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).

The U.S. Department of Health and Human Services’ Office of Inspector General (“OIG”) recently issued a report critical of FDA’s clinical trial oversight along with recommendations to improve such oversight.  Congress requested the OIG report after a series of news articles published in 2005 highlighted various clinical trial vulnerabilities.  The objective of the report is two-fold: (1) to determine the extent to which FDA conducted inspections of clinical trials between Fiscal Years 2000 and 2005; and (2) to assess the Agency’s process for inspecting clinical trials.

OIG found that FDA had no method in place to identify all clinical trials or Institutional Review Boards (“IRBs”), which are responsible for approving and monitoring research involving human subjects within their institution.  This lack of information reportedly impeded FDA’s ability to both inspect clinical trials and to ensure that IRBs are providing appropriate oversight.  The report also notes that FDA only inspected an estimated 1% of clinical trials, and that these inspections were spread across a number of different divisions within the Agency.  Further, nearly 75% of the inspections that did take place occurred only after the trial concluded, and were designed to assess the quality of the data rather than the safety of the human subjects involved.

To remedy this problem OIG recommends that FDA take five steps to improve its clinical trial oversight:

1. Develop a database that includes information on all clinical trials;
2. Create an IRB registry;
3. Create a database to allow inspection tracking between FDA components;
4. Seek legal authority for clinical trial oversight; and
5. Establish an institutional procedure to provide feedback to local FDA inspectors on their reports and findings.

FDA concurred in all of the recommendations, except establishing a feedback mechanism (on which the Agency did not comment).

The recently-enacted FDA Amendments Act includes new provisions intended to improve the availability of clinical trial information, including expanding the current clinical trial registry database and creating a new results database. The clinical trial database recommended in the OIG report would be a separate database for internal FDA use only. 

On October 4, 2007, FDA issued a Federal Register notice announcing that the Agency will hold a public meeting to address the possible creation of a third category of drugs for the U.S. market – so-called Behind-the-Counter (“BTC”) drugs.  Such drugs would be available without a prescription, but only after intervention by a pharmacist.  Currently, the law only recognizes two categories of drugs – prescription and Over-the-Counter (“OTC”).  FDA states in the notice that the Agency would like to “explor[e] the public health benefit of certain drugs being available BTC that were previously prescription medications,” and that “BTC [drugs] could be comprised of certain medications available behind the counter at the pharmacy without a prescription and require the intervention of a pharmacist before dispensing.”  FDA seeks written comments on the BTC category by November 28, 2007.  The public meeting is scheduled for November 14, 2007.  Because seating is limited, people wishing to attend the meeting must register with FDA by November 5, 2007.

Several other countries, including Australia, Canada, France, New Zealand, United Kingdom, Denmark, Germany, Italy, Netherlands, Sweden, and Switzerland, already recognize BTC drug status.  These countries generally use the following criteria to determine whether a drug’s switch from prescription to BTC class is warranted:  “(1) [i]ndications suitable for self-medication, including self-diagnosis, with the intervention of a pharmacist and (2) the medicine has a low potential for side effects or overdose, and intervention by a pharmacist could minimize these risks.” 

FDA’s notice lists several issues that the Agency would like feedback on, including: (1) which drugs should be made available BTC and why; (2) whether BTC status should be used as a temporary or transitional status for drugs that move from prescription to OTC; (3) whether BTC availability will be cost-effective to patients; and (4) what impact BTC drugs will have on the practice of pharmacy.  Given the complex issues that a new BTC drug category raises, FDA will likely receive significant public input with widely varying points of view.  Indeed, there was considerable discussion and differing points of view expressed about BTC status in 2005 and 2006 when FDA considered various issues related to the prescription-to-OTC switch of the contraceptive drug PLAN B (levonorgestrel) Tablets.

Moreover, FDA has previously considered and declined to create BTC drug status.  Specifically, in 2003, Pharmacists Planning Service, Inc., a non-profit organization that promotes consumer public health education and pharmaceutical information, submitted a citizen petition to FDA (that was later amended) requesting that the Agency “switch Nicotrol Inhaler (Nicotine Inhalation System) from prescription only to [OTC] status TO BE SOLD ONLY UNDER A PHARMACIST’S SUPERVISION as a third class of drugs.”  FDA denied the petition in April 2004 in a 3-page response without substantively discussing BTC status.

By Cassandra A. Soltis

In response to recent scares over tainted food imports and E.coli outbreaks in produce, several members of the U.S. House of Representatives and Senate have introduced (and plan to introduce) a variety of bills aimed at improving food safety and security.  In late September alone, three new bills were introduced.  In addition, two food safety-related amendments to the 2007 “Farm Bill” (H.R. 2419) are expected in the Senate.  Specifically, Representative John Dingell (D-MI) introduced a food safety import bill in the House, and in the Senate, Senators Sherrod Brown (D-OH) and Robert Casey (D-PA) introduced a food safety bill and Senator Tom Harkin (D-IA) introduced a produce safety bill.  Senator Richard Durbin (D-IL) announced plans for an amendment to the 2007 Farm Bill that would force Congress to reauthorize all food safety agencies in 2010, and Senator Harkin announced plans to propose an amendment to the Farm Bill to create a Food Safety Commission.  In addition, the recently-enacted FDA Amendments Act includes various food-related provisions (in Titles IX [Section 912] and X of the new law).

As we previously reported, Rep. Dingell’s bill, the “Food and Drug Import Safety Act of 2007” (H.R. 3610), establishes user fees of up to $50 per line item of imported food and up to $1,000 per line item on imported drugs.  Not less than 90% of the fees would be used to fund inspections, and no more than 10% of the fees could be used for research.  The bill would also restrict food importation to specific points of entry, require food to be labeled with its country of origin, create a voluntary program for import companies to abide by specific food safety guidelines, enhance civil monetary penalties, prevent the U.S. Department of Health and Human Services (“DHHS”) from terminating or consolidating any FDA field laboratories or FDA district offices, increase food and drug inspections, and create labeling requirements for food containing carbon monoxide.  Rep. Dingell’s bill has already raised concerns over mounting user fees, and two House members, Rep. Gene Green (D-TX) and Rep. Janice Schakowsky (D-IL), question limiting imports to ports with an FDA lab, which could result in ports without an FDA lab losing a significant amount of business, including Houston and Chicago, and logjams at others. 

Sen. Harkin’s bill, the “Fresh Produce Safety Act of 2007” (S. 2077), is much more narrow in scope and is specifically directed at improving the safety of fruits and vegetables.  The bill would require the inspection of facilities that process produce, and would require DHHS to establish standards for agricultural production, including standards for manure application management, exclusion of domestic animals during harvesting and growing season, water standards, and ground water monitoring.  The bill would also create a public education program related to food safety for fresh produce and require DHHS, in consultation with the U.S. Department of Agriculture (“USDA”), to promulgate regulations for equivalency with foreign nations that export produce to the U.S.

Sens. Brown and Casey’s bill, the “Food and Product Responsibility Act of 2007” (S. 2081), is a lengthy bill that covers nearly all types of food and many consumer goods.  The bill would give greater authority to FDA and USDA to recall the products they regulate, and would require manufacturers to demonstrate the means to cover the cost of potential recalls before they can place their products into the stream of commerce.  Products covered in the bill include food, drugs, devices and cosmetics, biological products, consumer products, and meat, meat products, poultry, and poultry products, eggs and egg products.

The 2007 Farm Bill, which the House passed earlier this year and the Senate Agriculture Committee is currently considering, has also become vehicle for food safety legislation.  Sen. Durbin, in an effort to force Congress to reform the current food safety system and place all food safety responsibilities in a single federal agency, announced on September 28th that he would propose an amendment to sunset all food safety agencies by 2010.  Sen. Harkin, who chairs the Senate Agriculture Committee, has voiced support for the proposed Durbin amendment, and has also announced plans for his own amendment to the Farm Bill.  The Harkin amendment would create a domestic food safety panel to work with President Bush’s import panel to recommend ways to improve food safety.  Sen. Harkin’s panel would be modeled after the 2002 Food Safety Commission, which never received the appropriations it needed to begin work. 

At this point, with no fewer than 20 FDA-related bills circulating in Congress, the greatest barrier to passing meaningful legislation may be weeding through the sea of bills to decide which to pass and which to scrap. 

By Susan J. Matthees

On September 28, 2007, the U.S. Department of Justice announced that Bristol-Myers Squibb (“BMS”) agreed to pay more than $515 Million Dollars to settle off-label promotion, anti-kickback, Average Wholesale Price (“AWP”), and Best Price (“BP”) allegations, and related False Claims Act claims.  The enforcement action comes just three months after BMS earned praise from a federal monitor as a company “that today is governed by the highest standards of integrity, ethics and accountability, and one that reflects its commitment to those principles in both words and deeds,” and correspondingly, having a U.S. Attorney dismiss a two year old a criminal complaint and terminate a deferred prosecution agreement (“DPA”).  Despite the seeming inconsistency between glowing praise followed by new allegations and a large settlement, the settlement documents suggest that while this is not “old news,” the “covered conduct” stopped relatively shortly after the company entered into the DPA in June 2005.  Specifically, according to the government’s allegations, the covered conduct ceased in December 2001 (anti-kickback), December 2000 (AWP), December 2003 (anti-kickback again), December 2005 (off-label promotion), and 1997 (BP).

The $515M includes a $328M federal share, $25M of which comes as disgorgement of profits under the FDC Act.  The states will share in $187M.  False Claims Act relators in seven actions will share $50M.

As is usual in these types of resolutions, BMS also entered into a Corporate Integrity Agreement with the Office of the Inspector General for the U.S. Department of Health and Human Services.

ADDITIONAL INFORMATION:

• BMS Press Release
• Boston Globe Article

By James P. Ellison

Earlier today, FDA announced a new initiative, called the Generic Initiative for Value and Efficiency (“GIVE”), which is intended to increase the number and variety of generic drug products.  According to Gary Buehler, R.Ph., Director of FDA’s Office of Generic Drugs (“OGD”):

GIVE is an initiative aimed at optimizing OGD’s generic drug review process to increase efficiency. The goals of GIVE are to approve higher numbers of applications for generic products and expedite review of applications for which there are few generics available.

Over the last three to four years, the number of [ANDAs] submitted to [OGD] has increased. This has led to a growing list of pending applications. We’ve made a number of successful process improvements during this time. In fact, the office approved a record number of applications during the past two years. We approved 510 products in 2006, and approved more than 650 in the fiscal year that just ended.

But the advancement of medical science and the related increasing cost of health care and disease prevention have caused the role of OGD and its review staff to grow. The number of firms producing generic products and the number of products each firm proposes are growing at an unforeseen pace. The improvements we have made serve to unify and enhance the review process to address the growing workload, and to increase the efficiency of our office’s review efforts.

As part of GIVE, FDA will revise the review order for certain ANDAs. “For example, first generic products, for which there are no blocking patents or exclusivity protections on the reference listed drug, are identified at the time of submission for expedited review. This will mean that these products, for which there are currently no generic products on the market, may reach the consumer much faster.”  Although there are about 215 full-time FDA staff working on ANDA reviews, under GIVE, FDA will also “hire and train new generic drug reviewers and focus on enhanced use of electronic programs for handling drug submissions and internal documents,” and, when possible, engage the efforts of other FDA components.  A diagram of how OGD will make more drugs available under GIVE is available here.

OGD’s GIVE program is the latest of several initiatives intended to accelerate the generic drug development and approval processes.  Last year, OGD announced changes to its “First-In, First-Reviewed” policy to provide for exceptions under certain circumstances (see Orange Book Blog post).  In May 2007, FDA issued its “Critical Path Opportunities for Generic Drugs,” which identifies what FDA believes are challenges in the generic drug development process and outlines some actions intended to address those challenges (see FDA Law Blog post).  Also in May, FDA announced the availability of a draft guidance document and database providing recommendations on how to design product-specific bioequivalence studies to support ANDAs (see FDA Law Blog post).

It is unclear the extent to which OGD’s GIVE initiative might or might not affect the Agency’s push for generic drug user fees.  Earlier this year, FDA proposed creating generic drug user fees as part of the Agency’s Fiscal Year 2008 budget.  The recently-enacted FDA Amendments Act does not include such a user fee program.