FDA Lawyers Blog

In a recent 43-54 vote, the U.S. Senate defeated a proposed amendment to the FDA Safety and Innovation Act (S.3187), which we previously reported on here, that would have allowed Americans to purchase drugs from Canadian pharmacies. The Amendment, proposed by Sen. John McCain (R-Ariz.) sought to lower the cost of prescription drugs for Americans.

In the days leading up to the vote, McCain had been critical of the pharmaceutical industry for lobbying the Senate to defeat the Amendment. "In a normal world, this would probably require a voice vote, but what we're about to see is the incredible influence of the special interests, particularly pharma, here in Washington, that keeps people who cannot--that have to make a choice between eating and medicine," McCain said. "So what you're about to see is the reason for the cynicism that people have for the way we do things in Washington. Pharma, one of the most powerful lobbies in Washington, will exert its influence again at the expense of average, low income Americans who, again, will have to choose between medication and eating."

Written by Kenneth J. Szeto

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While the Amendment was defeated, several fellow Republicans voiced support for McCain's proposal. Sen. Charles Grassley (R-Iowa), a proponent of importation of Canadian pharmaceuticals, reasoned that allowing importation would provide economic incentives. "I have always considered drug importation a free-trade issue," Grassley said. "Imports create competition and keep domestic industry more responsive to consumers. If Americans could legally and safely access prescription drugs outside the United States, then drug companies will be forced to re-evaluate their pricing strategies."

On May 16, Judge Leonard Stark of the District Court of Delaware held that a Paragraph IV certification is not a necessary predicate to an infringement claim under 35 U.S.C. § 271(e)(2)(A). Section 271(e)(2)(A) states that it is an act of infringement to submit an abbreviated new drug application ("ANDA") for a drug or the use of a drug claimed in a patent. If an act of infringement is found under Section 271(e)(2)(A), Section 271 (e)(4)(A) states that "the court shall order the effective date of any approval of the drug . . . involved in the infringement to be a date which is not earlier than the date of the expiration of the patent which has been infringed."

In March 2009, Galderma sued an ANDA filer for infringement under section 271 (e)(2)(A) based on the applicant's ANDA for a generic doxycycline product. In its ANDA, the applicant included certifications under 21 USC §355(j)(2)(A)(iv) that four of Galderma's patents (later listed in the Orange Book for Galderma's Oracea® product) were either invalid or not infringed by the applicant's manufacture, use, or sale of its generic product. FDA later granted the applicant a tentative approval for its ANDA.

Written by Julie E. Kurzrok

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Following the ANDA applicant's tentative approval, another patent issued (U.S. Patent No.7,749,532 ("the '532 patent") that was listed in FDA's Orange Book as covering Oracea®. The ANDA applicant did not amend its ANDA to include the '532 patent, but instead brought a declaratory judgment action asserting that its generic product does not infringe the '532 patent. The District of Delaware consolidated the declaratory judgment action with the ANDA suit, and after a bench trial, Judge Stark held that the '532 patent claims were valid and infringed by the generic products. Judge Stark also held that FDA must withdraw the tentative ANDA approval, and FDA cannot approve the ANDA until at least December 19, 2027, the expiration date of the '532 patent.

On May 24, the Senate passed the FDA Safety and Innovation Act (S.3187), which reauthorizes the user fee programs for brand-name drugs and medical devices and creates new user-fee programs for biosimilars and generic drugs. The Bill (previously discussed here), sponsored by Sens. Mike Enzi (R-Wyo.) and Tom Harkin (D-Iowa), passed by a 96-1 vote. The sole dissent came from Sen. Bernard Sanders (I-Ver.), who said that the Bill did "far too little" to address the high prices Americans pay for prescription drugs."

In terms of user fees, the Bill will require drug and devices makers to pay FDA $6.4 billion over five years to help finance the evaluation and review of their products. Specifically, brand-name drug companies will pay $4.1 billion, generic drug companies will pay $1.6 billion, device makers will pay $609 million, and biotechnology companies will pay $128 million. In exchange for the user fees, FDA will be required to meet certain performance goals throughout the five years. These performance goals are intended to decrease the average review time for FDA approvals of drugs, devices, and biosimilars.

Written by Scot B. Pittman

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User fee agreements are not the only topic addressed in the now-passed Bill. The Bill contains provisions addressing:

• Increased inspection of foreign drug manufacturing facilities and the ability for U.S. border agents to turn away drugs from companies that have denied or delayed FDA inspections.


• Mandatory reporting of potential drug shortages.


• Protection of confidential information received from foreign government agencies relating to drug inspections.


• Independent assessment and evaluation of FDA's review of drug and biologic applications.

On May 11, FDA reportedly told attendees of the Consumer Healthcare Product Association's Regulatory & Scientific Conference in Washington, D.C. to be patient while FDA implements its "new paradigm" for prescription to over-the-counter ("Rx-to-OTC") switch applications (The Tan Sheet (May 21, 2012). Andrea Leonard-Segal, M.D., Director, Division of Nonprescription Clinical Evaluation, Office of Nonprescription Products, Center for Drug Evaluation and Research, said that FDA's anticipated, revised Rx-to-OTC regulations will allow for expanded conditions of safe nonprescription use.

Leonard-Segal acknowledged, however, that the process will take time, warning "if you submit [a new drug application] where we don't have the regulations to support the switch, if you're ahead of your time compared to the regulations, then I think the project won't go where you want it to go." While waiting for FDA to final the regulations, Leonard-Segal suggested that firms make business decisions about initiating switch programs that employ new diagnostic technologies and other measures, according to their internal estimate project timelines. Leonard-Segal, however, sympathized with sponsors that had failed to meet FDA's current, less flexible regulations that only permit OTC conversions where the Drug Facts label has full comprehension. An example of failed Rx-to-OTC switches cited was statins to lower cholesterol, but other categories of products that may benefit from the new regulations are sleep aids and triptans to treat migraines.

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Commenting further, Leonard-Segal said at the Conference: "One of the frustrations of being in the switch business . . . has been watching the regulations interfere with, what in my perspective have been some very interesting and very innovative ideas, but that just can't move forward because the regulations don't allow us to go there." Leonard-Segal further noted that a priority for the new regulations will be to consider how diagnostic devices could work together with OTC drugs, which is currently a complex approval process involving multiple centers and considerations.

On May 17, Health Canada approved Prochymal® (remestemcel-L) for the treatment of acute graft-versus-host disease ("GvHD") in children. GvHD, a complication of bone marrow transplantation, occurs when the white blood cells in the grafted tissue recognize the host's organs as foreign and attack the host. Acute GvHD usually presents within three months of the bone marrow transplant, and most often causes damage to the liver, skin, stomach, and intestines. Acute GvHD is categorized as stage I, II, III, or IV based on the number of affected areas, and the severity of the damage. Prochymal® is the first approved treatment for GvHD worldwide, and it receives eight and one half years of exclusivity in Canada.

Currently, the standard treatment for GvHD is intravenous steroids, which suppress the immune system to prevent attack of the transplant recipient's organs. Treatment with steroids, however, is only successful in 30 to 50 percent of patients, as suppressing the immune system can lead to infections or even death. Health Canada approved Prochymal® for use in children with acute GvHD where steroid treatment has been unsuccessful.

Written by Julie E. Kurzrok

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Prochymal® is comprised of mesenchymal stem cells from the bone marrow of a healthy adult donor. Prochymal®'s approval falls under Canada's Notice of Compliance with Conditions ("NOC/c") Pathway, which requires that Osiris Therapeutics, the drug's maker, continue with confirmatory clinical testing. Osiris presented data to Health Canada showing clinically meaningful responses in 61 to 64 percent of children with severe GvHD that failed to respond to steroids. This data is very encouraging, considering that severe GvHD has a mortality rate of close to 80 percent. Health Canada relied on this data in granting regulatory approval to Osiris. Prochymal® is currently available in the U.S. (and several other countries) under the Expanded Access Program, for patients "2 months to 17 years with acute GvHD, grades B-D, that is not responsive to steroid therapy."

FDA has required additional data from Osiris before it will consider Prochymal® for approval, so Osiris plans to apply for approval in the U.S. later this year after it collects the required information. Osiris also plans to use Prochymal® for the treatment of Crohn's disease, heart attack, COPD, Type I diabetes, and for potential Acute Radiation Syndrome. The company is currently conducting clinical studies for these indications.

Off-Label Communications:
The Definitive Legal and Regulatory Forum on the Evolving Off-Label Landscape
Monday, June 25 to Tuesday, June 26, 2012
The Carlton on Madison, New York, NY

Attendees of ACI's Off Label Communications Conference will:

• Benchmark best practices against leading companies such as Endo Pharmaceuticals, Lundbeck Pharmaceuticals, Novo Nordisk, Pfi zer, Purdue Pharmaceuticals, Sandoz and many more
• Learn how to reposition your company's policies and protocols according to these shifting boundaries and determine what's fair and foul in off-label communications and promotion
• Master preparation skills for the new off-label framework based on the free speech defense
• Hear directly from the FDA and DOJ and several former federal prosecutors on how to guard proactively against impermissible off-label communications
• Over the years, previous attendees have demanded even more in-depth information on responding to government investigations so this year we are pleased to offer a customized post-conference Master Class on Creating a Culture of Compliance: Best Practices for Working with the FDA and DOJ in an Off-Label Investigation.

For more information on how to register, please visit our website: www.americanconference.com/offlabel.

Patent challenges prior to product marketing are part of the landscape for applicants filing generic drug applications (Abbreviated New Drug Applications or "ANDAs"), new drug applications under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act ("505(b)(2) NDAs"), and now biosimilar applications. As with all other products, patent challenges also can be made subsequent to market entry of an allegedly infringing item. On September 16, 2011, President Obama signed into law the Leahy-Smith America Invents Act ("AIA"). The AIA makes significant changes to United States patent law, such as creating new post-grant procedures in the United States Patent and Trademark Office ("USPTO"). Leahy-Smith America Invents Act, Pub. L. No. 112-29, §19(b ), 125 Stat. 284, 331-32 (2011). Congress is now reportedly considering making additional changes to the AIA that could impact how applicants pursue their options to challenge patents.

Relevant here, the AIA creates a new post-grant review procedure whereby within nine months of a patent's issuance, a person other than the patent owner may challenge the validity of the patent. 35 U.S.C. §§ 321-329. The Director of the USPTO may authorize the initiation of post-grant review if the Director is satisfied that the information set forth by the petitioner, if not rebutted, demonstrates that it is more likely than not that at least one of the claims challenged in the petition is unpatentable. Id. § 324. Through this procedure, Congress seeks to encourage early resolution of patent validity challenges.

Written by Jonathan Herstoff

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However, of concern to some is an estoppel provision in the post-grant-review statute. Specifically, if the USPTO reaches a final written decision with regard to the patent's validity, the petitioner is thereafter estopped from raising invalidity arguments in litigation "that the petitioner raised or reasonably could have raised during that post-grant review." Id. § 325(e)(2). In a recent Congressional hearing, Robert Armitage, General Counsel for Eli Lilly & Co., expressed the concern that the "reasonably could have been raised" language could potentially cause the post-grant review provision to become a "dead letter." Mr. Armitage explained that this estoppel is "so draconian in character that it would be highly problematic for a patent challenger to use." This is because a post-grant review proceeding, unlike an inter partes reexamination, is not limited merely to issues of novelty and non-obviousness based upon published materials, but instead can be used to challenge the patent's validity on any ground. By way of example, the post-grant review procedure can be used to challenge lack of utility or patentable subject matter under section 101, public use under section 102, or sufficiency of the specification under section 112. By estopping petitioners from later asserting invalidity on grounds that "reasonably could have been raised," rather than limiting the estoppel to grounds that were actually raised during the post-grant review, Mr. Armitage expressed concern that challengers would find the post-grant review procedure too risky. Therefore, Mr. Armitage argued, accused infringers would choose to mount its validity challenges in court rather than in the USPTO.

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On July 17, Frommer Lawrence & Haug LLP Partner Brian Malkin will speak on a tough, new topic concerning what type of clinical trials FDA will require for supporting marketing applications for biosimilar products entitled: "Safely Conducting Biosimilars Clinical Trials: Understanding FDA's Requirements for Biosimilar Clinical Trials". Topics that Mr. Malkin will cover include understanding FDA's "selective and targeted approach" for biosimilar clinical trials, relying on clinical trial data from the innovator's product, and assessing the risks and benefits for conducting such clinical trials. Mr. Malkin's presentation will be part of the American Conference Institute's 14th Advanced Summit on Clinical Trials: Ensuring Safe and Compliant Domestic and International Clinical Trials on July 17-18, 2012 in Boston.

ACI Clinical Trials 2012

ACI's 14th Advanced Forum on Clinical Trials provides a comprehensive forum for the key stakeholders -- current and former government enforcers, top in-house counsel from sponsor biopharmaceutical and medical device companies, CROS, hospitals, universities, and research institutions -- to unite and share best practices when structuring a safe and compliant clinical trials program which maximizes data integrity and human subject protection

Facilitate drug approval and protect market share as you share best practices with the experts who have already put successful large-scale clinical trials in place including representatives from:

Novartis Institutes for BioMedical Research * Abbott Laboratories * GE Healthcare * Endo Pharmaceuticals * Johnson & Johnson * The Medicines Company * MedStar Health * Mitsubishi Tanabe * Prometheus Laboratories * Rigel Pharmaceuticals * Stryker Orthobiologics and many more

On May 17, FDA's Centers for Drug Evaluation and Research and Biologics Evaluation and Research released an Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals. Recognizing the need for greater harmony in the regulatory standards for biotechnology-derived pharmaceuticals among Europe, Japan, and the United States, FDA issued the original Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals Guidancein July 1997.

According to the original guidance, preclinical safety evaluations have three goals: (1) to identify an initial safe dose and subsequent dose escalation scheme in humans; (2) to identify potential target organs for toxicity and for the study of whether such toxicity is reversible; and (3) to identify safety parameters for clinical monitoring. That guidance set forth a basic framework for the preclinical safety evaluation of biotechnology-derived pharmaceuticals to "improve the quality and consistency of the preclinical safety data supporting the development of biopharmaceuticals."

Written by Scot B. Pittman

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The Addendum is meant to "complement, provide clarification on, and update" the original guidance. According to FDA, following the Addendum's guidance should "facilitate the timely conduct of clinical trials, reduce the use of animals . . . and reduce the use of other drug development resources." Specifically, the Addendum addresses the following topics: species selection, study design, immunogenicity, reproductive and developmental toxicity, and assessment of carcinogenic potential.

On May 8, the Federal Circuit vacated and remanded a decision In re Youman, (Fed. Cir. May 8, 2012) by the Board of Patent Appeals and Interferences ("Board") that affirmed the rejection of certain claims in a reissue patent application as barred by the recapture rule under 35 U.S.C. § 251. The Federal Circuit concluded that Board improperly analyzed the extent to which surrendered subject matter from the original patent's prosecution "crept" into the claims in the reissue application ("reissue claims"). While not a pharmaceutical patent, this is a good case for FDA attorneys to understand why reissued patents may not have the same scope as the original patent that was reissued yet be similar.

U.S. Patent No.5,629,733 ("the '733 patent") which issued from U.S. Patent Application No. 08/346,603 ("the '603 application") is directed to an electronic program schedule system for a television that allows the user to access and navigate television program information efficiently. Claim 1 of the '603 application ("Original Claim 1") originally recited, in relevant part, a means for selecting a television program title ("selection means") by selecting a certain number of characters from the title ("Original Claim 1"). Original Claim 1 was rejected for obviousness over several prior art references. In response, Original Claim 1 was amended, in relevant part, to narrow the selection means limitation to a selection means "comprising means for causing each of [the characters] to cycle forward and backward through a plurality of alphanumeric characters" ("Amended Claim 1"). The application was then allowed, and the '733 patent issued, with claims 1-23.

Written by Jonathan Herstoff

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Two years after the issuance of the '733 patent, the applicants filed a reissue application, seeking, in part, to broaden the '733 patent's scope of coverage. Importantly, the applicants no longer wanted to be limited to a selection means that operated by way of cycling. Rather, they sought protection for a selection system that worked "by changing from a first character to a second character using . . . nonalphanumeric keys." The examiner rejected this claim, alleging that the applicants were impermissibly seeking to recapture subject matter surrendered by Amended Claim 1. The Board affirmed this rejection. The applicants then appealed to the Federal Circuit.

On May 9, Jonathan D. Rockoff of The Wall Street Journal reported that Pfizer Inc. said it plans to discontinue marketing efforts to promote its landmark, cholesterol-fighting drug Lipitor® (atorvastatin) in the U.S. The company had recently ceased sending sales representative to promote Lipitor® to physicians and discontinued print, television, and online advertisements. Pfizer's actions conclude a novel experiment in brand marketing, where it aggressively marketed Lipitor® for a limited time even after the expiration of its patent on November 30, 2011.

Upon the expiration of Lipitor®'s patent protection, the first generic began selling its generic version of Lipitor®, enjoying the luxury of its 180 days of exclusive generic market exclusivity. Once this exclusivity period expires, however, subsequent ANDA filers may then enter their generic product on the market (i.e, the second generic wave). Generally, a drug maker will cease marketing its branded drug product once one or more cheaper generic versions enter the market. In this case, Pfizer aimed to extract as much revenue as it could from Lipitor® sales, while generic competition was still in its early stages, through heavy marketing, promotion, and price rebates.

Written by Kenneth J. Szeto

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According to The Wall Street Journal, Pfizer has been able to maintain approximately a 33% market share through the first quarter of 2012 through its marketing efforts. In order to wring out more sales from Lipitor®, Pfizer spent over $87 million on advertising, physician marketing, and samples since Lipitor® lost patent protection. In response to generic competition, Pfizer cut the price of Lipitor®, offered price rebates, and reached deals with 50 health plans that agreed to sell branded Lipitor® instead of the generic version. However, once the first generic applicant's exclusivity expires and the second wave of generics enter, Pfizer expects the price for generic Lipitor® to drop further, reducing its market share considerably.

Two versions of an FDA reform Bill, which includes FDA user fee reauthorizations, are quickly passing through the House and Senate. Last week, the House Energy and Commerce Committee unanimously passed H.R. 5651, with support from both sides of the aisle. Earlier that week, S. 2516 was placed on the Senate Legislative Calendar after an 11-1 approval in the Senate's Health, Education, Labor, and Pension Committee. Lawmakers believe that the final Bill will be ready for President Obama's signature by Independence Day.

In contrast to the heated negotiations between the industry and FDA over the amount of the fees and the FDA's review requirements (last discussed here), both versions of the Bill appear to have significant support. Democrat and ranking member of the House Energy and Commerce Committee, Frank Pallone, praised the Bill calling it "a consensus product that we should all be proud of." Rep. Brian Bilbray, R-Cal. echoed those sentiments noting, "Bipartisanship is breaking out in this committee."

Written by Scot B. Pittman

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Despite the unanimous vote, a few members of the Committee believe the Bill lacks some important provisions. For example, Rep. Joe Barton, R-Tex., proposed an amendment that would see FDA's user fees cut by 20% if the agency failed to meet at least 90% of its user-fee linked performance goals in the preceding year. Rep. Barton withdrew that amendment during the full Committee markup but explained that the aim of the proposed amendment was to encourage FDA to meet its goals and not to cut its user fees. Another provision missing from the Bill that cleared the Committee is one that would have given FDA the power to deny a 510(k) submission that relied on a predicate medical device that had undergone a safety recall. Originally proposed by Rep. Edward Markey, D-Mass, this proposal was not raised during the Committee meeting.

As of 2009, 46 percent of the drug products listed in the electronic Physician's Desk Reference ("ePDR") contained information for pediatric use. While this is a substantial increase from the mere 22 percent of labels that included this information in the 1970's, more than half of all drug labels still lack pediatric-use information. This scarcity of pediatric data in drug labels was recognized at least as early as 1968, when Dr. Harry Shirkey coined the term "therapeutic orphans."

In 1975, Dr. John Wilson performed a research study on the availability of medicines for children (and pregnant or breast-feeding women). Dr. Wilson studied the labeling of approximately 2000 drugs found in the 1973 print Physician's Desk Reference ("PDR") and found that only 22 percent of these drugs included adequate pediatric labeling. For the labeling to be deemed adequate, it had to contain effectiveness and safety data in children as well as dosage information for all pediatric age groups. Regarding the 78 percent of labels that were inadequate, 16 percent contained a disclaimer for the drug's use in children (a contraindication, a "use with caution" or a "use restricted by age"), while 62 percent either did not list a pediatric dose, or only included a dose for a single age group.

Written by Julie E. Kurzrok

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Dr. Wilson published an update in 1999 which demonstrated the continuous presence of the therapeutic orphan dilemma. Between 1973 and 1991, little had changed with the PDR -- while 22 percent of drugs in the 1973 PDR had adequate pediatric labeling, the 1991 PDR had only 19 percent (most having age disclaimers). As further validation for the dilemma, Dr. Wilson presented an analysis of off-label use of various drugs that had pediatric age restrictions. Drugs such as Albuterol, Ampicillin, Zoloft, and Prozac were frequently prescribed off-label to children despite the age-disclaimer present in the label.

On May 7, the Federal Circuit affirmed a decision (Otsuka Pharm. Co. v. Sandoz, Inc. et al. (Fed. Cir. May 7, 2012) by the United States District Court for the District of New Jersey, sustaining the validity of the asserted claims of U.S. Patent No. 5,006,528 ("the '528 patent"). The Federal Circuit concluded that the asserted had not been proven invalid. Relevant here is the Federal Circuit's determination that obviousness under 35 U.S.C. § 103 had not been proven. Patent attorneys reading this blog should be advised that they should work with their FDA attorney colleagues as part of their obviousness analyses related to FDA-approved products, as will become apparent by the end of this blog.

The '528 patent is directed to carbostyril derivatives that treat schizophrenia. Importantly, Claim 12 of the '528 patent recites aripiprazole, a carbostyril derivative that is the active ingredient in Otsuka's antipsychotic drug Abilify®. The defendants filed an ANDA, seeking to market a generic version of Abilify®, and alleging that Claim 12 of the '528 patent was invalid for obviousness. Otsuka then sued the defendants for patent infringement.

Written by Jonathan Herstoff

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After a bench trial, the District Court held that Claim 12 had not been proven invalid, and that the defendants had infringed Claim 12. The District Court found that one of ordinary skill in the art would have chosen clozapine or risperidone as lead compounds--both of which are FDA-approved antipsychotic drugs, and due to their structural dissimilarity to ariprazole, would not have rendered Claim 12 prima facie obvious. The District Court further found that one of ordinary skill in the art attempting to find an improved antipsychotic compound would not look to the prior art proffered by the defendants which disclosed carbostyril compounds. Contrary to the defendants' arguments, the Court found that one of ordinary skill in the art would not look to such references, because there is no indication that the prior art carbostyril compounds possess antipsychotic properties. Accordingly, the District Court held that the defendants failed to prove Claim 12 invalid for obviousness. Some of the defendants appealed the finding of nonobviousness to the Federal Circuit.

On February 9, 2012, FDA released draft guidances on biosimilars on scientific considerations, quality considerations, and general questions related to the new 351(k) approval pathway for biosimilars. One of the exclusivity provisions found in the 351(k) pathway provides for 12 years of innovator exclusivity. The duration of the innovator exclusivity was a contentious topic and debated fiercely during the development of biosimilar legislation. The 12-year term was viewed by the branded industry as a major victory.

Now, FDA's proposed approach to awarding 12 years of exclusivity for novel biologics and its protection of reference product trade secrets during the course of examining a biosimilar application has ignited new concerns. Innovators are upset over the language in the draft guidances that proposes that biological license application ("BLA") sponsors should request 12 years of innovator marketing protection. Furthermore, innovator drug companies are dubious of the protection afforded by FDA in shielding innovators' trade secret information during FDA's communications with biosimilar sponsors during the evaluation process.

Written by Kenneth J. Szeto

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The draft guidance states that an applicant:

[M]ay include in its BLA submission a request for reference product exclusivity under section 361(k)(7) of the [Public Health Service] Act, and FDA will consider the applicant's assertions regarding the eligibility of its proposed product for exclusivity. At this time, FDA suggests that an applicant's request for reference product exclusivity specifically describe how the proposed product meets the statutory requirements in section 351(k)(7) of the PHS Act, and include adequate data and information to support the request.

On May 11, 2012, a public meeting is planned where FDA will discuss its recent draft guidances on biosimilars, which we previously discussed here. One area of particular concern that may be addressed is the lack of detail or insight the guidances provide on how FDA plans to make interchangeability determinations. What little the guidances currently say on the issue has been met with disapproval from various sectors of the pharmaceutical industry that believe FDA's approach is too conservative.

The draft guidances indicate that FDA is currently still evaluating the data that would be needed to support a finding that a biosimilar product is interchangeable. Specifically, one guidance states that "at this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability in an original 351(k) application given the statutory standard for interchangeability and the sequential nature of that assessment. FDA is continuing to consider the type of information sufficient to enable FDA to determine that a biological product is interchangeable with the reference product."

Written by Kenneth J. Szeto

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Furthermore, FDA has indicated that it is currently not making any comparisons of non-U.S. licensed products for purposes of interchangeability, stating "at this time, as a scientific matter, it is unlikely that clinical comparisons with a non-U.S.-licensed product would be an adequate basis to support the additional criteria required for a determination of interchangeability with the U.S.-licensed reference product." At the time the draft guidances were released, FDA's Center for Drug Evaluation and Research, Office of Medical Policy Director, Rachel Sherman, opined that a determination of interchangeability would likely not be possible without clinical data that demonstrates that switching back and forth between the reference product and the biosimilar does not diminish the safety or efficacy of the product. (The Pink Sheet, April 30, 2012).

On March 26, Janssen Pharmaceuticals , Inc. ("Janssen") filed a Citizen Petition requesting that FDA require that any ANDAs that rely on Elmiron® (pentosan polysulfate sodium or "PPS") as the reference listed drug include bioequivalence studies with clinical endpoints. According to FDA's Manual of Policy and Procedures 5210.4, a bioequivalence study with clinical endpoints is "a comparative clinical trial in humans that can determine the bioequivalence of dosage forms intended to deliver the same active moiety at an equivalent rate and extent to the site(s) of activity."

Before FDA approves an ANDA, the generic applicant must show that its drug is bioequivalent to the reference listed drug ("RLD" or "listed drug"). According to Section 505(j)(8)(b) of the Federal Food, Drug, and Cosmetic Act: "A drug shall be considered to be bioequivalent to a listed drug if (i) the rate and extent of absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug when administered at the same molar dose of the therapeutic ingredient under similar experimental conditions in either a single dose or multiple doses . . . ." Depending on the type of drug involved, there are various guidelines that FDA uses to demonstrate bioequivalence.

Written by Julie E. Kurzrok

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For solid oral dosage forms, FDA typically evaluates the drug or metabolite concentration in the blood, plasma, or urine. Elmiron® is a solid oral dosage form used to alleviate the pain and discomforts of interstitial cystitis ("IC"), also referred to as "bladder pain syndrome." PPS, the active ingredient in Elmiron®, consists of a group of small polymers of differing lengths and composition, and both the molecular makeup and PPS's mechanism how it treats IC in the body remain unknown. Elmiron®'s actions in the body include absorption from the gastrointestinal tract, metabolism in the liver and kidney, and local delivery to the bladder. Due to PPS's unique characteristics and the unknown etiology of interstitial cystitis, Janssen argues that FDA's standard pharmacokinetic studies used to measure the drug or metabolite concentration in blood, plasma, or urine will not accurately determine whether generic PPS formulations are bioequivalent to Elmiron®.

On April 25, a U.S. Senate Panel approved a Bill, S. 1995, aimed at improving safety measures for the medical device sector of the FDA. However, the tightened measures failed to impress consumer advocates. The Bill was introduced by Senators Chuck Grassley (R-Iowa), Herb Kohl (D-Wis.), and Richard Blumenthal (D-Conn.) and is called the "Food & Drug Administration Safety and Innovation Act". The goal of the Bill is to improve the FDA's safety regulations with respect to medical devices by permitting the FDA to conduct safety studies on medical devices post approval. The Bill also gives the FDA the ability to grant conditional approvals contingent on further trials.

Furthermore, the Bill is also designed to fortify the FDA's 510(k) approval procedures that allow medical device makers to show that their products are similar to already approved devices without requiring clinical trials. While the Bill was approved by the Senate's Health, Education, Labor, and Pensions Committee, the advocacy branch of Consumer Reports, Consumers Union, issued a statement proclaiming that the Bill did not do enough to ensure patient safety in light of the flaws in the 510(k) system.

Written by Kenneth J. Szeto

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Lisa McGiffert, director of Consumers Union's Safe Patient Project, state that "[t]he FDA's current fast track review process has allowed too many dangerous and defective devices onto the market." McGiffert continued by adding, "[t]o make matters worse, the FDA doesn't have the tools it needs to react quickly when safety problems with medical devices arise. Unfortunately, this bill doesn't fix some of the most serious flaws in our current system and leaves patients at risk."

On April 27, FDA recertified its Manual of Policies and Procedures ("MAPP") mechanism for abbreviated new drug application ("ANDA") applicants to request an expedited review of a supplement to an approved ANDA, MAPP 5240.1, Requests for Expedited Review of Supplements to Approved ANDAs. In essence, the procedure recognizes that there are situations where ANDA holders will want expedited review of their ANDA supplements that may concurrently meet or a "public health need" or be in the "government's best interest."

FDA's regulations at 21 C.F.R. Section 314.70(b) provides: "An applicant may ask FDA to expedite its review of a supplement if a delay in making the change described in it would impose and extraordinary hardship on the applicant." Such requests require, among other things, marking the supplement, "Supplement - Expedited Review Requested."

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FDA's Office of Generic Drugs ("OGD") considers requests for expedited review on a case-by-case basis. In addition to the special marking described above, the ANDA holder must provide the basis for expedited review. The government may apply its own need criteria, however, to expedite the supplement without a specific request from the applicant. For the applicant, "extraordinary hardship" reasons include: 1) catastrophic events such as explosion, fire, or storm damage to manufacturing facilities, or 2) events that could not have been reasonably forseen including an abrupt discontinuation of an active ingredient or component of a drug product or relocation of a facility or change in an existing facility due to a catastrophic event. For the government, there either are public health needs such as events that affect the availability of the drug for which there are no alternatives or a nation wide drug shortage, or government needs, including: 1) government drug purchase programs, 2) federal or state/legal regulatory actions including necessary formulation or labeling changes (not as a result of an FDA inspection requiring a new supplement).

According to the MAPP, the initial request should be sent to OGD's document control room, which will be forwarded to the appropriate review division. ANDA applicants will obtain from the Product Quality Regulatory Project Manager a rationale for any denials. If denied, the ANDA applicant may appeal the decision by providing supporting documentation, referencing the ANDA. The team leader will make an initial recommendation and consult with the division director. The division director's decision will be final.

While it appears that a version of this MAPP was in effect as of November 1, 1995, FDA's recertification appears to be motivated by FDA's proactive efforts to help prevent drug shortages, particularly when unforeseen events occur or the government itself wants to expedite ANDA supplements to prevent ongoing or future drug shortages, including the government's needs for stockpiling certain drug products for current public health needs or emergency preparedness.