Tag: biosimilars

California Tackles Big Pharma’s Anticompetitive ‘Pay for Delay’ Practices That Slow Down Lower-Cost Generic Drug Development

California Gov. Gavin Newsom has signed AB 824, known as the “Pay-for-Delay” bill, blocking pharmaceutical companies from paying generic drug makers to not develop and bring lower-cost medicines to market. The law makes these so-called “reverse payment” settlements of patent disputes – which the Federal Trade Commission says cost consumers $3.5 billion a year – “presumptively anticompetitive.”

The new law provides that an agreement resolving a patent infringement claim is anticompetitive if the generic drug or biosimilar drug makers receive anything of value from the brand name company that’s claiming infringement, and if the generic maker agrees to slow-walk or stop research, development, manufacture, marketing, or sales of a generic product for any period of time. Exceptions are made in cases in which an agreement promotes competition.

The state Attorney General is authorized to seek civil penalties within four years of any violations of the law. Other remedies would be available under California’s Cartwright Act, Unfair Practices Act, or unfair competition laws.

Sidestepping Competition

The FTC has prosecuted brand name and generic drug companies and has sued to stop these reverse payment agreements which allow drug companies to “sidestep competition.” Earlier this year, for example, the FTC announced a global settlement of three separate federal antitrust lawsuits involving subsidiaries of pharmaceutical manufacturer Teva Pharmaceuticals Industries Ltd.

There is no legitimate pro-competitive justification for pay-for-delay of generic drugs by brand name pharma companies. It's the consumer who pays the price. In one of the cases, Teva’s Cephalon company paid four generic drug manufacturers $200 million to back off on their plans to sell a generic version of Cephalon’s Provigil, a medication used to treat excessive sleepiness caused by sleep apnea, narcolepsy, or shift-work sleep disorder. Teva, which was able to delay the generic version for six years, agreed in its settlement to create a $25 million consumer fund and pay $69 million plus another $200,000 to cover the state’s legal fees. Teva was also barred from engaging in reverse-payment patent settlement agreements for 10 years.

In another instance, the FTC announced the settlement of its case against Endo Pharmaceuticals Inc., which paid Impax Laboratories $112 million not to go to market with a competing generic version of Endo’s Opana ER – a pain reliever in the opioid family.

Collusive Arrangements

Attorney General Xavier Becerra, AB 824’s sponsor, wrote that these kinds of pay-for-delay agreements are “collusive arrangements between brand-name drug companies and rival drug manufacturers” that allow the companies to charge monopolistic prices. “Pay-for-delay agreements hurt consumers twice – once by delaying the introduction of an equivalent generic drug that is almost always cheaper than the brand name and second by stifling additional competition because we know that when multiple manufacturers of generic drugs compete with each other, prices can be up to 90% less than what the brand name drug cost originally,” Becerra wrote.

Supporters of the bill included Health Access of California, the California Labor Federation, and the Small Business Majority. Another supporter, the California Public Interest Research Group, said brand-name drugs cost an average of 10 times and sometimes 33 times more than generics, adding that brand-name companies make billions in sales while generics are delayed.

All Those Opposed

The Association for Accessible Medicines (AAM) opposed the bill, saying it “penalizes procompetitive patent settlements that significantly expedite generic and biosimilar access.” Besides, the group argued, a federal framework already exists to review patent settlements, citing FTC v. Actavis, the 2013 decision in which the Supreme Court held that a brand drug manufacturer’s reverse payment to a generic competitor to settle patent litigation can violate the antitrust laws. The Supreme Court refused to call these agreements presumptively unlawful, instead saying the FTC had to prove its case as it would in any other “rule of reason” cases. The likelihood that a pay-to-delay settlement would have anticompetitive effects “depend[s] on its size, its scale in relation to the payor’s anticipated future litigation costs, its independence from other services for which it might represent payment, and the lack of any other convincing justification,” the Supreme Court ruled.

The pro-industry pro-tort reform Civil Justice Association of California called the bill “an enhanced, steroid infused codification” of the California Supreme Court’s 2015 decision in In re Cipro, which followed the U.S. Supreme Court’s FTC v. Actavis ruling.

Biopharmaceutical company Biocon opposed the bill for, it said, replacing the FTC with the State of California in the commission’s role as prosecutor of anticompetitive conduct.

The FTC’s Competition Bureau has been keeping track of the effectiveness of the Supreme Court’s FTC v. Actavis decision. In May 2019, FTC Chairman Joe Simons announced: “The data are clear: the Supreme Court’s Actavis decision has significantly reduced the kinds of reverse payment agreements that are most likely to impede generic entry and harm consumers.”

Commentary

There is simply no legitimate procompetitive justification for pay-for-delay settlements. There is simply no legitimate procompetitive justification for pay-for-delay settlements. They are explicit agreements between competitors to restrain competition and serve only to keep pharmaceutical prices unnecessarily high in this country. According to FTC data, pay-for-delay settlements cost consumers billions of dollars per year.

AB 824 simply aligns the law with the reality of this burden on the consumer, creating a presumption that such settlements are anticompetitive and requiring the settling parties to demonstrate why this is not the case. In fact, AB 824 essentially codifies the rule the FTC argued should govern pay-for-delay settlements in Actavis.

Critics of the law will challenge its legality, including its constitutionality under the dormant commerce clause. And while it may not withstand these legal challenges, AB 824 is an encouraging sign that lawmakers are beginning to understand the negative impact that pay-for-delay settlements have on competition in the pharmaceutical industry. We hope more states follow suit.

© MoginRubin LLP

ARTICLE BY Jennifer M. Oliver and Timothy Z. LaComb of MoginRubin. Edited by Tom Hagy for MoginRubin LLP. Photo of “worried man” by Nik Shuliahin via Upsplash.
For more on pharmaceutical regulation, see the National Law Review Biotech, Food & Drug law page.

Federal Circuit Requires 180 Day Notice For All Biosimilars, Even After Patent Dance

biosimilars patent danceIn Amgen v. Apotex, the Federal Circuit rejected Apotex’s arguments that the 180-day pre-marketing notice requirement does not apply to biosimilar applicants who participated in the “patent dance” process of the Biologics Price Competition and Innovation Act (“BPCIA”), expanding on its decision in Amgen v. Sandoz that 42 USC § 262(l)(8)(A) is a mandatory, stand-alone requirement. The Supreme Court has asked the Solicitor General to weigh in on whether it should grant certiorari in Amgen v. Sandoz. Will this decision make the Court more or less likely to review the Federal Circuit’s interpretation of this important biosimilar statute?

The Biosimilar Patent Dance

The biologic product at issue is Amgen’s Neulasta® (pegfilgrastim) product. Amgen describes pegfilgrastim as “a recombinantly expressed, 175-amino acid form of … human granulocyte-colony stimulating factor (‘G-CSF’) conjugated to a 20 kD monomethoxypolyethylene glycol (m-PEG) at the N-terminus.” After Apotex filed a Biologic License Application (BLA) seeking FDA approval to market a biosimilar version of Neulasta® (pegfilgrastim), the parties followed several steps of the patent dance procedures, which resulted in Amgen asserting U.S. Patent Nos. 8,952,138 and 5,824,784 in the U.S. District Court for the Southern District of Florida. Those infringement claims are being litigated, although the ‘784 patent has been dropped since it expired.

The Biosimilar 180-Day Notice Dispute

As noted in the Federal Circuit decision, Apotex sent Amgen a letter on April 17, 2015, stating that it was “providing notice of future commercial marketing pursuant to 21 USC § 262(l)(8)(A), though Apotex lacked (as it still lacks) an FDA license.” Amgen sought a preliminary injunction to “require Apotex to provide … notice if and when it receives a license and to delay any commercial marketing for 180 days from that notice.” The district court granted that motion, citing the Federal Circuit decision in Amgen v. Sandoz that notice cannot be given before the biosimilar product is approved. Apotex appealed.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Taranto and joined by Judge Wallach and Judge Bryson. The bottom line of the court’s decision is this:

The [§ 262(l)](8)(A) requirement of 180 days’ post-licensure notice before commercial marketing … is a mandatory one enforceable by injunction whether or not [the biosimilar applicant provided a copy of its biosimilar application to the reference product sponsor in accordance with  § 262(l)(2)(A)].

As it had in Amgen v. Sandoz, the court emphasized the “categorical” language used in the statute:

The subsection (k) applicant shall provide notice to the reference product sponsor not later than 180 days before the date of the first commercial marketing of the biological product licensed under subsection (k).

The court noted that § 262(l)(8)(A) “contains no words that make the applicability of its notice rule turn on whether the applicant took the earlier step of giving the [§ 262(l)](2)(A) notice that begins the § 262(l) information-exchange process,” and stood by its holding in Amgen v. Sandoz that the statute is “‘a standalone notice provision’ not dependent on the information-exchange processes that begin with [§ 262](l)(2)(A).”

Further justifying its decision, the court emphasized that the BPCIA created a “two stage” patent litigation process, and found that the 180-day pre-marketing notice is essential to the second stage. In that regard, it explained that the 180 day period “gives the reference product sponsor time to assess its infringement position for the final FDA-approved product as to yet-to-be-litigated patents,” and “gives the parties and the district court the time for adjudicating such matters without the reliability-reducing rush that would attend actions for requests for relief against immediate market entry that could cause irreparable injury.”

The court also considered and rejected Apotex’s arguments based on the relationship between § 262(l)(8)(A) and other sections of the BPCIA, such as § 262(l)(9)(B) and § 262(l)(9)(C), which give the reference product sponsor the right to bring delcaratory judgment actions when the biosimilar applicant fails to follow some or all of the patent dance procedures.

Requiring 180-Days Notice Does Not Extend The 12-Year Exclusivity Period

Perhaps Apotex’s most compelling argument was that the court’s interpretation of 262(l)(8)(A) effectively gives original biologic products 12.5 years of exclusivity rather than the 12 years provided by Congress in § 262(k)(7). The court dealt with this argument in two ways. First, the court noted that “§ 262(k)(7) by its terms establishes the 12-year date only as an earliest date, not a latest date, on which a biosimilar license can take effect” (emphasis added). Second the court hypothesized that the FDA could implement the 12-year exclusivity period by “issu[ing] a license before the 11.5-year mark and deem[ing] the license to take effect on the 12-year date.” In that case, the 180-days notice could be given in time to expire when the 12-year exclusivity period expires.

(The FDA has not yet issued guidance or regulations on this issue, and is not bound by the Federal Circuit decision. Indeed, the U.S. Court of Appeals for the District of Columbia is the appellate court most likely to review the FDA’s interpretation of § 262(k)(7).)

What Will the Supreme Court Do?

As noted above, the Supreme Court has asked the Solicitor General to weigh in on whether it should grant certiorariin Amgen v. Sandoz. Since this decision is consistent with that one, it is not clear that it will make the Court more or less likely to hear the case. The opinion here provides a detailed summary of the patent litigation procedures of the BPCIA and the related sections of the patent infringement statute, 35 USC § 271. That analysis may make the Court more comfortable with the Federal Circuit’s interpretation, or could lead the Court to try its own hand at deciphering a statutory scheme that Judge Lourie characterized as deserving of  “a Pulitzer Prize for complexity.”

ARTICLE BY Courtenay C. Brinckerhoff of Foley & Lardner LLP

© 2016 Foley & Lardner LLP

Senate Judiciary Introduces CREATES Act To Expedite Access To Affordable Drugs

affordable drugsFollowing months of public outcry and Congressional probes into significant drug price increases, the Senate Judiciary Committee introduced legislation targeting “behavior that blocks competition and delays the creation of affordable generic drugs” and biosimilar products. The bill, entitled the Creating and Restoring Equal Access to Equivalent Samples (CREATES) Act of 2016, S. 3056, would punish the strategic refusal of “innovator” companies to (1) share drug samples needed for generic and biosimilar regulatory testing and approval; and (2) agree on a shared safety protocol for so-called “REMS products.” The CREATES Act is the latest in a string of legislative efforts around the country focusing on drug affordability and price transparency.

A. Regulatory Background

When and how a generic or biosimilar product (or brand drug or biologic) enters the pharmaceutical supply chain varies depending on whether the product is subject to Risk Evaluation and Mitigation Strategies (“REMS”) requirements. REMS originated with the FDA Amendments Act of 2007, which authorizes distribution restrictions and other REMS for medicines with higher toxicity and risk potential.  A REMS may include Elements to Assure Safe Use (“ETASU”), such as restricted distribution, physician and patient education, and/or evidence of safeuse conditions.

By law (21 U.S.C. § 355-1(f)(8)), REMS requirements cannot be used to “block or delay” generic approval. Nevertheless, FDA has publicly stated“we have found cases in which sponsors have tried to use the REMS to block generics.” Such efforts have been challenged in private antitrust litigation and generated more than 100 inquiries to FDA. The Federal Trade Commission has told Congress it “continue[s] to be concerned about potential [REMS] abuses . . . to impede generic competition,” which “may violate the antitrust laws.” Enter the CREATES Act.

B. The CREATES Act

Section 3 of the CREATES Act would establish causes of action for “delays of generic drugs and biosimilar biological products.” An “eligible product developer,” i.e., an ANDA applicant or 351(k) applicant, could bring a federal civil action against the license holder for a “covered product”—defined as an approved drug or biological other than one for which there is a short-term shortage—alleging the license holder

(1) “has declined to provide sufficient quantities of the covered product to the eligible product developer on commercially reasonable, market-based terms”; or

for products subject to a REMS with ETASU

(2) (i) “failed to reach agreement with respect to a single, shared system of elements to assure safe use with respect to the covered product[] or . . . at least 120 days have elapsed since the developer first initiated an attempt to reach an agreement”; or

(ii) “refused to allow the eligible product developer to join a previously approved system of elements to assure safe use with respect to that product.”

The Act would authorize judges to award injunctive relief and damages “sufficient to deter” similar delaying conduct. Damages could not exceed the revenue earned from sale of the drug during the refusal period, however.

The CREATES Act would exempt innovators from liability from “the failure of an eligible product developer to follow adequate safeguards to assure safe use of the covered product during development or testing activities.” Additionally, innovators would not be liable if, in fact, they “had [no] access to inventory of the covered product to supply to the eligible product developer on commercially reasonable, market-based terms” or if “the covered product could be purchased by the eligible product developer in sufficient quantities on commercially reasonable, market-based terms from the agents, distributors, or wholesalers of the license holder.”

C. Reactions and Implications

The CREATES Act enjoys broad support from the generic industry, physicians, pharmacists, hospitals, consumer advocacy groups, antitrust experts, and insurers. During a recent Congressional hearing, the CREATES Act waspraised for confronting anticompetitive regulatory manipulation by promoting competition and, in turn, improving consumer choice and welfare. The hearing’s lone dissenter, the Pharmaceutical Research and Manufacturers of America (“PhRMA”), claimed the bill “uses a blunt instrument to address a narrow issue.”  Among other things, PhRMA objected to litigation as the mechanism for resolving product safety concerns and breakdowns in complex, multiparty REMS negotiations.

These criticisms raise legitimate issues. Reliance on litigation to remedy delays in generic entry risks a slow, expensive, and unpredictable enforcement process. Determining if a “term” is “commercially reasonable,” for example, presents fact-bound, context-specific questions typically reserved for a finder of fact. What legal consequence, if any, flows from a generic’s failure to engage in good faith negotiations to join the brand’s shared REMS?

The law also could leave innovators facing conflicting statutory obligations. It would allow “[a]n eligible product developer [to] submit . . . a written request for the eligible product developer to be authorized to obtain sufficient quantities of an individual covered product subject to a REMS with ETASU,” in which case “provision of the covered product by the license holder under the terms of [an] authorization will not be a violation of the REMS for the covered product.” Yet, it (currently) does not amend the statutory provisions governing the enforcement of REMS programs (21 U.S.C. § 355(p)(1)(B); 21 U.S.C. § 333(f)(4)(A)). Without a legislative fix, sharing samples of a drug with REMS with ETASU could expose a brand company to civil and criminal penalties.

Some or all of these matters may be mooted by amendments to the CREATES Act as it makes it way through the legislative process.  Time will tell.

D. Striking A Balance

The CREATES Act seeks to tweak the elusive balance between encouraging development and continued research for new drugs and biologics while ensuring timely availability of lower-cost generic and biosimilar drugs.  While the fate of the CREATES Act remains uncertain, its impact on the American healthcare system would be significant for stakeholders on all sides of the public debate over drug affordability.

ARTICLE BY James W. Matthews, David L. Rosen, Katy E. Koski & Jason L. Drori of

Foley & Lardner LLP
© 2016 Foley & Lardner LLP

Behind the Curtain: Shkreli was NOT the Big Story on the Hill Today

Congress’s complex relationship with prescription drugs was on display today in the House of Representatives.  In the House Committee on Oversight and Government Reform (OGR), Martin Shkreli pleaded the 5th at a hearing investigating drug pricing.  Meanwhile, the Energy and Commerce Committee (E&C) held a hearing regarding implementation of biosimilars.  While all the attention will be on the former, the latter was more important, especially for participants in the biosimilar space.

First, the OGR Committee was a media show built around the flamboyant Shkreli.  Shkreli took the 5th when given the opportunity to testify and later tweeted – after being excused from the hearing for refusing to answer any of the Members questions – that the Committee Members were ‘imbeciles’.  The tone of the hearing was very aggressive towards drug pricing and what were described as unsavory business practices. Members were also critical of the FDA generic drug programs.  However, Member interest in strengthening the program to bring competition to the marketplace was clear. Dr. Janet Woodcock, Director of the Center for Drug Evaluation and Research at the FDA,  stated that funds collected as a result of the Generic Drug User Free Amendments (GDUFA) helped expedite the review process and that by October there will be a 10-month review process on all new applications. The Senate HELP Committee held a hearing last week on reauthorization of GDUFA, which will expire next year, and this bipartisan interest, coupled with the prescription drug cost crisis, could lead to increased resources for the FDA review process. Beyond some public shaming of specific drug companies, there was little suggestion of substantive action on drug pricing.

Second, the E&C Committee was less about drug pricing, but more so about the ability of manufacturers to get new biosimilar products to the market. Notably, Committee Members on BOTH sides of the aisle were critical of CMS for trying to price biosimilars more like generic drugs and categorize different products under a single billing code.  They said the CMS ruling undermines the intent of the Biologics Price Competition and Innovation Act of 2010 (BPCIA) by removing incentives for a robust marketplace. Biologics make up a $200 billion market, so the consequences of policy decisions are significant. Members were also critical of delays in approving more biosimilars and issuing guidance on product labeling. Rep. Frank Pallone (D-NJ) asked if additional appropriations would address these problems, to which Dr. Woodcock replied that she’s more concerned the FDA will be unprepared for a rapid expansion of the biosimilar market.

While 2016 may be devoted to campaigning against drug prices, the Committees responsible for the regulatory regimes for drugs are still very focused on preserving the ability of manufacturers to successfully bring drugs to the market.  That is a much bigger deal than the plethora of Martin Shkreli smirks you will be subjected to in the media.

Article By Rodney L. Whitlock of Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C.

©1994-2016 Mintz, Levin, Cohn, Ferris, Glovsky and Popeo, P.C. All Rights Reserved.

FDA Issues Final Guidance on Biosimilars

Shortly after approving the first biosimilar under the abbreviated approval pathway created by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), the FDA has recently issued 3 final guidances regarding biosimilars. Biological products, or “biologics,” are pharmaceutical products created from biological sources. Unlike chemically synthesized pharmaceuticals, biologics are isolated from natural sources, and are typically more complex than conventional pharmaceutical drugs.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics: biosimilar and interchangeable biological products. Similar to the 1984 Hatch-Waxman Act’s abbreviated pathway for pharmaceuticals, the BPCIA allows a sponsor to seek approval of a “biosimilar” product under section 351(k) of the Public Health Service Act (“PHS Act”) by relying on certain existing scientific knowledge about the safety, purity, and potency of the reference product. The BPCIA defines “biosimilar” as (1) “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and (2) having “no clinically meaningful differences between the biosimilar product and the reference biological product in terms of the safety, purity, and potency of the product.” To meet the higher standard of “interchangeability,” the application must further show (1) the biosimilar is expected to produce the same clinical result as the reference product and (2) a patient can switch back and forth between the biosimilar and the reference product with no adverse effects.

The BPCIA provides abbreviated pathways for the FDA to approve two types of follow-on biologics

The FDA has been slow to accept and approve biosimilar applications, which has left open questions about how to establish biosimilarity and interchangeability under the statutory definitions. On April 28, 2015, the FDA finalized three draft guidances originally published in 2012:

  • Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

  • Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

The new guidances provide insight into the FDA requirements for establishing biosimilarity.

Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

This final guidance addresses three categories of commonly asked questions regarding FDA implementation of the BPCIA: (1) biosimilarity or interchangeability; (2) definitions relevant to the BPCIA; and (3) exclusivity. With regard to biosimilarity or interchangeability, the guidance states that a proposed biosimilar may have a different formulation, delivery device, or container closure than the reference product under certain circumstances. Additionally, the guidance discloses conditions permitting an applicant to obtain licensure for fewer than all routes of administration, presentations, and conditions of use for which the reference product is licensed. Further, the guidance describes conditions in which a sponsor may support biosimilarity using comparative data with a non-U.S.-licensed product or extrapolated clinical data designed to support a different condition of use. The guidance additionally instructs applicants how to describe the “strength” of a proposed injectable biosimilar. Finally, the guidance states that a biosimilar product that cites a reference product subject to the Pediatric Research Equity Act must include a pediatric assessment unless the applicant initially seeks approval as an interchangeable biological product.

With regard to the BPCIA’s definition of “biological product,” the guidance discloses the FDA’s regulatory definitions of “protein” and “chemically synthesized polypeptide.” Additionally, it defines when a proposed biological product is considered to be within the same “product class” as previously approved protein products.

With regard to exclusivity, the guidance instructs applicants and sponsor to search an online database to identify whether the reference product is subject to unexpired orphan exclusivity. The FDA will not approve a biosimilar during the 7-year exclusivity period.

Scientific Considerations in Demonstrating Biosimilarity to a Reference Product
This final guidance provides an overview of the FDA’s recommendations for establishing biosimilarity and discusses in detail relevant scientific principles for designing data and information to show biosimilarity. The FDA stresses that it will apply a totality-of-the-evidence approach in its assessment of biosimilarity and will use a risk-based approach to evaluate all data and information submitted. The FDA further emphasizes that the information sufficient to demonstrate biosimilarity will be determined on a product-specific basis.

The BPCIA requires an application to include analytical, animal, and clinical studies demonstrating that the biological product is “biosimilar” to a single reference product. As discussed above, the application must establish the product is “highly similar” to the reference product and has “no clinically meaningful differences.” Although the reference product must be U.S.-licensed, the application may rely on data from comparative studies with a non-U.S. licensed comparator product if the data is scientifically relevant. Because the FDA has discretion to determine what data is required to establish biosimilarity in a particular application, it encourages sponsors of the application to meet with the FDA early during product development to discuss adequate scientific justifications.

The FDA encourages sponsors to use a three step approach to develop evidence necessary to establish biosimilarity.

First, the sponsor should characterize the structural and functional aspects of both the proposed product and the reference product to identify potentially clinically relevant safety or efficacy risks. Structural analyses must use “state-of-the-art technology” to analyze multiple representative lots and show the proposed product will encode the same primary amino acid sequence as the reference product. Any minor modifications must be explained by the sponsor. The structural analyses for all relevant characteristics of the protein product (such as primary, secondary, tertiary, and quaternary structure; posttranslational modifications; and biological activities) must also be included. The FDA further recommends structural analysis of the finished dosage form to assess the effect of excipients or any other formulation effects. In vitro and/or in vivo functional assays must also be used to evaluate the pharmacologic activity of protein products.

Second, the sponsor should demonstrate safety and biosimilarity through animal studies. These studies generally do not establish safety, but are relevant to support the demonstration of biosimilarity through evidence of PK and PD measures. Nevertheless, animal toxicity and immunogenicity studies may be useful where uncertainty about safety remains after the initial structural and functional characterization.

Third, the sponsor should conduct comparative human PK and PD studies and a clinical immunogenicity assessment of the two products in an appropriate study population. The sponsor should discuss study proposals and overall clinical development plan with the FDA before initiating such studies. A sponsor should provide adequate scientific justification for choices in study design, population, endpoints, and other parameters. Human PK and PD measures comparing the proposed product to the reference product are typically fundamental to demonstrate biosimilarity. Even where relevant PD measures are not available, sensitive PD endpoints may be assessed. The FDA further expects at least one comparative clinical study regarding immunogenicity in order to assess the safety and effectiveness of the proposed product. The overall immunogenicity assessment should consider the nature of the immune response, the clinical relevance and severity of consequences, the incidence of immune responses, and the population being studied. Generally, the FDA expects studies to present statistical evidence that the proposed product is neither significantly inferior nor superior to the reference product. An applicant may provide sufficient scientific justification to extrapolate clinical data to support a determination of biosimilarity for various indications.

If there is uncertainty at each step, the sponsor should evaluate the uncertainty and consult with the FDA to adequately address it.

Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein Product to a Reference Product

This guideline relates to the biosimilarity of therapeutic protein products and describes nine factors that are relevant in developing analytical studies to show a proposed product is “highly similar” to a reference product.

1. Expression System. The application should seek to minimize differences between the proposed and referenced expression systems. The FDA expects the expression construct for a proposed product encodes the same primary amino acid sequence as its reference product. However, minor modifications (such as N- or C- terminal truncations) that are not expected to change the product performance may be justified.

2. Manufacturing Process. The application should demonstrate its manufacturing process does not result in significant differences between the proposed product and its reference product.

3. Assessment of Physiochemical Properties. Physicochemical assessments are designed to maximize the potential for detecting differences between the proposed and reference products. The sponsor should consider all relevant characteristics of the protein product and design tests to account for the heterogeneity of the proposed product and the reference product as well as the ranges of variability for each.

4. Functional Activities. Functional assays are designed to complement physicochemical analyses and evaluate the function of the protein product. Sponsors should perform appropriate assays to evaluate the range of relevant functional activities for a product.

5. Receptor Binding and Immunochemical Properties. Sponsors should analyze specific binding or immunochemical properties when they are part of the activity attributed to the protein product.

6. Impurities. Sponsors should characterize, identify, and quantify impurities in the proposed product and reference product. Sponsors should further perform a risk-based assessment regarding any differences in process-related impurities between the proposed and reference products.

7. Reference Product and Reference Standards. Sponsors should provide a broad comparison of the proposed product to the reference product that is not strictly limited to analysis of each product in isolation. For example, the biosimilarity analysis may further consider applicable reference standards and relevant publicly available information.

8. Finished Drug Product. Product characterization studies should be performed on the most downstream intermediate best suited for each analytical procedure. Thus, sponsors should analyze the finished drug product if it is best suited for a particular analysis. If the analysis is performed on an earlier intermediate, sponsors should provide additional information. Additionally, sponsors should clearly identify excipients used in the proposed product that differ from those in the reference product.

9. Stability. Sponsors should include comparative studies conducted under multiple stress conditions to establish degradation profiles of the proposed and reference product.

Conclusion

The recently issued final guidances provide insight into how the FDA will evaluate biosimilarity and directions for sponsors throughout product development. However, many additional questions surrounding the BPCIA remain. For example, the currently issued guidances do not address how the FDA will determine “interchangeability.” Interchangeable drugs are likely to be more profitable than mere biosimilars because they can be sold in place of the reference drug without a prescribing doctor’s approval.

Upcoming draft guidances plan to provide additional information regarding the required scientific requirements for establishing biosimilarity and interchangeability as well as naming and labeling requirements for approved biosimilars. In January, the FDA’s Center for Drug Evaluation and Research (CDER) announced plans to publish five draft guidances on biosimilars in 2015:

  • Biosimilars: Additional Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

  • Considerations in Demonstrating Interchangeability to a Reference Product

  • Labeling for Biosimilar Biological Products

  • Nonproprietary Naming for Biological Products

  • Statistical Approaches to Evaluation of Analytical Similarity Data to Support a Demonstration of Biosimilarity

ARTICLE BY Imron T. Aly, Sailesh K. Patel, John K. Hsu and Helen H. Ji of  Schiff Hardin LLP
© 2015 Schiff Hardin LLP

FDA Finalizes Guidance Documents on Biosimilarity

On Tuesday, and over three years after the initial guidance documents were released, the US Food and Drug Administration released final versions of three guidance documents discussing how FDA will evaluate applications for regulatory approval of biosimilar products:

•Scientific Considerations in Demonstrating Biosimilarity to a Reference Product

•Quality Considerations in Demonstrating Biosimilarity of a Therapeutic Protein

•Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009

Draft versions of the guidance documents were originally released by FDA for public comment in February 2012. In general, the final versions released Tuesday track the draft versions fairly closely, with a few noteworthy differences.

The guidance documents reiterate that the FDA will use a totality of the evidence approach to review applications for biosimilar products, and encourages a stepwise approach to demonstrating biosimilarity which with rare exceptions will include a comparison of the proposed biosimilar product with the reference product in terms of structure, function, animal toxicity, human pharmacokinetics (PK) and pharmacodynamics (PD), clinical immunogenicity, and clinical safety and effectiveness. This stepwise approach is intended to better address residual uncertainty about biosimilarity that might remain at each step of the approval process.

The final guidance documents contain a few changes from the draft versions that are noteworthy:

•Most of the discussion of issues related to demonstrating the heightened standard for interchangeability was removed from the guidances with a note that it will be the subject of a separate guidance document that is forthcoming.

•The final guidances reiterate that, in most instances, a sponsor will need to provide information to demonstrate biosimilarity based on data directly comparing the proposed biosimilar product to FDA-approved reference product. However, they elaborate on the type of bridging data needed when a biosimilar applicant seeks to use a non-US licensed comparator product to support a demonstration of biosimilarity.

•Specific comments have been provided for biosimilar developers considering manufacturing/process changes after completing the initial analytical similarity assessment including a requirement to demonstrate comparability between the pre- and post-change proposed product.

•More detailed comments regarding animal toxicity studies were added.

•Previous Q and As relating to what constitutes the “publicly-available information” that should be included in a 351(k) application and whether an applicant can include a request for reference product exclusivity in its 351(a) application were deleted – an indication that the FDA is still considering its position on these points.

Authored by: Paul A. Calvo, Ph.D. and Timothy J. Shea, Jr., PhD. by Sterne Kessler

© 2015 Sterne Kessler

Clash Of Titans over Biosimilars at Federal Trade Commission (FTC) Workshop

Bracewell & Giuliani Logo

 

On Tuesday, February 4, the Federal Trade Commission (FTC) conducted an all-day public workshop at its headquarters in Washington, D.C. on competition issues involving biologics and biosimilars.1 During highly informative presentations and roundtable discussions, the FTC and various stakeholders, including top-level representatives from originators of biologics (Pfizer and Amgen), biosimilars developers (Sandoz, Momenta and Hospira), payors (Aetna), prescribers (CVS and Express Scripts) and academia (Harvard Medical School), analyzed the likely impact of recent state substitution laws and naming conventions on biosimilars.

No one denied nor debated that the future of the drug industry lies in the robust and dynamic area of biologics. In 2010, 4 of the top 10 drugs were biologics and it is anticipated that in 2016 biologics will account for 7 of the top 10 drugs worldwide.2 At the same time, all panelists were concerned that the costs associated with biologics are rising at a staggering rate and are therefore not sustainable for patients nor payors, and that many patients will be unable to afford biologics if competition is not introduced.

According to Harry Travis, Vice President at Aetna, patients currently spend about $1 a day on non-specialty medication (traditional drugs) whereas they spend roughly $100 a day for specialty medication (biologics).3 He stated that only 1% of Aetna’s customers use specialty products, which account for 50% of Aetna’s total drug spending. This trend was confirmed by Steve Miller, Chief Medical Officer at Express Scripts, who underlined that specialty products (biologics) currently account for 30% of total drug spending, but this number will rise to 50% in 5 years.

It is thus not surprising that all participants urged for FDA-approved biosimilars in order to improve access to biologics while at the same time protecting public health and safety. Participants were also virtually unanimous in their recommendations that fostering public confidence in biosimilars will be crucial to their success and that unnecessary obstacles to substitution may restrict competition.4

The following points were discussed, relying on a large amount of data and comparative studies between countries:

  • Competition between originators of biologics and biosimilars developers: Panelists agreed that competition is not expected to have the same effects on the biologics industry as it has had in the small-molecule drugs space when generics penetrated the latter. Because the dynamics are completely different, the entry of biosimilars is unlikely to result in either steep price discounting or rapid acquisition of market share by manufacturers of biosimilars.5
  • Premature state biosimilar substitution laws: 18 states have already decided to introduce bills to regulate biosimilars, and 4 of them have enacted laws, all of which may seem slightly premature given that the FDA has yet to approve a biosimilar. Certain provisions of these substitution laws appear controversial as they place onerous requirements on the substitution of biosimilars for branded biologics. Of particular concern are certain substitutions laws requiring pharmacists to promptly notify patients and/or prescribers when dispensing a biosimilar, and to keep special records. These state-level restrictions not only deter substitution by imposing on pharmacists burdensome recordkeeping and additional communications with the physician, they also contradict federal law, namely the Biologics Price Competition and Innovation Act (BPCIA), which expressly provides for substitution.6 These state laws are arguably inconsistent with the BPCIA and could undermine the attractiveness and access to more affordable biologics.
  • Impact of naming on biosimilars: There was debate as to whether biosimilars should bear different non-proprietary names and whether such a requirement would have anticompetitive effects. Some argued that requiring distinct non-proprietary names is simply an effort to cause doubt and distrust among physicians and patients by making biosimilars appear different from biologics. As noted by Bruce Leicher, General Counsel at Momenta, the Biotechnology Industry Organization opposes GMO labelling on genetically modified foods precisely for the same reason – requiring a different name for biosimilars would communicate a different (and perhaps suspicious) product and would therefore grant a competitive advantage to branded biologics. Other panelists argued that names and other types of identifiers were justified by the need for an effective pharmacovigilance system, while some speakers expressed the need for distinguishable naming or other identifiers for purposes of linking a responsible product to a specific adverse event in the event of product liability.

The FTC did not express its own views on the effect of state-level restrictions and naming conventions on competition in the biosimilars market, but did note that securing more prescribing physicians on the panel might have added to the debate.

We will continue to monitor federal and state activities in the regulation of biosimilars.

1 The Food and Drug Administration defines biologics as medical products made from a variety of natural sources (human, animal or microorganism).  Moreover, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product.

2 As presented by Steve Miller, Senior Vice President and Chief Medical Officer at Express Scripts.

3 More alarming to Mr. Travis is that the cost of biologics increased by approximately 15% annually, as compared to the approximately 5% increase in the cost of small molecule drugs.

4 Substitution, by allowing the pharmacist to automatically substitute an interchangeable biosimilar for the branded biologic without the intervention of the physician, provides a strong incentive to use biosimilars.

5 According to Dr. Sumant Ramachandra, Hospira’s Senior Vice President and Chief Scientific Officer, it takes approximately $5 million and 2-3 years for a generic manufacturer to bring a small molecule drug to market, whereas it takes over $100 million and 8-10 years for a biosimilar manufacturer to bring a biosimilar to market.

6 The BPCI provides that “the [interchangeable] biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.”

Article by:

Of:

Bracewell & Giuliani LLP