ANDA drugs.jpgThis is a the second part of the blog on the Generic Pharmaceutical Association (“GPhA”) / FDA / United States Pharmacopeia (“USP”) ANDA Labeling Workshop/USP User Forum held in Bethesda, Maryland on September 11-12, 2013. Following Rudy Wu, Pham. D., M.P.H., Team, Leader, Labeling Branch, OGD, Scott Dallas, R.Ph., Labeling Reviewer, OGD, provided an overview of OGD’s view of medication errors, which has built upon several reports by the Institute of Medicine in 1999 and 2006. FDA has been working with a Merck labeling initiative to see how products can be modified to be more easily distinguished in particular on the pharmacist’s shelf. Generic drugs, just like their innovator counterparts, may be confused by similar trade dress or packaging, which should be a consideration when filing an application, Dallas noted. In addition, specialty packaging, such as blister packs or clear parenteral doses have been an issue, Dallas explained, where space for labeling is tight and often difficult to read for practitioners.

Carrie Lemley, OGD’s only current Labeling Project Manager, described OGD’s labeling review as a multidisciplinary process. Regarding products with mandated risk evaluation and mitigation strategies (“REMS”), Lemley said OGD is tracking FDA’s process to standardize REMS (see related blogs here and here). In particular, if generic applicants are supposed to use a single, shared system for the elements to assure safe use (“ETASU”), FDA expects the RLD sponsor and generic drug applicants to work together to develop the single, shared program.

To date, FDA has only granted one waiver (buprenorphine) to permit both an RLD and shared generic REMS, but FDA contemplates that waivers will only be granted with well-rationalized reasons, i.e., more than an inability to get along. ANDA applicants, however, are not responsible for developing a communication plan or assessments for REMS but is expected to update its REMS in line with the RLD, e.g., if FDA with draws the REMS requirement, a generic applicant should also request to withdraw its REMS (The process is not automatic.) In response to questions about the waiver process, Lemley stated that there is no formal process but the elements to include in a waiver request are:

  1. Description of efforts to negotiate and decision makers,
  2. Justification for waiver including inability to work out issues regarding control or finances,
  3. Explanation how a waiver would affect everybody in that system and how two systems could co-exist instead of one,
  4. Accounting of cost issues for implementation, and
  5. Anticipation of the burden on the healthcare system and consumers for the separate systems.

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ANDA drugs.jpgOn September 11-12, 2013, the Generic Pharmaceutical Association (“GPhA”) in coordination with FDA and the United States Pharmacopeia (“USP”) hosted an ANDA Labeling Workshop/USP User Forum in Bethesda, Maryland. The first day featured FDA speakers from FDA’s Office of Generic Drugs (“OGD”) who focus on labeling and filing/approval issues, and the second day featured speakers from USP.

Peter Rickman, M.S., Director, Division of Labeling and Program Support, OGD, kicked off the program, noting that OGD had a lot of challenges implanting the efficiency goals of the Generic Drug User Fee Act of 2012 (“GDUFA”), including their new 10-month review goals. Rickman stressed that for OGD to meet those goals, abbreviated new drug applications (“ANDAs”) will need to be high quality, which is why FDA is spending time educating industry about quality.

Rudy Wu, Pham. D., M.P.H., Team, Leader, Labeling Branch, OGD, explained that labeling reviews can take longer when a consult is needed, i.e., checking with another FDA office for labeling acceptability, including the Office of Chief Counsel (“OCC”), Office of New Drugs (“OND”), surveillance, epidemiology, pediatric, and other centers. When a consult is requested, OGD must wait for the other entity to respond, which may create additional delays. Wu said there are many reasons why labeling reviews may take longer than expected: waiting for a final United States Pharmacopeia standard to issue or be met, standardizing the generic risk evaluation mitigation strategies (“REMS”), consults, citizen petitions, pending regulations or guidances, new clinical experience, patents and exclusivity may cause generic applicants to submit formulations that differ from the reference listed drug (“RLD) or include labeling carve-outs, and nomenclature differences. For example, regarding nomenclature, Wu said sometimes the RLD may use non-compendia-standard terms where the Orange Book uses another term, and FDA is concerned that both the RLD and the generic versions include labeling to ensure that pharmacists understand that they are substitutable for one another.
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On September 11-12, FLH’s Partner Brian J. Malkin will attend GPhA[Generic Pharmaceutical Association]/FDA’s ANDA [Abbreviated New Drug Application] Labeling Workshop / USP [United Pharmacopeial Convention] User Forum. The Conference provides a unique opportunity for attendees to hear straight from FDA’s Office of Generic Drugs (“OGD”) Labeling Review Staff, who are responsible for reviewing and approving ANDAs. The Workshop will provide industry with current information on the ANDA labeling review process as well as the many issues facing the generic industry when submitting ANDA labels. Some key topics to cover include:

  • Recommendations for industry on handling last-minute labeling “carve-outs”
  • The impact of REMS on the ANDA labeling review process
  • MedGuide Requirements>

functional foods.jpgOn September 10, 2013, the Food and Drug Law Institute (“FDLI”) hosted a conference, “Safeguarding the Functional Food and Dietary Ingredient Supply Chain“. The Conference concerned a variety of emerging requirements and compliance issues for functional foods and dietary ingredient or supplement manufacturers and distributors in view of the FDA Food Safety Modernization Act (“FSMA”). Signed into law on January 4, 2011, FSMA has been called “the most sweeping reform of our food safety laws in more than 70 years.” Among other things, FSMA shifts the focus from responding to contamination to preventing it to ensure the U.S. food supply is safe.

The Conference Keynote, Daniel Fabricant, Ph.D., FDA’s Director, Division of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, Office of Foods and Veterinary Medicine, remained throughout the program and provided insights regarding FDA’s view on “functional foods” and dietary ingredients. First off, FDA has not officially recognized that there are “functional foods”, despite understanding that many people are self-treating based on information gleaned on the Internet or elsewhere with the hopes to either prevent or mitigate potential or current health issues. According to Fabricant, while dietary supplements may make certain health (structure/function) claims with adequate scientific evidence, FDA does not authorize foods to make health claims; instead, FDA considers foods to make statements about taste, aroma, and nutritive values.

In Fabricant’s view, it is not clear where industry should go when looking for guidance on functional foods, which are viewed by industry as foods with legal structure/function claims. FDA is concerned about the potential for harm: (1) invisible (hard to detect), (2) conscious (deliberately tainted), or (3) catastrophic (affects many people). Fabricant suggested that energy drinks, for example, have been suggested as a functional food, but many of these products include caffeine, which is a drug or conventional food. But the physical attributes of the product is not the primary determinant. Here, FDA is developing guidance to distinguish liquid dietary supplements from conventional, food-type beverages. What FDA has seen is that companies engage in “category hopping” to pick the category that where they best meet the requirements, but good manufacturing practices (“GMPs”) often remain an issue. And in FDA’s view, many products over rely on “bad” information rather than “competent and reliable scientific evidence.” Here, FDA looks whether a particular claim is substantiated– what is the meaning of claim, the relationship of scientific evidence to the claim, the quality of evidence, and the totality of evidence in view of the claim. The biggest “pitfall” Fabricant mentioned is an over-reliance on disease treatment studies and confusion regarding intended use.
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On September 10, 2013, FLH’s Partner Brian J. Malkin will be attending the Food and Drug Law Institute’s (“FDLI”) Conference, “Safeguarding the Functional Food and Dietary Ingredient Supply Chain“. The Conference will address a variety of compliance issues and the emerging requirements for functional foods and dietary supplement manufacturers and distributors in view of the FDA Food Safety Modernization Act (“FSMA”). FSMA has been called “the most sweeping reform of our food safety laws in more than 70 years” and was signed into law by President Obama on January 4, 2011. FSMA shifts the focus from responding to contamination to preventing it to ensure the U.S. food supply is safe.

Conference attendees will hear from top FDA officials. For example, the Conference features a Keynote Address from the Director of FDA’s Division of Dietary Supplement Programs, Daniel Fabricant, Ph.D. In addition, industry experts will provide insight on how FDA may implement FSMA’s supplier verification requirements of the Food Safety Modernization Act (FSMA). In particular manufactures will gain a greater understanding of what regulatory requirements can be expected in the coming months by discussing the key regulatory provisions of supply chain safety, the differing definitions for ingredients used in functional foods versus ingredients used in dietary supplements, and by analyzing trends in supply chain quality testing.

Thumbnail image for Thumbnail image for Thumbnail image for Q1 ProductionisPreserving the Integrity and Quality of Captured Data through the Utilization of Innovative Technologies and EDC Systems while Effectively Managing Limited Resources and Oversight of Outsourced Clinical Data Management Team

Throughout the life science industry, executives responsible for clinical data management face a host of escalating challenges as regulatory authorities and internal stakeholders continually demand increased levels of data from clinical studies. As trials have evolved and taken on a role where they are exploring a wide variety of concerns, from regulatory clearance to reimbursement and economic support, the amount of data, and therefore the role of the clinical data manager have become increasingly complex. Adding to this challenge are clinical sites overburdened with multiple studies being conducted simultaneously, varied systems for data collection and entry as well as pressure from clinicians who want the data accessible as soon as possible. Within all of these challenges caused by varied stakeholders, clinical data managers are harnessing technology and new solutions in ways not seen previously, to enable their corporations to excel in research and development and to meet their scientific goals.

This two day conference will take place in Alexandra, Virginia on October 28-29, 2013. Innovative strategies and technologies used by forward thinking companies will be the cornerstone of this conference program, as presenters and audience members discuss methods for ensuring the integrity and quality of clinical data, the evaluation and selection of new technological systems, as well as strategies for ensuring data meets increasingly rigorous FDA requirements. Case studies will show hands on application of advanced technologies, allowing participants an opportunity to road-test the latest and greatest technologies available on the market.
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Thumbnail image for 120px-Components_of_a_MiniCiggy_e-cigarette.jpgOn September 5, the Centers for Disease Control and Prevention (“CDC”) released a Morbidity and Mortality Weekly Report “Electronic Use Among Middle and High School Students – United States, 2011-2012“. According to the Report, electronic cigarette or “e-cigarette” use among middle and high school students doubled in just one year from 4.7 percent in 2011 to 10.0 percent in 2013. In the same period, high school students using e-cigarettes within the last 30 days rose from 1.5 to 2.8 percent. Yet among current e-cigarette users in high school (2012), 80.5% reported current conventional cigarette smoking, and current use of both e-cigarette and conventional cigarettes increased from 1.2% to 2.2%.

E-cigarettes are designed to look and feel like conventional cigarettes but do not ignite tobacco leaf products. Instead, they include a vaporizer or atomizer, powered by a battery and controlled by a sensor and microcomputer chip, which heats and vaporizes fluid in a cartridge containing various chemicals. These chemicals often include liquid nicotine derived from natural tobacco plants. Back in 2011, we blogged on an FDA announcement that the Agency would regulate e-cigarettes as “tobacco products” under Family Smoking Prevention and Tobacco Control Act of 2009. At that time, FDA was reacting to a loss that the Agency had in Sottera, Inc. v. FDA, where FDA first had attempted to regulate e-cigarettes as combination drug/devices. In Sottera, the D.C. Circuit Court of Appeals concluded that unless the e-cigarettes were marketed with therapeutic claims, such as smoking cessation or reduction, FDA had the authority to regulate e-cigarettes as “tobacco products,” because the nicotine used in the products was obtained from tobacco leaves.

To date, however, FDA has not issued regulations to expand its jurisdiction for “tobacco products” to include e-cigarettes, and, as a result, FDA has little information to understand the types of components or potentially-harmful ingredients contained therein. According to the CDC’s Press Release covering this topic, FDA’s Director for the Center for Tobacco Products, Mitch Zeller, said reacting to the CDC’s Report, “These data show a dramatic rise in usage of e-cigarettes by youth, and this is cause for great concern as we don’t yet understand the long-term effects of these novel tobacco products. . . . These findings reinforce why the FDA intends to expand its authority over all tobacco products and establish a comprehensive and regulatory framework to reduce disease and death from tobacco use.” So while it remains unclear when FDA will act to regulate e-cigarettes, FDA still seems committed to do so.
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RISK.jpgFLH Partner Brian J. Malkin was recently featured in an InsideHealthPolicy’s article, “Buprenorphine Decision Spurs Further Call For Shared REMS Rulemaking” The article focused on various suggestions for FDA to initiate rulemaking for shared REMS programs in view of a failed attempt to share a risk evaluation and mitigation strategies program (“REMS”) for buprenorphine-containing transmucosal products for opioid dependence (“BTOD”). In the end, FDA permitted a group of generic manufacturers to form their separate but similar shared BTOD REMS.

FDA has not explained the expectations for a shared REMS other than it is up to the parties to negotiate one or request a waiver from FDA if certain conditions are met. The Food and Drug Administration Amendments Act of 2007 (“FDAAA”) required generic manufacturers to share certain REMS with Elements to Assure Safe Use (“ETASU”). ETASU REMS include some form of restricted distribution, such as only in hospital settings or certain “registered” pharmacies or prescribed only by physicians with special training or following evidence of safe-use conditions. FDA may waive the shared REMS requirement, if FDA determines the burden of creating a single, shared REMS between competitors outweighs the benefits or an aspect of the ETASU is claimed by a patent, the patent has not expired, and the generic applicant(s) has/have sought a license but was unable to secure a license. If waived, the generic applicant(s) must use a comparable element to assure safe use of the product.

Some of the quotes from Mr. Malkin the article include:

Brian Malkin, a partner at Frommer Lawrence & Haug, said FDA should initiate rulemaking and issue guidance on the shared REMS negotiation process, and consider providing branded companies an incentive like exclusivity to encourage participation in shared risk mitigation plans. The comments came during a public meeting where FDA sought input on standardizing REMS. Drug industry groups and other stakeholders encouraged FDA to limit standardization efforts to drugs with similar risk profiles

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research.jpgOn August 27, 2013, FDA issued a new guidance, “IRB Responsibilities for Reviewing the Qualifications of Investigators, Adequacy of Research Sites, and the Determination of Whether an IND/IDE is Needed“. An IRB is an appropriately-constituted group that has been formally designated to review and monitor biomedical research involving human subjects. Following FDA’s regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research. Accordingly, IRBs serve an important role in the protection of the rights and welfare of human research subjects.

The Guidance applies to drugs, biologics, and medical devices and was developed in consultation with the Department of Health and Human Services Office for Human Research Protections (“OHRP”), largely based on recommendations from previously-issued resources. FDA said that it issued the guidance to clarify the Institutional Review Board (“IRB’s”) responsibilities related to the selection of clinical investigators and research sites, because these items are normally considered a sponsor’s responsibility yet they have an impact on the rights and welfare of study subjects. The recommendations in the guidance apply to any IRB, whether serving as a local or centralized review process for multi-site studies. This guidance was developed as part of FDA’s and OHRP’s efforts to harmonize the agencies’ requirements and guidance for human subject protection.

While sponsors of clinical research select clinical investigators who are “qualified by training and experience as appropriate experts,” IRBs have a role in reviewing the investigators’ qualifications to conduct clinical research as proposed in a study protocol. Depending on the IRB’s relationship to the institution conducting the investigation and knowledge of the research, the IRB may already know that a proposed investigator is qualified to conduct the research or may need to dig deeper. In particular, for more high risk investigations, FDA and OHRP expects IRBs to apply a greater amount of scrutiny, especially if the study involves a sponsor-investigator, is outside the investigator’s expertise, or involves other characteristics that may increase risk to human subjects. For example, an IRB may observer, or have a third party observe, the consent process and the research.
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Thumbnail image for Thumbnail image for Q1 ProductionisStreamlining Clearance & Approval Processes by Thoroughly Understanding Implications of New FDA Guidances Surrounding 510(K) Device Modifications & Refuse-to-Accept Policy while Successfully Addressing Inconsistency in Reviewer Feedback

The medical device regulatory landscape continues to evolve as new guidances are released by FDA, & global regulatory bodies are emerging or developing stricter guidelines for product approvals. Regulatory affairs executives in the device industry must stay abreast of these changing regulations in order to implement forward-thinking strategies for streamlining product approvals, & ultimately bring new & innovative products to market that will advance healthcare outcomes. The 3rd Annual Medical Device Regulatory Clearance & Approval Conference will build off the success from previous meetings by bringing together perspectives & insights from leading regulatory affairs professionals & innovative device manufacturers on how to ensure positive regulatory clearance & approval decisions in the US & internationally.

This two day conference will take place in Alexandria, Virginia on October 28-29, 2013. Attendees of this year’s program will have an exclusive opportunity to gather the latest insights into new & evolving FDA guidances & the implications for device manufacturers. Two key guidances of concern for regulatory affairs executives include the re-release of the 510(K) Device Modifications guidance along with the recent Refuse-to-Accept Policy. Presentations will also address internal strategies for tackling inconsistencies amongst FDA reviewer feedback & an increase in data requirements Continue reading