refusetoreceive.pngOn September 30, 2013, before the federal government shut down hit, FDA published a new guidance, “ANDA Submissions-Refuse-to-Receive Standards“. FDA’s guidance explains many of the principles that have been articulated in FDA’s “ANDA [Abbreviated New Drug Application] Checklist for Completeness and Acceptability of an Application” (“ANDA Checklist”), which is reviewed quarterly basis (calendar year) and updated on an “as needed” basis. The Guidance reported that refusal-to-receive decisions (“RTRs”) “underscore the need for improvement in the quality of original ANDAs.” Between 2009 and 2012, FDA’s Office of Generic Drugs (“OGD”) refused to receive 497 ANDAs, the Guidance explains. RTRs occurred with regard to original submissions, in 2009 – 12%; 2010 – 18%; 2011 – 15.5%, and 2012-9.4% (estimated). The most common reasons for RTRs included serious bioequivalence deficiencies and serious chemistry deficiencies, with other lead causes being format or organizational flaws, clinical deficiencies, and inadequate microbiology. As a result, FDA believes that it would help to clarify its RTR criteria to help improve ANDA quality.

First, FDA noted that as part of its threshold determination for filing, FDA reviews ANDAs following the ANDA Checklist, which is formatted to mirror the organization of the Electronic Common Technical Document (“eCTD”). As a matter of general policy, FDA will notify an applicant if it will issue a RTR and provide the applicant with the opportunity to withdraw its ANDA, amend to correct the deficiencies, or take no action. FDA intends to work with applicants if there are fewer than ten minor deficiencies, with such notification by phone, e-mail, or facsimile. If the applicant can correct the deficiencies within five business days and FDA so finds, then FDA will still receive the application from its original receipt date; if not so corrected, FDA will RTR the application. FDA will issue an RTR, however, if the application contains more than ten minor deficiencies or one or more major deficiencies.

Author's photo

Written by Brian J. Malkin

biotechgiant.jpgOn October 3, 2013, the Tech Council of Maryland (“Tech Council”) hosted a Bioscience Series presentation “Industry Giants” in Bethesda, Maryland. The Tech Council’s is Maryland’s largest trade association for bioscience and technology companies employing more than 200,000 in the region. The Industry Giants event was kicked off by the Tech Council’s new Chief Executive Officer, Philip Schiff, formerly chief strategy officer of the American Association of Blood Banks (“AABB”) (also known as “Advancing Transfusion and Cellular Therapies Worldwide”, which is a not-for-profit trade association based in Bethesda, Maryland, that that advances the practice and standards of transfusion medicine and cellular therapies to optimize patient and donor care and safety.)

The Industry Giants panel was moderated by Ray Briscuso, Annual Conference Chief Executive AdvaMed, former Executive Director, Biotechnology Industry Organization (“BIO”), and featured speakers: Steven Dubin, former Chief Executive Officer of Martek Biosciences (“Martek”); Charles Fleischman, former President, Chief Operating Officer and Chief Financial Officer of Digene Corporation (“Digene”) (now Qiagen), and Tom Watkins, former Chief Executive of Human Genome Sciences (“HGS”). All three former executive speakers came from companies that were acquired for over a billion dollars yet have managed to maintain their ties to the life sciences field.

Dubin’s Martek focused on a microbial platform with a unique technology for nutrition and functional ingredients. Dubin recounted how it took a long time for the company to become profitable (18+years), which he thought would be a hard model to follow in today’s times, particularly since they went public at least 6-7 years before there was a profit. Dubin thought that he learned by getting involved in the biotech community and by bringing in people who he thought were smarter than he was to help build passion in the company culture, which he found critical. He thought that emerging biotechnology companies should not focus so much on the exit strategy and found going public a “huge distraction” for the company to continuously answer to its investors. When asked what he respected from individuals looking to provide services for his company, he said that he thought it was important to first build a relationship and understand the company’s problems before asking for work.
Continue reading

Thumbnail image for drugmoney.jpegOn September 30, 2013, FLH Partner Brian J. Malkin was quoted in an article in “The Pink Sheet” entitled “GDUFA Plus One: Stakeholders, FDA Confident As Review Goals Near” (subscription or article fee required). The article summarized progress since the Generic Drug User Fee Act (“GDUFA”) was enacted last year. GDUFA permitted FDA to collect fees from generic drug applicants and holders of drug master files (“DMFs”) in exchange for certain efficiency enhancements and the promise for considerably shorter review times for abbreviated new drug applications (“ANDAs”) in coming years. While FDA does not have to meet any ANDA review deadlines this year, starting with applications received from the fiscal year beginning October 1, 2014, FDA will need to review 60% within 15 months, then 75% within 15 months the following fiscal year, and 90% within 10 months of submission the next year.

FDA has reported progress with collecting fees, hiring new reviewers, and beginning to train these reviewers, as well as making a dent in the ANDA backlog. Regarding fees, FDA reported collecting $255 million collected in fiscal year 2013, about $44 million less than the target. GDUFA required FDA to hire 231 new employees in fiscal year 2013 and on September 11, 2013, FDA said it had hired 234 GDUFA-tagged employees, which FDA is in the process of training. FDA also has reported that it has reviewed about 40% of the application backlog since GDUFA went into effect and has conducted completeness assessments for about 900 DMFs. At the same time, however, review times have remained at a mean of 30+ months and have appeared to now be even longer. FDA has attributed part of this to the need to train new reviewers, which takes seasoned reviewers away from ANDA reviews, with the new reviewers not up to speed yet. Malkin was quoted in two sections on early improvement and budget sequesteration. Excerpts from the full quotations in the article include, for example:

There also does not appear to be much evidence that inspection parity is evolving. Brian Malkin, an attorney at Frommer, Lawrence and Haug, said there continue to be delays getting facilities reviewed and approved for first-to-file generic applicants.

. . .

Budget sequestration may have hindered some implementation efforts, but Malkin said ultimately the changes taking place at FDA were necessary to improve its generic drug systems.

Continue reading

biotechnology.jpgOn September 26, the Massachusetts Biotechnology Council (“MassBio”) hosted the fourth part of its “Adventures in Biotech” Forum series entitled, “Executing the Dream II: Eyes on the Price – Strategic Science Tactics & the Pursuit of Business Objectives” . The purpose of this Forum was to discuss ways that scientific strategy may be worked into the philosophy of a new company, how the scientific strategy can propel the growth of the company, and how the scientific strategy may change over time as a result of that growth. The speakers included Birgit Schoeberl, Vice President, Early Stage Discovery, Merrimack Pharmaceuticals (“Merrimack”); Muthiah Manoharan, Ph.D., Senior Vice President Drug Discovery, Alnylam Pharmaceuticals (“Alnylam”); Laurence Reid, Ph.D., Senior Vice President, Chief Business Officer, Alnylam; and Steven Tregay, Ph.D., Founder, President and Chief Executive Officer, Forma Therapeutics (“Forma”).

Each of the speakers had a different approach as to how they incorporated their scientific strategy into their business. Tregay, for example, described Forma as a “sustainable research and development discovery engine” focused on oncology therapies that can screen 30-40 individual (not combinational) targets a year using an iterative process that includes: computational and medicinal chemistry, parallel synthesis, X-ray crystallography and relevant biology studies. According to Tregay, Forma’s science permits it to mitigate risk by running in parallel a large number of discovery programs while continuously assessing the molecules, prioritizing targets for their pipeline at the appropriate scale, and maintaining communication between all scientists, and project teams. As part of its strategy, Forma first goes broad to investigate a cancer target technology and then more specific as aspects of that technology are validated and ready for candidate screening. Integral in Forma’s strategy is forming partnerships with companies interested in screening many potential cancer candidates quickly rather than few candidates exhaustively, where it already has formed partnerships with Celgene, Boehringer Ingelheim, Genentech, and Johnson & Johnson, as well as some research universities.

Reid explained that Alnylam’s focus has been on building its platform technology on ribonucleic acid interference (“RNAi”), a natural mechanism for silencing specific genes. RNAi is a biological process in which ribonucleic acid (“RNA”) molecules inhibit gene expression, typically by causing the destruction of specific messenger RNA (“mRNA”) molecules. RNAi has gone by other names in the past, including co-suppression, post transcriptional gene silencing (“PTGS”), and quelling. Genes provide cells with the instructions for making proteins, and abnormal proteins are frequently the cause of human disease. The theory behind RNAi therapy, therefore, is to use double-stranded RND (“dsRNA”) to silence certain genes involved in the diseased state and reduce the occurrence of the associated disease. Scientists at Alnylam developed a new strategy to trigger RNAi in mammalian cells using relatively-small dsRNAs–long enough to induce RNAi, but small enough to avoid inducing an immune response–to permit RNAi to be considered as a new therapeutic strategy.
Continue reading

medical app.pngOn September 25, 2013, FDA issued a final Guidance for Industry and Food and Drug Administration Staff entitled, “Mobile Medical Applications“. This Guidance discusses FDA’s intention to oversee the use of mobile applications (“apps”) that qualify as medical devices and that pose a risk to the user if they do not function as intended. These “mobile medical apps” meet the definition of a medical device, and are either intended “to be used as an accessory to a regulated medical device; or transform a mobile platform into a regulated medical device.” Section 201(h) of the Federal Food, Drug and Cosmetic Act (“FD&C Act”) defines a device as

[A]n instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is . . .
[I]ntended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or . . .
[I]ntended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

Author's photo

Written by Julie E. Kurzrok

Other Posts By This Author

FDA places mobile medical apps in the same category of risk as currently regulated devices and intends to regulate them in the same way. The Guidance aims to assist manufacturers in determining whether a product qualifies as a mobile medical app and, if so, provides FDA’s regulatory requirements. FDA sets forth three types of mobile medical apps that it intends to apply regulatory oversight to:

  1. Mobile apps that connect to medical devices and are extensions of these devices that control, display, store, analyze, or transmit data from the medical device.

    For example: an app that controls the delivery of insulin by transmitting signals to an insulin pump.

  2. Mobile apps that transform the mobile platform into a regulated medical device.
  3. For example: an app that attaches electrocardiogram electrodes to a mobile platform to measure, store, and display electrocardiogram signals.

  4. Mobile apps (software) that perform patient-specific analyses and then provide patient-specific diagnoses or treatment recommendations.
  5. For example: an app that calculates radiation dosages or creates dosage plans for radiation therapy

Continue reading

Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for Thumbnail image for gpha-headerLogo.gifOn September 17, 2013, the Generic Pharmaceutical Association (“GPhA”) formally jumped into the biosimilars naming fray by recently submitting a Citizen Petition to FDA on the issue. GPhA’s Petition argues that a biologic approved under Section 351(k) of the Biologics Price Competition and Innovation Act of 2010 (“BPCIA”) should share the same International Non-Proprietary Naming (“INN”) system name as the reference protein product (“RPP”). GPhA’s position stands in sharp contrast to a position voiced by the Biotechnology Industry Organization (“BIO”) and Pharmaceutical Research and Manufacturers Association (“PhRMA”), which was outlined in a letter addressed to Margaret Hamburg last year. The BIO/PhRMA letter asserts that biosimilars are merely similar to–but not the same as–an RPP, and therefore each product should be assigned a unique INN. Requiring a unique INN will very likely require biosimilar applicants to market and detail biosimilar products themselves (instead of relying on the automatic substitution which occurs for generic small molecule drugs in most states).

The BPCIA does not provide a naming convention for biosimilar products. GPhA argues that FDA’s experience with biologic products that undergo post-approval manufacturing changes should serve as an exemplar for biosimilars. For example, GPhA argues that FDA applies “conceptually the same standard” to approving biologic manufacturing changes as the “highly similar” standard required by the BPCIA. And for biologic manufacturing changes, FDA allows the RPP product to maintain the same INN as prior to the manufacturing change. Thus, GPhA argues that FDA should apply its naming standard for manufacturing changes to biosimilars as well. If FDA determines that biosimilars require different INN names than the RPP, then GPhA argues that FDA will be forced to require “new INNs for any product, originator or biosimilar, which undergoes a manufacturing change using comparability.”

GPhA also addressed concerns that shared RPP and biosimilar INNs would interfere with product tracking. GPhA counters that notwithstanding a shared INN, biosimilar product labeling will contain sufficient information for tracking, such as manufacturer name, brand name, lot number, and NDC code. What is more, the results of a survey commissioned by GPhA reveal that “[h]ealth professionals typically report multiple elements whenever possible and include only the INN as the sole data point less than 30% of the time.” On the other hand, GPhA argued that requiring a unique INN for each biosimilar could jeopardize patient safety by resulting in: (1) prescribing errors by clinicians, such as the possibility of double-dosing, (2) untreated patients due to compromised access, and (3) a failure to pick up safety issues that would only be apparent in aggregated data.
Continue reading

Thumbnail image for ANDA drugs.jpgOn September 18, 2013, FDA provided a response to two citizen petitions filed by David B. Clissold, Director, Hyman, Phelps & McNamara P.C. (“Clissold’s Petitions”). Clissold’s Petitions requested that FDA refuse to file any new drug application (“NDA”) filed under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) (hereafter, “505(b)(2) NDA”) seeking approval of a buprenorphine/naloxone drug product in the form of a polymer film for oral mucosal membrane absorption unless the application referenced NDA No. 22-410 for Suboxone® sublingual film (buprenorphine hydrochloride / naloxone hydrochloride) (“Suboxone Film”). As a quick summary, a 505(b)(2) NDA is not identical (i.e., generic) to a previously-approved drug. Instead, a 505(b)(2) NDA contains full reports of safety and effectiveness where at least some of the information required for approval came from studies that the applicant did not conduct/sponsor or have a right to reference. Clissold’s Petitions also asked that FDA refuse to approve such application unless any genotoxic or potentially genotoxic impurity associated with naloxone are appropriately limited. FDA granted and denied in part Clissold’s Petitions following a review of the Petitions, a supplemental letter from Clissold, and additional filed comments from a 505(b)(2) NDA applicant for buprenorphine/naloxone buccal film.

Following a discussion of the 505(b)(2) NDA approval framework, FDA agreed that it could refuse to file certain 505(b)(2) NDAs that did not “on its face contain required information” yet declined to so hold for the buprenorphine/naloxone product in question, if it failed to reference Suboxone Film. Like Clissold, FDA referenced its 2004 citizen petition response to Abbott Laboratories and Laboratories Fournier regarding fenofibrate (“Fenofibrate Petition”). In FDA’s response to the Fenofibrate Petition FDA explained that when there is no pharmaceutical equivalent to a listed drug, an applicant should submit its 505(b)(2) NDA referencing the most similar product to reduce the amount of additional data to submit for approval.

FDA further explained in its response to Clissold’s Petitions, however, that while an applicant’s failure to reference the most similar product would not be a basis for a refusal to file, it could become an approval issue, if the applicant cited to an inappropriate reference product. In essence, an applicant’s “approach to its development program” should be the guide to the appropriate reference product. And if there were a pharmaceutically-equivalent product, then the 505(b)(2) NDA applicant should identify such product and file the appropriate patent certifications. This latter situation generally describes a situation where a 505(b)(2) NDA may be submitted instead of an abbreviated new drug application (“ANDA”) following approval of a suitability petition for certain allowed changes to previously-approved NDA products. Some of the situations where a suitability petition may be submitted are for ANDAs that differ from the listed drug in route of administration, dosage form, strength, or if it contains a different active ingredient in a combination product.
Continue reading

HHSOn September 4, 2013, the Department of Health and Human Services (“HHS”) released a report entitled “National Action Plan for Adverse Event Prevention” (“Plan”). The 176-page report purports to “engage all stakeholders in a coordinated, aligned, multi-sector, and health literate effort to reduce ADEs [adverse drug events] that are most common, clinically significant, preventable, and measurable.” For this effort, the Plan focused on the intended end-users, “policymakers, health care professionals, public and private sector organizations, and communities who can organize and take action toward preventing high-priority ADEs.” The high priority targets identified to prevent ADEs are the drug classes of anticoagulants, diabetes agents, and opioids. The four-pronged approach includes: surveillance, prevention, incentives and oversight, and research.

ADEs may occur in both inpatient (hospital) and outpatient and long-term settings. According to statistics cited in the Plan, ADEs account for about two million hospital stays annually and prolong hospital stays by about 1.7 to 4.6 days. ADEs in outpatient settings account for reportedly over 3.5 million emergency department visits, resulting in 125,000 hospital admissions each year.

The Plan acknowledges that a certain amount of passive (voluntary) reporting of ADEs comes via FDA’s Adverse Event Reporting System (“FAERS”) as well as FDA’s Sentinel Initiative that monitors over 125 million lives but, the Plan says, “which do[es] not constitute a nationally representative sample, but for specific studies, FDA’s Sentinel Initiative has the potential to access health records to confirm coded data or provide additional data.” FDA’s Sentinel Initiative was established in response to the FDA Amendments Act (“FDAAA”) passed in 2007, which mandated that FDA establish an active surveillance system for monitoring drugs, using electronic data from healthcare information holders. The goal of the Sentinel Initiative is a new active surveillance system that could be used to monitor all FDA-regulated products. In particular, the Sentinel System draws on existing automated healthcare data from multiple sources to actively monitor the safety of medical products continuously and in real time.
Continue reading

pharmacymortarpestle.pngLast week, Representatives Morgan Griffith (R-Virginia), Diana DeGette (D-Colorado), and Gene Green (D-Texas) introduced in the House compounding legislation entitled the “Compounding Clarity Act of 2013” (H.R. 3089) that could give FDA additional official authority under the Federal Food, Drug, and Cosmetic Act (“FD&C Act”) over compounding facilities. The Bill comes after almost a year after contaminated drugs from a Massachusetts compounding facility caused 64 people to die from fungal meningitis.

According to Green, “For the last several weeks, a bipartisan and bicameral group of lawmakers have been meeting to make sure we never relive the tragedy of the 2012 fungal meningitis outbreak that originated in a compounding pharmacy in Massachusetts.” Griffith said that the bill would “prevent another [New England Compounding Center]-type outbreak from occurring and ensuring the quality and safety of all compounded drugs in the country.”

The Bill would amend Section 503A of the FD&C Act with a new framework and standards for traditional compounding pharmacies and additional FDA oversight for large-scale compounding like the New England Compounding Center. The legislation would help remove the Constitutional concerns concerning advertising that had been raised in various court cases and had raised certain questions about FDA’s regulatory authority over compounding.
Continue reading

canada.jpgEli Lilly (“Lilly”) filed a CDN$500M North American Free Trade Agreement (“NAFTA”) suit against the Canadian Government as a direct consequence of losing patent protection in Canada on two of its major drugs, Zyprexa® (olanzapine) and Straterra® (atomoxetine hydrochloride). The formal notice of arbitration came after it had failed to settle by negotiation the dispute it lodged in June 2013.

NAFTA obligates Canada to grant patents for inventions that are new, non-obvious, and useful. Lilley’s position is that Canadian utility patentability rules are different than the Untied States and Europe. In the United States, the utility requirement is met by an assertion of a specific and substantial use, and in Europe the utility requirement is met by a use that is specified and “plausible.” However, in Canada there can be the added requirement that if in the patent specification there is a “promise,” for example, to treat a human disease with fewer side effects, then the utility is measured against that promise, and the patentee is required to prove that it has demonstrated or soundly predicted the promised result as of the date the patent was filed.

Lilly pointed out that Canada is a party to international treaties that require Member countries to offer a uniform level of substantive patent protection on a non-discriminatory basis, and Lilly argued this sound prediction requirement is discriminatory. The Canadian courts have been applying this “promise doctrine” since around 2005 and have invalidated 19 pharmaceutical or biopharmaceutical patents for lack of utility under this doctrine between 2005 and 2012. This doctrine has been codified within the Canadian Intellectual Property Office. The Manual of Patent Office Practice describes the “promise of the patent” as follows:

Where the utility of an invention is self-evident to the person skilled in the art, and no particular promise has been made in regard to any advantages of the invention (e.g. if the invention was to simplify a known invention), the self-evident utility is sufficient to meet the required standard.

Where, however, the inventors promise that their invention will provide particular advantages (e.g. will do something better or more efficiently or will be useful for a previously unrecognized purpose) it is this utility that the invention must in fact have.

Continue reading