consumer spending on medical needs and/or increased reliance on government healthcare resources.

At 450 pages, H.R. 1 is a complex and dense bill — the list above is not exhaustive, of course.  We will keep you updated as tax reform continues.

 

[1]          Title V amends several provisions relating to exempt organization that are beyond the scope of this article, but may be of interest to research universities and foundations. If you have questions on the potential impact of Title V, please contact us and we will refer you to our tax and benefits colleagues for further information.

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Finding against the Federal Circuit once again on a patent case, the Supreme Court issued a unanimous decision in Sandoz v. Amgen relating to the interpretation of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) in its first decision on the Act.  The Supreme Court’s decision firmly establishes the availability of a third biosimilar “dance,” at least as far as Federal law is concerned.

The BPCIA provides the mechanism by which companies can bring to market “biosimilar” compounds, i.e., products that can compete with biological drugs much the same way as generic drugs compete with traditional “brand” pharmaceutical products.  On appeal, the Supreme Court considered two issues.  First, the biosimilar applicant, Sandoz, challenged the Federal Circuit’s interpretation of the BPCIA as requiring an applicant to wait until after the FDA approved its biosimilar application before providing the requisite 180-day notice of commercial marketing to the brand company.  This meant that a biosimilar applicant had to wait an additional 180 days after its application was granted before it could launch a competing product.  The FDA cannot approve (“license”) a biosimilar product until twelve years after the biologic was first approved by the agency.  Thus, the Federal Circuit’s decision effectively provided the brand manufacturer with 12½ years rather than 12 years of market exclusivity.

The Supreme Court reversed the Federal Circuit and explicitly determined that applicants can provide notice before or after FDA approval. According to the Supreme Court, the pertinent statutory language in the BPCIA has two separate requirements:  (1) that the biosimilar application is “licensed” before it is marketed; and (2) that the biosimilar applicant gives notice 180 days before marketing occurs.  The Federal Circuit thus erred in requiring licensure before notice could be given.

The second issue tackled by the Supreme Court relates to the “patent dance” provisions of the BPCIA. The “patent dance” is a statutory scheme through which the biosimilar applicant and the brand manufacturer exchange information and legal theories until deciding upon which patents to litigate first.  Sandoz refused to provide the biosimilar application and manufacturing information contemplated in the dance, leading Amgen to seek an injunction under federal and state law to compel participation.  The district court and Federal Circuit determined that an injunction was not available.

On cross-appeal, the Supreme Court agreed with the Federal Circuit that injunctions under federal law are not permitted, but remanded the case to review state law remedies.  According to the Court, the BPCIA allows the brand company immediately to bring a declaratory judgment action against the biosimilar applicant if they do not provide their application and manufacturing information.  This remedy deprives the applicant of the ability to control the scope of the litigation (i.e., which patents to litigate) and the timing of the suit.  The Supreme Court determined that the remedy of immediate suit was the only federal remedy contemplated for an applicant’s failure to dance.  The Supreme Court remanded the case to address whether non-compliance with the BPCIA can be considered a violation of California law entitling Amgen to an injunction and/or whether the BPCIA’s remedy pre-empts any state law remedies.

Seyfarth will be closely monitoring the remand of Sandoz in the coming months.

The SANDOZ Dance

Step 1:   Skip
42 U.S.C. § 262(l)(2)(A)

  BIOSIM good Applicant refuses to provide aBLA and information describing manufacturing

Step 2: File Suit
42 U.S.C. § 262(l)(9)(C)

  BRAND good Reference sponsor chooses what patents to sue upon and when to bring suit against Applicant

 

The FAST BPCIA Dance

Step 1:   Disclose
42 U.S.C. § 262(l)(2)(A) – 20 days

 BIOSIM good Applicant provides a copy of aBLA and information describing manufacturing

Step 2: Disclose
42 U.S.C. § 262(l)(3)(A) – 60 days

  BRAND good Reference sponsor provides list of assertable patents and identifies any patents it is willing to license

Step 3:   Disclose
42 U.S.C. § 262(l)(3)(B) – 60 days

 BIOSIM good Applicant provides its own list of assertable patents, responds to licensing offer, and gives “detailed statements” why all listed patents are invalid, unenforceable, or will not be infringed

Step 4: Disclose
42 U.S.C. § 262(l)(3)(C) – 60 days

  BRAND good Reference sponsor gives “detailed statements” why the claims of all listed patents are infringed and responds to Applicant’s detailed statements

Step 5: Negotiate
42 U.S.C. § 262(l)(4)(A)

 NEG SUCCESS Applicant and Reference sponsor negotiate to develop a final and complete list of patents for the initial patent infringement lawsuit and agree

Step 6:  File Suit
42 U.S.C. § 262(l)(6)(A) – 30 days

  BRAND good Reference sponsor files suit on agreed-upon patents

 

The SLOW BPCIA Dance

Step 1:   Disclose
42 U.S.C. § 262(l)(2)(A) – 20 days

 BIOSIM good Applicant provides a copy of aBLA and information describing manufacturing

Step 2: Disclose
42 U.S.C. § 262(l)(3)(A) – 60 days

  BRAND good Reference sponsor provides list of assertable patents and identifies any patents it is willing to license

Step 3:   Disclose
42 U.S.C. § 262(l)(3)(B) – 60 days

 BIOSIM good Applicant provides its own list of assertable patents, responds to licensing offer, and gives “detailed statements” why all listed patents are invalid, unenforceable, or will not be infringed

Step 4: Disclose
42 U.S.C. § 262(l)(3)(C) – 60 days

  BRAND good Reference sponsor gives “detailed statements” why the claims of all listed patents are infringed and responds to Applicant’s detailed statements

Step 5: Negotiate
42 U.S.C. § 262(l)(4)(B) – 15 days

NEG FAILS

 Applicant and Reference sponsor negotiate to develop a final and complete list of patents for the initial patent infringement lawsuit but FAIL TO agree

Step 6:  Choose
42 U.S.C. § 262(l)(5)(A)

  BIOSIM good Applicant gives reference sponsor the number of patents it proposes to litigate

Step 7:  Exchange
42 U.S.C. § 262(l)(5)(B) – 5 days

 Exchange Applicant and Reference sponsor simultaneously exchange list of patents that should be part of infringement action; Reference sponsor’s list limited to same number given by Applicant

Step 8:  File Suit
42 U.S.C. § 262(l)(6)(B) – 30 days

 BRAND good Reference sponsor files suit on all patents on lists.

 

shutterstock_279495203One goal of BioLoquitur is to provide commentary and analysis on important developments in U.S. law affecting the pharmaceutical and biologics industry. It can be easy to forget that legal developments are not limited to the latest court decisions or agency actions, however.  The most profound changes in U.S. law arise from legislation.   This post thus provides a snapshot of relevant legislative proposals for the first quarter in 2017.

While the bills highlighted in this post have yet to make significant progress in the legislative process, they provide insight into what issues Congress is concerned about and how they might address such issues.

Currently, there over a dozen bills pending in the House of Representatives and Senate relevant to pharmaceutical and biologics companies. Common themes include (1) expediting the market entry of generic drugs and biosimilar products; (2) addressing drug shortages; and (3) discouraging certain settlement provisions between brands and generic companies that are thought to have anti-competitive effects, such as “pay-for-delay” requirements.  Below is a short summary of key bills and their status to date.  For a Quick View table, click here.

“Improving Access to Affordable Prescription Drugs Act,” H.R. 1776; S. 771. On March 29, 2017, Representative Janice Schakowsky and Senator Al Franken, both democrats, introduced identical bills that would enact comprehensive reforms relating to pharmaceutical drugs and biologics products. Provisions of the bills would impose reporting requirements, levy taxes and eliminate tax deductions for certain actions, reduce market exclusivity periods, and imposing de facto limits on settlements between generic drug companies and brand companies. The bills have been referred to committees. Significant provisions include:

  • Sec. 101. Requiring Mandatory reporting for drug and biologic manufacturers, including disclosure of sales volume, gross and net revenue and profit, drug pricing, information executive compensation, and a breakdown of expenditures for research and development, costs of goods sold, acquisition and licensing costs, and marketing and advertising spend.
  • Sec. 202. Imposing a tax on revenue earned because of any “price spike” in prescription drug pricing.
  • Sec. 204. Permitting the importation and sale of drugs by foreign wholesale distributors and licensed foreign. pharmacies, starting initially with Canadian pharmacies.
  • Sec. 303 (a)(1). Allowing the early submission of an abbreviated new drug application (ANDA) for a new chemical entity (NCE) (three years after approval) and shortening the approval time for ANDAs under certain conditions. Currently, the earliest date for submitting an ANDA is four years after the approval of the NCE.
  • Sec. 303(a)(2). Restricting the current three year supplementary regulatory exclusivity granted for new indications, formulations, dosages and the like to only those approvals that show a “significant clinical benefit over existing therapies.
  • Sec. 303(a)(3). Slashing the market exclusivity afforded to new biologic drugs from 12 years to 7 years.
  • Sec. 304. Revoking market exclusivities for drugs and biologics for certain violations, including misbranding, illegal marketing, kickbacks, and other acts of fraud.
  • Sec. 404. Creating a legal presumption that the Federal Trade Commission (FTC) can rely on that the following settlements between brand companies and ANDA filers have an anticompetitive effect:
    • Settlements that provide the ANDA filer with anything of value, including an exclusive license, other than the right to market before the expiration of the patents covering the drug, payment of legal expenses up to $7.5 million, and/or a covenant not to sue;
    • Settlements where the ANDA filer agrees to limit or forego research and development, manufacturing, marketing or sales of the ANDA product for any period of time.
  • Sec. 405. Preventing deductions for direct-to-consumer advertising of prescription drugs.
  • Sec. 406. Requiring the FTC to prepare a report accessing the impact of “product hopping,” where “product hopping” refers to when a manufacturer develops a new formulation of a known drug or biologic product for a particular indication and then acts to reduce or eliminate demand for the original product,

“Medical Innovation Prize Fund Act,” S.495. Introduced by Independent Senator Bernie Sanders on March 2, 2017, this bill would broadly eliminate patent and market exclusivity provisions for drugs and biologics and instead establish a fund to award prizes and payments for medical innovations. The bill has been referred to committee.

Affordable and Safe Prescription Drug Importation Act, H.R. 1245; S. 469. On February 28, 2017, Democratic Representative Elijah Cummings and Independent Senator Bernie Sanders introduced identical bills to permit importation of drugs from foreign wholesales and foreign pharmacies. The provisions of these bills are largely subsumed within the more comprehensive “Improving Access to Affordable Prescription Drugs Act.” The bills are currently in committee.

The “OPEN ACT,” H.R. 1223. On February 27, 2017, Republican Representative Gus Bilirakis introduced the OPEN ACT, i.e., the Orphan Products Extension Now Accelerating Cures and Treatments Act of 2017. The OPEN ACT would grant an additional 6 months of market exclusivity for an approval of a new indication treating rare diseases and conditions. This exclusivity would extend any existing market exclusivity, such as the five-year exclusivity period for NCE products. The bill has been referred to committee.

“Increasing Competition in Pharmaceuticals Act,” S. 297; “Lower Drug Costs through Competition Act,” H.R. 749. Senator Susan Collins, Republican, and Representative Kurt Schrader, Democrat, introduced these related bills on February 2, 2017 and January 30, 2017 respectively. The legislation requires the FDA to prioritize and complete an expedited review of ANDA applications for generic drugs where there is a shortage or where there is only one current manufacturer and no more than two tentative approvals for other manufacturers. The bills also authorize a study on the REMS program, which allows the FDA to require Risk Evaluation and Mitigation Strategies from manufacturers of drugs or biological products that have known or potential serious risks. The bill is currently referred to committee.

“Short on Competition Act,” S. 183. Introduced by Democratic Senator Amy Klobuchar on January 20, 2017, the Short on Competition Act also addresses drug shortages. In addition to authorizing expedited reviews of ANDA applications, the Act would permit temporary importation of drugs from foreign countries. The bill is currently referred to committee.

“Preserve Access to Affordable Generics Act,” S. 124. On January 12, 2017, Senator Klobuchar (D) introduced a bill directed to prohibiting certain settlement agreements provisions between brand and generic drug companies. The provisions of this Act are mostly subsumed within the more comprehensive “Improving Access to Affordable Prescription Drugs Act.” Senator Klobuchar’s bill has been referred to committee.

Bioloquitur will continue to track legislative proposals throughout the year and report on any relevant developments.

shutterstock_96589270The Biologics Price Competition and Innovation Act of 2009 (“BPCIA”) amended Section 351(k) of the Public Health Service Act (42 U.S.C. § 262(k)) in providing ways to obtain licenses for certain biological products via abbreviated applications from the Food and Drug Administration (“FDA”) in order to market biosimilar products or interchangeable products for therapeutic uses. According to 42 U.S.C. § 262(i)(1), the term “biological product” is defined as “a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except chemically synthesized polypeptide), or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound)” useful for preventing, treating, or curing a human disease or condition. By allowing abbreviated applications for biological products biosimilar to, or interchangeable with, FDA-licensed reference biological products, BPCIA could do for therapeutic biological products, similar to what the Hatch-Waxman Act does for small molecule drugs, in fostering the development of generic therapeutic products.

A biosimilar product is a biological product (a) highly similar to a reference product even though there could be minor differences in clinically inactive components; and (b) having no clinically meaningful differences from the reference product regarding safety, purity, and potency (42 U.S.C. § 262(i)(2)). A reference product is a biological product which has obtained a biologics license via 42 U.S.C. § 262(a), i.e., a biological product for which a Biologics License Application (“BLA”) has been approved by the FDA for its introduction into interstate commerce. An interchangeable product is a biological product that (a) is biosimilar to a reference product;  (b) “can be expected to produce the same clinical result as the reference product in any given patient;” and (c) would have a risk based on safety or diminished efficacy not greater than the risk of using the reference product alone without any switch or alternation, when the biological product is switched or alternated with the reference product administered more than once, so that the interchangeable product “may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.” 42 U.S.C. § 262(i)(3) and (k)(4).

One of the requirements of an abbreviated BLA (“aBLA”) to show that a proposed biological product is interchangeable with a reference product is to demonstrate that the proposed biological product and the reference product are biosimilar. Biosimilarity must be demonstrated with data obtained from (a) analytical studies showing that the proposed biological product and the reference product are highly similar other than minor differences in clinically inactive components; (b) animal studies including toxicity assessments; and (c) a clinical study or studies, including assessments of pharmacokinetics, pharmacodynamics and immunogenicity to show safety, purity, and potency in at least one of the therapeutic uses licensed for the reference product. 42 U.S.C. § 262(k)(2)(A)(i)(I).

As mentioned above, the terms “biosimilar product” and “interchangeable product” pertain to certain biological products, and the term “biological product” covers a number of biological substances. However, regarding guidance on the various studies that should be performed to gather the data or information needed for the aBLA, FDA has taken a stepwise approach in concentrating on only therapeutic protein products so far, but not on other biological products such as viruses, therapeutic sera, etc.  For proposed therapeutic protein products, FDA has published a guidance document on analytical studies that should be conducted to obtain the needed chemistry, manufacturing, and controls (CMC) information relevant to the assessment of whether the reference product and the proposed therapeutic protein product are highly similar.[1] There is also an FDA guidance document pertaining to only proposed therapeutic protein products for gathering data or information in order to demonstrate biosimilarity based on structural studies, functional assays, animal studies, and clinical studies.[2]   Nevertheless, despite the focus of the above mentioned guidance documents on only therapeutic protein products,  FDA did publish a guidance to help sponsors of biosimilar products in general to design and use clinical pharmacology studies to gather pharmacokinetic and pharmacodynamic data on proposed biological products, without limitation on the types of the biological products.[3]

The FDA guidance documents referred to above concern only the demonstration of biosimilarity, but not interchangeable products per se. In fact, in one of the guidance documents, the FDA cautioned that the document was not intended to present the FDA’s approach to determining interchangeability, which would be dealt with in a separate guidance document.[4] Recently, the FDA finally published a draft guidance on the demonstration of interchangeability for therapeutic protein products.[5] The intention of the draft guidance is to help sponsors in showing that a proposed therapeutic protein product is interchangeable with a reference product. The FDA invited public comments for the draft guidance, and at the closure of the comment period on March 20, 2017, nine public comments have been received.

As pointed out in the draft guidance, to show interchangeability, an aBLA is required to also demonstrate that the proposed biological product is biosimilar to the reference product.[6] In addition, the sponsor of the proposed interchangeable biological product must show that the proposed product is “expected to produce the same clinical result as the reference product in any given patient” as set forth in 42 U.S.C. § 262(k)(4)(A)(ii). Based on this statutory requirement, the FDA expects data and information to show that the proposed interchangeable biological product can be expected to produce the same clinical results as the reference product in all of the conditions of use licensed by the FDA for the reference product.[7] However, that is only a recommendation by the FDA, and the draft guidance indicates that an aBLA is permitted to demonstrate the same clinical results in less than all of the conditions of use.[8] The data and information needed may vary depending on the nature of the proposed interchangeable biological product, and may include (a) any analytical differences between the proposed product and the reference product, and an analysis of the resulting potential clinical impact, if any; (b) “an analysis of the mechanism(s) of action in each condition of use,” including the target receptor(s), binding to the target receptor(s),  molecular signaling associated with the binding, dose or concentration response, the expression and location of the target receptor(s), and the relationship between product structure and interactions with the target receptor(s); (c) pharmacokinetics and distribution of the proposed product in the bodies of different patients; (d) immunogenicity; (e) any differences in expected toxicities in each condition of use and patient population; and (f) any other factor that may influence the efficacy or safety of the proposed product in each condition of use and patient population.[9]

Furthermore, for any biological product expected to be administered more than once, the statute requires that “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,” 42 U.S.C. § 262(k)(4)(B). The FDA expects that the aBLA would present data from a switching study or studies in one or more conditions of use, and that the data will be useful in assessing the safety risk and risk of diminished efficacy of switching or alternating between the proposed product and the reference product.[10]

The draft guidance includes detailed description of the scientific studies recommended by the FDA for the sponsors to perform in order to gather data and information useful for assessing interchangeability.  A discussion of all the scientific studies is beyond the scope of this blog post, which is merely a summary intended to alert the blog readers of the existence of the draft guidance, so that the readers could consult with the draft guidance directly if more scientific information is needed.

The draft guidance shows that more data and information, as a result more studies, would be needed in an aBLA for an interchangeable product, than for a biosimilar product, which is consistent with the statutory requirements. That may explain why as of today the FDA has not approved any interchangeable product, while four biological products have been licensed by the FDA as biosimilar to reference products.[11]  However, a sponsor putting in more effort and expenses for getting a biologics license for an interchangeable product, compared with only a biologics license for a biosimilar product, could be rewarded in at least two ways. First, under the statute, an interchangeable product may be substituted for the corresponding reference product without the intervention of the health care provider who prescribed the reference product. 42 U.S.C. § 262(i)(3). That means if a prescription of the reference product does not specify no generic substitution, a pharmacy could legally fill the prescription by substituting the prescribed reference product with an interchangeable product upon the patient’s request. Second, if the sponsor obtains an FDA license on the first interchangeable product for any condition of use of a reference product, the sponsor will obtain exclusivity so that the FDA will not determine whether a proposed biological product of the second or later aBLA is interchangeable for any condition of use until the earlier of (a) one year after the first commercial marketing of the first interchangeable product licensed for the reference product; (b) 18 months after a final court decision on all patents in suit in an action instituted against the aBLA applicant for the first interchangeable product, or after the dismissal of the court action; or (c) 42 months after approval of the first interchangeable product if the applicant has been sued and such litigation is still ongoing within the 42 months, or 18 months after approval of the first interchangeable product if the applicant has not been sued. 42 U.S.C. § 262(k)(6).

Takeaway

It should be noted that “FDA’s guidance documents do not establish legally enforceable responsibilities.  Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited.”[12] That means the FDA could not properly force a sponsor of a proposed interchangeable therapeutic protein product to perform all the studies mentioned in the guidance documents discussed herein. However, the FDA guidance documents are useful for the sponsor to design studies to be carried out in order to gather the required information to demonstrate that a proposed therapeutic protein product is interchangeable with a reference product because the guidance documents show how the FDA interprets the law pertaining to biosimilar and/or interchangeable products.

[1] See the guidance for industry, Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, April 28, 2015.

[2] See the guidance for industry, Scientific Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, April 28, 2015.

[3] See the guidance for industry, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, December 28, 2016.

[4] See Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product, 2015, page 4, Section III.

[5] See the draft guidance for industry, Considerations in Demonstrating Interchangeability with a Reference Product, January 17, 2017.

[6] Id, page 3.

[7] Id, page 3, emphasis added.

[8] Id, page 3.

[9] Id, page 3.

[10] Id, page 4.

[11] See CDER List of Licensed Biological Products with (1) Reference Product Exclusivity and (2) Biosimilarity or Interchangeability Evaluations to Date,    https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM549201.pdf

[12] See Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, 2016, page 1.