Yesterday, Representatives Henry Waxman (D-CA) and Tom Allen (D-ME) and Senator Ted Kennedy (D-MA) announced plans to introduce the Non-Prescription Drug Modernization Act of 2007 (“NDMA”).  The bill comes in the wake of recent concern over the use of Over-the-Counter (“OTC”) cough/cold drugs in children under 6 years old and FDA’s ability to quickly take action to address those concerns by amending OTC drug monographs. 

In October 2007, FDA’s Nonprescription Drugs and Pediatric Advisory Committees recommended, during a joint committee meeting, a ban on the use of OTC cough/cold drugs in children under 6 years old.  The joint committee was scheduled and occurred after a citizen petition submitted to the Agency in March 2007 raised concerns about the safety and efficacy of OTC cough/cold products in this pediatric population.  Subsequently, FDA announced the Agency’s plans to hold a public workshop in December 2007 with the National Institutes of Health and the Consumer Healthcare Product Association (“CHPA”) to “gain an understanding of current use of OTC drug products by adolescents.”  In addition, Rep. Waxman, following the advisory committees’ mid-October recommendation, sent a letter to CHPA urging the organization to “take prompt action to ensure that the advisory committee’s recommendations are promptly carried out by your member companies.”  On November 1, 2007, Sen. Chris Dodd (D-CT) also sent a letter to FDA Commissioner Andrew von Eschenbach asking the Agency to “take swift and comprehensive action” on the advisory committees’ recommendation by immediately removing OTC cold/cold drugs indicated for children under 6 years old, or at least mandate that new product labels state “do not use” for children under that age.

The NDMA, a summary of which is available here, would amend the Federal Food, Drug, and Cosmetic Act (“FDC Act”) by adding section 568 (“Amending or Repealing Monographs”) to provide FDA with explicit expedited rulemaking authority to amend or repeal OTC drug monographs under two circumstances:

(1) When FDA finds (on its own initiative) that an OTC drug monograph must be amended or repealed because a drug under the monograph may pose a significant risk; or

(2) When FDA finds, after an advisory committee meeting, that a drug under the OTC monograph lacks evidence of effectiveness.

No specific appeal procedure is provided in the bill.

The NDMA would expand FDA’s authority to regulate OTC drug advertising.  Currently, the Federal Trade Commission regulates OTC drug advertisements, while FDA regulates prescription drug advertisements.  The bill would also amend the FDC Act to provide civil monetary penalties for violative Direct-to-Consumer (“DTC”) OTC drug advertisements.  The recently-enacted FDA Amendments Act added civil monetary penalties for violative DTC prescription drug advertisements.  Finally, the NDMA would require FDA to identify (by establishing a public docket) and report to Congress (not later than 2 years after the NDMA is enacted) on any OTC drug monographs requiring further review to determine whether they should be amended or repealed.

In September, we reported that FDA established a public docket (#2007N-0417) soliciting comment on certain 180-day exclusivity forfeiture and Orange Book patent “delisting” issues concerning the diabetes drug acarbose (marketed by Bayer Pharmaceuticals under the tradename PRECOSE).  Specifically, FDA’s September 26, 2007 letter states:

As of the date of this letter, which is more than 30 months from March 22, 2005, no first applicant’s ANDA has been approved. Also, on April 16, 2007, Bayer requested that the ‘769 patent be “delisted” as to Precose, i.e., they withdrew the patent information.  On September 26, 2007, FDA indicated in [the Orange Book] that the request to delist this patent had been submitted on April 16, 2007.

To determine whether any ANDA referencing Precose is eligible for final approval, the agency must consider how the 180-day generic drug exclusivity forfeiture provisions at section 505(j)(5)(D) of the [FDC Act] apply to this set of facts.  As part of the process for making such a determination, we are seeking your views regarding the applicability of sections 505(j)(5)(D)(i)(IV) — failure to obtain tentative approval within 30 months — and 505(j)(5)(D)(i)(I)(aa)(BB) — failure to market by 30 months. We also are interested in your views regarding the applicability of section 505(j)(5)(D)(i)(I)(bb)(CC) — relating to the delisting of a patent.

At that time, the identity of any first ANDA applicant eligible for 180-day exclusivity was not publicly known.  Since then, however, Cobalt Pharmaceuticals Inc. (“Cobalt”) has publicly disclosed its status as a first applicant. 

This became apparent when Cobalt submitted a 4-page emergency petition for stay of action in late October requesting that FDA stay the approval of all subsequent acarbose tablets ANDAs until Cobalt’s 180-day exclusivity period expires.  Cobalt argues that such a stay is necessary to prevent substantial and irreparable harm to the company.  “Here, Cobalt accepted the quid pro quo that Congress created with the exclusivity incentive and filed the first ANDA with a paragraph IV certification challenging the ‘769 patent.  As a reward, Congress intended that Cobalt reap the benefits of 180-day generic market exclusivity.  Sound public policy requires FDA to safeguard that exclusivity and to preclude others from circumventing it based on unlawful interpretations of the forfeiture provisions.” 

Upsher-Smith Laboratories (“USL”) and Teva Parenteral Medicines (“Teva”) submitted comments to docket #2007N-0417. (The deadline for submitting comments to the docket has been extended from October 10, 2007 until November 12, 2007.)  USL takes the position that because the ‘769 patent has been disclaimed, it should be removed from the Orange Book, and no first applicant should be awarded 180-day exclusivity — thereby making FDA’s solicitation unnecessary. 

Teva takes the position that the first applicant appears to have forfeited 180-day exclusivity eligibility because of a failure to obtain tentative ANDA approval within 30 months after the date on which the application was filed (i.e., FDC Act § 505(j)(5)(D)(i)(IV)).  Teva also comments on the “failure to market” and patent delisting forfeiture provisions at FDC Act §§ 505(j)(5)(D)(i)(I) and 505(j)(5)(D)(i)(I)(bb)(CC), respectively, on which FDA also requested comment. 

With respect to the “failure to market” provision, Teva states “we do not believe that, under the apparent facts of this case, the first applicant for generic Acarbose tablets has forfeited its exclusivity under [FDC Act § 505(j)(5)(D)(i)(I)].”  This position is consistent with Teva’s September 28, 2007 letter to FDA regarding 180-day exclusivity for generic granisetron (Docket #2007N-0389; 10/12/2007 FDA Law Blog post), in which the company takes the position that a first applicant’s failure to commence commercial marketing within 30 months of submitting its exclusivity-qualifying paragraph IV certification is not (on its own) sufficient to trigger 180-day exclusivity forfeiture.

With respect to the patent delisting forfeiture provision, Teva cites the District of Columbia Circuit’s 2006 decision in Ranbaxy Labs. Ltd. v Leavitt, and states:

[W]e do not believe that the reference to the withdrawal of patent information in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(CC)] abrogates the D.C. Circuit’s holding that FDA may not “delist a patent upon the request of the NDA holder [where] the effect of delisting is to deprive the applicant of a period of marketing exclusivity.”  Instead, the reference to delisting in [this forfeiture provision] merely reflects the fact that delisting may result from a court order entered pursuant to [FDC Act § 505(j)(5)(C)(ii)(I)], which for the first time authorized ANDA applicants who are sued by the NDA holder to “assert a counterclaim seeking an order requiring the holder to correct or delete the patent information submitted [to the Orange Book].”

We will continue to update you on this and other 180-day exclusivity issues for which FDA has recently requested public comment.

Title VI of the recently-enacted FDA Amendments Act (“FDAAA”) amended the FDC Act to establish a non-profit corporation whose purpose is to advance FDA’s Critical Path Initiative to “modernize medical, veterinary, food, food ingredient, and cosmetic product development, accelerate innovation, and enhance product safety.”  (The Critical Path Initiative is FDA’s effort to modernize the scientific process through which a potential drug, biologic, or medical device is transformed from discovery into a medical product.)  This corporation, known as the Reagan-Udall Foundation for FDA, is intended to allow FDA to collaborate with other researchers to foster newer methods of testing that are needed to assess newer technologies. 

On October 3, 2007, FDA issued a Federal Register notice seeking nominations for the Reagan-Udall Foundation.  The Foundation’s Board of Directors will initially include four ex-officio members — the FDA Commissioner, and the Directors of the National Institutes of Health, Centers for Disease Control and Prevention, and the Agency for Healthcare Research and Policy — who appoint the remaining 14 members from industry, academia, patient/consumer groups, and health care providers. 

On November 1, 2007, Representative Rosa DeLauro (D-CT) issued a press release with a copy of a letter sent to FDA Commissioner Andrew von Eschenbach requesting that FDA cease all activities related to the creation of the Reagan-Udall Foundation.  According to Rep. DeLauro’s letter:

Although the mission of the foundation is intended to support research that encourages an expedited FDA approval process, I believe the Reagan-Udall Foundation has the potential of endorsing the approval of drugs and devices based on lower standards for safety and efficacy, and without appropriately designed clinical trials.  For example, rather than having new drugs be tested to ensure their efficacy in reducing symptoms or curing diseases, the Foundation could play a significant role in recommending the use of biomarkers and other measures that may not be true measures of efficacy. . . .  The result could be patients spending billions of dollars on drugs that are not as effective as other products on the market.  Therefore, I am very concerned that undue influence by industry could harm the work of the FDA.

Rep. DeLauro’s letter to Dr. von Eschenbach was presumably related to a recent press report in which Francesca Grifo, Director of the Union of Concerned Scientists, stated with respect to the Reagan-Udall Foundation that “Given FDA’s track record in the past, I’m not confident in their ability to create something that is free of influence from industry.”

Peter Pitts, the co-founder of the Center for Medicine in the Public Interest (“CMPI”) and former FDA Associate Commissioner for External Relations (and who has referred to the Reagan-Udall Foundation as the “bi-partisan crown jewel” of the FDAAA), immediately authored an article published in the Journal of Life Sciences stating that “FDA should not be chastised, but applauded for working with industry to tackle the big problems of drug development.” 

CMPI runs the blog DrugWonks.com.  In his latest post on this issue, Mr. Pitts pillories Rep. DeLauro for her press release and letter.  Mr. Pitts’ colleague, Robert Goldberg, also recently posted on this issue stating that Rep. DeLauro and the media have been misled on what biomarkers do and can offer people in terms of safer drugs.

FDA has not (to our knowledge) indicated whether the Agency plans to cease activities to create the Reagan-Udall Foundation.  We will update you as we learn more information.

In our second installment of the “Lighter Side” (our first post is available here) we pass along to you an article from The Birmingham News, which reported on a comical case of a “shaming penalty” the CEO of a medical device company agreed to as part of a plea agreement for marketing an unapproved device.  As you will read, if civil penalties are not reason enough to avoid violating the Federal Food, Drug, and Cosmetic Act, then perhaps the possibility of an alternative sanction like that agreed to by James Lee is reason enough.

Earlier this year, after the success of the Department of Health and Human Services’ Pandemic Flu Leadership Blog (and no doubt also due to the success of FDA Law Blog), Secretary Michael Leavitt decided to test the waters of blogdom with his own blog, aptly named Secretary Mike Leavitt’s Blog.  The blog was launched on August 13, 2007 with this post, and a commitment by Secretary Leavitt to personally write the posts, rather than relying on staff.  Since then, Secretary Leavitt has posted about once a week.  His posts cover a broad range of topics (from personalized health care to import safety) that FDA Law Blog readers might find of interest.  You can sign up for Secretary Leavitt’s blog here.

The Department of Health and Human Services’ (“DHHS”) Office of Inspector General (“OIG”) recently announced its Fiscal Year 2008 Work Plan.  The OIG Work Plan, issued annually, sets forth various projects to be addressed during the coming fiscal year by the Office of Counsel to the Inspector General, the Office of Audit Services, the Office of Evaluation and Inspections, and the Office of Investigations.  The various factors OIG takes into account to identify the areas most worthy of attention in the fiscal year include:

• Requirements for OIG reviews, as set forth in laws, regulations, or other directives;
• Requests made or concerns raised by Congress and DHHS management;
• Significant management and performance challenges facing DHHS; 
• Work performed by DHHS and other organizations; and
• Actions to implement OIG recommendations from previous reviews.

The 2008 Work Plan includes 12 planned studies involving FDA policy – 9 of which are new, and 3 of which are a continuation from the Fiscal Year 2007 Work Plan.  The summary below is taken from OIG’s description of the planned and continued studies.  The 2007 Work Plan led to the publication of various reports, including the September 2007 OIG report on FDA’s clinical trial oversight.

New Studies

Implementation of Pandemic Influenza Preparedness Strategic Plan – OIG will review FDA’s implementation of its Pandemic Influenza Preparedness Strategic Plan.  The plan focuses on accelerating development, production, and regulatory reviews of vaccines, antivirals, and diagnostic devices for an effective national response.  OIG will determine whether FDA is meeting the timeframes it has established for deliverables in the plan.

Food and Drug Administration’s Implementation of Select Agent Regulations – OIG will review FDA’s implementation of select agent Federal regulations at its laboratories.  This effort continues our previous work at university, State, and private laboratories, which generated recommendations aimed at strengthening control of select agents. Pursuant to 42 CFR Part 73, OIG will assess compliance with select agent Federal regulations regarding security plans, accountability for select agents, and access to select agents.

Oversight of Off-Label Drug Promotion – OIG will assess FDA’s oversight and review of allowable off-label drug promotion and enforcement. Pursuant to provisions of the Food, Drug, and Cosmetic Act at 21 U.S.C. §§ 331 and 355, among others, FDA has the authority to regulate the labeling and promotion of drugs and to restrict off-label marketing.

Submission of Electronic Drug Labels – OIG will review FDA’s oversight of drug manufacturers’ compliance with the requirement to electronically submit to FDA complete and accurate drug labels for currently marketed prescription drugs.  In December 2003, FDA published final regulations (21 CFR §§ 314.50(l), 314.94(d), 601.14(b), and 314.81(b), respectively) requiring drug manufacturers to ectronically submit to FDA specific labeling content for new drug applications, abbreviated new drug applications, certain biologics license applications, and annual reports.  In November 2005, drug manufacturers were required to begin electronic submission of prescribing and product information for prescription drug labels in a structured product-labeling format.  The format is intended to give health care providers accurate, up-to-date drug information using standardized medical terminology in a readable, accessible format. OIG will examine the accuracy and completeness of electronic labels submitted to FDA and identify any factors that contribute to inaccurate or missing information.

Adverse Event Reporting for Medical Devices – OIG will review FDA’s adverse-event-reporting system for medical devices. Medical device manufacturers are required under 21 CFR Part 803 to report deaths, serious injuries, and device malfunctions to FDA within 30 calendar days or within 5 working days if the event requires remedial action to prevent substantial harm to the public.  Device reporting is a key part of FDA’s oversight of new medical devices, providing an early warning of problems with devices after they reach the market.  OIG will evaluate the extent to which FDA ensures compliance with adverse-event-reporting requirements and the way in which FDA uses medical device adverse event reports to identify and address safety concerns.

Oversight of Research Misconduct by Clinical Investigators – OIG will review FDA’s oversight and discipline of clinical investigators found to have engaged in research misconduct. Regulations at 21 CFR Part 312 provide FDA with authority to oversee and discipline clinical investigators for research misconduct. OIG will review FDA’s progress in implementing recommendations made by OIG during a 2000 review. OIG recommended at the time that FDA develop internal guidance on the thresholds that violations must meet to justify disqualifying a clinical investigator from receiving investigational products for use in clinical trials.

Financial Disclosure Requirements for Clinical Investigators – OIG will review the disclosure to FDA of financial interests of clinical investigators, as required by 21 CFR § 54, associated with drug, device, and biologic applications.  Financial conflicts of interest create a potential for bias that may negatively impact the integrity of the data as well as human subject protection.  OIG will determine the nature of financial interests disclosed by clinical investigators, the extent to which applicants monitor their clinical investigators for financial interests, and the extent to which FDA oversees the process.

Oversight of Food Safety Operations – OIG will review FDA’s oversight and operations related to three broad areas: imported foods, imported pet food and feed products, and recall procedures for human food and pet food. In the area of imported foods, OIG will determine the extent of FDA’s enforcement authorities; whether and how it determines that foreign countries’ food safety standards and inspections meet U.S. food safety requirements (or that their food products exported to the United States are in compliance with requirements), whether and how it determines that foreign measures are equivalent to U.S. food safety measures, and how frequently FDA evaluates companies that export food products to the United States. In area of the area of imported pet food and feed products, OIG will determine the extent of FDA’s enforcement authorities, including whether it requires imported pet food and feed to be produced under the same safety standards as those under which pet food and feed are produced in the United States. OIG will also determine whether FDA samples imported pet food and feed for chemicals and microbial pathogens. If FDA is not sampling food and feed products, OIG will determine why. In the area of human food and pet food recall procedures, OIG will determine the extent of FDA’s enforcement authorities, identify FDA procedures to implement those authorities, determine whether and how FDA is carrying out the activities called for in its procedures, and determine whether FDA conducted tests for melamine in human food immediately after melamine was found in pet food.  These various reviews are being conducted in response to a congressional request.

Food Facility Inspections – OIG will review FDA’s food facility inspection process and its methods for determining which facilities will be inspected. FDA monitors the safety of domestic food primarily through inspections of farms, warehouses, manufacturers, packers, and other types of food establishments. Section 702(a) of the Food, Drug, and Cosmetic Act authorizes FDA to conduct inspections to enforce the provisions of that statute and other applicable laws. Under this authority, FDA carries out surveillance inspections to gauge overall industry compliance with manufacturing practices and compliance inspections based on known or suspected problems with specific manufacturers. FDA’s district officers, with guidance from FDA headquarters, determine the number, type, and specific firms to be inspected. OIG will identify trends in the types of FDA facility inspections and their effectiveness in protecting the food supply.

Continued Studies

Generic Drug Approval Process – OIG will review FDA’s timeframes for reviewing original generic drug applications and identify factors that affect the timely review of these applications. FDA is required by 21 CFR § 314.100 to approve or disapprove applications for generic drugs within 180 days of submission. As of 2006, the agency had a backlog of approximately 1,000 generic drug applications, one-third of which had exceeded the 180-day statutory time limit. OIG will assess average application review times and identify factors contributing to the backlog.

Management of Information Technology Projects – OIG will review the adequacy of management and contracting practices of the Office of Information Technology (OIT) within FDA’s Center for Drug Evaluation and Research.  Requirements found in the Federal Acquisition Regulation (FAR), specifically parts 5-16 and 39, govern FDA’s contracting practices. OIG will review a sample of FDA information technology contracts, including those for the Adverse Event Reporting System II, and determine the adequacy and effectiveness of OIT’s acquisition management processes.  Our review will also focus on contractor selection and oversight.

Traceability in the United States Food Supply Chain – OIG will review FDA’s ability to trace food products back through the U.S. food supply chain.  The food traceability model, known as “one-up, one back,” is incorporated in regulations that FDA has issued to implement section 306 of the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (the Bioterrorism Act) and is intended to help FDA respond to a deliberate attack on the Nation’s food supply or other public health emergency involving food. The Bioterrorism Act and FDA’s regulation at 21 CFR Part 1, Subpart J, require persons that manufacture, process, pack, hold, transport, distribute, receive, or import food under FDA’s jurisdiction to maintain records that identify the immediate previous sources and immediate subsequent recipients of food that they receive or release. Compliance with this requirement will enable FDA to trace back through the supply chain any food FDA believes may pose a serious health threat and to trace forward through the food chain to alert facilities of potentially contaminated food. OIG will assess selected food facilities’ implementation of Federal requirements to maintain records that FDA may access if it has a reasonable belief that the food may present a threat of serious adverse health consequences or death to humans or animals.

Earlier this month, Senator Bernie Sanders (I-VT) announced the introduction of the “Medical Innovation Prize Act of 2007” (S. 2210).  If enacted, the bill would replace the current patent and non-patent market exclusivity system for drugs that has been in place since the enactment of the Hatch-Waxman Act in 1984 with a new “prize system” (for both drugs and biologics) that is intended to “provide incentives to encourage entities to invest in research and development of new medicines . . . and to enhance access to such medicines by allowing any person in compliance with [FDA] requirements to manufacture, distribute, or sell an approved medicine.”  According to the bill’s findings:

Exclusive rights to market products are one way to reward successful product research and development, but not the only way. Prize funds are another way and have been used successfully to stimulate inventions and solutions to difficult problems.

Awards to companies through a prize fund mechanism that reward successful product research and development can de-couple the reward for product research development from the price of the product. . . .

The substitution of prize fund awards to companies for successful product research and development in place of marketing exclusivity for new medicines will lead to more competition, greater utilization of generic products, lower prices, and savings to Federal, State and local governments, private employers and individual consumers of more than $200,000,000,000 per year.

Specifically, the bill provides that notwithstanding the U.S. patents laws (i.e., U.S.C. Title 35), the Hatch-Waxman Act, the Medicare Modernization Act, the Orphan Drug Act, the Best Pharmaceuticals For Children Act, and “any other provision of law providing any patent right or exclusive marketing period for any drug, biological product, or manufacturing process for a drug or biological product . . . , no person shall have the right to exclusively manufacture, distribute, sell, or use a drug, a biological product, or a manufacturing process for a drug or biological product in interstate commerce, including the exclusive right to rely on health registration data or the 30-month stay-of-effectiveness period for Orange Book patents. . . .”  Instead, a person could receive a “prize payment” “in lieu of any remuneration the person would have otherwise received for the exclusive marketing, distribution, sale, or use of a drug, biological product, or manufacturing process,” and “in addition to any other remuneration that such person receives by reason of the nonexclusive marketing, distribution, sale, or use of the drug, biological product, or manufacturing process.”  This provision would apply only with respect to “the marketing, distribution, sale, or use of a drug, a biological product, or a manufacturing process for a drug or biological product that occurs on or after October 1, 2007.”

The “prize payment” would come from a fund (the “Fund for Medical Innovation Prizes”) established in the U.S. Treasury Department.  Each fiscal year, an amount equal to 0.6% of the U.S. gross domestic product for the preceding fiscal year would be appropriated to the fund.  To be eligible to receive a prize payment a person must be either: (1) “the first person to receive market clearance with respect to the drug or biological product;” or (2) “the holder of the patent with respect to [ a manufacturing process].”  Prize payments would be made by the fund’s 13-member Board of Trustees based on several criteria specified in the bill.  Among other things, “[t]he Board may award prize payments for a drug, a biological product, or a manufacturing process for not more than 10 fiscal years, regardless of the term of any related patents,” and “[f]or any fiscal year, the Board may not award a prize payment for any single drug, biological product, or manufacturing process in an amount that exceeds 5 percent of the total amount appropriated to the Fund for that year.”

S. 2210 has been referred to the Senate Health, Education, Labor, and Pensions Committee where it will either be considered, or more likely languish and die.

Although S. 2210 is (to our knowledge) the first attempt to legislatively abolish patent and non-patent market exclusivities in lieu of a prize system, the idea is not new.  Earlier this year, Democratic Presidential Candidate John Edwards proposed such a system as part of his health care plan.  In addition, the World Health Organization mentioned prizes as a complementary mechanism to stimulate research and development in a July 2007 draft Global Strategy and Plan of Action.

ADDITIONAL READING:

• Knowledge Ecology International (“KEI”) comments on S. 2210
• KEI research paper – “The Big Idea: Prizes to Stimulate R&D for new Medicines”
• Huffington Post article on the Edwards prize proposal

On October 15, 2007, FDA issued two Federal Register notices announcing the availability of draft guidance documents related to serious adverse event reporting for OTC drugs and dietary supplements.  The first draft guidance is titled “Postmarketing Adverse Event Reporting for Nonprescription Human Drug Products Marketed without an Approved Application” and concerns the reporting of serious adverse events associated with certain Over-the-Counter (“OTC”) drugs.  The second draft guidance document is titled “Questions and Answers Regarding Adverse Event Reporting and Recordkeeping for Dietary Supplements as Required by the Dietary Supplement and Nonprescription Drug Consumer Protection Act.”  Both draft guidance documents stem from the December 22, 2006 enactment of the Dietary Supplement and Nonprescription Drug Consumer Protection Act.  The reporting requirements described in the guidance documents become effective on December 22, 2007.

OTC Drug Draft Guidance

Consistent with FDC Act § 760, the OTC drug draft guidance provides that the “manufacturer, packer, or distributor whose name . . . appears on the label of an OTC drug marketed in the United States without an approved application . . . must submit to FDA any report received of a serious adverse event associated with such drug when used in the United States,” with a copy of the product’s label “on or within the package.”  The statutory reporting requirement does not apply to OTC “switch” drugs, such as CLARITIN (loratadine), approved under a New Drug Application (“NDA”) (i.e., either a 505(b)(1) NDA or a 505(b)(2) application).  In addition, retailers whose names appear on OTC drug labels may authorize the drug manufacturer or packer to submit these reports on the retailer’s behalf. 

In accordance with the requirements of the FDC Act, the draft guidance provides that “[s]erious adverse event reports received through the address or telephone number described on the product label, as well as all follow-up reports of new medical information, must be submitted to FDA no later than 15 business days after a report of a serious adverse event or the new medical information is received” (emphasis added).  The guidance clarifies, however, that “[a]lthough the [FDC Act] does not expressly provide a timeframe for serious adverse event reports that [are received] by other means (such as by e-mail or fax), the reporting of such adverse events is required by the plain language of [FDC Act §] 760(b)(1).”  Accordingly, FDA “strongly recommends” that all such reports be submitted to the Agency within 15 business days of their receipt.      

The draft guidance duplicates the FDC Act’s definition of “serious adverse event” – that is, (1) death, (2) a life-threatening experience, (3) inpatient hospitalization, (4) a persistent or significant disability or incapacity, or (5) a congenital anomaly or birth defect – but clarifies that “[i]npatient hospitalization includes initial admission to the hospital on an inpatient basis, even if released the same day, and prolongation of an existing inpatient hospitalization.”  Furthermore, the draft guidance indicates that, at a minimum, each serious adverse event report requires: (1) an identifiable patient; (2) an identifiable reporter; (3) a suspect drug; and (4) a serious adverse event or fatal outcome.  The draft guidance clarifies these elements in detail.  In addition, the draft guidance advises that companies should “actively seek information on any minimum data element not initially provided . . . and wait to submit a report on the incident to FDA until the information is obtained.”   However, FDA guidance is not legally binding, and as a practical matter, compliance with this advice could prove difficult.  The FDC Act requires that companies maintain records related to reports of any adverse event, whether serious or not, for 6 years.

According to the FDC Act, new medical information related to a previously submitted serious adverse drug event report must be submitted to FDA if the information is received within 1 year of the initial report.  The draft guidance provides direction on how to correct inaccurate information and highlight new information in follow-up reports. 

Reports must be made on FDA Form 3500A and can be submitted either by regular mail or electronically.   

Dietary Supplement Draft Guidance

The reporting of serious adverse events for dietary supplements is very similar to the reporting requirements for OTC drugs.  Dietary supplement serious adverse event reports must also be made using FDA Form 3500A, and the reporting timeframe is generally the same as well.  Unlike OTC drugs, however, the draft guidance for dietary supplement reporting states that FDA will only accept reports via regular mail (i.e., dietary supplement reports cannot be submitted electronically or by facsimile).  There appears to be no rational reason for FDA’s refusal to accept electronic filings for OTC drugs but not dietary supplements, and companies submitting comments on the draft guidance might insist on equal treatment for both OTC drugs and dietary supplements.  Companies that submit reports or simply store reports electronically should keep in mind, however, that such electronic reports are subject to FDA’s regulations pertaining to electronic records, 21 C.F.R. Part 11.

Serious adverse events for dietary supplements are defined the same as for OTC drugs, and the manufacturer, packer, or distributor whose name “appears on the label of a dietary supplement marketed in the United States is required to submit to FDA” all such reports “associated with use of the dietary supplement in the United States.” 

The “minimum data elements” that should be included in a serious adverse event report for dietary supplements are:  (1) an identifiable injured person, (2) an identifiable initial reporter, (3) identity and contact information for the reporting firm (i.e., the manufacturer, packer, or distributor), (4) a suspect dietary supplement, and (5) a serious adverse event or fatal outcome.  Both this draft guidance and the OTC drug draft guidance provide that FDA “encourage[s companies] to attach the following, as appropriate,” as part of the serious adverse event report:  (1) hospital discharge summaries, (2) autopsy reports, (3) relevant laboratory data, and (4) other critical clinical data.  As with OTC drug serious adverse event reports, dietary supplement serious adverse event reports should not be submitted until all five elements listed above are obtained.  The FDC Act requires that all records relating to each report of an adverse event, which would include documented efforts that the companies make to obtain any missing information, be maintained for 6 years.  The draft guidance provides more detail on each of the five elements of a report.

The draft guidance provides that FDA Form 3500A must be used for the reporting of serious adverse events.  However, FDA Form 3500 can be used for the reporting of adverse events by consumers, health care providers, or any other entity that is not a dietary supplement manufacturer, packer, or distributor; a report of a non-serious adverse event by a company for one of its products; or to report a serious adverse event by a manufacturer, packer, or distributor for one of its products, where the company is not the “responsible person” (i.e., the company’s name does not appear on the label).

FDA will not confirm receipt of serious adverse event reports but “is working to implement processes that will provide a confirmation of receipt and [a] tracking number to the responsible person.”

By Cassandra A. Soltis

Earlier today, FDA issued a Federal Register notice explaining the new Direct-to-Consumer (“DTC”) user fee program established by the FDA Amendments Act of 2007 (“FDAAA”) and requesting companies to notify the Agency within 30 calendar days whether they intend to participate in the program during FY 2008 – and if so to identify the number of planned DTC television ads in that period.  The notice, as well as other information, is also available on FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) DTC user fee website.  FDA’s DTC advertisement user fee Performance Goals are available here (see Section B) and describe the Agency’s phased-in performance metrics through FY 2012.

The new DTC user fee program, codified at FDC Act § 736A (“Fees Relating to Advisory Review of Prescription-Drug Television Advertising”) is voluntary and authorizes FDA to assess and collect fees for the pre-dissemination review of DTC televisions ads.  Under the new program, FDA will review and provide comments regarding its view of a submitted DTC advertisement’s compliance with the FDC Act, provided that the established user fee has been paid and that the advertisement has not yet been disseminated.  Applicants need not avail themselves of this new system and can instead continue to submit DTC advertisements to FDA in their normal course of business.  Any advertisements for which FDA pre-dissemination review is required are not subject to the user fees authorized by FDC Act § 736A. 

Although FDAAA established an upper limit of $83,000 per submission for the FY 2008 fee, FDA explains in the notice that:

The fee will be based on the number of advertisements identified in response to this participation notice. The advisory review fees in FY 2008 will be set at a level to generate target revenues of $6.25 million in the first year of the program. Individual fees will be determined by dividing the target revenue, established in the statute, by the number of proposed television advertisements that all companies have indicated (in response to the participation notice) that they intend to submit during FY 2008.

The DTC user fees the Agency collects will be used to fund approximately 27 additional DDMAC staff for the Division’s pre-dissemination advisory review. 

Whether or not the new DTC user fee program will actually be implemented will depend on how many companies commit to the program.  FDAAA provides that the program will not commence if FDA fails to receive at least $11.25 million within 120 days after enactment of FDAAA (i.e., January 25, 2008).

The DTC user fee program is one of two DTC provisions included in FDAAA.  FDAAA also amended the FDC Act to create § 503B (“Prereview of Television Advertisements”), which gives FDA the authority to require pre-review of television advertisements.  FDA’s authority under this provision is generally limited to providing recommendations after reviewing an ad.  FDA may require a change if it addresses a serious risk with the drug, or if the Agency requires the inclusion of the approval date in the ad (which may occur for up to 2 years after approval).   

We previously reported on a May 2007 Proposed Decision Memorandum issued by the Centers for Medicare and Medicaid Services (“CMS”) that would restrict the use of Erythropoiesis Stimulating Agents (“ESAs”) in cancer-related anemia and similar conditions.  The proposed memorandum was finalized in a July 30, 2007 National Coverage Determination (“NCD”).  The final NCD provides coverage, with restrictions, for treatment of chemotherapy-induced anemia in certain cancer types, such as solid tumors, multiple myeloma, lymphoma, and lymphocytic leukemia. ESAs are FDA-approved to stimulate red blood cell production, thereby preventing the need for blood transfusions.  Had this been the end of the matter, this might have posed an interesting administrative law hypothetical.  Recent inquires and proposed legislation from Congress on the ESA coverage issue, however, have raised interest in the issue.

On October 2, 2007, Representatives Henry Waxman (D-CA) and Pete Stark (D-CA) sent a letter to FDA asking for the Agency’s view on the NCD.  FDA responded in an October 12, 2007 letter in which the Agency essentially agreed with the CMS decision.  Specifically FDA’s response notes a number of health risks associated with the use of ESAs, including promotion of tumor growth and increased mortality and cardiovascular events.  ESAs are FDA-approved for hemoglobin levels of up to 12 g/dL; however, the July 30, 2007 NCD restricts ESA coverage to when hemoglobin is less than 10 g/dL.  FDA reconciled this difference by noting that the 12 g/dL level in FDA-approved labeling is “an upper safety limit for ESA dosing, not a target for the therapy.”  FDA further explained that ESAs are intended and approved to prevent the use of transfusions in patients with cancer and related diseases.  This is consistent with the CMS decision, because transfusions are rarely given to patients with a hemoglobin level of greater than 10g/dL.  FDA also noted that there was no corresponding higher quality of life in patients whose hemoglobin levels were higher than that needed to avoid blood transfusions. 

This decision certainly has monetary implications for drug manufacturers, as preliminary estimates on the cost of pending legislation (i.e., House Joint Resolution 54) that would overturn the July 30, 2007 NCD are estimated to cost Medicare $2.1 billion over the next 5 years.  But it also raises interesting questions about labeling.  FDA had previously issued a Black Box warning for ESAs expressing the same concerns about efficacy and advising that “the lowest dose necessary to avoid the need for blood transfusions” be used.  FDA has not, however, changed the 12 g/dL limit in the labeling itself.  This could therefore be considered a liberal interpretation of the requirement that the labeling set forth the conditions for which ESA use would be “safe and effective.”

UPDATE:

The American Society of Clinical Oncology (“ASCO”) and the American Society of Hematology (“ASH”) announced updated ESA Treatment Guidelines.  Among other things, the updated Treatment Guidelines recommend “the use of ESAs as a treatment option for cancer patients who become anemic as a result of chemotherapy when their hemoglobin approaches or falls below 10 g/dL, as well as patients with low-risk myelodysplasia.”  Additional information on the updated ASCO/ASH guidelines is available here and here.

Many pharmacies send letters to consumers advising them about refill or alternative products.  Generally, these “refill reminders” are paid for by pharmaceutical manufacturers.  A recent decision, however, will require more specific disclosure about the funding of such letters in the future.  The Superior Court of Massachusetts in Suffolk County recently decided that pharmacies can use a third party to send prescription-related letters to customers, but if they profit from sending the letters, they must disclose that information to recipients. 

In Kelley v. CVS Pharmacy, the plaintiff, Jeffrey Kelley, used a CVS pharmacy to fill his diabetes drug prescriptions.  In 1997, Mr. Kelley received a letter on CVS stationery from the “Staff of CVS/Pharmacy” explaining to him the detrimental effects of high cholesterol and the benefits of cholesterol-lowering medication, and encouraging him to have his cholesterol checked.  At the very bottom of the letter in small print was the statement “[f]unding for this mailing was provided by Merck & Co. Inc.”  CVS used a third party, Elensys, to send the letters.  Mr. Kelley sued on the basis that the letter violated his right to privacy and that CVS, Elensys, and Merck engaged in an unfair and deceptive act by sending the letters. 

The court held that the letter did not violate Mr. Kelley’s right to privacy.  In Massachusetts, an invasion of privacy requires an “unreasonable, substantial, or serious interference” with privacy.  In this case, CVS did not disclose Mr. Kelley’s name to Merck, and only provided his name, date of birth, and address (all of which is public information) to Elensys.  Elensys did not know why Mr. Kelley had been selected to receive the letter and did not receive any information about his medical or pharmaceutical history.  The court reasoned that there is nothing improper about a pharmacy reviewing its prescription database and providing relevant information to its customers, and that the fact that CVS used a third party to do this was essentially the same as hiring extra clerks to send the information directly from the pharmacy.  The court also noted that Mr. Kelley “readily disclosed” his diabetes to friends and associates, which made it “even clearer that the information disclosed by CVS cannot reasonably be deemed a substantial or serious interference with his privacy.” 

The court, however, did find that CVS engaged in an unfair and deceptive act by concealing the fact that it profited from sending the letters.  Merck paid CVS $2 per letter sent, but CVS only paid Elensys 93 cents per letter, with CVS pocketing the difference as profit.  The disclosure at the bottom of the letter did not mention that CVS profited from sending the letters.  The court explained that in order to fully evaluate the medical information in the letter, a patient should know that CVS is making a profit from the letters.  Although CVS could send information to its customers and drug companies could reimburse CVS for the cost of mailing, once CVS began to make a profit from the letters and failed to reveal this to its customers, it became an unfair and deceptive act.  Merck, for whose benefit the letter was sent, was also found liable. 

We note that the decision is consistent with what we have been hearing for several years from the offices of Attorneys General (most notably that of Florida) concerning similar pharmacy mailing programs.   

Buried in Title V of the recently-enacted FDA Amendments Act ("FDAAA") is a provision requiring FDA, with certain limitations, to either publish final regulations to provide for the addition of a toll-free number to product labeling to report adverse events, or to make the Agency’s proposed regulations effective beginning on January 1, 2008.

When the Best Pharmaceuticals for Children Act ("BPCA") was enacted in January 2002, Congress required FDA to promulgate regulations to add to product labeling a toll-free number to report adverse events.  Specifically, BPCA § 17(a) states:

Not later than [January 4, 2003, FDA] shall promulgate a final rule requiring that the labeling of each drug for which an application is approved under [FDC Act § 505] (regardless of the date on which approved) include the toll-free number maintained by [FDA] for the purpose of receiving reports of adverse events regarding drugs and a statement that such number is to be used for reporting purposes only, not to receive medical advice. With respect to the final rule: 

(1) The rule shall provide for the implementation of such labeling requirement in a manner that the Secretary considers to be most likely to reach the broadest consumer audience. 

(2) In promulgating the rule, [FDA] shall seek to minimize the cost of the rule on the pharmacy profession. 

(3) The rule shall take effect not later than 60 days after the date on which the rule is promulgated.

On April 22, 2004, FDA published proposed regulations in the Federal Register.  In the preamble to FDA’s proposed regulations, the Agency explained that:

the MedWatch system should be used to fulfill the requirements of the BPCA for providing a toll-free number for the purpose of receiving adverse event reports regarding drug products.  FDA is proposing that the side effects statement be distributed with each prescription drug product, both new prescriptions and refills, approved under [FDC Act § 505] and dispensed to consumers by pharmacies and authorized dispensers in an outpatient setting. FDA is proposing a number of options/alternatives to meet this proposed requirement.  FDA also is proposing to require the side effects statement in two categories of drug product labeling: (1) FDA-approved Medication Guides for drugs approved under [FDC Act § 505], and (2) the labeling for OTC drug products approved under [FDC Act § 505].

Although FDA received relatively few comments on the proposed rule, the Agency has not yet published final regulations.  According to an October 11, 2007 Federal Register notice and Supporting Statement submitted by FDA, "[a]fter the publication of the proposed rule and based on the comments received, it was decided to delay the issuance of the final rule in order to conduct research to study the wording of the proposed side effects statements."

Apparently frustrated with FDA’s failure to make sufficient progress to issue final regulations, Congress included the following provisions in FDAAA § 502(f) (Title V reauthorizes the BPCA through Fiscal Year 2012):

(1) IN GENERAL- Notwithstanding [the Administrative Procedure Act] and any other provision of law, [FDA’s April 22, 2004 proposed rule] shall take effect on January 1, 2008, unless [FDA] issues the final rule before such date.

(2) LIMITATION- The proposed [or final] rule that takes effect under [BPCA § 17(a) (2002)] shall, notwithstanding [BPCA § 17(a) (2002)], not apply to a drug —

(A) for which an application is approved under [FDC Act § 505];

(B) that is not described under [FDC Act § 503(b)(1)]; and

(C) the packaging of which includes a toll-free number through which consumers can report complaints to the manufacturer or distributor of the drug.

FDAAA § 502(f)(2) therefore limits the application of FDA’s proposed regulations (if they go into effect in January 2008) or any final regulations issued before January 1, 2008 to exclude OTC drugs approved under a marketing application if certain labeling requirements are met.  The limitation to prescription drugs is presumably intended to clarify Congress’ original intent in BPCA § 17(a).  Indeed, at least one comment submitted in response to FDA’s April 2004 proposed rule noted that OTC drugs were not the intended target of BPCA § 17(a).

It is unclear at this time whether FDA will be able to meet the January 1, 2008 deadline when the Agency’s proposed regulations are scheduled to go into effect.  Given FDA’s recent activity as noted in the Federal Register, however, the Agency appears to be moving ahead with its plans to finalize the proposed rule. 

Last week we reported on an influx of food safety bills that have been and that are planned for introduction in both the U.S. House of Representatives and the U.S. Senate.  The already crowded field became a little more congested when Representative Rosa DeLauro (D-CT), chairwoman of the House Appropriations Committee, Subcommittee on Agriculture, Rural Development, Food and Drug Administration Appropriations, announced her plans during a speech at George Washington University on FDA’s future to introduce her own bill, the Food Safety Modernization Act (“FSMA”).  A copy of Rep. DeLauro’s speech is available here.

FSMA appears to be the most ambitious food safety bill planned for introduction, as it would remove FDA’s jurisdiction over foods and create a new federal agency dedicated to regulating foods.  The new agency, dubbed the Food Safety Administration, would fall under the Department of Health and Human Services.  FDA would be renamed the Federal Drug and Device Administration.  The Food Safety Administration would be headed by a newly appointed Commissioner of Food Safety and Nutrition Policy. 

Rep. DeLauro has long been critical of the current regulatory structure, which places food safety in the hands of 15 different federal agencies.  She hopes that her bill, if enacted, would streamline food regulation, place greater emphasis on food safety, and allow the government to more effectively respond to emerging threats.  Rep. DeLauro currently plans to introduce FSMA in 2008 after several details are worked out; however, given the fact that 2008 is an election year, it seems unlikely that Congress will have the time to carefully consider and pass broad food safety legislation anytime soon.     

The recently-enacted FDA Amendments Act addresses some food safety issues (both human and pet food).  In particular, Title X of the new law creates a Reportable Food Registry under FDC Act § 417 for foods “for which there is a reasonable probability that the use of, or exposure to, such article of food will cause serious adverse health consequences or death to humans or animals,” and it requires FDA to develop a more efficient and effective system for communicating information during a food recall.  In addition, § 912 of the new law (i.e., “Prohibition against food to which drugs or biological products have been added”) may also create new hurdles for the development of functional food ingredients.

For the third time in as many weeks, FDA has requested public comment to help resolve 180-day exclusivity issues.  This time FDA’s request concerns the antinauseant and antiemetic drug granisetron HCl, which is marketed by Roche under the tradename KYTRIL.  In late September, FDA solicited comment on acarbose (PRECOSE) (9/26/2007 FDA Law Blog post) generic exclusivity issues, and earlier this week the Orange Book Blog reported that FDA requested comment on ramipril (ALTACE) 180-day exclusivity issues.  These requests follow others from earlier this year on a variety of exclusivity issues concerning amlodipine besylate and midodrine HCl.

FDA’s latest solicitation is the result of a letter submitted by Teva Parenteral Medicines (“Teva”) and involves the “failure to market” 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I).  Under these provisions, a generic applicant whose ANDA contains a paragraph IV patent certification and who is a “first applicant” eligible for 180-day exclusivity forfeits eligibility for such exclusivity if the firm fails to market the drug by the later of:

(aa) the earlier of the date that is —

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant; or

(bb) . . . the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in subitem (AA), a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under [FDC Act § 505(b)].

These forfeiture provisions, which were added to the FDC Act by the Medicare Modernization Act (“MMA”) in December 2003, have been controversial.  Indeed, Senator Orrin Hatch (R-UT) expressed concern about how to interpret them within 24 hours of the MMA’s enactment.  Teva’s letter to FDA illustrates a current example of the complexity of the statutory forfeiture provisions. 

In May 2004, Teva submitted the first ANDA to FDA containing a paragraph IV certification for a generic version of KYTRIL.  The application also contained a paragraph III certification (date of patent expiration) and a section viii statement to a method-of-use patent.  Roche did not sue Teva (or any subsequent ANDA applicant) for patent infringement, and FDA tentatively approved Teva’s ANDA in August 2005.  To date, FDA has not approved Teva’s ANDA, and cannot do so until the patent subject to the paragraph III certification expires in December 2007.  Nevertheless, the 30-month period described in FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB) above expired in November 2006. 

Teva argues that despite the expiration of the 30-month period, the firm remains eligible for 180-day exclusivity, which would be triggered by Teva’s commercial marketing of the drug.  Specifically, Teva’s letter states:

[T]he plain language and structure of the [FDC Act] compel the conclusion that Teva is entitled to 180-day exclusivity because Teva is the first applicant that submitted a substantially complete paragraph IV ANDA . . . .  Teva’s exclusivity has not been forfeited . . . because there is a continuing possibility of ANDA-based patent litigation that could result in a “later” forfeiture event under [FDC Act § 505(j)(5)(D)(i)(I)]. . . .

[The FDC Act] requires FDA to determine which is “the later of” (1) a determinate forfeiture trigger . . . “or” (2) a contingent forfeiture trigger . . . .  But there is no conceivable way for FDA to determine which of those 2 potential triggers occurs “later” until (a) one of the contingencies that could give rise to a forfeiture trigger [under FDC Act § FDC Act § 505(j)(5)(D)(i)(I)(bb)] has occurred, or (b) none of the contingencies can occur.  After all, it is impossible to know whether a contingent event has occurred before it does occur — and twice as hard to determine that such an event will not occur until it no longer can occur.

FDA’s increasing trend to attempt to resolve post-MMA 180-day exclusivity issues on a case-by-case basis, instead of the Agency proactively addressing such issues more broadly in proposed and final regulations, may very well mean that the courts will end up setting the ground rules for interpreting the FDC Act’s exclusivity provisions, even more so than under the pre-MMA exclusivity provisions. 

Earlier today, Hyman, Phelps & McNamara, P.C. issued its detailed summary and analysis of the recently-enacted FDA Amendments Act (“FDAAA”).  A copy of the summary and analysis is available here. 

FDAAA reauthorizes several user fee and pediatric-related laws, and includes a host of new provisions, the longest reaching of which concern drug safety.  FDAAA also creates a new Direct-To-Consumer (“DTC”) television ad user fee system.  Last week, FDA’s Division of Drug Marketing, Advertising, and Communications established a website dedicated to DTC user fee issues.  In addition, FDA issued its PDUFA IV Performance Goals.  A copy of the transmittal letter to Congress is available here, and the Performance Goals document is available here.  Information on medical device user fees is available here.  FDA’s drug and device user fee rates for Fiscal Year 2008 will be published in the Federal Register tomorrow.  Pre-publication versions of those notices are available here (drug) and here (devices).