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 ‘831 patent claims a method of treatment of a α-galactosidase A deficiency disease using “recombinant enzymatically-active α-galactosidase A or enzymatically-active fragment thereof” and in a dependent claim, “wherein the disease is Fabry disease.”  The Fabrazyme® package insert describes its indication for use thus: “Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease.”

Fabry disease is a rare genetic lysosomal storage disease, which causes a wide range of systemic symptoms affecting the GI tract, kidneys, heart, and skin.  Fabrazyme® is essentially an enzyme replacement therapy for the metabolic enzyme that is defective in Fabry patients.

There will be a one-day bench trial in September to address Genzyme’s inequitable conduct allegations and other equitable defenses.  Because those defenses seldom prevail, and assuming the parties don't settle, Genzyme will probably appeal the decision early next year, with a decision from the Federal Circuit in 2014.

Given the breadth of claims and their congruence with the Fabrazyme® label, one imagines that any appeal will focus on attacking the validity of the '831 patent.  In its trial brief, among other arguments, Genzyme focused on the fact that the examples of the '831 patent concern production of α-galactosidase A in insect cells, whereas the claims cover any active glycosylated α-galactosidase A.  The argument is poignant, since the commercially useful drug is made in mammalian cells, which glycosylate proteins differently than insect cells.  Genzyme argues that insect cell-produced drug as described in the patent would not even be an effective treatment.  Nor, in Genzyme's view, would an ordinarily skilled artisan at the time have been able to use the patent's teaching to make the drug in mammalian cells without engaging in undue experimentation.  In contrast to Genzyme's anticipation and inadequate written description defenses, which are issues of fact to which the court of appeals will give great deference to the jury, this non-enablement defense is an issue of law and may be more susceptible to appellate scrutiny.

Genzyme has not publicly commented about the verdict.

The issue is whether the Supreme Court's ruling in Mayo, which found method claims utilizing natural laws to be unpatentable, should apply to product claims for DNA isolated from living organisms.

On the case's first pass before this appellate panel, the Court held, 2-1, that isolated DNA claims were patentable subject matter because the claimed molecules have "a distinctive chemical identity" from their counterparts in the organism's genome.  Myriad argues that the original decision is correct because Mayo addressed only process claims, and relied only on process claim precedent.  AMP argues that the rationale behind Mayo should be broad enough to prevent patenting of naturally occuring molecules which have been "trivially" modified from their native state.

According to most of the commentaries we've seen, during oral argument the panel seemed entrenched in their original positions.  There was little to suggest that either of the majority (Lourie and Moore) were inclined to extend Mayo.  Indeed, given the tens of thousands of isolated DNA patents in force, it would be hard to imagine this panel upsetting the industry's settled expectations.  Of course, the panel could surprise, or either the Federal Circuit en banc or the Supreme Court could decide to wade in.

Unlike in the U.S., the Indian authorities have been approving Indian-produced “generic” biologics with reference products that have been approved in the U.S. or Europe under an ad hoc abbreviated approval pathway for many years. Guise and Carson, Biogeneric Regulatory Policies in China and India: A Comparison Study India has already approved about twenty biologics under this regime. In many cases the Indian regulatory authorities have approved these biologics based on phase 3 bioequivalence studies comprised of about 100 patients.

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