FDA Lawyers Blog

by Brian Malkin

On April 9, FDA simultaneously denied ViroPharma's Citizen Petition regarding bioequivalence and labeling requirements for generic Vancocin® capsules (vancomycin hydrochloride)
and approved three generic applications to Akorn, Strides Acrolabs Ltd. and Watson Pharmaceuticals. In an unprecedented 87-page response (with index), FDA responded to a myriad of arguments presented in ViroPharma's original Citizen Petition dated March 17, 2006, as well as its 20 additional supplements and 16 submissions to a public docket for FDA's Draft Vancomycin Bioequivalence Guidance.

FDA's response provides numerous insights into FDA's decision-making process for bioequivalence determinations in addition to FDA's affirmation of its draft generic Vancocin recommendation as "scientifically sound" and "the most accurate, sensitive, and reproducible approach for demonstrating bioequivalence for generic vancomycin capsules." For generic Vancocin® FDA will continue to permit in vitro dissolution data alone to demonstrate bioequivalence for generic Vancocin® capsule versions that contain the same active and inactive ingredients in the same amounts ("Q1/Q2"). Non-Q1/Q2 formulations must perform clinical endpoint studies in patients with Clostridium difficile Associated Diarrhea.

FDA's decision secondarily answered an issue raised in a later supplement regarding certain labeling changes to Vancocin® that was supported with clinical data, which FDA determined would not be eligible for 3 years of clinical data exclusivity because it is not a new indication. According to FDA, "old" antibiotics, such as vancomycin, may only obtain 3-year new data exclusivity for a significant new use or new indication, not for "refinements in labeling related to previously approved used for Old Antibiotics."

by Howard E. Rosenberg, Ph.D.

The general public's expectation for transparency in the regulation and assessment of the safety of medicines is characterized by the number of Freedom of Information Act ("FOIA") requests to FDA asking for detailed information regarding this data and the multitude of blog articles covering this subject matter. To some extent, public postings on FDA's website, particularly Drugs@FDA, has quelled the need for some FOIA requests. In Europe there is the same public pressure and an increasing trend for the release of information contained in the Marketing Authorization Applications ("MAAs") after they are granted. For example the release of clinical and safety data is regularly requested.

Feedback from initial European proposals found that in general the pharmaceutical industry had concerns regarding the release of contractual arrangements between companies, personal data of experts, and clinical and non-clinical data. Pharmaceutical companies also raised special concerns with regard to the disclosure of non-clinical data, while the release of clinical data was supported by most stakeholders.

The European Medicines Agency ("EMA") and the Heads of Medicines Agencies ("HMA") have now adopted a joint guidance document, providing, for the first time, a consistent Europe-wide approach to the identification of commercially-confidential information and personal data in a MAA. This "major step for transparency," will apply in the future to identify which parts of an application dossier can or cannot be released in response to requests throughout the regulatory authorities in the European Economic Area ("EEA"). This policy applies regardless of whether the product concerned was authorized using the centralized, mutual recognition or decentralized procedures.

by Brian Malkin

On March 23, U.S. District Judge Colleen Kollar-Kotelly for the District of Columbia dismissed without prejudice AstraZeneca Pharmaceuticals LP's ("AstraZeneca's") suit against FDA requesting declaratory and injunctive relief to prevent FDA from granting final approval to generic versions of Seroquel® (quetiapine fumarate) or Seroquel XR® (extended-release quetiapine fumarate). As we reported here, AstraZeneca asserted that FDA could, based on FDA's denial of AstraZeneca's citizen petitions, approve generic versions of both products as early as March 27, 2012 (tomorrow), after the pediatric exclusivity associated with the product expired.

Judge Kollar-Kotelly agreed with AstraZeneca that the Agency's denial of AstraZeneca's two related citizen petitions constituted "final agency action" but disagreed that AstraZeneca's claims were ripe. As the Judge stated in her Memorandum Opinion:

Long has it been established that even a "purely legal challenge" to "final agency action" may not be fit for judicial review. Indeed, the Court of Appeals found that a challenge to the FDA's denial of a citizen petition raising an abstract question that could affect the approvability of related ANDAs [abbreviated new drug applications] submitted by generic competitors, although constituting final agency action, may not be ripe until the agency makes a concrete determination on the related applications. (citations omitted).

FDA had denied AstraZeneca's petitions "without comment on whether [FDA] will take the actions that [AstraZeneca] request[s]." While FDA's actions on citizen petitions are typically considered final agency action, in this case, FDA only has tentatively approved several generic applicants referencing both Seroquel® and Seroquel XR®. FDA has not approved any generic applications to date.

by Brian J. Malkin

Last week, the U.S. Sentate unanimously passed a bill sponsored by Patrick Leahy (D-VT), S. 1886, the Counterfeit Drug Penalty Enhancement Act of 2011. The Bill increases penalties for trafficking counterfeit drugs.

Currently, it is illegal to introduce counterfeit drugs into interstate commerce, but the penalties are the same as for illegal trafficking other goods, such as electronics or other merchandise. In essence, the penalties for copying a company's logo on a prescription bottle were more severe than for making and selling counterfeit drugs. The Bill targets violators who knowingly manufacture, sell, or traffic counterfeit medicines in the United States.

Senator Leahy was clearly pleased with the result and is urging the House to act quickly on the Senate's lead, stating:

We cannot allow the counterfeiting of life-saving medicine to be just one more low-risk venture from which international organized criminals can profit . . . While we should not expect that enactment of this or any legislation will completely deter the serious problem of counterfeit medication entering the American supply chain, it is an important step in the fight. I urge the House of Representatives to act quickly on this legislation.

Worldwide counterfeit medicines are a multi-billion dollar industry, and growing at an alarming pace, especially over the internet. These medicines pose a serious threat to the health and safety of unsuspecting Americans . . .The House should act as quickly as possible to ensure that counterfeit drug traffickers are punished accordingly for putting people's lives at risk with this serious crime.

by Brian Malkin

On March 12, FDA issued a new draft guidance, "Guidance for Industry: Direct-to-Consumer Television Advertisements--FDAAA DTC Television Ad Pre-Dissemination Review Program." The guidance applies to drugs and biologics and describes how FDA plans to implement a requirement for pre-dissemination review of direct-to-consumer television advertisements ("TV ads") according to Section 503 B of the Federal Food, Drug, and Cosmetic Act ("FD&C Act") as amended by the Food and Drug Administration Amendments Act of 2007 ("FDAAA"). The guidance describes the types of TV ads that FDA plans to make subject to this provision, how FDA plans to notify sponsors that a TV ad will be subject to this provision, and the general and FDA Center-specific guidelines for sponsors to submit their TV ads to FDA for pre-dissemination review.

According to FDAAA, FDA may "... require the submission of any television advertisement for a drug . . . not later than 45 days before dissemination of the television advertisement." Section 901(d)(2), codified at 21 U.S.C. § 353(b). FDA may make recommendations on:

• Changes that are necessary to protect the consumer good and well-being, or that are consistent with prescribing information for the product under review; and


• Statements for inclusion in the advertisement to address the specific efficacy of the drug as it relates to specific population groups, including elderly populations, children, and racial and ethnic minorities, if appropriate and if such information exists.


• 21 U.S.C. §§ 353(b)(1) and (2).

by Brian Malkin

On March 7, FDA announced in a Request for Comments in the Federal Register a two-day public hearing to obtain feedback and suggestions regarding ways that FDA can modernize its regulations, policies, and practices that apply to the conduct of clinical trials for FDA-regulated products. FDA hopes that with this input it can modernize the regulatory framework that govern clinical trials and form approaches for good clinical practice ("GCP") providing for greater effectiveness and efficiencies in the process.

FDA explained in its Request for Comments that FDA's clinical trial regulations are now more than twenty-five years old and has been showing its age. In the past years, clinical trial management has changed dramatically, including increased size and complexity of clinical trials, increased number of clinical trials performed globally, greater use of contract research organizations ("CROs"), increased participation of "vulnerable" populations (children, individuals with orphan-designated diseases, others), and numerous scientific and technological advances, including increased use of the Internet. FDA has learned in various forums that FDA's current regulations and compliance policies may not facilitate the use of innovative methods to improve clinical trial quality, the Request for Comments observes. For example, CROs or other clinical investigators may continue to use older data collection methods given the uncertainties involved in using new procedures that may not be aligned with FDA's older guidances and recommended procedures.

FDA said that its focus is on good clinical practice, including enhanced clinical protocol design to take advantage of newer technologies to ensure reliability of data, safety surveillance reporting, quality control processes including auditing, data integrity, and human subject protection. FDA is interested in workshops or strategic alliances that may help to encourage the implementation of innovative methods in clinical trials including risk-based methods in the design, oversight, and conduct of clinical investigations.

by Brian Malkin

On February 9, FDA issued a Federal Register Notice announcing the availability of a new guidance, "Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations. FDA issued the guidance because it believes that more selective or targeted safety data may be possible for some late stage premarket trials and postmarket trials because certain aspects of a drug's safety profile may be well-established from previous studies or what is already known about the medical product's safety profile. While many general principles in this guidance apply to the clinical development of oncology drugs, FDA has developed a specific guidance for oncology drugs, Cancer Drug and Biological Products - Clinical Data in Marketing Applications. The guidance also does not modify general reporting of postmarketing adverse events.

Safety Data Collection Guidance

The guidance notes that while extensive safety-related data are collected through the course of drug development, in late stages or development or during a postmarket period, a selective and better targeted approach may be warranted, especially when certain safety aspects are already known. In the past, selective or specifically-targeted data collection and reporting during clinical trials has been implemented on a case-by-case basis, and there has been little public discussion of this practice. The more targeted approach reflects the view that less serious, less severe, and more common side effects are often characterized in earlier data collection, so little additional information would be gained by further collection of these events.

According to the guidance, the circumstances when targeting safety data is most appropriate are when the following conditions are present:

• The number of subjects exposed to the drug in previous studies in sufficient to characterize the safety profile for all but rare events;


• The occurrence of adverse events has been generally similar across multiple studies; and


• There is a reasonable basis to conclude that occurrence of adverse events in the population to be studied will be similar to previously observed rates.

by Brian Malkin and Andrew S. Wasson

Yesterday, hot on the heels of a federal court's affirmation of FDA's Generic Lovenox® (enoxaparin) bioequivalence determination, which we reported on here, and curiously missing a corresponding Federal Register announcement, FDA released a suite of highly-anticipated draft guidance documents relating to FDA's implementation of the Biologics Price Competition and Innovation Act of 2009 ("BPCIA"). The BPCIA authorizes FDA to approve biological products under the Public Health Services Act ("PHS Act") if FDA finds them biosimilar to or interchangeable with an already-approved biological product. These draft guidance documents are the first guidance documents issued by FDA on the standards of biosimilarity for applications submitted under 351(k) of the PHS Act ("351(k) application"). For the foreseeable future, these documents are likely to be the subject of intense scrutiny by industry stakeholders, lawyers, and academics as they present numerous complex and hotly-debated issues.

FDA appears to be trying to get across a few overarching concepts that they hope will generally guide the development of a biosimilars industry based on the BPCIA: (1) potential biosimilar applicants should use a "stepwise approach" to develop a biosimilar product while minimizing residual uncertainty as a touchstone; (2) robust analytical characterization (a "fingerprint-like analysis algorithm") up front may allow for a selective and targeted approach to animal or clinical trials, which should include an initial meeting with the agency to obtain input on a proposed biosimilar development program; (3) FDA will review applications using a risk-based, "totality-of-the-evidence" approach; and (4) interchangeability is a high standard unlikely to be met by an applicant at the present time and not in its initial 351(k) application. Innovator and potential biosimilar applicants will likely square off on the role of European data in the development of a biosimilar product, even though the referenced product will likely have to be a U.S. biological and bridging data will be required.

The guidance documents underscore a "stepwise approach." The foundation of this approach is the robust and exhaustive characterization of the proposed and reference products. The draft guidance titled "Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product" contains details about potential methods of characterization. FDA sets out the following as steps in development following analytical characterization:

• animal data (at base for toxicity assessment);


• comparative human PK and PD studies;


• comparative clinical immunogenicity; and


• comparative clinical safety and effectiveness data.

by Brian Malkin

On January 18, FDA announced in the Federal Register the availability of a new final guidance, "Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage." Dated December 2011, the Guidance finalizes a draft guidance of the same title dated July 2007 and is a joint collaboration of the Center for Biologics Evaluation and Research ("CBER") and the Center for Devices and Radiological Health ("CDRH"), reflecting that products in this category typically are a biologic, medical device, or combination of the two. The guidance does not apply to prostheses such as unicondylar or total knee implants, or meniscus replacement products, nor does it apply to human cells, tissues, and cellular products and tissue-based products regulated solely under Section 361 of the Public Health Service.

According to FDA, it received "numerous" comments on its 2007 draft guidance, resulting in new sections and clinical study schedules with elaborations on nonclinical data considerations, as well as input from a public meeting of the Cellular, Tissue, and Gene Therapy Advisory Committee meeting on May 15, 2009.

The Guidance notes that FDA believes investigational devices for articular cartilage repair or replacement are significant risk devices requiring the submission of an investigational device exemption or investigational new drug exemption meeting there requisite requirements prior to initiating human research. In particular, FDA notes that approval of an Institutional Review Board ("IRB") alone is not sufficient to commence a clinical study for these types of products.

by Brian Malkin

Late last year, FDA announced a new standard operating procedure ("SOP") for managing review staff changes during the review of premarket approval applications ("PMAs") for medical devices. According to the SOP, the goal of the SOP is to help provide more consistent feedback and guidance to medical device applicants, particularly when there is staff turnover. The SOP replaces an older guidance from 1990.

The SOP states that "As a general matter, a newly assigned review team member is expected to follow the decisions and advice given by the individual he or she is replacing." If the new review team member identifies a need to change in the amount or type of information, however, the SOP now mandates a policy that this new member obtains appropriate supervisory concurrence before so informing applicants:

To promote consistency and to assure that any significant proposed changes are sufficiently justified, the newly assigned review team member must seek appropriate supervisory concurrence prior to contacting the submitter about the identified issue. In other words, when staff becomes aware of information that may alter the information and data required for premarket review, they should receive concurrence from the appropriate management level before taking any action.

For proposed changes in data requirements, staff should ask for data that imposes the least justified burden on the applicant.

by Scot B. Pittman

On January 3, FDA released proposed amendments to its regulations governing submitting citizen petitions and petitions for stay of action ("PSAs") that involve requests for FDA to take action regarding pending abbreviated new drug applications ("ANDA") or 505(b)(2) new drug applications ("NDAs"). The changes are meant to execute provisions in the Food and Drug Administration Amendments Act of 2007 ("FDAAA") (Pub. L. 110-85).

Citizen Petition Regulation Amendments

Specifically, the proposed changes are meant to address Section 505(q) of FDAAA (21 U.S.C. § 355(q)) and codify certain aspects of FDA's thinking presented in its Guidance on 505(q) citizen petitions, which we reported on here. Enacted in September 2007, section 505(q) governs how FDA handles certain citizen petitions and PSAs that call for any form of action related to pending ANDA or 505(b)(2) NDAs. FDA notes that it receives many petitions asking it to delay approving an ANDA or 505(b)(2) NDA until certain criteria in the petition have been met. While many of these petitions, especially if submitted early in the approval process, can aid FDA, some, especially those submitted late in the review process raising minimally valid scientific or legal issues, can improperly delay the approval of an application.

by Brian Malkin

On December 27, FDA issued a draft guidance, "Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices," which was jointly issued by the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research, the Center for Veterinary Medicine, and the Center for Devices and Radiological Health. The Guidance "updates and clarifies" FDA's current thinking and policies for providing unsolicited, off-label information to consumers, including information provided by "emerging electronic media." "Off-label" uses are unapproved or uncleared indications or conditions of use for products that are otherwise approved or cleared by FDA for other uses. Medical professionals with prescribing authority may generally prescribe any product approved by FDA for any conditions or uses, whether FDA approved or not, as part of their practice of medicine.

FDA explained that its rationale for providing the guidance is an effort to balance the desire or need of individuals to obtain additional information about approved products with the potential for a product's manufacturer to provide information that may be viewed as promotional. FDA's Guidance, however, appears motivated, at least in part by a Citizen Petition filed by seven medical product manufacturers asking FDA to clarify FDA its regulations and policies governing communication of new or off-label use of marketed products. According to the Petition, FDA's vagueness regarding permissible manufacturer speech regarding off-label use has significant consequences to manufacturers, the government, physicians, and patients., as we reported here.

As part of FDA's rationale, the Guidance stated that on the one hand, a product's manufacturer typically maintains a large database of information about their FDA-approved products, including information obtained about possible off-label uses that may over time become the medically-recognized standard of care. On the other hand, a manufacturer's statements that promote their products for off-label uses are considered potential evidence of a manufacturer's illegal intent to promote its products for those off-label uses or conditions. FDA also recognizes that the Internet with its emerging news sources, such as social media or chat rooms, provides additional opportunities for consumers to seek medical information and receive information that is both accurate and useful or biased and otherwise inaccurate from product manufacturers or third-party sources.

by Andrew S. Wasson

FDA recently released a draft guidance setting forth recommendations for device applicants who plan to submit an Investigational Device Exemption ("IDE") or a premarket approval ("PMA") application for an Artificial Pancreas Device System ("APDS"). Throughout the draft guidance, FDA maintains that its goal is to provide maximum flexibility to sponsors and applicants but at the same time maintain stringent safety and effectiveness standards.

Despite the connotations surrounding a term like "artificial pancreas," the APDS is not a synthetic organ or tissue system. Rather, the "artificial pancreas" contemplated by the FDA draft guidance is a combination of existing technologies which would work together to automatically regulate blood glucose levels in the human body. For example, an APDS would comprise a continuous glucose monitor, a control algorithm, and an infusion pump to deliver the glucose according to the algorithm. FDA takes pains to note that the patient is also an integral part of the APDS because the levels of circulating glucose depend closely on diet, activity level, and metabolism.

According to FDA, the draft guidance seeks to: (1) facilitate an expedient path to outpatient studies for sponsors, (2) create "maximum flexibility" for sponsors to determine clinical study size and duration, (3) describe standards for both non-inferiority and superiority criteria, and (4) explain approaches to allow for the "leveraging" of existing safety and effectiveness data from currently-marketed devices. FDA recommends that an APDS product be studied in an Early Feasibility Study phase, a Transitional Study phase, and a Pivotal Study phase.

by Brian Malkin

Less than a week after the Centers for Disease Control and Prevention ("CDC") reported on the growing epidemic of opioid pain reliever ("OPR") overdoses, which we reported on here and asked for FDA to take action, FDA announced in a Federal Register Notice that FDA had developed a draft blueprint entitled "Blueprint for Prescriber Education for the Long-Acting/Extended-Release Opioid Class-Wide REMS" ("Blueprint") . FDA has obviously been thinking about ways that its class-wide opioid Risk Evaluation and Mitigation Strategies ("REMS") can have an impact on the growing prescription drug abuse crisis. FDA's latest Blueprint appears triggered, at least in part, by a report released by the Obama Administration on April 19, 2011 entitled, "Epidemic: Responding to America's Prescription Drug Abuse Crisis", which we reported on here.

As indicated in FDA's Notice, FDA issued letters to application holders for long-acting and extended-release innovator and generic opioid drug products requiring them to submit a REMS within 120 days and providing certain elements that had to be included in each of the REMS. FDA's "central component" was the requirement for a cost-free, drug education program for prescribers, yet there is no prerequirement for training for prescribing. Instead, FDA requested that application holders set goals for numbers of prescribers trained, collect information about the number of prescribers who took the courses, and report the information to FDA as part of the required periodic assessments for REMS.

FDA's Blueprint is meant to provide the basic outline and core messages for continuing education that should be offered to all prescribers of long-acting and extended-release opioids, suggesting that the message be delivered in 2-3 hours. According to the Notice, the outline requires information weighing the risks and benefits of opioid therapy, choosing patients appropriately, managing and monitoring patients, and counseling patients on the safe use of these drugs. The education must also include information how to recognize evidence of, and the potential for opioid misuse, abuse, and addiction.

While the Blueprint goes a long way to provide valuable information to the prescribers who choose to be educated, it remains unclear why FDA is not mandating the prescriber education for all prescribers as a precondition to dispensing the medication to patients or more effectively targeting the perceived source of the problem. At least suggested by CDC's report, the majority of OPR overdoses seem to be attributed to a relatively small percentage of OPR prescribers with more loose prescribing practices. How could FDA's mandated REMS reach the prescribers who would most benefit from the training? One might think then it would make sense to either mandate the education for all prescribers (i.e., an even-playing-field approach) or at least mandate the training for prescribers who have had documented instances of OPR misuse or abuse (i.e., a more targeted approach to save resources). How, for example, will FDA's requirement lead the prescribers who need the training to take it rather than provide more information to the majority of prescribers who are already being cautions about prescribing OPRs? Also, why should the training exclude immediate-release OPRs? CDC's report did not single out extended-release and long-acting opioids as the only source of the problem with OPRs.

FDA's mandated REMS and Blueprint also does not seem to go far enough in its recommendations. For example, while the Blueprint describes the possibility for patient prescriber agreements ("PPAs") (i.e., agreements signed at the time of prescribing providing mutual commitments and goals in the treatment between prescriber and physician) and suggests a treatment plan, why are these PPAs only something prescribers should be "aware of"? Without making PPAs a requirement, it would seem most prescribers may choose to operate without them. Similarly, it would seem that other voluntary elements such as patient treatment plans, reassessments whether OPRs are still necessary, and plans to withdraw patients from OPRs including tapering doses, as well as the risks associated with diversion should be reconsidered as elements of the mandated class-wide REMS.

State legislators should consider passing complementary regulations to help provide pharmacists with the appropriate tools to be "gatekeepers" to prevent addictive OPRs from getting in the wrong hands. In Delaware, for example, new laws have been passed to require special "tamper-proof" prescription pads and prescribers will soon be able to electronically prescribe controlled drugs directly to a patient's pharmacy--measures designed to help prevent counterfeit prescriptions and to collect more detailed information about every prescription for controlled drugs written by Delaware doctors.

FDA has asked for comments on their draft education Blueprint by December 7, 2011.

By Andrew S. Wasson

FDA recently issued a Guidance for Industry titled "Clinical Considerations for Therapeutic Cancer Vaccines" which describes factors relevant to the design of clinical trials for a cutting-edge class of cancer treatments: therapeutic cancer vaccines. Therapeutic vaccines are different from preventative (or prophylactic) vaccines. While preventative vaccines are intended to prevent the development of disease in healthy people, therapeutic vaccines work toward strengthening the immune system to help the body fight an existing disease. FDA's recent Guidance finalizes a Draft Guidance dated September 2009.

The development of therapeutic cancer vaccines poses a number of difficult issues compared to conventional chemotherapeutic therapies. Most therapeutic cancer vaccines work on a longer timetable than conventional therapies. In many therapeutic cancer vaccines, tumor-specific antigens are presented by antigenic determinants via APCs (antigen presenting cells) to T cells. The T cells, now programmed to recognize a tumor, will attach tumor cells expressing the antigenic determinants. This sensitiziation, however, takes time, especially compared to conventional therapies. Throughout the Guidance, FDA presents factors relevant to the design of clinical trials which speak to this critical difference.

FDA presented considerations relevant to (1) both early and late phase clinical trials, (2) early phase clinical trials alone, and (3) late phase trials alone. Determining the appropriate patient population is one consideration applicable to both early and late phase trials. For example, cancer treatments were often tested against a wide variety of tumors in order to find the maximum tolerated dose, optimum dosing schedule, and clinical activity. In traditional therapies, evaluating the desired effect can be accomplished in relatively short time periods, such as during the first eight weeks of treatment. Therapeutic cancer vaccines, however, require much long time periods in order to see possible effects - time periods on the order of 2-3 months.

Along the same lines, FDA discussed the advantages and disadvantages of clinical trials involving patient populations with relapsed or recurrent metastatic cancer versus patient populations showing no or little evidence of disease. On the one hand, patients with relapsed or recurrent metastatic tumors often have employed multiple therapies, including those which may interfere with immune response. Because the immune response is key to the mechanism of action for therapeutic cancer vaccines, these other therapies may interfere with the effectiveness of the studied vaccine. On the other hand, studying patients with no or little evidence of disease would avoid the confounding effect of other therapies, but would require longer study times to allow for relapse monitoring.