By Jamie K. Wolszon –

On August 31, Hyman, Phelps & McNamara, P.C. (“HPM”) submitted comments to FDA’s June 1 Draft Guidance regarding research use only (“RUO”) products (see our previous posts here and here).  Although HPM supports many parts of the Draft Guidance, in its comments, it objected to FDA statements indicating that the manufacturer must halt selling to a customer if the manufacturer knows or has reason to know that the customer is using the product for a clinical diagnostic use.  HPM also expressed concerns with statements in the Draft Guidance that suggest that only certain types of research could qualify for RUO status. 

HPM maintained that these statements in the Draft Guidance represent a departure from past agency regulations, case law and policy, would have sweeping implications for multiple categories of FDA-regulated products, and can only be issued through notice-and-comment rulemaking.

HPM stated that the manufacturer’s representations, not what the manufacturer knows or had reason to know, should determine the intended use of the product.  The agency’s expansive and novel approach to intended use has broad implications for other regulated products, such as drugs, biologics, and devices.  HPM argued that FDA should not require manufacturers to immediately halt selling RUO products based on customer behavior.  HPM also called on the agency to clarify that all types of research qualify for the RUO exemption. 

If FDA insists upon these aspects, according to the HPM comments, FDA should only do so through notice-and-comment rulemaking.  HPM’s views that rulemaking is required is supported by a recent decision by a Florida district court rejecting FDA’s request for an injunction against a compounding pharmacy.  

Over thirty comments were submitted, including comments from representatives of manufacturers, laboratories, and academic institutions.  These comments criticized the proposal for: requiring manufacturers to police the activities of their customers; inappropriately expanding the concept of intended use; limiting patient access to standard-of-care laboratory-developed tests that had been appropriately validated in accordance with the requirements of the Clinical Laboratory Improvement Amendments of 1988 ("CLIA"); impeding research and the development of new tests; interfering with the practice of medicine; and violating the Administrative Procedure Act.  Virtually all comments criticized one or more of these aspects of the draft guidance.

By Wes Siegner, John R. Fleder & Ricardo Carvajal –

In U.S. v. Scenic View Dairy, LLC, et. al., the government prevailed on summary judgment in an injunction action against dairy farms alleged to market cows bearing unlawful drug residues.  Although nominally a veterinary drug case, the court’s decision offers a number of gems of general interest.

Defendants operate three dairy farms from which they periodically cull cows for sale to slaughterhouses for human beef consumption.  On numerous occasions, USDA/FSIS detected new animal drug residues that were above tolerance levels in the edible tissues of Defendants’ cows.  The government alleged in part that Defendants violated § 301(a) of the FDC Act by delivering food for introduction into interstate commerce that was adulterated within the meaning of § 402(a)(2)(C)(ii) and § 402(a)(4), and also violated § 301(k) by adulterating drugs while held for sale and after shipment in interstate commerce.

FDC Act § 402(a)(2)(C)(ii) deems a food adulterated “if it is or if it bears or contains… a new animal drug (or conversion product thereof) that is unsafe” under § 360(b).  Based on relevant provisions of the FDC Act and its implementing regulations, the court held that a drug is unsafe if the drug’s use is extralabel (i.e., the drug is used in a manner that does not accord with the approved labeling), unless used “by order of a licensed veterinarian in the context of a valid veterinarian-client-patient relationship” (“VCPR”).  Even if there exists a VCPR, the drug is unsafe if its use results in illegal tissue residues.  In finding that the drugs at issue were unsafe, the court relied in part on sworn affidavits in which Defendants admitted to extralabel use, thereby rendering moot the possible existence of a VCPR.  FDA routinely requests inspected companies to sign “affidavits” on FDA forms that are filled in with information that is written by the FDA inspector.  As this case illustrates, such affidavits can be powerful evidence against a company in any civil or criminal case that FDA subsequently brings based on the inspection.  There is no requirement that companies sign such affidavits, and, except in very rare circumstances and after review by counsel, companies would be best served by not signing (or even reading or listening to the inspector read) such affidavits.

Section 402(a)(4) deems a food adulterated “if it has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health.”  The government argued that Defendants’ failure to maintain adequate drug treatment records (i.e., records that document dosage, route of administration, and withdrawal period) constituted an insanitary condition whereby Defendants’ food may be rendered injurious to health.  The court agreed, relying in part on an FDA Compliance Policy Guide that articulated the same position – a timely reminder of the potential impact of guidance documents, notwithstanding the fact that they are not legally binding.  In passing, the court rejected Defendants’ argument that the Bioterrorism Act’s exemption of farms from recordkeeping requirements applied to drug treatment records.

With respect to the alleged violation of § 301(k), the court held that Defendants’ extralabel use of the drugs rendered those drugs unsafe, and therefore adulterated.  Further, the court agreed with the government that the criterion of “held for sale” in § 301(k) is “satisfied if the item is used for any purpose other than personal consumption.”

Notably, although the court found that an injunction was appropriate, it also found that the government had sought an injunction that was too broad.  The court disclaimed any intent to put Defendants out of business, and expressed concern about the terms and the length of the injunction.  The court noted that, “if the record-keeping is put into compliance as a system and by the individuals, then the problems will be largely solved.”  The court therefore concluded that a permanent injunction was not necessary.  Finally, the court noted that “without knowing the specific facts and background of injunctions entered by other district courts, this Court is not too impressed with the fact that such injunctions exist.”

By Susan J. Matthees –

The Center for Inquiry, a non-profit organization with a mission to “promote scientific inquiry,” recently submitted a Citizen Petition to FDA requesting that the Agency initiate rulemaking for a proposed rule that would require all homeopathic drugs to be tested for effectiveness and, until the drugs are tested, require all advertisements for the products carry to state “WARNING:  The FDA has not determined that this product is safe, effective, and not misbranded for its intended use.” 

FDC Act § 505 prohibits a new drug from being introduced into interstate commerce without an application approved by FDA based, in pertinent part, on substantial evidence of effectiveness.  Although homeopathic drugs are not exempt from FDC Act § 505, most are marketed under FDA’s Compliance Policy Guide (“CPG”) “Conditions Under Which Homeopathic Drugs May be Marketed” and are not approved by FDA.  Pursuant to the CPG, marketed homeopathic drugs must meet the standards for strength, quality, and purity set forth in the Homeopathic Pharmacopeia of the United States, must have indications included in a Materia Medica, and must be labeled in accordance with the FDC Act and FDA’s regulations. 

The Center for Inquiry does not explicitly ask FDA to revoke the CPG, remove homeopathic drugs from the market, or approve homeopathic drugs; the only explicit requests are that FDA use its authority to require efficacy testing for homeopathic drugs and a warning label for homeopathic drugs that are not tested.  The petition is short on legal analysis, and instead is dedicated to explaining that scientific evidence demonstrates that homeopathic drugs are not effective.  In particular, the Center for Inquiry mentions a product manufactured by Boiron as a product that allegedly has no credible scientific evidence of effectiveness.  As you may recall, a federal court in California recently decided to allow a case against Boiron to proceed.  The plaintiffs in that case allege that Boiron violated the California Legal Remedies Act and the California Unfair Competition Law and committed common law fraud by marketing homeopathic drugs that are not effective.  The Center for Inquiry does not mention the California case. 

The Practising Law Institute ("PLI") has released a new Medical Devices Law and Regulation Answer Book 2011–12, edited by Suzan Onel (K&L Gates LLP) and Karen M. Becker (Becker & Associates Consultants).  This Q&A guide is intended to orient and guide those new to the industry, and to be a useful annotated resource for the more experienced regulatory professional.  It has 19 chapters covering a wide range of topics in the life cycle of a medical device, including:

• Device Premarket Submissions 
• Post Market Considerations 
• In Vitro Diagnostic ("IVD") Devices 
• Interacting with FDA 
• International Considerations 
• HIPAA’s Impact on Manufacturers

The book has more than 30 contributors from leading law firms and consulting firms specializing in medical device work.  In the interest of full disclosure, we (proudly) note that Jeff Shapiro, a Director of our firm, contributed Chapter 3 on Device Premarket Submissions.  We also received a free review copy.

The single volume Medical Devices Law and Regulation Answer Book 2011–12 is $235 and is available for a 30-day free examination.

The table of contents is unusually detailed because it shows the questions that the book answers in each chapter.  The table of contents (and other information about the book and the contributing authors) can be found here.  The FDA Law Blog is pleased to offer its readers a 25% discount off the purchase price.  When ordering, contact Andrew Given at 212-824-5887 or agiven@pli.edu and let him know you would like the FDA Law Blog discount.

By Ricardo Carvajal –

FDA and FSIS have published a notice seeking information on issues related to reduction of dietary sodium.  Last year, the CDC determined that the government’s recommendation to limit sodium to no more than 1,500 mg/day applied to nearly 70% of adults (those deemed to be at greater risk for hypertension), but even the higher recommended limit of 2,300 mg/day has proven difficult to meet.  Average intake among those over 2 years of age is nearly 3,500 mg/day.  According to CDC, 40 percent of daily sodium intake comes from grain-based products (regulated by FDA) and 30 percent comes from processed meat products (regulated by FSIS).  Given the government’s estimate that 75% of dietary sodium is added during food manufacture and restaurant preparation, the topic of sodium reduction is of obvious interest to industry.

The notice catalogues 25 years’ worth of government and industry efforts to help consumers reduce sodium intake.  Given little progress on the issue, the two agencies are now “considering potential ways to promote gradual, achievable and sustainable reduction of sodium intake over time,” and acknowledge the need for “research on a variety of issues, including the development of possible targets” for sodium reduction.  The notice acknowledges that a number of factors “may inform judgments about appropriate opportunities for sodium reduction,” including the role of sodium in food safety, its impact on food processing, and the fact that consumers prefer salty foods.  The notice seeks information on a number of sodium reduction issues, including current industry initiatives, potential effective strategies, incentives for innovation in reformulation, establishment of targets, potential unintended consequences, and economic impacts.

Those wishing to submit information should note that any information not marked confidential “will be included in the public version of the official record without prior notice.” 

By Carmelina G. Allis - 

Below is a summary of some of the key issues discussed during FDA’s September 12 and 13, 2011, public meeting on the recently issued draft guidance document for mobile med apps.  During the meeting, FDA also requested input on how to regulate stand-alone software that provides clinical decision support, even though those support systems are not specifically addressed in the draft guidance.

In general, FDA received positive feedback regarding the draft guidance document on mobile apps.  However, it is clear that the agency still has some work to do, in particular, it needs to define the regulatory landscape in the area of stand-alone clinical decision support software.  There are some unanswered questions in both areas, as you will see from the discussion below:

Mobile Medical Apps

• There were three main proposals regarding mobile medical apps: (1) FDA should classify apps based on the level of risk to patient health; (2) FDA should issue guidance to explain what kinds of apps and/or claims the agency will not regulate; and (3) there should be a way to ensure that apps do not adversely affect the main device they connect to (and vice versa), such as requiring good software practices.

• Because many app “manufacturers” are not FDA-regulated entities, the draft guidance document needs clarity and information in order to help those that are having to learn the regulatory landscape.  The discussion on mobile medical apps centered around what does “intended use” mean and how to apply it.  A simple roadmap that helps entities/individuals to determine “how do I know that I am a mobile med app manufacturer” was suggested.

• The discussion on mobile med apps as “accessories” centered around proposals that FDA classify accessories based on intended use and functionality rather than specific characteristics or technology.

• There was some discussion that the draft guidance goes too far – for example, could general-purpose websites that have dosage calculators fall within the definition of a mobile medical app if that website (and, thus, the dosage calculator) can be accessed via a mobile phone?

• Another issue discussed was that of “interoperability” – there are apps that get information from many different sources/devices, and then an action is triggered.  How does FDA intend to regulate those apps?  Some suggested a risk-based approach.  However, the problem with the risk-based approach is how to define it: the risk if something goes wrong with the app vs. the risk that the use of the app poses?  FDA’s Bakul Patel noted that the agency discusses those issues internally all the time, but that at the end of the day, the issue is about patient safety.  Another issue regarding interoperatibility relates to who has the regulatory burden to ensure safety and effectiveness.  Is it the app manufacturer only?  But how do you ensure that the hardware (e.g., the iPad or Android platform, which FDA has said will not regulate) is safe for a particular app?

• It was suggested that FDA not discourage people from being able to make claims about the platform because of fear of becoming a medical device.  This issue came up because of comments regarding the Ford car that will supposedly provide access to apps specifically targeted to diabetics.  Does the car become an accessory to the app?  Does it all depend on the claims made by Ford?  Or could FDA allow certain claims and not regulate the car?

Stand-Alone Clinical Decision Support Systems

• FDA said that the factors it generally considers on how to regulate stand-alone clinical decision support systems involve: (1) the level of impact on subject health/condition; (2) the degree of acceptance in the clinical practice; and (3) the ability to identify erroneous output (due to incorrect output or clinically wrong information).

• There appears to be a strong concensus among some that national/international standards should be imposed/required to ensure that clinical decision support systems adhere to good software practices.

• Others suggested that regulatory requirements for clinical decision support systems should be based on intended use and risk.  Two general types of support software systems were outlined: (1) those that provide generic decision support, such as providing summaries of clinical articles or anecdotes, which FDA has said it does not intend to regulate, and (2) those that provide patient-specific support.  Among the latter, three main types were discussed:

– systems that provide or assist with simple functions;
– systems that provide assistance with therapeutics; and
– systems that assist with diagnoses.

No particular regulatory approach was proposed, as the landscape of clinical decision support systems varies immensely on intended use, intended population, functionality, and technological characteristics.  For example, while some clinical decision support systems are based on simple rules, like medication reminder software, others are based on more complex algorithms, such as assisting medical practitioners with diagnoses assessments or computing chemotherapy doses.  One possible approach not publicly discussed at the meeting would be for FDA to create a classification regulation requiring 510(k)s with special controls that applies to a well defined, but broad group of stand-alone clinical decision software (e.g., a classification regulation for software intended to assist medical practitioners with therapy determinations).

At this time it is difficult to advocate a particular regulatory pathway to clients for these device types, because there are no classification regulations that apply to many of these stand-alone clinical decision systems.  In addition, FDA has not defined what system types it intends and does not intend to regulate.  And because the 510(k)/de novo pathway is unpredictable and inefficient, manufacturers are unwilling to pursue any specific pathway to market until FDA further defines the regulatory landscape.  FDA does not want to be inundated with de novos or PMAs (which would be the default for lack of a predicate device), both of which are time-consuming and resource-intensive regulatory processes.  And that is why the suggested approach of creating a regulation with special controls for a defined, but general-scope stand-alone clinical decision support system looks appealing.

By Kurt R. Karst –      

September 12th marked the beginning of the eighth round of Trans-Pacific Partnership (“TPP”) negotiations, which are taking place in Chicago, Illinois.  The TPP is an Asia-Pacific regional trade agreement being hammered out among the United States and eight other partners.  The TPP would cover trade in goods and services and also includes a proposed chapter on intellectual property.  As we previously reported, the chapter on intellectual property is where the latest battle over biologics exclusivity is happening, and which was the subject of several letters from Members of Congress sent earlier this year. 

In a new round of letters reported on by Patent Docs, several U.S. Senators urge U.S. Trade Representative (“USTR”) Ron Kirk to support a 12-year period of exclusivity for biological products.  Colorado Senators Mark Udall (D) and Michael Bennett (D) state in their letter that “[b]eginning the biologics negotiations on an intellectual property standard consistent with U.S. law will make sure that Coloradans can continue to lead the world in the innovation of biologics while also assuring a reasonable pathway for biosimilar products.”  Meanwhile, another letter signed by a bipartisal group of 37 U.S. Senators says that they are united in urging the USTR to “propose a strong minimum term of regulatory data protection for biologics consistent with U.S. law.”

On the same day the letters were sent to USTR Kirk, the USTR issued a white paper outlining a new strategic initiative, titled “Trade Enhancing Access to Medicines” (or “TEAM”).  The TEAM strategy, which is supported by the U.S. Agency for International Development, is “designed to deploy the tools of trade policy to promote trade in, and reduce obstacles to, access to both innovative and generic medicines, while supporting the innovation and intellectual property protection that is vital to developing new medicines and achieving other medical breakthroughs,” according to the white paper.  “The TEAM initiative reflects fresh thinking about trade and access to medicines.  It is about more than allowing access to medicines.  It is about working with trading partners to develop strong and common standards to help drive access – propelling the TPP countries to the front of the line for important innovative medicines and for generic competition, while promoting U.S. jobs and exports.”

The USTR’s white paper identifies several goals, including:

Expedite access to innovative and generic medicines through a “TPP access window”: Promote the availability of life-saving and life-enhancing medicines in TPP markets and simultaneously establish a pathway for generics to enter those markets as quickly as possible by conditioning obligations to apply certain pharmaceutical-specific intellectual property protections on the requirement that innovators bring medicines to TPP markets within an agreed window of time.

The white paper is silent on the term of any biologics exclusivity period; however, we note that President Obama’s Budget for Fiscal Year 2012 proposed that “beginning in 2012, innovator brand biologic manufacturers would have 7 years of exclusivity. . . .”  A letter sent to President Obama this past summer concerning TPP negotiations stated that “[w]ere the TPP ultimately to contain a 12 year biologics exclusivity provision, it would impede the ability of Congress to achieve the Administration’s proposed 7 year change without running afoul of U.S. trade obligations.”

By Riëtte van Laack –

As we previously reported, on December 29, 2010, the Food Safety Inspection Service ("FSIS") published its final rule on nutrition labeling of single ingredient meat and poultry products and ground or chopped meat and poultry products. The new rule requires nutrition labeling on the major cuts of single-ingredient raw meat and poultry products and on all ground or chopped meat and poultry products, with or without added seasonings, unless an exemption applies. The new rule also provides that a lean percentage statement of the fat percentage may be included on ground or chopped product that does not meet the regulatory criteria for a “low fat” label as long as the label meets certain specified criteria.  The rule takes effect on January 1, 2012. 

In August, FSIS issued a notice, informing Inspection Program Personnel of the upcoming implementation date of this rule and instructing the Inspection Personnel to make plant management aware of the final rule and the implementation date of January 1, 2012.  In further efforts to prepare industry for the implementation of this rule, FSIS announced a series of webinars regarding the implementation of the rule. 

FSIS’s website includes a presentation that gives an overview of the nutrition labeling final rule and its requirements, and answers to questions that were submitted via askFSIS. 

By Carmelina G. Allis –

If you thought you’ve had enough trying to figure out whether FDA regulates your mobile app, watch out for the FTC.  The FTC has brought its first case targeting health claims related to mobile medical apps.

The mobile apps, sold in Apple’s iTunes Store and Google’s Android Marketplace under the names “AcneApp” and “Acne Pwner,” claimed that they could treat acne with colored lights emitted from the mobile devices.  According to the FTC, the marketers alleged that the blue and red lights emitted by the apps kill acne-causing bacteria.  The apps advised consumers to hold the display screen next to the area of skin to be treated while the app was activated.

The FTC alleged that the acne treatment claims made for both apps were unsubstantiated.  The marketers of the apps have agreed to stop making claims about the products in order to settle charges with the FTC, which would bar them from making certain health-related claims without supporting scientific evidence.

The market for mobile medical apps appears to have grown exponentially recently, and one can only wonder whether FTC’s interest in this area will also intensify.  If you worry about FDA, enforcement actions may not be at the top of its agenda quite yet; the FDA regulatory landscape for these products, although somewhat defined, is still being carved out.  We previously blogged that FDA has proposed to exert regulatory authority over select mobile medical apps that meet the “device” definition in the Federal Food, Drug, and Cosmetic Act, and that are either used as an accessory to a regulated medical device, or transform a mobile platform into a regulated medical device.  The FDA is now seeking public input on that proposal, and it is holding a public workshop on mobile medical apps on September 12-13, 2011.

By Ricardo Carvajal –

That question is presented in class actions recently filed against ConAgra Foods, Inc. in California and New York.  The complaint in the California case alleges that ConAgra’s labeling and advertising of Wesson Oils as “100% natural” violates California law because the oils are “derived from plants grown from GMO seeds,” and such plants are not “natural.”  In support of their position, plaintiffs cite Monsanto Company’s definition of “genetically modified organism (GMO)” (“Plants or animals that have had their genetic makeup altered to exhibit traits that are not naturally theirs…”), as well as the World Health Organization’s definition of that term (“organisms in which the genetic material (DNA) has been altered in a way that does not occur naturally…”).  The complaint in the New York case includes similar allegations.  We note that FDA disfavors use of the term “genetically modified organism,” preferring instead the term “bioengineered foods” to describe foods derived from plant varieties that are developed using rDNA technology.

Surprisingly, FDA does not appear to have publicly addressed the question of whether a bioengineered food can properly be labeled as “natural” under the agency’s policy on the use of that term (FDA interprets “natural” to mean that nothing artificial or synthetic (including colors regardless of source) is included in, or has been added to, the product that would not normally be expected to be there).  For its part, ConAgra maintains that “[p]laintiff’s claims do not depend on the FDA’s definition of ‘natural.’”  ConAgra contends in part that, under FDA’s regulatory framework for bioengineered foods, “[n]o special labeling requirements apply to foods made from bioengineered plants because those foods are not meaningfully different from other foods.  If a label is appropriate for food made from plants developed by older methods of genetic selection, then that same label – with each of the representations it makes, whether about the name of the product, the ingredients it contains or whether it is natural, artificial or an imitation – is appropriate for the food made from bioengineered plants too.”  

The broader issue of GMO labeling could gain greater visibility as the result of an upcoming 2-week march on Washington, DC planned by a number of consumer groups, businesses, and trade associations who assert that bioengineered foods should be labeled as such.  The marchers’ desired outcome would require new federal legislation – a doubtful prospect heading into 2012.

By Nisha P. Shah –

The U.S. Department of Health and Human Services recently revised conflict of interest rules for Public Health Service ("PHS") related grants and research (i.e., the National Institutes of Health (“NIH”)) in response to congressional and public concerns over potential conflicts between investigators and companies, such as drug and medical device manufacturers.  The final rules implement changes to regulations issued in 1995 on the Responsibility of Applicants for Promoting Objectivity in Research for which Public Health Service Funding is South and Responsible Prospective Contractors (42 C.F.R. Part 50 and 45 C.F.R. Part 94).  Below are some of the highlights of the final rules that will result in increased monitoring, disclosure, and reporting requirements for institutions and investigators.

Definitions (42 C.F.R. § 50.603, 45 C.F.R. § 94.3)

The most significant changes to the definitions are the changes to the definition of significant financial interest ("SFI") and the inclusion of a definition of financial conflict of interest ("FCOI").

• For SFI, the minimum threshold decreases from $10,000 to $5,000 for payments and/or equity interests, including non-publicly traded entities, related to their institutional responsibilities.  SFI also now includes certain intellectual property rights and interests and most reimbursed or sponsored travel.  Under the final rules, SFI excludes income from investment vehicles and income from seminars, lectures, or teaching, and service on advisory or review panels for government agencies, institutions of higher education, academic teaching hospitals, medical centers, or research institutes affiliated with an institution of higher education.
• An FCOI is an SFI that could directly and significantly affect the design, conduct, or reporting of PHS-funded research.  In this context, HHS explained that “significantly” means that the financial interest would have a material effect on the research.

Responsibilities of Institutions Regarding Investigator Financial Conflicts of Interest (42 C.F.R. § 50.604, 45 C.F.R. § 94.4)

• While the 1995 regulations required an institution to maintain a conflict of interest policy, the new rules add that an institution must make such policy available via a publicly accessible website.  If an institution does not have a presence on a website, the institution must make the policy available in writing within 5 business days of any request.
• The 1995 rules did not have a training requirement; the new rules require each institution to train each investigator on the institution’s conflicts of interest policy and the new regulations prior to engaging in research related to any PHS-funded grant or contract, at least every 4 years, and under specific circumstances, such as when the investigator is new to an institution. 
• Each investigator who is planning to participate in the PHS-funded research must disclose to the institution the investigator’s SFI (and those of the investigator’s spouse and dependent children) no later than the date of submission of the institution’s proposal to the NIH, and thereafter, the investigator must update disclosure within 30 days any newly discovered or acquired SFI and at least annually of any unreported SFI. 

Management and Reporting of Financial Conflicts of Interest (42 C.F.R. § 50.605, 45 C.F.R. § 94.5)

• While the 1995 rule did not require public disclosure of SFI, the new rules now require an institution to either post on a publicly accessible website or make available in a written report within 5 days of a request information concerning any SFI disclosed to an institution that meets the following 3 criteria: (1) the SFI was disclosed and is still held by senior/key personnel; (2) the institution determines that the SFI is related to the PHS-funded research; and (3) the institution determines that the SFI is a FCOI.  Information that must be made publicly available include (but is not limited to): the investigator’s name, the investigator’s title and role regarding the research project, the nature of the SFI, and the approximate dollar value of the SFI (ranges are permissible).  The institution must update this information at least annually and within 60 days of the institution’s receipt or identification of information concerning any additional SFI.
• While institutions implemented a “management plan” under the 1995 rules, the final rules now require that an institution must review all investigator disclosures of SFIs, determine whether a SFI is a FCOI, and, if so, develop and implement a management plan that specifies the actions that will be taken to manage such FCOI.  Examples of actions under a management plan include: public disclosure of FCOI when presenting or publishing research, disclosure of FCOI to participants in a research project involving human subjects, modification of the research plan, and change of personnel or personnel responsibilities.
• The number of requirement elements in the FCOI report submitted to the NIH has increased and now includes (but is not limited to): the name of the investigator with FCOI, the nature of the financial interest, the value of the financial interest, a description of how the financial interest relates to the PHS-funded research, and a description of the key elements of the institution’s management plan.
• If an investigator does not disclose a SFI in a timely manner, the institution must implement a management plan within 60 days and within 120 days must complete and document a retrospective review as to whether any portion of the PHS-funded research was biased.  If bias is found, the institution must notify and submit a mitigation report to the NIH.

The effective date of the final rule is September 26, 2011, and the compliance date is no later than August 24, 2012 and immediately upon making its FCOI policy publicly accessible.

By Karla L. Palmer & John A. Gilbert –

On September 8, 2011, the Drug Enforcement Administration (“DEA”) published a Notice of Intent to temporarily place into Schedule I of the Federal Controlled Substances Act (“CSA”) three synthetic cathinones.  75 Fed. Reg. 55616 (Sept. 8, 2011).  The action is based on a finding by the DEA Administrator that the substances mephedrone (methylcathinone), methylone (3,4-methylenedioxy-N-methylcathinone), and MDPV (3,4-methylenedioxypyrovalerone) are an imminent hazard to the public safety.

As reported here in December 2010 and March 2011, DEA has authority (as delegated by the U.S. Attorney General) to temporarily place a substance into Schedule I of the CSA for a one-year period (subject to a six-month extension) without having to comply with the usual scheduling requirements under 21 U.S.C. § 811(b) if the agency makes a finding that such action necessary to avoid imminent hazard to the public health.  DEA last invoked its temporary scheduling authority in December 2010 when it published a notice of intent to temporarily schedule five synthetic cannabinoids in Schedule I, and finalized that temporary scheduling in March 2011.  Prior to its emergency action concerning synthetic cannabinoids, DEA last invoked its temporary scheduling authority in 2004.

As described in yesterday’s Notice of Intent, in order to temporarily place a substance in Schedule I of the CSA to avoid an imminent hazard to the public safety, the DEA Administrator is required to consider three of the eight factors set forth in 21 U.S.C. § 811(c).  In this case, the Administrator considered the following three factors: (4) the substances’ history and current pattern of abuse; (5) the scope, duration and significance of abuse; and, (6) what, if any, risk each poses to the public health.  DEA explained that  consideration of these factors also “includes actual abuse, diversion from legitimate channels, and clandestine importation, manufacture, or distribution.” (Citing 21 U.S.C. § 811(h)(3)).

With respect to the first factor that the Administrator considered – the abuse history and current pattern of abuse – the pharmacological effects of synthetic cathinones are similar to those of highly abused products such as methamphetamine, cathinone, methcathinone and MDMA.  They cause, among other effects, agitation, tachycardia, dilated pupils, hyperthermia, sweating, and hypertension.  Thus, the abuse of synthetic cathinones is likely similar to those highly abused substances.  The DEA also noted that the three substances identified by DEA in its Notice of Intent represent more than 98% of the reported synthetic cathinones recently seized by law enforcement.

As to the second factor that it considered – the scope, duration and significance of abuse – the DEA cited to the recent emergence of these substances on the U.S. illicit drug market, yet noted that the products have been popular in Europe since 2007.  The three products (marketed as bath salts, plant food, or research chemicals; and labeled “not for human consumption”) are typically sold in smoke shops, head shops, adult book stores,  gas stations, and are routinely purchased via the internet.  The DEA noted that retailers promote that routine drug tests will not detect their presence in the body.  Surveys and other research also indicates that the substances are being widely abused, marketed to teens and young adults, and sold for their psychoactive properties – as alternatives to stimulants like cocaine and MDMA.  The DEA Notice of Intent describes that the methods of administration of the illicit substances include snorting, swallowing, and “bombing” (i.e., wrapping powder in a paper wrapper and swallowing), and are also reported to be used as  “binge” products.

Citing their rampant increase in popularity since these synthetic products appeared on the U.S. drug market scene back in 2009, DEA states that poison control centers have already received 4,137 calls relating to synthetic cathinones in the first seven months of 2011; which is up from the 303 calls received for such substances in all of 2010.  In addition, the U.S. Customs and Border Patrol has encountered at least 96 shipments of synthetic cathinones at one border; most of which originated from India or China and are being shipped throughout the United States.  Due to the potential for abuse, as of July 2011, at least 33 states have emergency scheduled or taken action to control synthetic cathinones.  All members of the European Union have placed controls on the possession or sale of them as well.

As to the required third factor in DEA’s consideration – the risk to the public health — the DEA stated that these substances have been the subject of serious abuse, and are associated with numerous emergency room admissions.  Given the frequent reports of adverse and significant health incidents (including three deaths) associated with the use of these substances, their high potential for abuse, and because there is no acceptable medical use in treatment in the United States for the substances, the DEA found it necessary to provide the requisite 30-day notice that the substances are subject to  expedited temporary scheduling as set forth in 21U.S.C. § 811(h).  The DEA Administrator will issue a final order temporarily scheduling the three substances into Schedule I upon the expiration of the 30-day notice period, or after October 11, 2011.  The temporary scheduling is effective for up to 18 months pending the DEA’s completion of the scheduling process.  After the expiration of the 30-day notice period, MDPV, mephedrone and methylone will be subject to the “regulatory controls and administrative, civil  and criminal sanctions applicable to the manufacture, distribution, possession, importing and exporting of a Schedule I controlled substance under the CSA.”

By Kurt R. Karst –      

On September 8th, the U.S. Senate passed, by an 89-9 vote, H.R. 1249, the Leahy-Smith America Invents Act.  Final passage of the bill, which will make significant changes to the U.S. patent system, was preceded by a contentious vote on, you guessed it, Section 37 (often referred to as “The Dog Ate My Homework Act” or the “Medco fix”), which would legislatively resolve The Medicines Company’s (“MDCO’s”) decade-long battle to obtain a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 covering ANGIOMAX (bivalirudin). 

As we previously reported (here, here, and here), as the prospects of patent reform grew over the past few months (after the House passage of H.R. 1249), so too did lobbying efforts to ensure inclusion of Section 37 in the Senate-passed bill.  Those efforts took the form of portraying Section 37 as a law of general applicability affecting multiple companies and products (3 that we know of, not including ANGIOMAX) rather than as single company (including a law firm and its malpractice insurer) legislation. 

That portrayal rankled some Senators.  Earlier this week, Senators Jeff Sessions (R-AL), Joe Manchin (D-WV), Tom Coburn (R-OK), and Mike Lee (R-UT) proposed Senate Amendment 600, the text of which states: “On page 149, line 20, strike all through page 150, line 16.”  Those line references are to entire Section 37 of the House-passed H.R. 1249, which states:

SEC. 37. CALCULATION OF 60-DAY PERIOD FOR APPLICATION OF PATENT TERM EXTENSION.

(a) IN GENERAL.—Section 156(d)(1) of title 35, United States Code, is amended by adding at the end the following flush sentence:

‘‘For purposes of determining the date on which a product receives permission under the second sentence of this paragraph, if such permission is transmitted after 4:30 P.M., Eastern Time, on a business day, or is transmitted on a day that is not a business day, the product shall be deemed to receive such permission on the next business day. For purposes of the preceding sentence, the term ‘business day’ means any Monday, Tuesday, Wednesday, Thursday, or Friday, excluding any legal holiday under section 6103 of title 5.’’.

(b) APPLICABILITY.—The amendment made by subsection (a) shall apply to any application for extension of a patent term under section 156 of title 35, United States  Code, that is pending on, that is filed after, or as to which a decision regarding the application is subject to judicial review on, the date of the enactment of this Act.

Senators Sessions and Coburn urged the Senate in a September 7th “Dear Colleague Letter” to support passage of their amendment, stating:

While many of us had supported the Senate version of H.R. 1249, the  “Leahy-Smith America Invents Act,” the House version contains a controversial special interest provision (Section 37) that was added via amendment during a confusing and highly-unusual floor debate. Initially, the amendment failed by a vote of 209 to 208.  When some Members objected that they had not been able to vote, the original vote was vacated.  The second time around, the amendment was adopted by 19 votes.  We believe this apparent confusion is attributable to the fact that Section 37, or the “Medco fix,” looks like a benign, technical change to an obscure section of the U.S. Code. But it is actually an illustration of Washington at its worst – a bailout for a well-connected, big law firm and its malpractice insurer and a brand pharmaceutical manufacturer, which have hired an army of lobbyists. The provision is a special interest matter which is currently in litigation and cannot be justified.

The letter goes on to provide several reasons why the Senate should vote to strike Section 37: “First, this case is in active litigation. . . .  Second, this provision addresses a problem that does not exist. . . .  Third, if this language becomes law, it would permit Medco to delay the launch of a generic version of Angiomax by an additional five years (2015). . . .  Finally, Congress has a private relief process for dealing with cases such as this.” 

Despite these pleas, the Senate rejected, by a 51-47 vote, Senate Amendment 600, paving the way for a final vote on, and passage of, H.R. 1249.  (The September 8th Senate floor debate on Senate Amendment 600 is available here.)  If President Obama signs the Leahy-Smith America Invents Act into law, the ongoing battle in the U.S. Court of Appeals for the Federal Circuit will presumably be mooted, and the last chapter in this story may very well have been written.

As we say goodbye (or is it “hello”?) to “The Dog Ate My Homework Act” (although there may still be more interesting things to come on this drug), we leave you with a list of all the FDA Law Blog postings on this topic (a blogography of sorts).  Queue up Green Day’s Time Of Your Life:

• August 2, 2007 – The “Dog Ate My Homework Act” Resurfaces
• June 25, 2008 – Going Once . . . Twice . . . Sold – One PTE to the Company from Massachusetts for $65 Million
• October 26, 2009 – The Medicines Company Continues Lobbying Push for ANGIOMAX Patent Term Extension Legislative Fix; Latest Iteration of the “Dog Ate My Homework Act” Maintains $65 Million Late Fee
• December 15, 2009 – The Medicines Company Initiates an 11th Hour Push for ANGIOMAX Patent Term Extension; Petitions PTO to Adopt a Rule of Construction for Determining NDA Approval Date
• January 20, 2010 – Down and Out in MA – The PTO Denies The Medicines Company’s Request for Reconsideration for ANGIOMAX Patent Term Extension
• February 1, 2010 – The Medicines Company Tosses Up a Hail Mary Pass – Sues PTO and FDA Over ANGIOMAX Patent Term Extension Decisions
• March 17, 2010 – PTO’s ANGIOMAX PTE Denial is Vacated and the Case Goes Back to PTO – What Happens in the Interim?
• March 22, 2010 – PTO Once Again Denies PTE for ANGIOMAX Patent . . . But Not Before Issuing an Interim Extension; MDCO is Outraged
• March 26, 2010 – Here We Go Again! MDCO Launches Another Lawsuit Against the PTO Over ANGIOMAX PTE
• May 24, 2010 – Court Orders and PTO Grants Second Interim PTE for ANGIOMAX
• May 27, 2010 – Sen. Kerry Introduces ANGIOMAX PTE Amendment to Tax Extenders Act of 2009
• August 3, 2010 – MDCO Prevails in ANGIOMAX PTE Case – District Court Grants Summary Judgment; Will the PTO Appeal?
• September 2, 2010 – APP Moves Forward With Appeal Notice in ANGIOMAX PTE Litigation in Light of PTO/FDA Indecision
• September 9, 2010 – All Eyes are on APP’s Intervention Motion as the Government Bows Out of ANGIOMAX PTE Litigation
• February 6, 2011 – The Fat Lady Goes Back to Her Dressing Room; Federal Circuit Denies MDCO Motions in ANGIOMAX PTE Litigation
• April 20, 2011 – Amendment to the America Invents Act Would Give MDCO Some Legislative Security in Battle Over ANGIOMAX PTE
• June 28, 2011 – Efforts to Obtain a PTE for ANGIOMAX Patent Continue as the U.S. House Passes an Amendment to the America Invents Act in “After Business Hours” Vote
• August 11, 2011 – ANGIOMAX – The Other Patent Battle
• August 21, 2011 – Strength in Numbers? The Lobbying Push for a PTE

On September 9, 2011, FDA will publish in the Federal Register a notice granting a 60-day extension, until December 2, 2011, to file comments on the draft guidance on New Dietary Ingredient (“NDI”) notifications that the Agency issued on July 5, 2011 (see our previous post on the draft guidance here).  In late July, Hyman, Phelps & McNamara, P.C. filed a request for a one-year comment period to allow affected businesses adequate time to respond to the lengthy and controversial draft guidance (see our previous post here).

By Kurt R. Karst –      

The National Organization for Rare Disorders (“NORD”) announced the submission of a Citizen Petition to FDA  requesting “that a documented policy be established regarding the review of potential treatments for people with rare diseases.”  The petition comes on the heels of a Report to Congress FDA issued earlier this year and required by Section 740 of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80) (see our previous post here), in which the FDA reports on the findings and recommendations of two Agency groups to improve the current regulatory/scientific armamentarium to facilitate the development of products for rare and neglected diseases. 

In addition to the Report to Congress, Section 740 of the Appropriations Act also requires FDA to “issue, not later than 180 days after submission of the report to Congress . . . . guidance based on such recommendations for articles for use in the prevention, diagnosis, and treatment of rare diseases and for such uses in neglected diseases of the developing world,” and to “develop, not later than 180 days after submission of the report to Congress . . . internal review standards based on such recommendations for articles for use in the prevention, diagnosis, and treatment of rare diseases and for such uses in neglected diseases of the developing world.”  “Because the report was issued to Congress June 27, 2011, this guidance document is due to be issued no later than December 27, 2011,” says the NORD petition. 

NORD requests that FDA’s guidance explicitly include:

• Acknowledgement that the conduct of clinical trials for most orphan drugs is qualitatively and quantitatively different from the conduct of trials for drugs that treat common conditions.
• Acknowledgement that FDA review of marketing applications for most orphan drugs is accordingly qualitatively and quantitatively different from FDA review of applications for articles that treat common conditions.
• In recognition of the above, and notwithstanding the unchanged requirements that articles for rare diseases must demonstrate both efficacy and safety, we request a statement that it will now be FDA official policy to afford special flexibility to the regulatory review of submissions for all orphan drugs.

“This petition does not request any itemization of past actions – rather, through the language of forthcoming guidance, we request the establishment of a policy to direct future actions,” says NORD in the Citizen Petition.

In addition, NORD requests that FDA “incorporate mandatory training in this new policy and other matters related to orphan drug development for all full-time FDA review professionals,” and that this training become a requirement of FDA’s core curriculum.  As we recently reported, the Proposed PDUFA V Reauthorization Performance Goals and Procedures for Fiscal Years 2013 through 2017 includes an initiative, styled as “Advancing Development of Drugs for Rare Diseases,” that would require FDA to, among other things, “develop and implement staff training related to development, review, and approval of drugs for rare diseases.  The training will be provided to all CDER and CBER review staff, and will be part of the reviewer training core curriculum.”

In addition to the Report to Congress, NORD states in the petition that the organization’s requests are consistent with the recommendations of a recent finding of the Institute of Medicine, which released a report in October 2010, titled “Rare Diseases and Orphan Products: Accelerating Research and Development,” and with the testimony delivered by Hyman, Phelps & McNamara, P.C. Director and Chair of the Board of NORD Frank J. Sasinowski at a June 2010 FDA Part 15 hearing.