By James E. Valentine* & David B. Clissold –

The pendulum has been swinging: the medical research community and public health advocates want access to clinical trials data used to support marketing applications of FDA-regulated medical products.  In 2007 that pendulum picked up momentum, with the enactment of Section 801 of the FDA Amendments Act of 2007 (“FDAAA”), which amended the PHS Act § 402 to expand the clinical trial registry data bank created by Section 113 of the FDA Modernization Act of 1997 (“FDAMA”).  Areas of expansion included the types of clinical trials that must be registered in ClinicalTrials.gov, the data elements that must be submitted, and the required submission of certain results data. 

Requiring the registration and submission of summary results of clinical trials of medical products was seen as a way to, among other things, allow the use of research results to contribute to medical knowledge for the benefits of patients, the research community, and the general public.

As it turned out, FDAAA Section 801 was not the end-all-be-all solution, especially since the statute left a plethora of questions on how to comply with the requirements: including questions as to who is a “responsible party” and what is an “applicable clinical trial” that would be subject to results reporting (we covered these early developments in 2008 and 2009 here, here, here, here, here, and here; NIH has a webpage with current information on the FDAAA 801 requirements). 

Although no refinements were made in the  latest round of FDA-focused legislation, the FDA Safety and Innovation Act of 2012 (“FDASIA”), policymakers on both sides of the aisle, as well as FDA, have recently proposed additional ways to increase transparency and access to clinical trial data and results in hopes of spurring medical product innovation and improving public health.

Rep. Ed Markey (D-MA) reintroduces The Trial and Experimental Studies Transparency (“TEST”) Act

For over a year now, Rep. Markey, along with Rep. Waxman and other House democrats, have been discontent with the underreporting of clinical trial results as required by FDAAA Section 801 (we previously reported here).  Rep. Markey first introduced the Trial and Experimental Studies Transparency (“TEST”) Act in August 2012 (see here), but it never made it out of the committee stage.

As it was introduced this session, on May 16, 2013, H.R. 2031 would increase results reporting by expanding the reporting requirements for ClinicalTrials.gov, closing what is describes as “loopholes” in the original 2007 scheme.  The TEST Act would do so by:

• Expanding reporting requirements to include interventional studies conducted outside the United States.
• Expanding reporting requirements to postmarket surveillance of class II or class III devices that involve data collection from human subjects. 
• Requiring the submission to ClinicalTrials.gov of supporting documents, including protocol documents and consent documents used to enroll trial subjects.
• Requiring all interventional studies to be registered with the database before the first participant is enrolled in the trial.
• Strengthening reporting requirements so that results from all covered trials are posted on ClinicalTrials.gov within one year of the completion of the trial, while also limiting the delayed submission of results to only trials on medical products that have never before been approved for any use and up to only two years after trial completion.

The TEST Act also attempts to increase compliance by:

• Requiring the NIH Director and FDA Commissioner to report to Congress on the number of clinical trials with information submitted and steps taken to enforce compliance.

Rep. Tom Reed (R-NY) reintroduces the renamed Clinical Trial Cancer Mission 2020 Act

Another advocate for increasing clinical trials results reporting to ClinicalTrails.gov is Rep. Reed, who sees clinical trial results availability not only as a way to improve medical knowledge and research, but as a way to “safeguard taxpayer dollars from funding redundant research” (see Reed’s press release here).   His legislation, the Clinical Trial Cancer Mission 2020 Act (“CTCM 2020”) Act came just about a month after the introduction of the TEST Act, and takes a different approach to increasing clinical trial results reporting to ClinicalTrials.gov.

As it was introduced this session, on May 16, 2013, H.R. 2301 (no, this is not déjà vu, the bill number is just very similar to the TEST Act’s) addresses what he describes as a “lack of enforcement in reporting clinical trial results.” 

The CTCM 2020 Act would do two primary things:

• Adds a provision to include a clinical trial whether or not it results in a positive or negative outcome, as well as subject Department of Defense-funded clinical trials to the requirements to certify information submission to the NIH.
• Adds an “enhanced enforcement” subsection that would make the penalty for failure to report required clinical trial information to ClinicalTrials.gov within a 30-day correction period ineligibility for grant funding from the United States government, as well as create a repayment obligation for any grant amount provided.

(For a more detailed overview of this legislation, see our previous post here from last session).

FDA announces “Availability of Masked and De-Identified Non-Summary Safety and Efficacy Data”

Going beyond the summaries of clinical trials data that FDAAA Section 801 requires to be reported to ClinicalTrials.gov, FDA is proposing to use its new mandates under FDASIA Section 1124, “Advancing regulatory science to promote public health innovation,” to make available de-identified (i.e., cannot identify individual study participants) and masked (i.e., cannot identify a specific product or application) data derived from medical product applications.

In a Federal Register notice (Docket No. FDA-2013-N-0271), FDA announced as part of its Regulatory Science Initiative, this effort which has goals similar to that of the results reporting to ClinicalTrials.gov:

• To improve efficiency and effectiveness of medical product development by making available this clinical and preclinical data derived from marketing applications, which would then facilitate innovation in the development of new products. 
• To maximize the contribution of patients who participate in clinical trials to the benefit of society.

FDA expects that allowing other experts outside of the Agency to conduct analyses of the data will contribute to identification of potentially valid endpoints for clinical trials, understanding of the predictive value of preclinical models, clarification of how medical products work in different diseases, and information for development of novel clinical designs and endpoints.  Additionally, FDA hopes that this information could be used by sponsors, e.g.,  being used as a model of disease progression in control arms for future studies of the same disease or indication even without the identification of a product or even product class, for the characterization of risk factors only involving control group data, and validating a biomarker as a surrogate clinical outcome or as a predictive classifier of potential treatment response using class-wide data to show consistency.

FDA is currently accepting comments on the availability of this data to aid the Agency in the difficult task of establishing methods to appropriately mask the clinical trial data to prevent someone from identifying the product or application. 

* Law student

By Larry K. Houck –

Pharmacists are under increasing pressure to take extraordinary steps to verify prescriptions for controlled substances, especially in light of the fact that the Drug Enforcement Administration (“DEA”) has asserted that pharmacists are the gatekeepers or the “last line of defense” in the fight against prescription drug abuse.  Alan G. Santos, DEA, Combatting Pharmaceutical Diversion: Targeting “Rogue Pain Clinics” & “Pill Mills,” Prescription Drug Awareness Conference, May 4-5, 2013, unnumbered slides.  However, if the American Medical Association (“AMA”) adopts either of two committee resolutions at its 2013 meeting, pharmacists who serve that gatekeeper role should not expect cooperation from prescribing physicians.  One AMA delegation has introduced a resolution to the Organized Medical Staff Section that would characterize routine pharmacist inquiries “for verification of the rationale behind prescriptions, including diagnosis, treatment plan, ICD-9 codes and/or previous medications/therapies that were tried/failed, and for routine pharmacist calls for such verification of this rationale, to be an inappropriate interference with the practice of medicine and unwarranted.”  AMA Organized Medical Staff Section Resolution 12 (A-13), AMA Response to Drug Store Chain Intrusion into Medical Practice, received May 15, 2013.  Delegations from New England have put forth an almost identical resolution to the AMA House of Delegates that also, while noting the regulations “only” require pharmacists to ensure the prescription is legitimate, pharmacists are “under no circumstances should be required to confirm the appropriateness of a prescription; the decision is purely a medical one, completely in the purview of the treating physician.”  AMA House of Delegates Resolution 218 (A-13), AMA Response to Drug Store Chain Intrusion into Medical Practice, received May 17, 2013.  Furthermore, calls from pharmacists to doctors’ offices to verify prescriptions will be deemed an “inappropriate interference with the practice of medicine and unwarranted ….”  Id.  If  pharmacists continue to conduct routine prescription verification, the AMA plans to take its fight to the implicated companies (i.e., drug store chains), DEA, and other involved state and federal regulators to stop what the AMA believes is interference in the physicians’ practice of medicine and their medical treatment decision-making.  If those efforts fail, the AMA will turn to Congress for legislation to eliminate any form of pharmacist prescription verification requirement, or to otherwise clarify physician and pharmacist roles in dispensing controlled substances. 

The impetus for the AMA resolutions appears to be the policy of a “national drug store chain” that requires its pharmacists to call and speak with the practitioner to “verify” controlled substance prescriptions prior to filling them.  While both proposed resolutions recognize a pharmacist’s “responsibility to vet any prescription for legitimacy,” they characterize pharmacist due diligence efforts not as a “last line of defense” against the prescription drug epidemic but instead an invasion of the patient-physician relationship.  The resolutions suggest that pharmacists’ questioning prescribers about their controlled substance prescriptions is a perversion “of the “spirit and intent” of DEA’s pharmacist corresponding responsibility regulations.  While DEA regulations do not specifically require a pharmacist to contact practitioners to verify controlled substance prescriptions, DEA’s interpretation of its regulations and recent administrative actions against pharmacies demonstrate that closely scrutinizing most if not all controlled substance prescriptions, including verifying prescriptions with prescribing physicians, is at a minimum exactly what DEA expects pharmacists to do. 

DEA regulations have long established that a corresponding responsibility rests with dispensing pharmacists to ensure, with the prescribing practitioner, that a prescription for a controlled substance has been issued for a legitimate medical purpose by the individual practitioner acting in the usual course of professional practice.  21 C.F.R. § 1306.04(a).  Many pharmacists, even with the current prescription abuse epidemic fueled by rogue practitioners, remain reluctant to question a practitioner about their controlled substance prescriptions.  This is not unreasonable, given that it is the physician, armed with a medical degree and clinical training, sees the patient, treats the patient, and determines the appropriate medical treatment.  While pharmacists are responsible for guarding against fraudulent prescriptions and potential doctor-shopping patients, questioning the prescribing practices and medical judgment of a physician and evaluating whether a prescription was issued for a legitimate medical purpose is far more difficult.

DEA traditionally viewed medical practitioners as the gatekeepers who determined through examination, administering, dispensing and prescribing which patients legitimately needed controlled medications.  However, in recent years, because of the diversion created by rogue Internet pharmacies and pain clinics, DEA has focused more on pharmacists as the controlled substance gatekeepers, holding them accountable for dispensing pursuant to prescriptions not issued for legitimate medical purposes.  See East Main Street Pharmacy; Affirmance of Suspension Order; 75 Fed. Reg. 66149 (Oct. 27, 2010).  DEA officials have expressed their belief that the pharmacist, with their pharmacological training, rather than practitioners, is the “drug expert” in the healthcare arena and therefore responsible for policing practitioners.  Responding to the Prescription Drug Abuse Epidemic: Hearing Before the S. Caucus on Int’l Narcotic Control, 112th Cong. 2 (2012) (Statement of Joseph T. Rannazzisi Deputy Assistant Administrator, DEA).  Pharmacists must fulfill their corresponding responsibility through reasonably diligent efforts and judgment to ensure that a prescription has been issued for a legitimate medical purpose.  See East Main Street Pharmacy; Affirmance of Suspension Order, 75 Fed. Reg. 66149 (Oct. 27, 2010). 

The AMA’s proposed resolutions are directly at odds with DEA’s legal and regulatory position on a pharmacist’s corresponding responsibility to ensure that prescriptions are issued for a legitimate medical purpose and in the course of a physician’s professional practice.  For example, DEA has based an Order to Show Cause, in part, on a pharmacist’s assertion that it was “not [his] job to question a physician.”  Id.  DEA also requires pharmacists to resolve certain “red flags” signaling invalid prescriptions, including at a minimum verifying controlled substance prescriptions with the physician’s office prior to filling those prescriptions.  See id.; Holiday CVS, L.L.C., d/b/a CVS/Pharmacy Nos. 219 and 5195; Decision and Order, 67 Fed. Reg. 62315 (Oct. 12, 2012).

Noticeably absent from the resolutions are any indication that the AMA will urge its physician members to assist pharmacists in their corresponding responsibility to ensure that controlled substances are issued for a legitimate medical purpose.  If the AMA adopts either of the proposed resolutions, pharmacists will not only encounter continued physician resistance to prescription verification, but also find it even more difficult to comply with their corresponding responsibility to ensure that the prescriptions they fill have been issued for legitimate medical purposes.

The AMA and DEA must come to a consensus concerning the scope of a pharmacist’s corresponding responsibility to ensure that prescriptions are legitimate in light of the prescription drug epidemic so that patients obtain needed medication, pharmacists are not second-guessing medical decisions, and pharmacists who fill controlled substance prescriptions are not legally culpable for a physicians’ illegal or otherwise improper prescribing practices.

The AMA Organized Medical Staff Section and House of Delegates will consider the resolutions during the association’s 30th Annual Assembly this week in Chicago.

By Kurt R. Karst –      

A Draft Committee Report made available by the U.S. House of Representatives Committee on Appropriations that would, once finalized, accompany the Fiscal Year 2014 Agriculture/FDA Apprropriations bill (currently available as a Full Committee Draft), lays out a laundry list of concerns and new action items for FDA to meet. 

Below we categorize each of the items in the Draft Committee Report.  Many of the items concern issues currently being debated in Congress, and, more broadly, within the food and drug-regulated industry.

General Issues

Transparency Concerns.—The Committee is concerned about the unpredictable nature and pace at which FDA moves guidance, rules, and regulations through the process. The Agency must understand that FDA is often viewed as a primary source of information for consumer decisions that impact their health and wellbeing. The Committee understands that many rules and regulations get through the agency and the department only to languish at the Office of Management and Budget (OMB). On the other hand, FDA has discretion to issue advisories and guidance without the need for OMB clearance. In a number of critical health areas, American consumers and industry are faced with no guidance at all or inconsistent messages on many important issues. The following is a list of examples: seafood advisory for pregnant women; sunscreen ingredients; new dietary ingredients for dietary supplements; and, Bisphenol A. The Committee directs FDA to report to the Committees on Appropriations by September 1, 2013, on how the agency plans to develop new methods of communicating with its stakeholders on future actions affecting critical policy issues, including estimated timeframes for when regulations, advisories, and guidance are planned for release and what decision points are necessary before these policy documents can be made.

Low-Risk, Expedited Imports.—The current fiscal environment and the growing number of import entries require that efforts to enhance safety must be directed towards the most serious compliance infractions. The Committee strongly encourages FDA to establish a pilot project to expedite imports for importers with strong safety records. Such project could be modeled on the Customs and Border Protection (CBP) Customs-Trade Partnership Against Terrorism and Importer Self-Assessment programs which address security of imported products. The goal would be new trade facilitation methods for low-risk importers that provide accurate and reliable data, have a history of importing compliant products, and low risk cargo that could be incorporated into the import inspection process, thereby enabling FDA to better leverage financial resources. FDA is strongly encouraged to provide clear guidelines for those importers that are low-risk and to collaborate with CBP and other relevant agencies to enhance information sharing between agencies on this work. FDA is directed to provide a report to the Committee on its efforts in this regard by December 1, 2013.

Statutory Deadlines.—The Committee is aware the Administration continues to miss statutory deadlines for rulemaking to implement Public Law 111–353. The Committee expects the Administration to meet the statutory timelines for implementing Public Law 111–353 and directs FDA to provide a report every 180 days detailing the reasons and justification for any proposed rule or final regulation being 120 days or more beyond its statutory deadline.

User Fees

FDA User Fee Collections/Obligations.—The Committee is concerned about the large unobligated balances that continue to occur in FDA’s user fee programs. While Congress did allow for some exemptions from fiscal year limitations and for some amounts to be carried forward into subsequent fiscal years, it could not have been anticipated that FDA would be carrying in excess of $1,000,000,000 in unobligated user fees halfway into any fiscal year. In the Tobacco user fee program alone, the fiscal year 2012 unobligated balance that carried over into fiscal year 2013 was $600,000,000. While FDA estimates this figure will drop to $250,000,000 by the end of fiscal year 2013, the Committee remains skeptical that this will occur. The Committee directs that not later than November 1, 2013, and each month thereafter through the months covered by this Appropriations Act, the Commissioner to submit to the Committees on Appropriations of the House and the Senate a report on user fees collected for each user fee program included in the bill. The report shall also include monthly obligations incurred against such fee collections. The first report shall include a distinct categorization of the user fee balances that are being carried forward into fiscal year 2014 for each user fee account as well as a detailed explanation of what accounts for the balance and what the balance will be used for.

User Fees.—The Committee is concerned about subjecting FDA user fees to sequestration as these fees are not normal tax revenue. It is important to maintain the integrity and industry support for user fee programs. The Committee encourages FDA to reevaluate its calculations of sequestration in regard to user fees.

Impact on Small Businesses.—The Committee is concerned by unintended consequences of the Generic Drug User Fee Act (GDUFA) fee structure. While the Committee understands that user fees provide the resources to facilitate generic drug approvals, the Committee believes FDA should study the impact of smaller generic manufacturers’ ability to pay at the same level as large manufacturers. The Committee directs FDA to provide a report to the Committees on Appropriations on the impact of the GDUFA fee structure on smaller generic drug manufacturers within 180 days of enactment of this Act.

Prescription Drugs & Biologics (Human)

Non-Tropical Diseases (NTD).— [NOTE: The reference to "Non-Tropical Diseases" should probably be a reference to "Neglected Tropical Diseases."] The Committee has become aware that Chagas disease is not on the list of neglected diseases as currently defined by FDA. The Committee urges FDA to make the necessary modifications to include Chagas disease in its list of neglected diseases in line with World Health Organization’s list of NTDs. Additionally, the Committee directs that FDA build stronger partnerships with global regulatory stakeholders and strengthen its internal capacity to review products for neglected diseases.

Food and Drug Safety and Innovation Act.—The Committee is aware that shortages of critical drugs persist following the enactment of the Food and Drug Safety and Innovation Act. Surveys conducted by the American Association of Nurse Anesthetists, the American Hospital Association, and the American Society of Health-System Pharmacists report persistent shortages of drugs used in anesthesia care, oncology, and other services, owing primarily to problems in manufacturing, which impair patient access to care and patient experiences in the healthcare system, delay surgical procedures, and possibly increase overall healthcare costs. The Committee directs the Commissioner to continue to prioritize the public reporting of manufacturing shortages and to work with industry to prevent conditions that might lead to drug shortages.

Compounded Drugs.—The Committee is concerned by the quantity and volume of recalls of compounded sterile products and therapies. The Committee awaits the results of a study by GAO providing updated information on state and Federal oversight of compounding. Furthermore, the Committee encourages FDA and the States to work together to improve and strengthen oversight and enforcement of compounding pharmacies.

Abuse-Deterrent Drugs.—The Committee supports FDA’s recent efforts to ensure that certain opioids are kept off the market and commends the agency for removal of those products for reasons of safety or effectiveness. The Committee understands that FDA established draft guidance in January 2013 entitled Evaluation and Labeling of Abuse-Deterrent Opioids, and encourages the agency to move expediently to finalize such guidance.

Prescription Drugs & Biologics (Animal)

Guidance for Industry.—The Committee directs the Secretary of Health and Human Services to finalize Guidance for Industry (GFI) #213 prior to January 1, 2014. The Committee directs the Secretary of Health and Human Services to publish a report not later than one year following the date of finalization of GFI #213 that (1) lists the following, for each medically important antimicrobial new animal drug administered in feed or water to food-producing animals with one or more approved production claims (including any growth promotion, feed efficiency, or weight gain claims) and/or that are approved for over-the-counter (OTC) marketing, provided that such antimicrobial is in a class of drugs that FDA determines accounts for 10 percent or more of all physician prescriptions: (a) the drug’s new animal drug application (NADA) number(s), (b) sponsor, (c) all antimicrobial active ingredients contained in the drug, and, (d) all production claims approved for the drug; and (2) specifies the number of sponsors of the new animal drugs listed that have notified the FDA of their intent to participate in the voluntary process described in GFI #213. The Committee further directs the Secretary, beginning not later than one year following the finalization of GFI #213, to publish annual reports that (1) specify the number of antimicrobial new animal drugs for which sponsors have submitted applications under GFI #213 to change existing approvals, broken out by type of change sought (i.e., removal of production claims; addition of treatment, control, and/or prevention claims; and removal of OTC marketing status); and (2) list the applications submitted under GFI #213 that have been approved by the agency by NADA number, and if not approved or rejected, indicate whether the inaction was a result of insufficient FDA resources, insufficient information from sponsors or some other reason.

Data Collection.—To assist efforts intended to address antibiotic use, the Committee directs the Secretaries of Health and Human Services and Agriculture to require appropriate agencies to collaborate to (1) identify approaches for collecting detailed data on antibiotic use in food-producing animals, (2) seek stakeholder and broad public input to develop a proposal for collecting this information, and (3) use the data to assess the effectiveness of policies to curb antibiotic resistance. The Committee further directs FDA to ensure that ARS continues to analyze, characterize, and report on data collected through NARMS.

Foods & Dietary Supplements

Nutrition Labeling.—The Committee remains concerned with FDA’s proposed rule to regulate Nutrition Labeling of Standard Menu Items at Chain Restaurants. The Committee urges FDA to use the proposed alternative Option 2 definition of the rule which only applies to restaurants or retail establishments where the primary and majority of business is the selling of food for consumption or the selling of food that is processed or prepared on the premises. The Committee believes the agency should take into account the increased costs and logistical challenges chain restaurants will face in meeting the requirements of the proposed rule. To meet the requirements of the law, FDA should consider a clear, conspicuous statement of required nutritional information on a prominently displayed poster adjacent to the menu board and nutritional information to be provided in pamphlet form prominently displayed next to drive-through menu boards as meeting such requirements.

Food safety monitoring.—The Committee notes that the National Agriculture and Food Defense Strategy Plan is being finalized as required by Section 108 of Public Law 111–353. As research needs are identified to carry out this section, the Committee encourages FDA to consider funding research that would provide portable and technologically advanced testing platforms needed to effectively monitor and protect against intentional adulteration of the food supply.

New dietary ingredients.—The Committee notes that FDA has not addressed issues relating to its July 2011 draft guidance on New Dietary Ingredients (NDI) for Dietary Supplements despite this Committee’s urging it to do so last year. The Committee continues to be concerned that this guidance is being utilized by FDA for enforcement activities despite the document only being draft guidance. The Committee directs FDA to report back within 60 days of enactment of this Act with a timeline on how it intends to re-engage the dietary supplement community to develop a final guidance on what constitutes a NDI.

Food Safety Centers of Excellence.—The funding provided for CFSAN supports the base funding for the CFSAN Centers of Excellence at the FY 2011 level, including Food Safety Modernization Act collaborative efforts with these Centers. The Committee encourages FDA to maintain an appropriate funding level for both Food Safety Modernization Act related and other food safety related activities performed by these Centers of Excellence.

Food and Veterinary Medicine.—The Committee is aware of the important support provided to FDA’s food and veterinary medicine programs and through its research and program relations with their centers of excellence. The Committee encourages FDA to maintain an appropriate funding level for both Food Safety Modernization Act related activities and the base work performed by these centers.

Food Product Tracing.—Pursuant to Section 204 of the Food Safety Modernization Act, FDA initiated pilot projects for improving product tracing along the food supply system and the establishment of recordkeeping requirements for high-risk foods. These pilots were conducted by the Institute of Food Technologists, in consultation with various industry sectors, USDA, state agencies, and consumer groups. A report on these projects was published on March 4, 2013, and that report affirmed that industry and government continue to pursue traceability goals on separate tracks and with little collaboration. The Committee directs the Commissioner, in consultation with the Secretary of Agriculture, to create a science-based, international food traceability initiative through a collaborative public-private partnership model. Furthermore, the Committee directs the Commissioner to provide a report within 180 days of enactment of this Act detailing the structure, goals, and implementation status of such traceability initiative.

Seafood Advisory.—FDA must publish a final seafood advisory in conjunction with all applicable parties as directed in House Report 112–101 and Senate Report 112–73. The advisory must be consistent with USDA’s dietary guidelines and be completed and available to the public by June 30, 2013.

Canned Tuna.—The Committee directs FDA to revise the standard of identity for canned tuna to adopt the drained weight fill of container standard as requested in the 1994 ‘‘Citizens Petition to Amend Canned Tuna Standard of Identity, 21 CFR 161.190, Docket No. 94P–0286.’’ According to the Congressional Research Service, the United States is the only country that uses the pressed cake weight fill of container standard that requires outdated 1950s technology. CODEX, the Association of Official Analytical Chemists, and all other countries use the drained weight fill of container. FDA shall revise the standard of identity for canned tuna to replace the pressed cake weight method with the drained weight method by December 31, 2013. FDA shall approve temporary marketing permits that adopt the drained weight method consistent with international standards until such time as final regulations are published updating the standard of identity for canned tuna.

Over-the-Counter Drugs & Cosmetics

Sunscreen.—Approximately two million cases of skin cancer are diagnosed each year and an estimated one in five Americans may develop skin cancer during their lifetime. Since sunscreen use can help prevent this disease, the Committee is concerned that FDA has taken no final action to approve new sunscreen ingredients  under the Time and Extent Applications (TEA) process. The Committee understands that new sunscreen ingredient TEAs have been pending at FDA for more than 10 years without any approvals despite their widespread safe and effective use in other countries. FDA has listed final action on sunscreen ingredient applications in its Unified Agenda every year since 2008; however, no such action has ever been taken. Therefore, FDA shall take final action on all sunscreen ingredient applications currently pending by June 1, 2014, and shall work with Congress and stakeholders—including ingredient manufacturers, finished product manufacturers, dermatologists, cancer prevention organizations and others—to develop a new process that will allow safe and effective sunscreen ingredient market applications to receive a final decision from FDA within one year of application date.

Cosmetics.—The Committee directs the Office of Cosmetics and Colors to respond by September 30, 2013, to a citizen petition setting safety levels for trace amounts of lead in cosmetics.

Cough and Cold Products for Children.—The Committee is concerned that FDA has not issued a proposed rule revising the monograph regulating the labeling of over-the-counter cough and cold products for children. The Committee directs the agency to publish a proposed rule by December 31, 2013, based on scientific evidence for safety and efficacy in pediatric populations and taking into consideration the October 19, 2007, joint recommendations of its Pediatric Advisory Committee and Nonprescription Drugs Advisory Committee.

Medical Devices & radiological Health

Mammography Quality.—The Committee urges FDA to follow up the November 2011 meeting of the National Mammography Quality Assurance Advisory Committee by promptly reviewing the evidence supporting including information related to an individual’s breast density in the mammogram patient report and physician report.

Tobacco Products

Regulations.—The Committee appreciates FDA’s acknowledgement that exclusive tobacco products may raise different questions of public health and may need to be treated differently. Further, the Committee notes that there are key differentiating and unique characteristics of premium cigars and that any effort to bring these products under the ‘‘deeming’’ rule should proceed with these factors being taken into consideration.

Center for Tobacco Products Performance.—The Committee understands that GAO is conducting a study of FDA’s premarket review of tobacco products. The Committee directs that, upon publication of that study, FDA shall use it to identify a set of regulatory performance standards that will address pending and new substantial equivalent applications, pending and new modified risk applications, citizen petitions, and meeting requests. The Committee further directs FDA to report to the Committees on Appropriations by March 31, 2014, on the implementation of such performance standards.

By Michelle L. Butler –

On June 12th, the final rule to amend FDA’s 1992 orphan drug regulations was published in the Federal Register.  78 Fed. Reg. 35117 (June 12, 2013).  This final rule, which largely finalizes the revisions as proposed in October 2011, will be effective August 12, 2013.  We previously posted on the details of the proposed rule, as well as litigation that is still ongoing concerning some of the issues discussed by FDA in the proposed and final rules.   

The main changes from the proposed rule are as follows:

(1) Added a definition of “orphan subset” that is consistent with the explanation of orphan subset in the proposed rule (21 C.F.R. § 316.3(b)(13));

(2) Added clarifying language consistent with “FDA’s long-standing practice that a designated drug is eligible for orphan exclusive approval only if the same drug has not already been approved for the same use or indication” (21 C.F.R. §§ 316.3(b)(12), 316.31(a), and 316.34(a));

(3) Removed language regarding the demonstration of a “major contribution to patient care” that stated that the drug must provide “safety and effectiveness comparable to the approved drug” because the language incorrectly implied that FDA would require direct proof of comparability (e.g., through non-inferiority trials) (21 C.F.R. § 316.3(b)(3)(iii));

(4) Clarified that a designation request need only include “relevant” in vitro laboratory data and data from “clinical experience” with the drug (21 C.F.R. § 316.20(b)(2));

(5) Clarified that FDA will notify the sponsor in writing whenever FDA considers a designation request voluntarily withdrawn (21 C.F.R. § 316.24(a));

(6) Clarified that the reasons for denying a designation request identified in 21 C.F.R. § 316.25 are not exhaustive and that FDA can refuse to grant a designation request if the drug is otherwise ineligible for designation under Part 316;

(7) Stated that, if a drug loses designation after the effective date of this final rule (either because the sponsor voluntarily withdrew designation or because FDA revoked designation), FDA’s publicly available posting of designated drugs will include identification of the fact that the drug is no longer designated and the date it lost designation (21 C.F.R. § 316.28);

(8) Clarified that the scope of orphan drug exclusivity is limited to the indications or uses for which the designated drug is approved (21 C.F.R. § 316.31(a) and (b)); and

(9) Clarified that a designated drug that is otherwise the same as a previously approved drug will receive orphan drug exclusivity upon approval only if the sponsor demonstrates that its drug is clinically superior to the previously approved drug.

Below we discuss some of the preamble statements in the final rule that we think merit special attention.

Demonstration of an “Orphan Subset” of a Non-Rare Disease or Condition.  FDA stated that it carefully considered whether to retain “medically plausible” in the discussion of the “orphan subset” concept.  Because of confusion over the term medically plausible and the fact that FDA believes that misinterpretation of medically plausible “could permit a non-rare disease or condition to be artificially subdivided into smaller groups for establishing subsets that are under the prevalence limit for designation,” FDA decided to finalize the description of orphan subset as proposed.  78 Fed. Reg. at 35119.  FDA also reiterated that the description of orphan subset “is consistent with how FDA has long interpreted ‘medically plausible’ in the context of orphan subsets” and “is intended to make clear to sponsors that an orphan subset is a regulatory concept specific to the Orphan Drug regulations [and] does not simply mean any medically recognizable or clinically distinguishable subset of persons with a  particular disease or condition (as the term ‘medically plausible’ in this context may have been erroneously interpreted to imply).”  Id.

For clarity, FDA also decided to add the concept to the definitions section as follows: “Orphan subset of a non-rare disease or condition (‘orphan subset’) means that use of the drug in a subset of persons with a non-rare disease or condition may be appropriate but use of the drug outside of that subset (in the remaining persons with the non-rare disease or condition) would be inappropriate owing to some property(ies) of the drug, for example, drug toxicity, mechanism of action, or previous clinical experience with the drug.”  21 C.F.R. § 316.3(b)(13). 

The preamble identified the following items as examples of factors that may inform whether an appropriate orphan subset exists:

• Toxicity of the Drug:  The toxicity profile of the drug may render it appropriate for use in only a subset of persons with a non-rare disease or condition.  For example, patients with the disease or condition who can be treated with other, less toxic therapies may not be appropriate candidates for the drug; however, a subset of patients with the disease or condition who are refractory to, or intolerant of, other less toxic drugs may exist and may be the only appropriate candidates for treatment with the more toxic drug.
• Mechanism of Action of the Drug (e.g., antibody-specific or biomarker-based drug):  The mechanism of action of a drug may limit use of a drug to only a subset of patients with a non-rare disease or condition.  For example, use of a certain targeted therapy (e.g., antibody-specific or biomarker-based drug) may be appropriate in only a subset of patients with a non-rare disease or condition owing to its targeting mechanism (e.g., only in patients with the subtypes of tumors that possess the specific antigen targeted or only those patients with the specific biomarker targeted).
• Previous Clinical Experience With the Drug:  Information on the drug’s activity available from completed clinical trials or published in clinical literature may be used to establish an orphan subset.  For example, if relevant data show that the drug has no significant activity in the remaining subset of patients with high grade tumors or with a certain biomarker, respectively, then patients with low grade tumors or without that biomarker may constitute an orphan subset within a given disease or condition.

78 Fed. Reg. at 35120.

The preamble also reiterated certain examples of factors that were addressed in the proposed rule that FDA believes may not inform whether an orphan subset exists: clinical trial eligibility; the sponsor’s plan to study the drug for a select indication; a particular disease grade or stage; and price.  Id.

FDA also discussed what constitutes a distinct “disease or condition” for the purpose of orphan drug designation.  According to the preamble, since FDA considers the prevalence for each disease or condition when determining whether to grant orphan drug designation, “[a] drug that shows promise in multiple different rare diseases or conditions may be eligible for multiple designations.”  Id.  “Whether a given medical condition constitutes a distinct ‘disease or condition’ for the purpose of orphan-drug designation depends on a number of factors, assessed cumulatively, including:  Pathogenesis of the disease or condition; course of the disease or condition; prognosis of the disease or condition; and resistance to treatment.”  Id.  In explaining these concepts, FDA provided the following examples:

• One drug may be eligible for three separate designations – e.g., for the treatment of ovarian cancer, for the treatment of multiple myeloma, and for the treatment of Kaposi’s sarcoma – even if the cumulative prevalence of all three diseases or conditions would exceed 200,000.
• FDA currently considers pneumonia in cystic fibrosis to be a different “disease or condition” than community-acquired pneumonia “based on a cumulative assessment” of the factors described above.  Id.  Therefore, assuming the prevalence of pneumonia in cystic fibrosis patients is under 200,000, but the pool of all pneumonia cases exceeds 200,000, a sponsor seeking designation for a drug to treat pneumonia in cystic fibrosis patients would not need to establish an orphan subset from the larger pool of all pneumonia patients and would not need to provide a rationale for why only cystic fibrosis patients with pneumonia would be appropriate candidates for the drug.  
• FDA currently considers stage 1 breast cancer to be the same “disease or condition” as stage 4 breast cancer.  Since the prevalence of breast cancer currently exceeds 200,000, a sponsor seeking designation for a breast cancer drug would need to demonstrate why only a subset of patients with breast cancer (e.g., patients with stage 4 breast cancer) would be appropriate candidates for the drug.

Eligibility for Orphan Drug Designation of a Drug That Was Previously Approved for the Same Use or Indication.  FDA decided to finalize its proposal to amend 21 C.F.R. §§ 316.3(b) and 316.20(a) and (b)(5) to delete the word “orphan” in the phrase “approved orphan drug” and to revise 21 C.F.R. § 316.25(a)(3) to read “already approved drug for the same disease or condition” in place of “[a drug] that already has orphan-drug exclusive approval for the same disease or condition.”  The purpose of these changes was to clarify, consistent with FDA’s long-standing practice, that a designation request is required to include a plausible hypothesis of clinical superiority if the drug is the same as an already-approved drug, regardless of whether the already-approved drug was designated as an orphan drug or has orphan drug exclusivity.  78 Fed. Reg. at 35121-22.

In the preamble, FDA addressed comments that opposed this change, including comments that interpreted the Orphan Drug Act “to mandate orphan-drug designation of any drug for a rare disease or condition, even those that are the same as a previously approved drug, regardless of clinical superiority, as long as the designation request for the drug is submitted before submission of the marketing application.  At the same time, these comments acknowledge that, in order for the drug to receive and/or break orphan exclusivity under [the statute], clinical superiority would need to be demonstrated upon approval if the drug is otherwise the same as a previously approved drug for the same use or indication.”  Id. at 35121.  According to FDA, the comments argued that more liberal granting of orphan drug designation, even if orphan drug exclusivity is not even theoretically possible, would expand the universe of drugs for rare diseases or conditions eligible for other benefits that inure to orphan-designated drugs, such as Federal tax credits, prescription drug user fee waivers, exclusion from the branded pharmaceutical fee, and exclusion from the requirement to offer discounted prices to certain covered entities under the 340B program.  According to the preamble, certain of the comments identified plasma protein therapies, which are macromolecules, as deprived of these benefits because “‘various drugs within each therapeutic class of products are considered to have the same principal molecular structures and would not be considered different under the regulations without a showing of clinical superiority, despite the fact that each therapy is a unique, non-interchangeable biological product.’”  Id. at 35121-22.  In response, FDA stated that, while it “appreciates this perspective from industry about the impact that obtaining – or not obtaining—orphan-drug designation” may have under other statutes, “FDA continues to believe that the current framework is the best means for giving effect to the intent of the Orphan Drug Act, to provide incentives for sponsors to develop promising drugs for diseases and conditions that would not otherwise be developed and approved, including drugs that are potentially safer or more effective than already approved drugs.”  Id. at 35122.

FDA stated that it is, however, “considering the feasibility of issuing a draft guidance document on what may constitute a plausible hypothesis of clinical superiority for certain categories of products, for example plasma-derived products, which may help address some of the concerns articulated previously.”  Id. 

Eligibility for Multiple Orphan Drug Exclusive Approvals.  Because of some confusion articulated in comments to the proposed rule on the issue of multiple exclusive approvals and subsetting, FDA has decided to clarify 21 C.F.R. § 316.31 regarding the scope of exclusive approval by replacing “subset [of uses]” with “select indication(s) or use(s).”  FDA also provided clarification on the concept of multiple exclusive approvals with the following example: 

A drug may be designated for use in ovarian cancer but approved for use in only stage 4 ovarian cancer, based on the data and information in the marketing application.  As new data emerge, FDA may approve the drug for additional indications or uses within the rare disease or condition for which the drug is designated (e.g., stages 1, 2, and/or 3 of ovarian cancer).  The advantage to the sponsor in this hypothetical scenario is that, if the drug is later approved for additional indication(s) or use(s) within the rare disease or condition for which it is designated, the sponsor would not have to submit additional designation requests for the drug to cover these additional indication(s) or use(s) – because they would fall within the original designation.  Additional orphan-drug exclusivity may attach upon approval of these new (not previously approved) indications or uses that are within the scope of the original designation.

78 Fed. Reg. at 35123-24.  FDA then followed the example to its logical conclusion as follows:

Assume, for example, that a drug is designated for use in ovarian cancer (all stages) but is approved for use in only stages 1 and 2 of ovarian cancer (‘first drug’).  A subsequent sponsor may seek designation of the same drug (‘second drug’) for the remaining unapproved uses within ovarian cancer (i.e., stages 3 and/or 4) without having to provide a plausible hypothesis of clinical superiority over the first drug, although the prevalence determination would be based on ovarian cancer regardless of stage (unless an orphan subset were shown).  Designation of the second drug for the uses already approved for the first drug (i.e., stages 1 and 2 of ovarian cancer) would require a plausible hypothesis of clinical superiority over the first already approved drug.

Id. at 35124.

Demonstration of Clinical Superiority – Major Contribution to Patient Care.  FDA decided to delete language it had proposed regarding the “major contribution to patient care” (or “MC to PC”) basis for clinical superiority (i.e., requiring “a demonstration that the drug provides safety and effectiveness comparable to the approved drug”) because the comments indicated that there was confusion over the proposed language.  FDA stated that it had not intended to change the standard for MC to PC or suggest that direct proof of comparability to the approved product was necessary (e.g., through non-inferiority trials).  FDA stated that, rather, it had “intended to convey that [MC to PC] determinations can be complex and encompass consideration of a number of factors that potentially implicate safety and effectiveness, which are evaluated on a case-by-case basis for each drug product.”  Id. at 35124.

FDA also identified the factors it believes may be taken into consideration when determining whether a drug makes a MC to PC (most of which were previously described in the preamble to the 1992 final rule):  “The following factors, when applicable to severe or life-threatening diseases, may in appropriate cases be taken into consideration when determining whether a drug makes a major contribution to patient care:  convenient treatment location; duration of treatment; patient comfort; reduced treatment burden; advances in ease and comfort of drug administration; longer periods between doses; and potential for self-administration.”  Id. at 35125.  FDA declined to add “increased quality of life” or “improved patient compliance” to the list of factors as it believes they are already reflected in the other factors.  Id.  FDA also stated that, in its experience, “showings of [MC to PC] remain unusual” and “FDA still expects these showings to be less frequent than greater safety and greater effectiveness showings.”  Id.

By William T. Koustas –

The Federal Trade Commission (“FTC”) has just released a revised guidance on its Red Flags Rule (“the Rule”) based on the amended Rule issued late last year in an effort to comply with the Red Flag Program Clarification Act of 2010 (“Clarification Act”). 

As we have previously reported (see, e.g., here), the Fair and Accurate Credit Transactions Act of 2003 (“FACT Act”) directed the FTC to promulgate regulations requiring creditors to enact procedures to prevent identity theft.  In 2007, the FTC adopted regulations that required creditors to implement these procedures.  However, in April 2009, the FTC issued a document explaining that the Rule applied to a variety of professions, including attorneys and healthcare providers, because they bill their clients after services are rendered, thus, according to the FTC, extending credit. 

In light of this overly broad interpretation, many professional organizations, including the American Medical Association and the American Bar Association, lobbied Congress for changes to the FACT Act.  The American Bar Association even prevailed in a lawsuit against the FTC to enjoin enforcement of the Rule.  Congress eventually enacted the Clarification Act that amended the definition of the term “creditor” in the FACT Act to exempt attorneys and other professionals who bill their clients for services rendered and the FTC issued an interim final rule to the same effect in November 2012.

Now, the last piece of this puzzle falls into place.  On June 12, 2013, the FTC announced a revised guidance that incorporates the changes from the Clarification Act and the interim final rule.  This guidance now clearly states that professionals that bill clients at the end of the month or pay for fees or materials incidental to providing services (e.g., filing fees) are not subject to the Rule. 

However, this document does not appear to change the legal obligations of entities regulated under the Rule.  Such entities are still required to create and implement a program that includes reasonable policies and procedures to identify red flags of potential identify theft, detect those red flags, prevent and mitigate identity theft when detected, and update the program periodically to reflect new red flags that emerge.

According to the FTC, this nearly six year journey with the Red Flags Rule has (probably) come to an end.

By Riëtte van Laack –

On Friday, May 24, 2013, the California Assembly unanimously voted (72-0) for bill AB 227, amending Proposition 65 by including a new provision allowing certain small business owners 14 days to fix an alleged violation of Proposition 65’s warning requirements. 

AB 227 does not apply to warnings for all products and all situations in which a warning is required. It only deals with certain instances where there is private citizen enforcement of California’s Proposition 65.  Proposition 65 contains provisions requiring all business owners and manufacturers to give clear and reasonable warnings about products that contain listed chemicals that are known (to the state of California) to cause cancer or reproductive harm.  Right now, this list includes approximately 800 substances. Companies that fail to warn the consumer face fines up to $ 2500 per day per violation.  Threatened by enforcement action (Proposition 65 permits private citizens to pursue actions), many businesses settle rather than litigate. 

This proposed amendment is limited to certain circumstances where there is an  alleged failure to warn for:

• exposure to alcoholic beverages and/or chemicals formed on the alleged violator’s premises by necessary preparation of food or beverages that are sold for immediate consumption on the premises; 
• exposure to environmental tobacco smoke caused by entry of persons (other than employees) on such premises where smoking is permitted; and 
• exposure to chemicals known to the state to cause cancer or reproductive toxicity in engine exhaust, to the extent the exposure occurs inside a facility owned or operated by the alleged violator and primarily intended for parking noncommercial vehicles.

Businesses covered under Bill AB 227 that receive a notice for an alleged violation are allowed 14 days to correct the violation.  If the business corrects the alleged violation, meets certain other requirements, and pays a fine of $500, no retroactive fines would apply (see here). 

Passage in the Assembly clears the first hurdle, but the bill must still clear the California Senate by a two-thirds majority and be signed by the governor.  Opposition by consumer advocates and Prop 65 private plaintiffs is anticipated.

By Kurt R. Karst –       

In a surprising turn of events, the Department of Justice (“DOJ”) sent a letter to Judge Edward R. Korman of the U.S. District Court for the Eastern District of New York indicating that FDA and HHS have complied with his April 10, 2013 Judgment by granting a 2001 Citizen Petition (Docket No. FDA-2001-P-0123) and will make PLAN B One-Step (levonorgestrel) Tablets, 1.5 mg (“PBOS”) available Over-the-Counter (“OTC”) without age or point-of-sale restrictions upon the aproval of a supplemental New Drug Application (“SNDA”) submitted by the application sponsor, Teva Branded Pharmaceutical Products R&D, Inc. (“Teva”).  The letter also states that once Judge Korman confirms that the government’s course of action fully complies with his April 10th Judgment, the Obama Administration intends to file with the U.S. Court of Appeals for the Second Circuit notice that it is voluntarily withdrawing its appeal of the District Court’s April 5th Memorandum and Order and April 10th Judgment (see our previous post here).  

The government failed to win a stay pending appeal from Judge Korman in May (see here), who had previously ordered FDA to make, within 30 days, levonorgestrel-based emergency contraceptives (e.g., PLAN B and PBOS) available OTC and without point-of-sale or age restrictions.  Last week, the Second Circuit granted in part and denied in part the government’s Motion for a Stay Pending Appeal, ruling that “[i]nsofar as the district court order requires Appellants to immediately provide over-the-counter access to the one-pill variants of emergency contraceptives [(i.e., PBOS)], a stay, pending appeal, is granted.  Insofar as the order mandates immediate over-the-counter access to the two-pill variants of emergency contraceptives [(i.e., PLAN B)], a stay is denied because the Appellants have failed to meet the requisite standard.”

According to the DOJ letter and petition response, FDA has invited Teva to promptly submit a SNDA to the PBOS NDA with proposed labeling that would permit the drug product to be sold OTC and without age or point-of-sale restrictions, which FDA will approve “without delay.”  The SNDA could apparently rely on a supplement Teva submitted to FDA on February 7, 2011 seeking to remove the prescription-only status of the drug product for women younger than age 17 and to make PBOS OTC for all women of childbearing potential.  The letter and petition response also explain that “FDA will not at this time take steps to change the approval status of the two-pill Plan B or its generic equivalents”  According to FDA, this scheme is consistent with Judge Korman’s Judgment:

[T]this Court’s April 10, 2013, judgment expressly authorized FDA to comply by making PBOS and not Plan B available, if FDA believes that there is a significant difference between Plan B and PBOS.  Specifically, while the Court’s judgment directed the defendants to “make levonorgestrel-based emergency contraceptives available without a prescription and without point-of-sale or age restrictions within 30 days,” it also provided that “FDA may determine whether any new labeling is reasonably necessary” and that “if the FDA actually believes that there is any significant difference between the one- and two- pill products, it may limit its over-the-counter approval to the one-pill product.”  FDA continues to believe, for the reasons that the government has previously explained in its briefs to this Court, that there are significant differences between Plan B and PBOS under FDA’s regulations and the [FDC Act]. . . .  FDA therefore believes it is appropriate and consistent with this Court's order to comply by making only PBOS (and not the two-pill product) available OTC for younger adolescents.  [(Internal citation omitted)]

The government’s decision, if accepted by Judge Korman, would likely bring to a close a battle that has raged on for 12 years.  But might FDA’s decision also create a new controversy? 

As we previously discussed, FDA apparently granted a period of 3-year exclusivity with respect to the PBOS SNDA approved on April 30th making the drug available OTC to women of childbearing potential aged 15 years and over who are in need of emergency contraception.  The existence of such exclusivity could affect the approval status of generic versions of PBOS approved under ANDAs and seems to raise the thorny issue of simultaneous prescription and OTC marketing of the same drug.  An FDA decision to approve a new SNDA with another period of 3-year exclusivity to remove the prescription-only status of PBOS for women younger than age 17 and to make the drug product available OTC for all women of childbearing potential might compound the potential problem.  Both the DOJ letter and FDA petition response recognize this, but don’t get into a lot of detail:

After FDA receives and approves Teva’s supplement, we expect the sponsors of the generic versions of PBOS to submit appropriate amendments to their abbreviated new drug applications.  If FDA grants Teva marketing exclusivity, the scope of that exclusivity may affect the labeling that could be approved for generic equivalents of PBOS.

So it seems that FDA may have teed up yet a new issue for debate – this time in the Hatch-Waxman realm.  The issue could be quickly resolved with a waiver of exclusivity by Teva, but that may not happen.  In any case, the issue may take a little while to work its way through the system.

By William T. Koustas & Jessica A. Ritsick –

In light of California’s looming electronic pedigree requirement, still scheduled to become effective in 2015, we have been following Congress’s progress toward a national prescription drug track and trace system (see our previous post here).  The U.S. House and Senate have been considering track and trace legislation this session, and on June 3, 2013, the House came one step closer to making a national prescription drug pedigree system a reality by passing the Safeguarding America’s Pharmaceuticals Act of 2013 (H.R. 1919).  The House bill has several sponsors, led by Representatives Latta (R-OH) and Matheson (D-UT).  A detailed outline of the bill prepared by Hyman, Phelps & McNamara, P.C. can be found here.

The House bill would amend the Federal Food, Drug, and Cosmetic Act (“FDCA”) to incorporate national standards for a prescription drug track and trace system as well as national standards for prescription drug wholesale distributors (“wholesalers”) and third-party logistics providers (“3PLs”).  Both the track and trace system and national standards (e.g., storage, facility requirements, maintenance of records, etc.) for wholesalers and 3PLs set forth in this legislation would preempt state pedigree and certain other wholesaler and 3PL requirements. 

This legislation provides specific track and trace requirements for prescription drug manufacturers, wholesalers, repackagers, 3PLs, and dispensers (e.g., pharmacies).  Beginning on January 1, 2015, manufacturers would be required to pass the transaction history (i.e., “pedigree”) with any prescription drug product they distribute.  Within five years of enactment, manufacturers would also be required to include a product identifier number on each “homogeneous case” of prescription drug product they produce.  By April 1, 2015, wholesalers would be required to pass and receive a transaction history for any prescription drug products they receive or distribute and, within seven years of enactment, would be permitted to distribute only those drug products that bear a product identifier.  Similarly, repackagers would be required to pass a transaction history for any prescription drugs they distribute by April 1, 2015 (with respect to drugs received from wholesalers) or January 1, 2015 (with respect to drugs received from entities other than wholesalers).  Repackagers would also be required to include product identifiers on “each package and homogenous case” of prescription drug products they repackage within six years after enactment.  By July 1, 2015, dispensers would not be able to accept prescription drug products unless they are accompanied by a transaction history.  Interestingly, 3PLs are not required to receive or pass a transaction history themselves, presumably because they do not own the product and are not responsible for directing its distribution.

In addition to the transaction history requirements, the legislation requires manufacturers, wholesalers, repackagers, dispensers, and 3PLs to implement a system to verify that the prescription drug products under their control are legitimate (e.g., not counterfeit, diverted, stolen, or otherwise adulterated).  If a “suspect” prescription drug product is determined to be illegitimate, the entity must take the necessary steps to purge it from the supply chain. 

Perhaps one of the most significant omissions from the House bill is the lack of near term electronic pedigree requirement.  Transaction histories required by the legislation may be transmitted and maintained in either paper or electronic format.  The legislation eventually allows for the creation of a national electronic track and trace system, but it calls for a variety of studies to determine the feasibility of implementing such a system, and it prohibits FDA from introducing regulations until January 1, 2027 at the earliest.    

In addition to a prescription drug track and trace system, the House legislation also standardizes many of the requirements wholesalers and 3PLs must comply with under current state laws.  It also requires wholesalers to submit annual reports to FDA that include, among other things, a list of their wholesaler licenses and any disciplinary actions.  FDA would be required to post certain of that information on its website.  This legislation does not, however, create a national wholesaler license and specifically notes that states may continue to license wholesalers and collect licensing fees.  The legislation does create a national 3PL license in cases where a state does not license 3PLs.

The Senate is also considering a prescription drug track and trace bill, the Drug Supply Chain Security Act (S. 957).  This bill recently passed the Senate Committee on Health, Education, Labor, & Pensions, but it was combined with the Pharmaceutical Compounding Quality and Accountability Act (S. 959) before going to the floor.  The Senate bill is similar to the House legislation in many respects, but there are significant differences regarding the timing of the implementation of an electronic track and trace system and preemption of state wholesaler and 3PL requirements. 

Though the House bill requires FDA to begin exploring the implementation of an electronic track and trace system shortly after enactment, it prohibits FDA from issuing regulations before January 1, 2027.  By contrast, the Senate bill mandates that an interoperable electronic track and trace system become effective within ten years after the date of enactment.  The House legislation also preempts state requirements with respect to standards for wholesalers and 3PLs, while the Senate bill permits states to enact more stringent requirements.  As such, the House bill may be more agreeable to industry while agencies may be more amenable to the Senate bill.  Indeed, according to recent trade press, the California Board of Pharmacy has even expressed a preference for the Senate bill.   

It is unclear when the full Senate will pass its bill and how long a potential conference committee would take.  Nonetheless, the Chairman of the House Committee on Energy and Commerce has said he hopes to have a bill for the President to sign by the August recess. 

By Joseph W. Cormier –

FDA recently issued a draft guidance, titled “Contract Manufacturing Arrangements for Drugs: Quality Agreements” (“the Draft Guidance”), detailing its thoughts regarding appropriate quality agreements between product “owners”, which FDA defines as persons who introduce or cause the introduction of a drug into interstate commerce, and “contracted facilities”, which are non-owner entities performing manufacturing operations for the product owner. 

As FDA acknowledges in the Draft Guidance, there is no statutory or regulatory requirement that owners include a quality agreement between themselves and contracted facilities. 

Rather, the FDCA holds owners liable for introducing or causing the introduction into interstate commerce of adulterated or misbranded products.  Last year’s FDA Safety and Innovation Act further clarified that GMPs include a owner’s “implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.” 

As such, industry practice has been to include regulatory compliance and product quality assurance terms, if not in a separate agreement, into master services agreements or services agreements in order to identify the roles and responsibilities of the parties involved. 

Existing FDA guidance already detail how GMP quality management principles apply to contract manufacturing scenarios.  Examples include ICH Q7A, ICH Q9, and ICH Q10 documents.  The Draft Guidance, however, details FDA’s specific thoughts regarding translating these existing concepts into a legally-binding agreement between parties. 

FDA recommends that Quality Agreements should be separate or severable documents from other commercial agreements such as Master Services Agreements or Supply Agreements.  Further, FDA recommends that a Quality Agreement:

• Clearly document responsibility for GMP activities;  
• Include a section assigning responsibility for the Quality Unit and a communication plan between the parties and the Quality Unit;
• Ensure that the Quality Unit has sufficient resources to conduct required product testing and approval;
• Provide audit authority and responsibility that rests with the owner and indicate procedures for reviewing and approving documentation;
• Define responsibility for setting raw material specifications; auditing, qualifying, and monitoring suppliers; and conducting sampling and testing of raw materials;
• Detail procedures for notification and documentation of manufacturing process changes, including, among other things, raw materials, starting materials, establishment locations, testing procedures, manufacturing equipment, shipping methods, and key personnel; and
• Document the types of changes that require prior approval by the owner and those changes that require only notification. 

Although industry organizations, such as the International Pharmaceutical Excipients Council ("IPEC") and the Active Pharmaceutical Ingredients Committee (APIC) of the European Chemical Industry Council ("CEFIC") have previously issued their own guidance documents on this topic (here and here), we note that FDA’s Draft Guidance is somewhat different in how it presents these concepts.  Whether and to what extent the Draft Guidance changes or merely reinforces industry practice is yet to be seen.

Although FDA likely did not intend to include distributors under the umbrella of “owner” in the Draft Guidance, the breadth of the definition would include such entities.  If FDA intended to include distributors, it is unclear what the Draft Guidance, if finalized in its current form, says about FDCA product guarantees under section 303(c) of the Act.  These guarantees, provided by drug manufacturers to distributors, exempt distributors from the responsibility for distributing adulterated or misbranded products they have received in good faith.  Would a distributor need to execute a quality agreement that would require their auditing of the drug manufacturer’s records and facilities?  This result seems to go too far, and will hopefully be corrected when the Draft Guidance is finalized. 

Comments on the Draft Guidance are due to FDA by mid-July.  

Environmental seals and certifications have received renewed attention recently.  The Federal Trade Commission (“FTC”), last week, submitted comments to a private group that is in the process of revising its certification program for “sustainable” seafood.  The FTC did not take a stance on the program, but reminded the group of the agency’s view of applicable law.  Also last week, two private groups, Green Peace and ForestEthics, filed joint comments with the FTC urging it to investigate another group’s certification system for “green” lumber and paper products. 

The FTC issued guidance last year specifically on Certifications and Seals of Approval used in marketing.  The spate of comments demonstrates that industry is still grappling with how to implement certification systems that are both effective and compliant.  This is perhaps not surprising given that certifying groups normally face the daunting tasks of not only distilling complex scientific data into certification standards that are manageable and realistic for industry, but also developing a seal or certification that is understandable and attractive to consumers. 

As seals and certifications remain in the regulatory crosshairs, we believe that two points are vital for certifying organizations and companies seeking to use seals to remember: (1) the Federal Trade Commission Act (“FTC Act”) does not demand absolute perfection; and (2) government certification programs already in existence may serve as helpful models. 

Interpreting the FTC Act, the FTC has concluded that the language of a seal used in marketing must be truthful and non-misleading to a reasonable consumer.  Every technical detail and nuance, however, need not be disclosed.  The underlying certification program, likewise, must be based on science that is reliable and generally acceptable to experts in the field, but it need not be exact or beyond any debate.  Popular government certification programs that may serve as useful guides include the U.S. Department of Agriculture’s National Organic Program; the U.S. Department of Transportation’s 5-Star Safety Ratings for motor vehicles; and the Environmental Protection Agency’s Energy Star certification program for home appliances, new homes, commercial buildings, and manufacturing plants. 

What may be heartening to industry is that government certification programs appear to recognize that standards that are too rigid or advertising language that is too technical can be the enemy of good.  For example, under the National Organic Program, the “USDA Organic” seal may be used even though agricultural products bearing the seal may not be entirely “organically” produced under a strict definition of the term.  The enabling law grants USDA the authority to allow exceptions for uses of materials that would not normally be allowed in organic farming.  According to the law, the excepted use must be, among other factors, “consistent with organic farming and handling.”  The USDA has, in turn, granted exceptions to allow the use of certain synthetic insecticides and rodenticides, and other synthetic substances, in limited situations.  Produce from farming operations that take advantage of the exceptions can still bear the seal, “USDA Organic.”  

By Jeffrey N. Gibbs, Jamie K. Wolszon & Jessica A. Ritsick –

For many years, FDA has wrestled with how to regulate Laboratory-Developed Tests (“LDTs”).  FDA Commissioner Margaret A. Hamburg is now renewing FDA’s call for more active FDA regulation of LDTs and touting the Agency’s risk-based framework for regulating LDTs that is “under development.”  LDTs are diagnostic tests developed and performed by a laboratory.  They are widely used; among other tests, this category includes genetic tests, tests for rare conditions, and companion diagnostics.  Thousands of different LDTs are currently available.

Dr. Hamburg discussed LDTs as a part of broader remarks at the American Society of Clinical Oncology (“ASCO”) meeting on June 2, 2013.  She noted that LDTs do not undergo premarket review, and asserted “that can be a problem.”

Dr. Hamburg commented that FDA historically exercised enforcement discretion for LDTs “because they were relatively simple, low-risk tests performed on a few patients being evaluated by physicians at the same facility as the lab.”  Today’s LDTs, by contrast, according to Dr. Hamburg, are “more sophisticated and complex.  Results from these tests are rapidly becoming a staple of medical decision-making, particularly for cancer.  And some people with a family history of cancer are using these tests to decide whether to take preventive action.” 

Echoing prior statements by FDA officials, she asserted that “the Agency is working to make sure that the accuracy and clinical validity of high-risk tests are established before they come to market.  The risk-based framework we have under development will ensure that diagnostics used in cancer treatment will provide medical professionals with a critical baseline for confidence in the tests they order for their patients.” 

Dr. Hamburg did not provide details as to what the risk-based framework would entail or when it would be issued.

FDA announced in June 2010 that it was revisiting its years-long policy of exercising enforcement discretion over LDTs and was holding a public workshop to discuss the issue in July 2010.  FDA officials subsequently indicated that it was developing a plan to more actively regulate LDTs under a risk-based framework, to be issued for comment as guidance.  Members of the laboratory community have expressed deep concerns about the particulars of such a framework.  We previously reported on the agency’s plans to adopt a risk-based framework for LDTs here, here, and here. 

The Food and Drug Administration Safety and Innovation Act (“FDASIA”), enacted last summer, requires FDA to notify Congress at least 60 days prior to issuing a draft or final guidance on the regulation of LDTs.  The notice must include anticipated details of the action.

FDA has, in the past, made similar comments to the ones Dr. Hamburg made in her June 2013 remarks about LDTs.  Many of Dr. Hamburg’s statements mirror prior statements by Center for Devices and Radiological Health ("CDRH") officials.  For instance, the June 2010 Federal Register notice announcing the July 2010 meeting contained virtually identical language characterizing the agency’s perception that LDTs have moved from simple tests to high-complexity, high-risk tests.  The Federal Register notice states: “Initially, laboratories manufactured LDTs that were generally relatively simple, well-understood pathology tests or that diagnosed rare diseases and conditions that were intended to be used by physicians and pathologists within a single institution in which both were actively part of patient care.”  In contrast to LDTs in the past, the notice stated, today’s LDTs “are often used to assess high-risk but relatively common diseases and conditions and to inform critical treatment decisions and are often performed in geographically distant commercial laboratories instead of within the patient's health care setting under the supervision of a patient's pathologist and treating physician, or may be marketed directly to consumers.”

Whether Dr. Hamburg’s comments indicate that FDA is about to unveil a new proposal for regulating LDTs remains to be seen. 

Only two days after Dr. Hamburg’s comments, the American Clinical Laboratory Association (“ACLA”) submitted a Citizen Petition expressly requesting that FDA refrain from issuing draft or final guidance, or a proposed or final rule, regarding the Agency’s regulation of LDTs, and also asks FDA to respond to its Citizen Petition by explicitly confirming that LDTs are not devices under the Federal Food, Drug, and Cosmetic Act (“FDCA”).

ACLA’s Citizen Petition echoes and expands on the arguments made in HP&M’s 1992 Citizen Petition, advocating against FDA’s assertion of authority to regulate LDTs, as well as the Washington Legal Foundation’s ("WLF") 2006 Citizen Petition, also advocating against FDA regulation of LDTs.  FDA denied HPM’s Citizen Petition in 1998, stating that the “Commissioner of Food and Drugs may regulate assays developed by clinical reference laboratories strictly for in-house use as medical devices.”  FDA has yet to respond to WLF’s Petition.  In 2008, Genentech submitted its own Citizen Petition to FDA regarding the Agency’s authority to regulate LDTs, but unlike HPM, WLF, and ACLA, Genentech supports FDA’s assertion that it has authority to regulate LDTs.  Genentech requests that FDA “require all in vitro diagnostic tests intended for use in drug or biologic therapeutic decision making be held to the same scientific and regulatory standards,” regardless of whether the test is an LDT or a kit.  As with WLF, FDA has yet to respond to Genentech’s Petition.

ACLA’s Petition advances four main arguments:  (1) FDA lacks statutory authority and jurisdiction to regulate LDTs; (2) FDA’s regulation of LDTs would have an adverse impact on public health; (3) FDA’s regulation of LDTs would pose significant burdens on the laboratory industry; and (4) FDA’s regulation will complicate, rather than enhance, the existing regulatory framework, which Congress intended to be governed by one statute – the Clinical Laboratory Improvement Amendments of 1988 (“CLIA”).

In arguing against FDA’s authority and jurisdiction over LDTs, ACLA asserts that LDTs are services or know-how, not devices:  “LDTs are proprietary procedures for performing a diagnostic test using reagents and laboratory equipment.  They are essentially know-how, not articles” (emphasis added).  FDA rejected this argument in its 1998 denial of HPM’s Citizen Petition, and stated that “[a]ny in-house assay, test, or system which is a diagnostic test produced using an ASR [(Analyte Specific Reagent)] falls within the definition of device as delineated in the FDCA and its regulations.”  ACLA appears to have attempted to preemptively rebut FDA from making this argument again by citing the legislative history of the Medical Device Amendments.  ACLA asserts that “the legislative history clarifies that this amendment did not expand the device definition beyond its tie to tangible articles.”  Thus, ACLA argues, “[w]hen Congress added in vitro reagents to the device definition, [which FDA leans on for assertion of authority], the definition was still tied to an ‘article,’” and not a service, such as LDTs.

ACLA asserts two additional arguments against FDA’s assertion of jurisdiction over LDTs:  (1) Congress gave the Centers for Medicare and Medicaid Services, not FDA, authority to regulate LDTs under CLIA; and (2) LDTs are not commercially distributed, and commercial distribution is a prerequisite to FDA regulation.  As to number one, ACLA asserts that CLIA gave FDA “authority only over the laboratory equipment used in tests, not the tests themselves.”  As to number two, ACLA asserts that commercial distribution is a prerequisite to FDA enforcement jurisdiction.  See 21 U.S.C. §§ 360(k), 360c(f); 21 C.F.R. §§ 807.81(a), 814.1(c)(1).  In its 1998 denial of HPM’s Citizen Petition, FDA asserted jurisdiction to regulate LDTs under the Agency’s new (at that time) ASR rule.  FDA reasoned that because it had authority to regulate ASRs, and because LDTs contain ASRs, FDA could thus regulate LDTs “consistent with the [ASR] final rule.”  In denying the Petition, FDA, however, did not address HPM’s assertion (now echoed by ACLA) that commercial distribution is a prerequisite to FDA’s exercise of jurisdiction.  Rather, FDA asserted that if “ingredients of the ASR as well as the ASR itself” are transported in interstate commerce, there exists an “interstate commercial nexus,” supporting FDA’s regulatory jurisdiction.

ACLA also argues that FDA’s regulation of LDTs will impose unnecessary burdens on patients and industry alike.  Regulation of LDTs could increase costs on industry exponentially, according to ACLA, thus making development of LDTs cost prohibitive.  Further, if LDTs become too expensive and stop being developed, certain diseases and conditions for which the only testing available is an LDT may no longer have any testing available.  Or, if LDT manufacturers do not go out of business, FDA regulation may take these tests out of use until they are FDA approved or cleared, thus removing these tests from the market from some period of time, leaving a diagnostic gap.  Whether FDA would allow a grace period and, if so, for how long, is one of the many issues that FDA will need to address in any policy.  In responding to HP&M’s 1992 Citizen Petition addressing these issues, FDA cited its need to balance benefits and risks, and asserted that the risks of unpredictable test quality and results needed to be balanced against any benefits to patients from the use of such test.

So what does all of this mean?  FDA still wants to regulate LDTs, and the laboratory industry is still opposed.  How this will play out is uncertain.  One thing is for sure, however:  based on the recent statements by FDA and ACLA’s Petition, at least for the near future, the debate about how FDA should regulate LDTs—if at all—has flared up yet again.

By Kurt R. Karst –      

Earlier this week, Momenta Pharmaceuticals, Inc. and Sandoz Inc. (“Petitioners”) filed their reply to the brief filed late last month by Amphastar Pharmaceuticals, Inc. (“Amphastar”) opposing Petitioners’ petition the U.S. Supreme Court to review the August 3, 2012 judgment of the U.S. Court of Appeals for the Federal Circuit in Momenta Pharmaceuticals v. Amphastar Pharma., 686 F.3d 1348 (Fed. Cir. 2012).  In that case, a divided (2-1) Federal Circuit panel ruled that the scope of the Hatch-Waxman “safe harbor” provision at 35 U.S.C. § 271(e)(1) is broad and exempts from infringement any commercial activity where FDA requires that a record of that activity be maintained, even if no record is ever submitted to the Agency (see our previous post here).  Momenta contends that, unless the Supreme Court takes up the case, “[a]n intolerable state of confusion will persist . . . .”

As we previously reported, the case involves a generic version of LOVENOX (enoxaparin) and a method patent – U.S. Patent No. 7,575,866 (“the ‘866 patent”) – assigned to Momenta.  Momenta sued Amphastar in the U.S. District Court for the District of Massachusetts for patent infringement alleging that Amphastar infringed the ‘886 patent by manufacturing for commercial sale enoxaparin using the patented method.  Relying on the Federal Circuit’s decision in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), in which the Court held that 35 U.S.C. § 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained,” the District Court ruled that Amphastar’s activity fell outside of the “safe harbor” provision at 35 U.S.C. § 271(e)(1) and enjoined Amphastar from advertising, offering for sale, or selling its enoxaparin product.  (Classen was appealed to the Supreme Court, but the Court refused to hear the case after the U.S. Solicitor General filed an amicus brief urging the Court to deny certiorari.)

On appeal, the Federal Circuit disagreed with the District Court and vacated an injunction in the case.  The Federal Circuit explained in its August 2012 decision that it is not inconsistent with Classen “because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug,” and that in this case, “the submissions are not ‘routine submissions’ to the FDA, but instead are submissions that are required to maintain FDA approval. . . ,” thereby bringing them within the scope of the 271(e)(1) safe harbor.  In November 2012, the Federal Circuit denied a Petition for Rehearing en banc (see our previous post here), leading Momenta to petition the U.S. Supreme Court to review the case.  

Amphastar argued in its May 2013 opposition brief that Supreme Court review is neither necessary nor warranted.  Among other things, says Amphastar, Federal Circuit law is correct and consistent with precedent on the 271(e)(1) safe harbor, and the interlocutory posture and unique facts of the case make it a poor vehicle for Supreme Court review.  Not so fast, says Momenta:

The Federal Circuit’s legal ruling is both sweeping and wrong. . . . [T]he Federal Circuit has immunized post-approval, commercial activity this Court has never held protected by the Hatch-Waxman safe harbor. . . .  Taken to its logical conclusion, [the Federal Circuit’s decision] would immunize any commercial use of a patented invention for which a record must be kept documenting compliance with an already-approved manufacturing process. . . .  Nor would the majority’s interpretation necessarily be limited to immunizing manufacturing method patents.

Momenta goes on to explain how the Federal Circuit’s decision is unfaithful to the safe harbor statutory text and Supreme Court precedent in Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661 (1990) and Merck KGaA v. Integra Lifesciences, Ltd., 545 U.S. 193 (2005):

[T]he [FDC Act] expressly distinguishes between “submitting” information to the FDA and “maintaining” records for multiple purposes, including possible FDA inspection. . . .  Consistent with this statutory scheme, Section 271(e)(1) uses “submission,” not “maintain”—thereby exempting uses reasonably related to the development of information to obtain regulatory approval, while not immunizing post-approval infringing uses in the course of ordinary commercial activity.  Amphastar has no answer to this statutory distinction . . . .  If Congress had intended the remarkable departure from patent law created by the Federal Circuit’s immunization of post-approval, commercial use of patented inventions, the text of Section 271(e)(1) would have been much different.

The Supreme Court is expected to conference on the petition (Docket No. 12-1033) on June 20, 2013.

For years now, the American Conference Institute (“ACI”) has put on a series of excellent FDA-related conferences.  Those of us in the Hatch-Waxman world look forward to attending the popular annual Paragraph IV Disputes, Maximizing Pharmaceutical Patent Life Cycles, and Hatch-Waxman Boot Camp conferences.  They are a kind of “family reunion” – a “Cheers”-type atmosphere where everyone knows your name. 

The latest conference to be added to the ACI lineup is the Legal and Regulatory Summit on Generic Drugs, which will take place on Wednesday, July 17 to Thursday, July 18, 2013 in New York City.  Developed as a “state of the union” of the legal and regulatory – as well as political and global – changes affecting the generic pharmaceutical industry, the conference is sure to be the banner conference of the summer.

Hyman, Phelps & McNamara, P.C.’s Kurt R. Karst (author of the latest edition of Generic and Innovator Drugs: A Guide to FDA Approval Requirements) and Seyfarth Shaw LLP’s Shashank Upadhye (author of Generic Pharmaceutical Patent and FDA Law) are co-chairing the conference.  (And, yes, they’ll probably be hawking their books at the conference.)

Importantly, the Summit on Generic Drugs is not designed to be a rehash of issues and topics discussed at other Hatch-Waxman-related conferences.  Presenters will delve into generic drug politics, the Generic Drug User Fee Amendments (“GDUFA”), and much, much more.  Take, for example, the panel discussion on Insights From the Office of Generic Drugs.  The panelists – Gary Buehler, Gordon Johnston, and David Rosen – have more than 30 years of experience working at FDA in the Office of Generic Drugs.  Their perspectives on how the Office has changed over the years, how the Office operates, and future challenges with GDUFA and recent reorganizations are something folks cannot get in another venue. 

To obtain a copy of the conference brochure and to register for the event, please visit ACI's website.  FDA Law Blog is a conference media partner.  As such, we can offer FDA Law Blog readers a special $200 discount.  The discount code is: FLB200.  We look forward to seeing you at the conference.

By Kurt R. Karst –      

Fumble!!  For years now we have discussed and tracked various FDA decisions (or non-decisions as the case may be) on what have been referred to as “180-day exclusivity punts.”  These are instances in which a first applicant eligible for 180-day exclusivity gets ANDA approval, but FDA decides not to decide on whether or not to grant exclusivity.  The first instance of a “180-day exclusivity punt” occurred with the July 31, 2006 approval of ANDA No. 076969 for Sandoz Inc.’s Metoprolol Succinate Extended-Release Tablets USP, 25 mg (see our previous post here).  In the years since then, FDA has used the punt mechanism with impunity, and in various contexts (see our previous post here), including in one instance under the law in effect prior to the December 2003 enactment of the Medicare Modernization Act (“MMA”) (see our previous post here).  But FDA had never resolved a punt – whether in the form of a “punt return” where FDA affirms a first applicant’s eligibility for 180-day exclusivity, or in the form of a “fumble return” where FDA affirms a first applicant’s forfeiture of 180-day exclusivity eligibility.  That all changed with the May 30, 2013 approval of Banner Pharmacaps’s (“Banner’s”) ANDA No. ANDA No. 200899 for a generic version of GlaxoSmithKline’s AVODART (dutasteride) Capsules, 0.5 mg.

FDA’s decision on Dutasteride Capsules, 0.5 mg, 180-day exclusivity came about in the context of the most familiar type of punt: failure to obtain timely tentative ANDA approval.  Under FDC Act § 505(j)(5)(D)(i)(IV), one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the MMA, 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act (“FDAAA”) clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).  The 2012 FDA Safety and Innovation Act (“FDASIA”) made further changes with respect to the application of FDC Act § 505(j)(5)(D)(i)(IV) to certain ANDAs (see our previous post here).  Neither the FDAAA, nor the FDASIA provisions are at issue in the Dutasteride case. 

FDA’s application of FDC Act § 505(j)(5)(D)(i)(IV) has led to scores of forfeitures of 180-day exclusivity eligibility.  Several more forfeitures have been avoided as a result of FDA’s application of the exception provisions above (see our previous post here), including one decision that led to an unsuccessful lawsuit last year over a generic version of DIOVAN (valsartan) Tablets (see our previous post here).  Sometimes the 30-month date is missed by just a few days (see our previous post here), or even by a day because of a natural disaster (see our previous post here).  Sometimes 180-day exclusivity eligibility is forfeited upon patent certification because of an FDA interpretation that FDASIA remedies on a limited basis (see our previous post here).  In other instances, however, FDA is able to tease out a basis for determining that failure to obtain timely tentative approval was due to a change that led to, for example, an “irrecoverable delay” (akin to ripples in a pond when a stone is cast in) (see, e.g., ANDA No. 200156 for Armodafinil Tablets, 100 mg and 200 mg).
 
FDA has discussed its application of FDC Act § 505(j)(5)(D)(i)(IV) on several occasions, including in Citizen Petition responses – see, e.g., Docket No.  FDA-2011-P-0486 and Docket No. FDA-2010-P-0632 – and in court briefs.  For example, FDA has explained:

This provision [(i.e., FDC Act § 505(j)(5)(D)(i)(IV))] establishes a bright-line rule: If within 30 months of submission, an ANDA has been determined by the agency to meet the statutory standards for approval and it is only patent and/or exclusivity protection that prevents full approval, then an applicant will be given a tentative approval and will maintain its eligibility for 180-day exclusivity.  If tentative approval is not obtained within 30 months, eligibility for 180-day exclusivity is generally forfeited unless “the failure (to obtain an approval) is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” (emphasis added).  Under this provision it is not sufficient to show that FDA changed or reviewed the requirements for approval while the application was under review.  The applicant must also show that its failure to obtain a tentative approval at the 30 month date is caused by this change in or review of approval requirements – that is, the issues holding up approval at the 30 month date must be causally connected to the approval requirements that FDA reviewed or changed.

A less known fact is that FDA has considered and rejected as too draconian “but for” causation in its application of FDC Act § 505(j)(5)(D)(i)(IV).  Thus, FDA has determined that even if one of the causes of failure to get tentative approval by the 30-month forfeiture date was a change in or a review of the requirements for approval imposed after the application was submitted, a first applicant will not forfeit eligibility notwithstanding that there may have been other causes for failure to obtain tentative approval by the 30-month forfeiture date that were not caused by a change in or review of the requirements for approval.  That is, to avoid forfeiture, an applicant need only show that acceptability of one aspect of its ANDA (e.g., chemistry, labeling, or bioequivalence) was delayed due, at least in part, to a change in or review of the requirements for approval, irrespective of what other elements may also have been outstanding at the 30-month date.  In other words, “but-for” causation is not required in order to qualify for the exception under FDC Act § 505(j)(5)(D)(i)(IV).  FDA has apparently determined that this interpretation best effectuates the policy embodied in the exception, insofar as it does not penalize first applicants for reviews of or changes in approval requirements imposed after their ANDAs are submitted that cause the failure to obtain approvals or tentative approvals within 30 months, and continues to incentivize applicants to challenge patents by preserving (in many instances) the opportunity to obtain 180-day exclusivity.

In the case of Dutasteride Capsules, 0.5 mg, Barr Laboratories, Inc. (“Barr”) was the first company to submit an ANDA with a Paragraph IV certification challenging an Orange Book-listed patent for the reference listed drug, AVODART.  Specifically, ANDA No. 090095 was considered received by FDA as of October 29, 2007 with Paragraph IV certifications to the three listed patents on AVODART.  Patent infringement litigation was initiated, but was ultimately dismissed by agreement of the parties on May 10, 2010.  FDA approved ANDA No. 090095 on December 21, 2010 with the now all too familiar 180-day exclusivity punt language:

The agency notes that Barr failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed.  See section 505(j)(5)(D)(i)(IV) (forfeiture of exclusivity for failure to obtain tentative approval).  The agency is not, however, making a formal determination at this time of Barr’s eligibility for 180-day generic drug exclusivity.  It will do so only if another paragraph IV applicant becomes eligible for full approval (a) within 180 days after Barr begins commercial marketing of Dutasteride Capsules, 0.5 mg, or (b) at any time prior to the expiration of the last listed patent if Barr has not begun commercial marketing.

Barr never commercially marketed its drug product, presumably as a result of the settlement of patent infringement litigation, nor did Barr, to our knowledge, market an authorized generic version of the drug.  Thus, Barr’s 180-day exclusivity was never triggered.  Meanwhile, FDA’s review of Banner’s ANDA progressed, and a tentative approval was granted on March 25, 2013.  This likely placed FDA in the position of having to decide on 180-day exclusivity for Dutasteride Capsules, 0.5 mg.  A further review of Barr’s ANDA file presumably did not show that forfeiture of exclusivity eligibility could be avoided, and FDA approved ANDA No. 200899 on May 30, 2013.  Thus, we now have the first instance in which FDA has resolved a 180-day exclusivity punt.

By Jeffrey K. Shapiro –

The Medical Device Amendments  of 1976 (“MDA”), Pub. L. No. 94-295, 90 Stat. 539 (1976), are commonly described as the beginning of the modern era of device regulation.  In one sense, this description is absolutely correct.  The MDA established for the first time a comprehensive scheme for the premarket and postmarket regulation of devices.  But, there has been less recognition of how little of the MDA actually survived contact with reality.  Many of the most prominent features of the statutory scheme did not function as expected and many proved to be dead letters almost from the beginning.  At the same time, one of the features that came to be most central – the 510(k) procedure – was expected to play a minor and transitory role.  The system we know today really has to be seen as originating in the MDA but not emerging with its present day contours until the Safe Medical Devices Act of 1990 (“SMDA”), Pub. L. No. 101 629, 104 Stat. 4511 (1990).  However, our story for today is about the fate of the major provisions of the MDA as originally enacted.

The MDA decreed that FDA would review all types of medical devices existing in 1976 and by regulation place them in Class I, II or III.  See 90 Stat. 540-41.  Class I devices would be subject to various general postmarket controls (e.g., establishment registration, device listing, good manufacturing practice, or GMP).  Class II devices would be subject to FDA established performance standards and general postmarket controls.  See 90 Stat. 546 552.  Class III would need premarket application (“PMA”) approval or a completed product development protocol (“PDP”) and would adhere to general postmarket controls.  See 90 Stat. 553 59.

After the existing device types were classified, all new device types developed after 1976 were to be placed in Class III, unless FDA could be persuaded to reclassify them to Class I or II.  Flexible reclassification of device types would occur as new information emerged with experience.  See 90 Stat. 544 45, 547, 553, 572.  FDA was granted broad authority to issue regulations restricting the sale, distribution and use of specific device types as appropriate.  See 90 Stat. 567.  FDA also could ban unsafe devices and/or require mandatory recalls and repair, refund, and notification remedies when needed.  See 90 Stat. 560, 562-63.  In short, FDA was to have ample statutory authority to conduct flexible, risk based regulation of the three classes of devices from cradle to grave.

Almost nothing went according to the statutory plan.  The mere classification of existing device types into Class I, II or III, took 14 years to complete, far longer than envisioned.  FDA struggled to develop performance standards, which had been mandated as the centerpiece of regulatory control over Class II devices, issuing not a single performance standard prior to the SMDA, in which Congress mercifully downgraded performance standards to one of several optional “special controls” for Class II devices.  All of the device types placed in Class III were supposed to be subject to a prompt call for PMAs, but that process went so slowly that even today (i.e., 37 years later) it is not complete.  Thus, for many years, “preamendment” Class III devices have reached the market via 510(k) clearance rather than PMA review, and that is still true for about two dozen of them. 

Numerous other provisions failed to function as intended.  The PDP option, intended to be on par with PMA approval, was a complete flop, although the detailed PDP provisions remain on the books even today.  A procedural regulation for banning devices was issued, but the authority was invoked once in 1983 (banning prosthetic hair fibers), and never again.  See 21 C.F.R. Part 895 (1979).  The refund authority has never been used.  FDA has only issued two restricted device regulations – one for hearing aids and the other for analyte specific reagents.  See 21 C.F.R. § 801.421 (1990); 21 C.F.R. § 809.30 (1997).  The reclassification procedures proved burdensome and slow, and have been rarely used.  (A recent statutory reform attempts to make this process less burdensome.  Food and Drug Administration Safety and Innovation Act ("FDASIA"), Pub. L. No. 112-144, § 608(a) (2012) (modifying section 513(e) of the FDCA).)  There is also a rarely invoked and rather mischievous procedure allowing any person to seek FDA review and potential withdrawal of another person’s PMA approval.  See 90 Stat. 558 (section 513(g)).

At the same time, the section 510(k) provision in the MDA unexpectedly emerged as the dominant premarket pathway.  It provided that if a new device were “substantially equivalent” to a preamendment device, it could proceed to market with the same classification and controls (or, if the device type were not yet classified, it would proceed to market subject to whatever classification and controls were later applied).  The concern was that those already in the market in 1976 not gain a competitive advantage during the transition to the final regulatory scheme envisioned in the MDA.  By 1984, however, a noted commentator could write that 510(k) provisions had “in many ways eclipsed detailed statutory [PMA] provisions so painstakingly drafted” as the route to market for most medical devices.  J. Kahan, Premarket Approval Versus Premarket Notification:  Different Routes to the Same Market, 39 Food Drug Cosm. L.J. 510, 510 (1984). 

If there is a pattern to the failures of the original MDA, it was over confidence by Congress in the capabilities of centralized agency regulation.  Congress seems to have imagined that FDA would orchestrate the device industry from Washington D.C. with a degree of mastery and subtlety that proved impossible.  In particular, the idea that FDA would promulgate performance standards for hundreds of Class II devices proved impossible to carry out.  The establishment of a viable PMA process for many Class III devices was somewhat more successful, but it took decades to complete most of it, and some Class III devices still utilize the 510(k) pathway.  It also was impractical to have supposed, as Congress apparently did in 1976, that the resource intensive PMA process could be widely applied.  (Annually, about 2% of devices requiring premarket review reach the market via PMA approval.)  Fortunately, FDA developed the 510(k) program from an ill defined transitional measure to a robust pathway to market, and Congress had the good sense to ratify it in the SMDA.  If that had not happened, the inventive and vibrant device industry we have today might have been strangled in the crib.