As an aside, Xyrem, is also known as gamma-hydroxybutyrate or “GHB.” GHB is a powerful and fast-acting central nervus system depressant that has been subject to abuse as a recreational drug and is classified by the Department of Health and Human Services (HHS) as a “date rape” drug.

Caronia was convicted under 21 U.S.C. § 333(a)(2) which makes misbranding an FDA-licensed drug product criminal.  A drug is misbranded if, inter alia, its labeling fails to bear "adequate directions for use," 21 U.S.C. § 352(f), which FDA regulations define as "directions under which the lay[person] can use a drug safely and for the purposes for which it is intended," 21 C.F.R. § 201.5.  The Food and Drug Act itself does not expressly prohibit or criminalize off- label promotion, but the FDA’s policy has been to consider off-label promotion as showing intent to misbrand per se in that the label would not have adequate directions for the off-label use.

In overturning Caronia’s conviction, the panel held:   

Accordingly, even if speech can be used as evidence of a drug's intended use, we decline to adopt the government's construction of the FDCA's misbranding provisions to prohibit manufacturer promotion alone as it would unconstitutionally restrict free speech. We construe the misbranding provisions of the FDCA as not prohibiting and criminalizing the truthful off-label promotion of FDA- approved prescription drugs.  Slip Op. at 51.

The panel majority reasoned that the pharmaceutical company’s First Amendment rights to speak about off-label uses is not trumped by any legitimate governmental purpose under Constitutional standards.  In fact, the panel made much of the fact that off-label prescription is not illegal and emphasized that as a result, the dissemination of truthful information about off-label uses has positive effects:

As off-label drug use itself is not prohibited, it does not follow that prohibiting the truthful promotion of off-label drug usage by a particular class of speakers would directly further the government's goals of preserving the efficacy and integrity of the FDA's drug approval process and reducing patient exposure to unsafe and ineffective drugs.   Slip Op. at 42-42.

It was the majority’s opinion that criminalizing off-label promotion is an ineffective means to achieve the FDA’s mission:

If the government's objective is to shepherd physicians to prescribe drugs only on-label, criminalizing manufacturer promotion of off-label use while permitting others to promote such use to physicians is an indirect and questionably effective means to achieve that goal. Thus, the government's construction of the FDCA's misbranding provisions does not directly advance its interest in reducing patient exposure to off-label drugs or in preserving the efficacy of the FDA drug approval process because the off-label use of such drugs continues to be generally lawful. Accordingly, the government's prohibition of off-label promotion by pharmaceutical manufacturers "provides only ineffective or remote support for the government's purpose."  Slip Op. at 47.

One panel judge, Debra Ann Livingston, strongly dissented from the holding.  She emphasized the long enforcement against off-label promotion and disagreed with the majority’s Constitutional reasoning.  This decision can be appealed to the entire Second Circuit sitting en banc, and/or the U.S. Supreme Court.

Enforcement against off-label promotion is a huge aspect of FDA regulatory power, and a major concern of pharma companies.  Many companies have paid fines in excess of a billion dollars to settle off-label marketing prosecutions.  Indeed, in 2007, Caronia’s employer, Jazz Pharmaceuticals, itself paid a $20 million settlement for off-label promotion of Xyrem.  Hence, companies heavily invest in compliance strategies to avoid prosecution, and are heavily limited in the means they have to convey information about their drugs.

It will be fascinating to see whether other courts follow the Caronia decision, and whether pharma companies alter their promotional techniques as a result of this case or its aftermath.

Some recent statements made by a leader in the U.S. biosimilar development community confirm the difficulty of this choice and reiterate the industry's need for clarity in the biosimilar approval pathway requirements before committing to this route.

Sumant Ramachandra, senior vice president for research and development, and regulatory and medical affairs and chief scientific officer at Hospira, was recently quoted in FDA Week (Sept. 23, 2012 Vol. 18 No. 37 (yes, it is dated in the future)) on the need for reliable biosimilars approval requirements. 

"Once you are collecting user fees, people have got to know what pathway you are going down," he told FDA Week. "A lot of things have to be fixed before that (Oct. 1) otherwise you leave people paying a fee to you to guess what you are going to do."

 As reported by FDA Week:

Ramachandra said FDA needs to make the biosimilars pathway predictable, including defining and clarifying the type of data that will be required so "people are not guessing their way down the pathway," adding that the agency needs to provide sufficient guidance so companies are not stuck "playing a game" with FDA regarding what types of studies they will need for approval.

 Further, Ramachandra expressly addressed the choice between BLA and the biosimilar pathway:

 "Some companies may say 'I don't want to go through the hassle of the (biosimilar) pathway if the BLA pathway is clearer to me and I have a marketing and sales force around it. I am going to go down the BLA pathway to avoid the hassle of the (biosimilar) pathway'," he said, adding that other companies may choose the abbreviated pathway if there is the ability to base approval on a reference product and less sales and marketing is required. 

So, if the biosimilar pathway presents uncertainty in timing or cost, and your company has the sales and marketing infrastructure to market a new molecule, you may still prefer the BLA route.  The BLA route will also afford a jump on biosimilar competitors who have to wait for the 12 year exclusivity period to end before their products can be approved, and the opportunity to market your product as a differentiated, improved molecule.

 With so many biologics with patent expiries on the horizon, we should start to see these manufacturers choices before too long.

As we addressed in an earlier post , Teva filed for approval of its G-CSF product before the U.S. biosimilar pathway was available.  Thus, Teva submitted a full BLA for its product.  In its press release, made it clear that it does not deem it to be biosimilar to Neupogen: “FDA has not approved tbo-filgrastim as a biosimilar to Neupogen (filgrastim), which is a previously licensed biological product that contains a related drug substance.”  Teva currently markets filgrastim in Europe under the trade name Tevagrastim, which is approved as a biosimilar to Neupogen®.  Returning to the U.S. BLA, comparison of the product inserts for the two products is interesting.  Tbo-filgrastim is approved for similar indications:

The adverse reactions and warnings and precautions are also similar between the two labels.  Also it appears that the phase three clinical trials included approximately the same number of patients.  Also, no comparison studies to establish any superiority were included in the BLA.  And, even though Neupogen® has been marketed for 20 years, FDA has required extensive post-marketing studies including development of an assay for neutralizing antibodies and a 426-person clinical study assessing anti-G-CSF antibody formation. Approval letter <>  So essentially FDA did not allow Teva to cut any corners compared to the Neupogen® regulatory package.

Although not a biosimilar per se, Teva’s approach to marketing tbo-filgrastim in the U.S. will be a guidepost for the nascent U.S. biosimilar industry.  Other than the fact that Teva will not be able to make any comparability claims, market conditions for tbo-filgrastim will be similar to biosimilars. So presumably, Teva’s approach and eventual experience with marketing, pricing, reimbursement, patient education, and post-marketing monitoring will inform biosimilar manufacturers.  And, tbo-filgrastim’s market share dynamics and financial performance should allow industry watchers to better predict the performance of biosimilars when they arrive.

One does wonder though, will prescribers prefer a “me-too” drug with completely independent proof of safety and efficacy, or a biosimilar whose performance has been validated against the established brand product?  It is not inconceivable that Teva is or will go back to FDA to acquire biosimilar or interchangeable status in order to better compete against Neupogen® and the biosimilars when they come.

The Indian Guidelines mirror the U.S. and European emphasis on detailed structural and functional characterization of the proposed biosimilar in comparison to the reference product. To earn reduced pre-clinical and clinical data requirements, there must be no “significant differences in safety, efficacy and quality studies”:

Generally, a reduction in data requirements is possible for preclinical and /or clinical components of the development program by demonstration of comparability of product (similarity to authorized reference biologic) and the consistency in production process, which may vary depending on the characteristics of the already authorized reference biologic.

Identification of any significant differences in safety, efficacy and quality studies would mean the need for a more extensive preclinical and clinical evaluation and the product will not qualify as a similar biologic. Indian Guidelines at 3.

It is unclear whether the new Indian Guidelines were intended to make the clinical requirements more or less stringent than they have been. The Guidelines merely state that the regulatory agencies felt the need to present clear guidance going forward. Interestingly, the main thrust of the press coverage on the Guidelines has been a single section which suggests that under certain circumstances biosimilars can be approved without involved clinical trials:

The confirmatory clinical safety and efficacy study can be waived if all the below mentioned conditions are met:

i. Structural and functional comparability of similar biologic and reference biologic can be characterized to a high degree of confidence by physicochemical and in vitro techniques

ii. The similar biologic is comparable to reference biologic in all preclinical evaluations conducted

iii. PK / PD study has demonstrated comparability and has preferentially been done in an in-patient setting with safety measurement (including immunogenicity) for adequate period justified by the applicant and efficacy measurements

iv. A comprehensive post-marketing risk management plan has been presented that will gather additional safety data with a specific emphasis on gathering immunogenicity data

The confirmatory clinical safety and efficacy study cannot be waived if there is no reliable and validated PD marker. Id. at 16.

Without knowing what the Indian regulatory authorities will deem comparability “to a high degree of confidence” or what proof is necessary for a PK/PD study to demonstrate comparability, it is hard to say whether many biosimilars will qualify for approval without full-fledged safety and efficacy trials. Presumably, the Indian authorities will base their determinations on the complexity of the molecule as well as prior international experience with the particular drug. It must be noted that the U.S. statute also expressly provides that FDA in its discretion may find that clinical studies are “unnecessary.” 35 U.S.C. §262(k)(2)(ii). And, as evidence of its intent to maintain that discretion, the recently published U.S. Guidance also holds out the possibility that under some circumstances, the need for detailed clinical studies may be “lessened”:

In general, the clinical program for a 351(k) application must include a clinical study or studies (including an assessment of immunogenicity and PK or PD) sufficient to demonstrate safety, purity, and potency in one or more appropriate conditions of use for which the reference product is licensed and intended to be used and for which licensure is sought for the biological product, as set forth in the PHS Act. The scope and magnitude of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting structural and functional characterization and possible animal studies. The frequency and severity of safety risks and other safety and effectiveness concerns for the reference product may also affect the design of the clinical program. Lessening the number or narrowing the scope of any of these types of clinical studies (i.e., human PK, PD, clinical immunogenicity, or clinical safety and effectiveness) should be scientifically justified by the sponsor. FDA Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product at 12.

The PK/PD study-only option may be unimportant in any case. If India will indeed maintain less stringent standards, Indian manufacturers may nonetheless be driven to greater stringency by the desire for approval by FDA and EMA.

One major difference between the Indian regulatory regime and that of the U.S. and Europe is the lack of regulatory market exclusivity for first-approved products. In the U.S. and Europe, biosimilars cannot be approved until 10 or more years after approval of the reference product. Without this limitation, sales of biosimilars in India are only restricted by patent exclusivity. And even patent exclusivity is less of a barrier, given their less well-developed patent regime for biologics.

There is one provision of the guidelines that will delay market entry for biosimilars in some cases. The Indian Guidelines provide that where “the reference biologic is not authorized in India, it should have been licensed and marketed for at least 4 years with significant safety and efficacy data.” Indian Guidelines at 3. Since for the foreseeable future, new biologics will be predominantly pioneered in the U.S. and Europe, there will be a number of recently-developed products that fall into this category, and will await either the approval of the reference drug in India, or the passage of four years after approval elsewhere.

The combination of an established biosimilar regulatory pathway which is similar to the major markets plus the lack of market exclusivity suggests a global biosimilar strategy for both Indian manufacturers and the big multinational players that begins in India. In order to hasten approval worldwide, first seek approval in India, which may be possible long before other jurisdictions, then use the same data package, plus long-term pharmacovigilance data gathered from sales in India and required post-marketing studies as the basis for approval elsewhere at the first moment possible. In this way, the regulatory package for other markets will be “paid-for” by sales in India, plus the likelihood of worldwide approval will be enhanced by a long history of safety in India.

Given the widely reported rush of international investment in Indian biosimilar manufacturers, such as the partnership between Merck Serono and Dr Reddy's Laboratories to develop biosimilar monoclonal antibodies for worldwide distribution, it looks like India will be right at the center of the continued evolution of the biosimilar industry.

The following is a comparison of some of the features of the Indian Guidelines to the U.S. and European regimes:

Definition of Biosimilar

The Indian authorities use the term “similar biologic” rather than “biosimilar” but like the U.S. and Europe, similarity is assessed by structural and functional comparisons to an approved reference product.

Stepwise Approach to Demonstrating Biosimilarity

The Indian Guidance lays out the same kind of stepwise approach, starting with detailed structural characterization of the proposed biosimilar and its reference product, followed by preclinical then clinical characterizations, and makes allowances for product-specific differences in analytical techniques and clinical endpoints.

Origin of the Reference Product

Indian manufacturers will be particularly interested in basing biosimilars off drugs that have been previously approved in other jurisdictions. The Indian Guidelines permit well-studied foreign-approved reference products.

Requirement for Safety and Efficacy Trials

Exclusivity Period

The 505(b)(2) and 505(j) approval pathways are available only for products for which the listed drug relied upon or RLD, respectively, was approved under section 505(c) of the FD&C Act.  Because the 505(j) pathway is not available for a proposed product that seeks to rely upon a biological product licensed under section 351(a) of the PHS Act, your Petition is denied in part.  The BPCI Act was enacted after the submission of your Petition.  A sponsor seeking to submit an abbreviated marketing application for a biological product that can be demonstrated to be “highly similar” (biosimilar) to, or interchangeable with, a reference product licensed under section 351(a) of the PHS Act may submit a 351(k) application. 

Response at 5.  The authors of the FDA Law Blog have written an interesting post about this and two earlier Citizen Petition Responses concerning biosimilars:  You Had Us At “Biosimilars,” FDA; Agency Ties Up Yet Another Biosimilars Loose End With Petition Response Concerning Certain “Biological Drugs.”

We’re still awaiting the first biosimilar litigation and/or approval under the BPCIA to see whether the biosimilar route is truly going to be an attractive opportunity in the U.S.

Of most interest here, the seventh category CDER identifies is “Enhance Individualization of Patient Treatment.”  This document amplifies the themes recently sounded in the FDA’s Draft Guidance Concerning In Vitro Companion Diagnostic Devices that was released a few weeks ago.  In short, CDER is emphasizing the importance of, and encouraging further research into, qualifying different biomarkers for making decisions concerning dosing, patient selection for efficacy, and patient exclusion for safety.  Clearly, CDER has the expectation that many clinical trials and approved treatment regimens will have one or more integrated diagnostic genetic tests and that personalizing treatments will lead to better patient outcomes.  But, as suggested in the report, large public/private collaborations will be necessary to identify novel biomarkers and to develop the tools to properly validate them for clinical use.

The panelists’ comments reflected guardedly positive views on prospects for development of biosimilar products in the US.  McMillan remarked that 5AM Ventures has invested in at least one biosimilar project and anticipates additional investments as attractive opportunities arise.  Bodary envisioned greater biosimilar development success for small, nimble biotech companies than large ones.  Buckley noted that there has been much faster market adoption of biosimilar products in Europe than was predicted.  For example, Germany has already seen almost 60% market adoption of biosimilar products, although many analysts predicted only 10-30% within the first two years after approval.  Several panelists noted that the market adoption rate is highly dependant on insurance reimbursements, tiered pricing regimes, and the medical payor situation, which are currently in flux in the US.  Buckley also observed that development of biosimilars will depend on the level of certainty regarding regulatory requirements for drug approval, and noted that Dr. Rachel Behrman, Associate Director of Medical Policy at CDER, recently predicted in an interview on BioCentury This Week that FDA’s requirements for establishing biosimilarity will be determined on a case-by-case basis, and that the FDA will not provide advice regarding necessary any animal and human testing until after it has reviewed the biosimilar applicant’s analytical data for the biosimilar in comparison to the reference biologic. 

On a more cautionary note, Kastelstein observed that because it already appears that the requirements on biosimilar products will be so high, and because the market exclusivity period for innovator drugs is discouragingly long, many qualified companies will opt to develop innovator products rather than attempt to navigate the uncertain biosimilar pathway.  Other panelists agreed and added that those companies that do choose to develop biosimilar drugs must use extraordinary care to avoid safety problems, as any problems with the first few approved biosimilars would almost certainly tank prospects for development of the industry in the US.

The FDA has now acted on Teva's Neutroval BLA.  On September 30, 2010 the FDA issued a complete response letter, which requested further information, but no additional clinical trials.  As discussed in an October 13 article in FDA Week entitled "Decision on Teva's Neutroval Forecasts Agency Posture on Biologics Data," it is believed that Teva relied on some Amgen data in its BLA package, given that it obtained European regulatory approval for the drug using the European biosimilar pathway.  The article therefore speculates that the FDA may be amenable to "skinny BLAs" that rely on reference product data.

While it seems unlikely that the FDA will allow companies to use BLAs in lieu of 262(k) biosimilar applications as an end-around the 12 year exclusivity period set in the new legislation by permitting use of reference product data, it may very well be that many prospective biosimilar entrants will stick with the tried and true BLA approach.  The FDA Week article quotes a Teva official as stating that given the regulatory uncertainty surrounding biosimilars, "Teva will continue to file BLAs in order to bring affordable biologics to the American public sooner."  Until at least one 262(k) application is fully reviewed by the FDA, we won't know whether the advantages of using innovator data are outweighed by the long exclusivity period and the uncertainty surrounding the requirements for approval.

Among the issues on which FDA sought comments:

• Scientific standards for biosimilarity
• Scientific standards for interchangeability
• Specific approaches to pharmacovigilance for biosimilars
• Use of comparative data from non-licensed comparator products
• FDA definitions for “protein” and “chemically synthesized polypeptide”
• What guidances are needed by industry
• Implementation of the 12 year exclusivity period for pioneers
• The transition period under the statute for products formerly regulated under Section 505 of the FD&C Act
• User fees

Subsequent to the meeting, FDA received detailed letters from the three major trade organizations impacted by the BPCIA addressing these topics:

• The Generic Pharmaceutical Association (GPhA)
• The Pharmaceutical Research and Manufacturers of America (PhRMA)
• The Biotechnology Industry Organization (BIO)

Unsurprisingly, the GPhA’s positions would serve to minimize the burden on biosimilar applicants, while PhRMA’s and BIO’s letters argue for very rigorous standards for approval under Section 351(k).  Some of the most interesting points from these letters are summarized below.

Clinical testing for biosimilarity.  The innovator and generic communities are miles apart on the need for clinical testing to establish biosimilarity.  Neither BIO nor PhRMA acknowledges there could be any circumstances where a biosimilar could be approved without clinical testing:

BIO: “We foresee no circumstances in which an applicant of a 351(k) application would not submit non-clinical studies and clinical studies.”

***

“Even if no structural differences have been detected it will be important to confirm the similarity of the biologic to the reference product using functional assays and appropriate non-clinical and clinical evaluations of the behavior of the biologic.”

PhRMA: “Given the limits of current scientific knowledge and for reasons of patient safety, PhRMA cannot envision a biosimilar product or class of products for which comparative clinical studies would be unnecessary for approval.”

In stark contrast, the GPhA opines that clinical testing “may be entirely unnecessary” if the biosimilar product is proved highly structurally similar to the reference product:

As a general principle, clinical testing should not be required to any greater extent that it is required for originator products under-going manufacturing changes, and should reflect the extent of “high similarity” demonstrated at the analytical level.  This would match the clinical experience accumulated in the literature, by the medical community and by the FDA, in the very same review divisions, from the use of the reference product over at least 12 years. ... Biogeneric sponsors, just like originators of products today, will be using highly-sophisticated analytical and validation tools that allow for detailed confirmation of the similarity of biological products.

The GPhA’s principal point is that the standard for determining biosimilarity, and indeed interchangeability, should be identical to the preexisting comparability standard used by the FDA in assessing whether changes to an approved biologic product’s manufacturing process are acceptable:

Fortunately, biologics and comparative product assessment is an area where FDA has significant experience. FDA has been evaluating originator products for biosimilarity, including the assumption of interchangeability . . . for years. This is done every time a branded biologic manufacturer changes its manufacturing process, such as making a piping modification, moving processes between buildings or adding new facilities (locally or even internationally), substituting an ingredient or even changing the master cell line. Some of these changes are quite extensive, including the case with Betaseron and Avonex where the FDA use of comparability was challenged and upheld by the courts. FDA worked with the biopharmaceutical industry to develop the original and now well established protocol for evaluating all these kinds of changes based on a time honored standard “Comparability”, and led the world into the discussion by the publication of the 1996 Guidance.

The GPhA goes on to observe that many manufacturing changes are deemed by FDA to produce a comparable product without any clinical testing.  BIO, however urges caution regarding the applicability of an analogy to comparability determinations:

Product comparability testing for intra-manufacturer changes can yield meaningful results because the innovator begins from its intimate and exhaustive knowledge of a process that has proven capable of producing a high quality, safe, and effective finished product over a period of time. Specifically, over the course of time, the innovator accumulates extensive historical data to which the biosimilar manufacturer generally would not have access. The experience of a biological products manufacturer with manufacturing a particular product provides the context within which comparability protocols – as that term is currently used by FDA – can legitimately be used.  Absent such context, the impact of any changes to the product or the process by which it is produced must be assessed differently. It is therefore incorrect to use the term “comparability” to describe the relationship between innovator and biosimilar products, as there is less assurance of continuity in process and testing methods when a different manufacturer is involved.

Moreover, there is an additional difference between when an approved product is subjected to manufacturing changes and when a potentially biosimilar product is proposed for approval.  Generally only one or a limited number of variables is changed between an approved manufacturing process, as opposed to manufacture of a biosimilar product (a) from a new DNA construct, (b) in a new cell line (c) by a new production and purification technique (d) in a new factory (e) which is assessed in a new testing environment.

Clinical testing for interchangeability.  Similar to its arguments concerning the quantum of proof to show biosimilarity, the GPhA argues that “interchangeability” as used in Section 351(k) should be addressed identically to comparability determinations that FDA now makes when innovator products undergo manufacturing changes.  Its arguments are based on fairness and economic policy:

The data burden on sponsors should also be irrespective of the traditional business model of the applicant, and an assumption of a greater degree of clinical assessment for biogenerics than is expected of originator sponsors making manufacturing changes is unfair and scientifically inappropriate.

***

Without an FDA willingness, when justified with data, to designate biogeneric biologics as interchangeable to the same extent as they do today pre- and post-manufacturing changes, we can expect to see detailing wars that are a net cost for all sponsors and that must be passed on to the payors and their patients. The expectation of Congress, in enacting legislation, was for biogeneric sponsors, including both GPM members and traditional originator companies, to put price pressure on originators whose patents and exclusivity have expired, thereby forcing prices down for consumers and the government, and ensuring savings in the billions over the next decades.

Again, the originators take the opposite view.  While BIO acknowledges that with rigorous clinical testing it may be possible to grant interchangeability status, it warns that it might not always be feasible.  Taking a more extreme tack, PhRMA presents the view that proof of interchangeability under the statute is impossible given current technology:

In order to protect patients who might be prescribed biologics for which there are interchangeable biosimilars, Congress intended the interchangeability standard to be an exceptionally high standard that could be met only with an additional showing beyond that which is required to establish biosimilarity. PhRMA does not believe that this high standard can be met given the current state of the science.

 Nomenclature.  The trade organizations also disagree about the need for unique non-proprietary names for biosimilars.  GPhA argues that since products deemed comparable after manufacturing changes are not required to be separately named from the original approved product, biosimilars should not require a different name either.  BIO and PhRMA take the position that separate names are crucial to avoid inadvertent switching without doctor’s direction between non-substitutable biologics and to ensure accurate post-marketing surveillance on each biosimilar introduced.

Distinction between Sections 351(k) and 351(a).  The innovator groups are clearly worried that generic manufacturers are going to “end around” the exclusivity provisions of Section 351(k) by submitting biosimilar applications under Section 351(a) instead:

BIO: BIO believes that FDA should not allow a sponsor to choose to submit a BLA under Section 351(a) unless it fully meets the data requirements for an innovator product. Doing otherwise would eviscerate the protections for sponsors of first-generation biological products provided by Congress, undermining the careful balance of benefits and burdens that the statute reflects.

PhRMA: FDA has long and consistently taken the position that applications submitted under section 351(a) may not rely on data and findings relevant to another product — i.e., that the section requires original applications demonstrating product safety, purity, and potency. It would upset the careful balance struck by Congress between biosimilar market entry, on the one hand, and incentives for biological product innovation, on the other hand, if FDA allowed section 351(a) applications to rely on prior findings, prior approvals, or previously submitted data without consent.

 Biosimilar manufacturers have, and will probably continue to file under Section 351(a) in order to avoid the 12 year data exclusivity provision of the BPCIA and the uncertainty of the requirements for approval under the new abbreviated pathway.  But it seems unlikely that FDA will let its guard down and lower the standards for approval of a full Section 351(a) BLA.

Definition of Biosimilar

• US: The biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product 42 U.S.C. §262(i)(1)
• Europe: Biosimilarity is not explicitly defined, but is situational: “Whether a medicinal product would be acceptable using the ‘similar biological medicinal product’ approach depends on the state of the art of analytical procedures, the manufacturing processes employed, as well as clinical and regulatory experiences.” CHMP/437/04. “Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the new similar biological medicinal product and the chosen reference medicinal product authorised in the Community.” CHMP/437/04.

Exclusivity Period for Reference Product

• US: A section (k) application may not be filed until 4 years after reference product approval. A biosimilar may not be approved until 12 years after reference product approval. 42 USC 262 (k)(7).
• Europe: “8+2+1.” A biosimilar application may not be filed until 8 years after the reference product approval. A biosimilar may not be approved until 10 years after reference approval. The market exclusivity may be extended by an additional year if the reference product sponsor obtains approval for a second significant new indication during the data exclusivity period.

Establishing Biosimilarity

• US: Required data comparing the applicant’s biological product to a reference product:
  • analytical studies that demonstrate that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components
  • animal studies (including toxicity)
  • a clinical study or studies (including the assessment of immunogenicity and pharmacokinetics or pharmacodynamics) that are sufficient to demonstrate safety, purity, and potency
  • identity of mechanism of action, if known. 42 USC §262(k)(2)(a)(I)

• Europe: “An appropriate comparability exercise will be required to demonstrate that the similar biological and reference medicinal products have similar profiles in terms of quality, safety and efficacy.” EMEA/CHMP/BMWP/42832/2005. Under the relevant guidelines, the comparability exercise will include:
  • PURITY. The purity and impurity profiles of the active substance and medicinal product should be assessed both qualitatively and quantitatively by a combination of analytical procedures for both reference and similar biological medicinal products. Both product and processs-related impurities should be examined. EMEA/CHMP/BWP/49348/2005.
  • PHYSIOCHEMICAL PROPERTIES. A physicochemical characterisation program should include a determination of the composition, physical properties, primary and higher order structures of the active substance of the similar biological medicinal product. An inherent degree of structural heterogeneity occurs in proteins due to the biosynthetic process, therefore, the similar biological medicinal product can contain a mixture of post-translationally modified forms. Appropriate efforts should be made to investigate and identify these forms. EMEA/CHMP/BWP/49348/2005.
  • BIOLOGICAL ACTIVITY. The comparability exercise should include an assessment of the biological properties of the similar biological medicinal product and the reference medicinal product. Biological assays using different approaches to measure the biological activity should be considered as appropriate (i.e. depending on the biological properties of the product). EMEA/CHMP/BWP/49348/2005.
  • PRECLINCAL.
  • In vitro studies: Assays like receptor-binding studies or cell-based assays
  • In vivo studies: Animal performed in a species known to be relevant and employ state of the art technology to study: Pharmacodynamic effect and Non-clinical toxicity
  • Other routine toxicological studies such as safety pharmacology, reproduction toxicology, mutagenicity and carcinogenicity studies are not required for similar biological medicinal products. EMEA/CHMP/BMWP/42832/2005.
  • CLINICAL TRIALS. Usually comparative clinical trials will be necessary to demonstrate clinical comparability between the similar biological and the reference medicinal product. EMEA/CHMP/BMWP/42832/2005
  • IMMUNOGENICITY. In view of the unpredictability of the onset and incidence of immunogenicity, long term results of antibody monitoring is required. EMEA/CHMP/BMWP/42832/2005

Interchangeability

• US: “the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product” §262(i)(3). It is unclear how this provision relates to state regulation of generic substitution by pharmacies.
• Europe: No equivalent to the “interchangeable” designation. No automatic substitution for biologics in the EU. Country by country regulation over pharmacy substitution, for example, biologics are excluded from substitution in Spain, no substitution list in France.

Incentives

• US: There is no incentive to be the first to file a section (k) application as a biosimilar. There is a market exclusivity incentive to be the first to file as an interchangeable product. The exclusivity period varies depending upon the status of any related patent litigation. §262 (k)(6).
• Europe: There are no exclusivity incentives for filing a biosimilar marketing authorization application.

Guidances

• US: The FDA is authorized to issue “general or specific” guidances to industry to define the requirements for proving biosimilarity. §262(k)(8). Guidances are not required before applications are filed. The FDA may determine that a particular product class (other than recombinant proteins) does not allow approval of an application for a license under the biosimilar pathway. No guidances have been proposed yet. The FDA held its initial public meeting on guidances in November 2010.
• Europe: The EMA has published a number of general and specific guidance documents, including:
  • Guideline on similar biological medicinal products. CHMP/437/04.
  • Guideline on similar biological medicinal products containing Biotechnology-derived proteins as active substance: Quality issues. EMEA/CHMP/BWP/49348/2005.
  • Guideline on similar biological medicinal products containing Biotechnology-derived proteins as active substance: Non-clinical and clinical issues. EMEA/CHMP/BMWP/42832/2005.
  • Guidelines on specific biologic classes, including (1) insulin EMEA/CHMP/BMWP/32775/2005, (2) somatropin EMEA/CHMP/BMWP/94528/2005, (3) granulocyte-colony stimulating factor EMEA/CHMP/BMWP/31329/2005, and (4) erythropoietin EMEA/CHMP/BMWP/301636/2008.
  • Draft guideline on monoclonal antibodies. EMEA/CHMP/BMWP/403543/2010.
  • Concept papers on low-molecular weight heparins EMEA/CHMP/BMWP/496286/2006, and interferon alfas EMA/CHMP/BMWP/86572/2010.

Litigation

Pre-litigation procedure

• US: Special pre-litigation procedure requiring (1) notice of marketing approval application by the biosimilar applicant; (2) disclosure of the biosimilar application to the reference product sponsor; (3) exchange of lists of patents where a claim of patent infringement could reasonably be asserted by the reference product sponsor; (3) exchange of infringement claims and defenses; and (4) dispute resolution negotiations before an infringement suit can be filed. Approximately 200-300 days will elapse between acceptance of the biosimilar application by the FDA and filing of any patent infringement lawsuit.
• Europe: No special pre-litigation procedure. No notice by biosimilar applicant required to reference product sponsor. But notice is sometimes given by follow-on manufacturers in order to allow patent issues to be addressed and thereby minimizing the chance for an injunction inherent in an at-risk launch.

Jurisidiction

• US: Pre-clinical and clinical investigation in preparation of a regulatory filing is exempt from infringement. 35 U.S.C. 271(e)(1). Filing of a section (k) biosimilar application is a constructive infringement sufficient for U.S. District Court jurisdiction. 271(e)(2)(C).
• Europe: Conducting necessary trials or studies for biosimilar approval is not infringement. Article 10(6) of Directive 2004/27/EC (“Bolar exemption” adopted in various forms by member states). Moreover, unlike the US, filing an application for marketing approval is not a constructive infringement. Declaratory and injunctive relief, however, may be available before actual biosimilar sales.

Thus, on the regulatory side, FDA can and should rely on EMA's experience in comparing proposed biosimilars to reference products. Unfortunately, on the patent side, because of the significant differences in the legal frameworks, US biosimilar litigation is terra incognita.