By Susan J. Matthees –

Last week, FDA announced a new grant program available to help support the development of new animal drugs to treat minor species or minor disease in major species (horses, dogs, cats, chickens, turkeys, cattle and pig).  The Minor Use and Minor Species Animal Health Act of 2004 amended the FDC Act to establish a grant program “to assist in defraying the costs of qualified safety and effectiveness testing expenses and manufacturing expenses incurred in connection with the development of designated new animal drugs.”  FDA finalized the implementing regulations in July 2007 and in March 2009, Congress appropriated $750,000 for MUMS grants for the fiscal year ending September 30, 2009.
    
FDA announced that grants will be available for up to $50,000 per year for up to 2 years for routine studies and up to $100,000 per year for up to 2 years for studies of unusual complexity, duration or size.  Interested parties can get a Request for Applications at Research Project Grant (R01) and must submit the application to Grants.gov (http://www.grants.gov/) by July 1, 2009. 

By Wes Siegner & Ricardo Carvajal –

The FTC has closed its investigation of Pharmavite’s advertising campaign for CholestOff dietary supplements, which contain free form phytosterols and are promoted to lower cholesterol.  According to the April 2009 letter, Pharmavite used “advertising and labeling claims that CholestOff is clinically proven to lower to lower cholesterol and, more specifically, that CholestOff lowers LDL cholesterol up to 24% or 42 points.”  FTC questioned whether there is adequate substantiation for these claims because most studies testing the effect of phytosterols on cholesterol involve either conventional foods, or dietary supplements that contain phytosterols in their esterified form (CholestOff contains phytosterols in their free form).  FTC also noted that the more specific cholesterol-lowering claims made by Pharmavite “singled out the most dramatic reductions” in the underlying studies.  FDA recently challenged similar claims made for General Mill’s Cheerios based on the allegation that the claims are illegal drug claims.

FDA regulations authorize health claims that “describe the relationship between diets that include plant sterol or stanol esters and reduced risk of heart disease,” but only in the labeling of certain types of conventional food and dietary supplements, and only those that contain esterified phytosterols (21 C.F.R. § 101.83).  In 2003, FDA issued a letter stating that the agency would consider exercising enforcement with respect to these requirements, thereby opening the door to the use of the claims in the labeling of other types of conventional food and dietary supplements, including those that contain phytosterols in their free forms. 

Citing FDA's letter of enforcement discretion and Pharmavite’s agreement to remove the claims to which the FTC had objected, FTC decided not to take action against Pharmavite’s more general claims even though in the FTC’s view there are concerns about whether even these claims are substantiated.

By Ricardo Carvajal –

The Obama administration’s Food Safety Working Group has launched a website through which it intends to keep the public informed of its activities (to date, the only activity listed on the website is a listening session and breakout discussion among stakeholders that took place on May 13). Curiously, a photo on the website shows a refrigerator in which raw ground beef (albeit wrapped and resting in a deep-edged plate) is stored above uncovered fresh produce.  Query: if you did this in a commercial context, would it constitute a violation of good manufacturing practice requirements (21 C.F.R. Part 110)?

By Jamie K. Wolszon & Jeffrey N. Wasserstein –

The Vermont legislature recently passed S. 48, a bill that would prohibit manufacturers of prescription drug, device, and biologics products from providing certain kinds of gifts or payments to physicians and other health care providers, and would require disclosure to the state of most other kinds of gifts or payments, regardless of amount.  We were told by the Vermont Governor's office that the bill is expected to be signed into law in the next week or so.  Vermont’s previous gift disclosure law required disclosure of gifts or payments of $25.00 or more to physicians and other health care providers in Vermont in connection with detailing or other promotional activities. This latest effort to limit pharmaceutical marketing further adds to the confusing patchwork quilt of state regulation, resulting in additional difficulty in complying with potentially 50 different sets of marketing requirements. While Justice Brandeis famously applauded states acting as laboratories and engaging in social and economic experiments, query whether he would view this level of experimentation to be the work of mad scientists. New State Ice Co. v. Liebmann, 285 U.S. 262, 52 S.Ct. 371, 76 L.Ed. 747 (1932) (Brandeis, J. dissenting).

The recently enacted law is far more sweeping than comparable gift disclosure laws in other states, particularly as it prohibits almost all gifts and requires disclosure regardless of amount. In comparison, the Minnesota law only prohibits the provision of certain gifts with an aggregate value of $50 per practitioner. The Minnesota law requires disclosure of certain types of gifts only if the value exceeds $100 in aggregate per practitioner per year.  Maine and Washington D.C. only require disclosure of gifts or payments of more than $25. West Virginia only requires disclosure of payments of more than $100 per year for a single health care practitioner (here and here). The Massachusetts law requires disclosure of the payment or gift of more than $50 made to a healthcare professional. We previously reported on the Massachusetts law (here and here).

The new Vermont law also is more encompassing than proposed federal legislation, the Physician Payments Sunshine Act, introduced by Senators Charles Grassley (R-IA) and Herb Kohl (D-WI). The proposed federal legislation only requires disclosure for transfers of value or payments of $100 or more per year per covered recipient. We previously reported on the proposed federal legislation.

Provision of Item of Value Prohibited Unless Allowable Expenditure or Specified Exempted Gift: The law bans any manufacturer of prescription drugs, devices or biologics, any wholesale distributor of medical devices, or their agents from giving gifts except for several categories of specified gifts. The law defines a manufacturer to include “any other person who is engaged in the production, preparation, propagation, compounding, processing, packaging, repacking, distributing, or labeling of prescribed products,” although it excludes a wholesale distributor of biological products or a licensed pharmacist.

The law’s definition of gift includes “anything of value provided to a health care provider for free” and “any payment, food, entertainment, travel, subscription, advance, service, or anything else of value provided to the heath care provider” that are not “allowable expenditures” or reimbursed by the health care professional at fair market value.

Items of value that do not fall within the definition of a gift because they are an allowable expenditure include:

• Payment to the sponsor of a significant educational, medical, scientific, or policy-making conference or seminar for bona fide educational purposes that do not discuss specific products, are objective and do not have industry control;
• Honoraria and payment of the expenses of a health care professional who serves on the faculty of a bona fide significant educational, medical scientific, or policy-making conference or seminar that meet certain criteria;
• Specified compensation, salary support and expenses related to a bona fide clinical trial or specified research projects;
• Reasonable expenses necessary for technical training of a health care professional on the use of a medical device if a written agreement between the health care provider and the manufacturer documents the amounts or categories of expenses;
• Certain royalties and licensing fees; and
• “Other reasonable fees, payments, subsidies, or other economic benefits provided by a manufacturer of prescribed products at fair market value.”

Items of value that are gifts under the law but are exempt from the prohibition include:

• Samples to be distributed for free to patients;
• Rebates and discounts provided in the normal course of business;
• Devices loaned for a period of less than 90 days to allow a health care provider or patient to evaluate the device;
• Reasonable quantities of demonstration or evaluation units of a device;
• Provision, distribution, dissemination or receipt of peer-reviewed academic, scientific, or clinical articles or journals and “other items that serve a genuine educational function provided to a health care provider for the benefit of patients”;
• Provision of FDA-approved labels; and
• Scholarship or other support for medical students, residents, and fellows to attend a significant educational, scientific or policy-making conference of a medical or professional association if the association selects the recipient.

Disclosure: Even if a device, drug or biologics maker can provide an item of value to a physician, the manufacturer must disclose information about the value, nature and recipient for those permitted items regardless of how little the manufacturer spent. The disclosure requirement applies to both allowable expenditures and to exempted gifts, however, the manufacturer does not have to provide information for royalties or licensing agreements, and rebates and discounts provided in the normal course of business.

The manufacturer also does not have to provide the information about the value, nature and recipient for samples. However, the law directs the attorney general’s office, in consultation with the commission on health care reform, to review whether to require disclosure of samples in the future. To that end, the law requires the attorney general’s office to provide a report to the relevant House and Senate committees no later than December 15, 2009.

The new Vermont law includes a provision that would delay the reporting requirement for permitted payments related to clinical trials: Manufacturers do not have to report until the earlier of: the date of the product approval or clearance or two years after the payment.  The proposed federal legislation also contains this reporting delay. Under the Vermont law, the manufacturer would have to identify the clinical trial, the start date of the trial, and the web link to the clinical trial registration on the national clinical trials registry.

The manufacturer must report specified information about the value, nature and recipient for those permitted items on October 1 each year for the fiscal year ending the previous June 30. On July 1 of each year, the manufacturer must provide the name of the person in charge of ensuring compliance with the law.

Civil Monetary Penalties: The Vermont attorney general may impose civil monetary penalties of up to $10,000 per unlawful gift or $10,000 per failure to report.

Effective Date: The law generally takes effect July 1, 2009, with a phase-in of the disclosure requirements. Pharmaceutical manufacturers must file by November 1, 2009, disclosures for the time period of July 1, 2008 to June 30, 2009 based on the previous version of the Vermont gift disclosure law. Device and biologics manufacturers must file by October 1, 2010 their disclosures, under the provisions of the new law, for the time period of January 1-June 30, 2010.

Open Questions: The law leaves open several questions. For instance, it is unclear whether the law would permit the dissemination of promotional materials (other than FDA-approved labels), or Risk Evaluation and Mitigation Strategies (REMS)-type educational materials as “other items that serve a genuine educational function provided to a health care provider for the benefit of patients"? Or is this “other items” language limited to educational materials such as textbooks or anatomical models?

Moreover, how does one determine the value of items that are not easily assessed such as loaner devices, articles and FDA-approved labels?

By Kurt R. Karst –      

The recent addition of numerous patents to the Orange Book covering various GlaxoSmithKline (“GSK”) drug products, such as VENTOLIN (albuterol sulfate), FLOVENT (fluticasone propionate), ADVAIR (fluticasone propionate; salmeterol xinafoate), and SEREVENT (salmeterol xinafoate), begs the question why?  Many of the new patent listings concern patents issued years ago and are therefore late-listed patents.  (Generic applicants with pending applications need not certify to late-listed patents; however, subsequent applicants must certify to them.)  Nevertheless, the FDC Act and FDA’s regulations require each NDA sponsor to submit to FDA for Orange Book listing  “the patent number and the expiration date of any patent which claims the drug for which the applicant submitted the [NDA] or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug.”  The answer as to why GSK decided to submit the patents to FDA for Orange Book listing might be related to a January 2005 advisory opinion request the company submitted to FDA – and that the Agency has not yet responded to – raising important questions about Orange Book patent listing. 

We previously reported on the GSK request, as well as two similar requests submitted by AstraZeneca in 2006 and 2007.  GSK’s request asks FDA the following question:

If a patent claims a drug delivery device or elements of a drug delivery device approved as part of a New Drug Applicatin (“NDA”), but the patent does not specifically claim the active ingredient or mention the active ingredient or ingredients contained in the approved drug product, or if a patent claims the protective overwrapping of a drug delivery device, should information concerning that patent be submitted to the FDA for listing in the Orange Book? [(italics in original)]

The advisory opinion request was apparently prompted by FDA’s response to comments stated in the preamble to the Agency’s June 2003 regulations implementing the FDC Act’s patent listing provisions.  Those comments sought clarification as to whether patents claiming delivery devices or containers “integral” to a drug product should be submitted to FDA for Orange Book listing.  FDA did not directly address the issue, but rather stated that the key factor in determining whether a drug product patent must be submitted for Orange Book listing is “whether the patent being submitted claims the finished dosage form of the approved drug product.” 

Many of the patents now listed in the Orange Book for the above-referenced GSK drug products appear to cover drug delivery devices and components of such devices.  For example, one patent claims:

An inhalation device for use with a medicament pack having a plurality of containers for containing medicament in powder form wherein the containers are spaced along the length of and defined between two peelable sheets secured to each other . . . .

GSK’s decision to submit such patents to FDA for Orange Book listing could be a creative way of pushing the Agency to more promptly address the three outstanding advisory opinion requests.  It is also possible that FDA will address the issue of the Orange Book listing of drug delivery device and device component patents in upcoming regulations implementing the Medicare Modernization Act (“MMA”).  We understand that such regulations are in the works and will (eventually) be issued in two sets – one set addressing the 180-day exclusivity forfeiture provisions added to the FDC Act by the MMA, and the other addressing other amendments made to the FDC Act by the MMA. 

By Dara Katcher Levy & Roger C. Thies –

For the past several years, industry has relied on Warning and Untitled Letters to determine DDMAC’s  “current” thinking on the presentation of risk information in various promotional pieces. 

On May 26, 2009, FDA issued a draft Guidance for Industry: Presenting Risk Information in Prescription Drug and Medical Device Promotion.  The Draft Guidance largely sums up the “minimization of risk” issues cited in those DDMAC Warning and Untitled Letters with few surprises.  Of note, the Agency states that it will apply the “reasonable consumer standard” to prescription drug and medical device promotion as it does for dietary supplements and food.  While noting that presentation of risk information should be crafted to reflect the audience, FDA also reiterates that the same standards on presentation of risk information apply to both healthcare professional and direct-to-consumer promotion.  Although the content may differ, FDA defines its principles as “universal concepts of communication and understanding of risk information.”  To support its positions about appropriate content and format of risk information, FDA cites to articles that FDA states reflect “well-developed social science principles supported by decades of scientific research.” 

The Draft Guidance gives little credit to physicians – their training and ethical obligations and responsibilities – in analyzing physician understanding of information presented in product promotion.  The Draft Guidance notes that physicians are influenced by product advertising and are “subject to the same cognitive biases and processing limitations as non-experts.”  Later in the Draft Guidance, FDA states that one of the serious effects of missing certain risk information in a direct-to-consumer advertisement is that “it may cause consumers to fail to inform their healthcare professionals of important considerations, and healthcare professionals to prescribe inappropriately or even dangerously.”  Clearly, FDA does not contemplate physicians making informed, medically appropriate decisions when prescribing product that may also be the subject of promotion.

The Draft Guidance does not answer the “big” questions with regard to the most rapidly evolving area of product promotion – the Internet.  Although FDA includes “internet web sites” as “promotional material” that is covered by the Draft Guidance, FDA has not addressed the unique challenges posed by product information included on the Internet (font size and screen shot variations by computer, individual webpages on a larger website, hyperlinks to content not controlled by the product’s manufacturer, etc.,). 

Although much of the Draft Guidance is known to those who follow DDMAC letters, it is “must” reading.  It brings to one document DDMAC’s approach to labeling and advertising review.  The 20 examples of flawed approaches to presenting risk information, while simplistic, aptly demonstrate DDMAC’s concerns and should help industry with its promotional copy review activities.

By William T. Koustas & Carrie S. Martin –

On May 7, 2009, FDA announced that it is requiring both approved testosterone gel products to include boxed warnings on their labels and to implement a REMS.  The two products are indicated for testosterone replacement therapy in men that either have a deficiency or absence of endogenous testosterone.  The products may be applied to the patient’s skin, including upper arms, shoulders, or abdomen.  The current product labels instruct users to wash their hands after using the products as well as covering the treated areas.  

According to the FDA’s announcement, as of December 1, 2008, FDA was aware of eight cases of children developing serious side effects after inadvertent exposure to these products and has since received additional reports of secondary exposure.  The children exposed range in age from nine months to five years.  Children in these cases experienced “inappropriate enlargement of the genitalia, premature development of pubic hair, advanced bone age, increased libido and aggressive behavior.”  In most cases, the symptoms subsided when the children were no longer exposed to the products, but some children did not completely recover and required invasive diagnostic procedures. One child was hospitalized after a delay in recognizing that exposure to testosterone gel was the likely cause of the symptoms.

In response, FDA has used its powers under sections 505(o)(4) and 505-1 of the Food, Drug, and Cosmetic Act (“FDC Act”) to mandate several labeling changes, including a boxed warning, and a REMS in the form of a medication guide.  FDA letters to the manufacturers of the testosterone gels note that they consider adverse event reports and peer-reviewed biomedical literature of children inadvertently affected by the drugs to be “new safety information” under the Food and Drug Administration Amendments Act (“FDAAA”), thus providing the basis necessary for the Agency to require these changes.  The focus of the labeling changes is a boxed warning that highlights the risks of virilization in children and women exposed to the products, warns that children and women should avoid contact with the areas on men using the products and a warning that patients should adhere to the instructions for use that come with the products.  FDA is also requiring testosterone gel manufacturers to submit a proposed REMS consisting of a medication guide in an attempt to mitigate risk of secondary exposure to women and children.

It is interesting to note, however, that the medication guide is intended to mitigate a risk that is not a risk to the patient using testosterone gels, but a risk to other persons not intended to use the product.  Under section 505-1 of the FDC Act, FDA can require a REMS post-approval if the Agency becomes aware of new safety information and determines that the REMS is necessary to ensure that the benefits of the drug outweigh its risks.  Although this language does not explicitly prohibit a REMS that is designed to protect a third-party, one might argue that the law intended that the benefits of the drug outweigh its risks to the patient.  Setting aside REMS for teratogens where the risk is to the fetus, this is the first product to receive a REMS exclusively for a non-patient related risk.  The proposed class-wide opioid REMS also includes measures to protect non-patients from certain risks, but it includes measures to protect patients as well. 

By Michelle L. Butler –

On May 20, 2009, the President signed the Fraud Enforcement and Recovery Act of 2009 (“FERA”), which is purported to be aimed at improving enforcement of fraud, including fraud related to Federal assistance and relief programs.  Among other things, this legislation included substantial amendments to the Federal False Claims Act (“FCA”), 31 U.S.C. §§  3729-3333.

Section 4 of FERA is titled “Clarifications to the False Claims Act to Reflect the Original Intent of the Law.”  These amendments are described by Congress as being primarily directed at closing loopholes made by recent court decisions that have undermined and limited the scope of the law (see, e.g., Allison Engine Co. v. United States ex rel. Sanders, 128 S. Ct. 2123 (2008) (holding that 31 U.S.C. § 3729(a)(2) of the FCA requires the Federal government to prove that a defendant intended the government itself to pay a claim, resulting in no liability under the FCA unless a subcontractor intended to defraud the Federal government, not just the general contractor to whom the subcontractor submits claims for payment from government funds); United States ex rel. Totten v. Bombardier Corp., 380 F.3d 488 (D.C. Cir. 2004) (holding that the “presentment clause” limits recovery for frauds committed by a government contractor when the funds are expended by a government grantee).

The most significant changes made by section 4 of FERA relate to when liability attaches.  To address the “presentment clause” issue presented by Totten and other court decisions, FERA deleted from the FCA the “presentment clause” that required direct presentation of a claim to the government in order for liability to attach.  See 31 U.S.C. § 3729(a)(1)(A).  The Senate Report accompanying this legislation identified FCA liability for Medicaid claims as an example of where defendants have argued that the presentment clause precluded liability.  The Report stated that removal of the presentment clause clarifies that “the FCA reaches all false claims submitted to State administered Medicaid programs.”  S. Rep. No. 111-10, at 11 (2009).  To address the issues presented by the decision in Allison Engine, FERA also amended the FCA to remove language that was interpreted by the Supreme Court to require an intent by a subcontractor that its false statement to be used by the prime contractor to get the government to pay the claim.  Specifically, FERA removed the language requiring a person use a false statement “to get” a false claim “paid or approved by the government” and replaced it with a requirement that the false statement be “material to” a false claim.  FERA also amended the definition of a “claim” and added a definition for “material.”  See 31 U.S.C. § 3729(a)(1)(B).

Section 4 of FERA also made changes, among other things, to procedural matters when the government intervenes, including providing that, for statute of limitations purposes, any government pleading (either a complaint or an amendment of the relator’s complaint) relates back to the filing date of the relator’s complaint, to the extent that the government’s claims arise out of the conduct, transactions, or occurrence set forth, or attempted to be set forth, in the prior complaint; civil investigative demands for information relevant to a FCA investigation; and relief for employees, contractors, or agents subject to retaliatory action because of lawful acts done by such employees, contractors, or agents in attempting to stop violations of the FCA.

The amendments to the FCA by FERA take effect on the date of enactment of FERA and apply to conduct on or after such date (May 20, 2009), with certain exceptions.  Specifically, 31 U.S.C § 3729(a)(1)(B) takes effect as if enacted on June 7, 2008 and applies “to all claims under the [FCA] that are pending on or after that date.”  In addition, certain of the procedural changes apply to cases pending on the date of enactment.

By JP Ellison –

In a Memorandum to the heads of Executive Departments and Agencies dated May 20, 2009, with the Subject Line “Preemption” (the “May 20, 2009 Memorandum”), President Obama stated that “executive departments and agencies have sometimes announced that their regulations preempt State law, including State common law, without explicit preemption by the Congress or an otherwise sufficient basis under applicable legal principles.”

The May 20, 2009 Memorandum cross-references Executive Order (“EO”) 13132, which President Clinton issued on August 4, 1999, and the May 20, 2009 Memorandum includes as one of its criteria that an agency or department can only make a preemption statement in regulations when it is consistent with EO 13132 to do so. 

Significantly, the May 20, 2009 Memorandum seems to go beyond EO 13132.  For one thing, unlike EO 13132, the May 20, 2009 Memorandum specifically calls out “state common law” for preemption protection.  EO 13132, which was negotiated with state and local government organizations, did not specifically address common law preemption. 

In addition to compliance with EO 13132, the May 20, 2009 Memorandum also requires that any new regulations must contain preemption provisions in the codified regulations if there are preemptions statements in the preamble.

The May 20, 2009 Memorandum further requires heads of departments and agencies to look back 10 years to determine whether regulations issued in that time frame, “contain statements in regulatory preambles or codified provisions intended by the department or agency to preempt state law.”  Once any such regulations are identified, the departments and agencies are required to “decide whether such statements or provisions are justified under applicable legal provisions governing preemption.”  Other than EO 13132, the May 20, 2009 Memorandum does not identify any guidance for this review.  Finally, the May 20, 2009 instructs heads of departments and agencies to take “appropriate action” if they conclude that existing preemption provisions cannot be justified, “which may include amendment of the relevant regulation.”

It is difficult to predict how may regulations may be affected by the review ordered by the May 20, 2009 Memorandum.  That being said, FDA’s changes being effected (“CBE”) regulation, which was finalized in August 2008 and contains preamble preemption statements, is certainly on the FDA/HHS list of regulations to be reviewed. 

Unlike the FDA regulation at issue in Wyeth v. Levine, the preemptive effect of the CBE regulation was subject to notice and comment rule-making.  While the absence of notice and comment rulemaking seemed to matter to the Supreme Court in Wyeth, the presence of notice and comment rulemaking has not been given much weight by several courts that have considered the preemptive effect of the CBE regulation in connection with private tort suits against drug manufacturers.

It will be interesting to watch how the regulation review process unfolds across departments and agencies and in the courts.  It certainly seems like a significant undertaking.  Moreover, as the Supreme Court recently noted in FCC v. Fox Television Stations, Inc.:

To be sure, the requirement that an agency provide reasoned explanation for its action would ordinarily demand that it display awareness that it is changing position. An agency may not, for example, depart from a prior policy sub silentio or simply disregard rules that are still on the books. See United States v. Nixon, 418 U. S. 683, 696 (1974). And of course the agency must show that there are good reasons for the new policy.

Thus, even when the agencies have completed the process outlined in the May 20, 2009 Memorandum – which could take years – one can imagine court challenges and litigation that could go on even longer.

In the interim, it will also be interesting to see whether the plaintiff’s bar can make use of the President’s statement that there are unspecified federal regulations containing preemption provisions that  lack “sufficient basis under applicable legal principles.”  While the Memorandum states that it “is not intended to, and does not, create any right or benefit, substantive or procedural, enforceable at law or in equity by any party against the United States, its departments, agencies, or entities, its officers, employees, or agents, or any other person” (emphasis added), it would be surprising if a citation to this Memorandum did not appear in a preemption brief soon. 

By Ricardo Carvajal –  

According to a DOJ press release, a federal judge has handed down a 63-month sentence to a seafood company president convicted of participating in a conspiracy to falsely label a certain type of fish from Vietnam to avoid paying federal tariffs.  The tariffs had been imposed in 2003 after U.S. catfish farmers contended that the Vietnamese fish, known as swai or striped pangasius, were being  imported and sold below market value.  In this case, the importers avoided paying the tariffs by mislabeling the fish as one of several types of more expensive fish, including grouper, flounder, and sole.  The investigation was conducted by agents  from FDA’s Office of Criminal Investigation, the National Oceanic and Atmospheric Administration, and U.S. Immigration and Customs Enforcement.

This case marks just one twist in a long-running battle by domestic catfish farmers to ward off lower priced imports.  In another twist, the 2008 Farm Bill transferred inspectional authority over catfish from FDA to USDA.  Now USDA is considering whether to classify the Vietnamese pangasius as catfish, a seemingly innocuous issue that has significant implications for both sides and has generated some strong opinions.

By Kurt R. Karst –

The Washington Legal Foundation is publishing a Legal Backgrounder authored by Hyman, Phelps & McNamara, P.C., attorneys Robert A. Dormer and Kurt R. Karst.  The article, titled “The Drug User Fee Catch-22,” argues that FDA should be more flexible in receiving and approving ANDAs for drug products whose formulations differ from that of the Reference Listed Drug (“RLD”). 

FDA’s regulations preclude the submission of an ANDA for certain drug product category inactive ingredient changes – so-called “non-exception excipients” – unless the Agency waives such regulations.  Historically, FDA policy limits granting waivers to cases in which an ANDA applicant seeks approval to market a drug product containing a non-exception excipient used in a discontinued, brand name RLD formulation that is not used in the currently-marketed RLD formulation.  As a result, manufacturers unable to obtain a waiver for a non-exception excipient change are effectively forced to submit a 505(b)(2) application.  While under earlier iterations of PDUFA such an application usually would not have qualified as a fee-paying 505(b)(2) application, the changes made to PDUFA under the 2007 FDA Amendments Act (“FDAAA”) require the payment of user fees for all FDC Act § 505(b) applications.  As we state in the article: 

In short, such applicants become the victims of a “Catch-22.”  That is,  FDA’s unnecessarily narrow non-exception excipient policies preclude the submission and approval of an ANDA, which is not subject to PDUFA user fees, and effectively force the submission of a 505(b)(2) application.  Meanwhile, Congress’ decision in passing FDAAA to make all 505(b)(2) applications fee-paying applications means that such applications are subject to user fees, which are quite substantial. . . . 

FDA could avoid a conflict between FDC Act § 505(j)(4)(H) and its exception excipient regulations by interpreting the list of excipients in its regulations as illustrative rather than as exhaustive, or by granting § 314.99(b) waiver requests for non-exception excipients outside of discontinued RLD formulation scenarios, provided there is sufficient information to show that an excipient in a proposed drug product is safe for use.  By doing so, a generic applicant would be able to submit an ANDA, rather that being effectively forced to submit a user fee-paying 505(b)(2) application, and could avoid the Catch-22 Congress created with FDAAA.

We published another WLF Legal Backgrounder in August 2005 discussing the applicability of PDUFA user fees to certain 505(b)(2) applications.  That issue was made moot with the enactment of FDAAA.

By JP Ellison –

Today Attorney General Eric Holder and HHS Secretary Kathleen Sebelius announced the creation of a new interagency effort, the Health Care Fraud Prevention and Enforcement Action Team (HEAT), to combat healthcare fraud. Medicare appears to be the primary focus of the initiative, but both Medicare and Medicaid were mentioned in the officials' prepared remarks.

The HEAT initiative builds on existing efforts within each agency.  According to the announcement, HEAT, as its full name suggests, will have both prevention and enforcement aspects.

The announcement also notes that President Obama's budget  for 2010 calls for $311 million to strengthen program integrity activities within the Medicare and Medicaid programs, a 50% increase over 2009 levels.

By David B. Clissold –  

FDA’s meeting guidance “Guidance for Industry: Formal Meetings With Sponsors and Applicants for PDUFA Products” was issued in final form in February 2000.  On May 19, 2009, FDA released Revision 1 to that guidance, now entitled “Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants” (“Revision” or “Guidance”).  The Revision retains the 3 classifications of meetings (Types A, B, and C) and the same scheduling goals (within 30, 60, and 75 days of FDA receipt of a meeting request, respectively).  However, the new Guidance provides some important clarifications and explanations of FDA’s policies and expectations.  For example, as in the 2000 meeting guidance, FDA explained that Type A meetings are designed “to help an otherwise stalled product development program proceed” and FDA provided the same three examples of such meetings (dispute resolution, clinical hold, and special protocol assessment).  Guidance at 2.  However, the Revision clarifies that Type A meetings to discuss a clinical hold are appropriate only after the applicant has submitted a complete response to the hold “but the FDA and the sponsor or applicant agree that the development is stalled and a new path forward should be discussed.”  Id.  In addition, if an applicant is considering submitting a request for a Type A meeting, FDA now advises contacting the review division “to discuss the appropriateness of the request” (Id. at 3) and a Type A meeting request must now include the rationale for the request (Id. at 4).

Meeting requests are generally to be submitted to the sponsor’s application (IND, NDA, or BLA) through the controlled document system.  If there is no application, then meeting requests may be mailed, faxed, or emailed but if faxed or emailed, should only be sent “during official business hours (8:00 a.m. to 4:30 p.m. EST/EDT) Monday through Friday (except Federal government holidays).”  Id. at 4.  For fax and email submissions, FDA urges the submitter to contact the appropriate review division first and arrange for confirmation of receipt of the request since “[p]rocessing and receipt may be delayed for requests where confirmation of receipt has not been pre-arranged.”  Id.  Questions in meeting requests should include “a brief explanation of the context and purpose” of each question.  Id.  The “affiliations” of the individuals attending with the sponsor or applicant should be included in the request.  The applicant or sponsor should now request the format of the meeting (face to face, teleconference, or videoconference).  FDA recognizes that the projected attendees can change and so advises companies to update the list when submitting the information package, and again shortly before the meeting.  Id. at 5.

The most extensive changes to the Revision explain the reasons that FDA may reschedule or cancel a meeting.  A decision to reschedule or cancel a meeting is at the discretion of the review division.  A rescheduled meeting should be arranged “as soon as possible after the original date” and no new meeting request should be submitted.  Id. at 6.  On the other hand, a cancelled meeting needs a new meeting request that is subject to the same time frames as a new request.  Rescheduling may occur if the sponsor or applicant experiences a minor delay in submitting the meeting package, the review team determines that the meeting package is inadequate but that the additional information can be submitted, the information submitted is too “voluminous,” essential attendees are unavailable due to an emergency, the sponsor or applicant submits additional questions or data after the meeting package is submitted, or because FDA attendees not originally anticipated or requested by the sponsor but deemed to be “critical” are not available.  Id. at 6-7.  FDA warns that it may cancel a meeting if the meeting package is late or “grossly inadequate.”  Id. at 6.  In addition, a sponsor or applicant may determine that FDA’s “premeeting responses to its questions are sufficient” and request that a meeting be cancelled.  Id. at 7.  In our experience, this is far and away the most common reason that meetings are cancelled.  FDA’s preliminary responses have proven to be an important communication that at the very least helps to focus the meeting, resulting in a more efficient use of both parties’ time and resources. Although it took some time for all of the review divisions to adopt the practice of sending premeeting responses to a sponsor’s questions, the practice is now practically universal and FDA is to be commended for this effort.  However, the Revision states only that FDA “may” communicate premeeting responses to the sponsor (Id. at 9), and contains a somewhat disturbing qualification to this practice.  If a sponsor requests that a meeting be cancelled because FDA’s premeeting responses are thought to be clear,

[t]he division will consider whether it agrees that the meeting should be cancelled.  Some meetings, particularly milestone meetings, can be valuable because of the broad discussion they generate and the opportunity for the division to ask about relevant matters (e.g., dose-finding, breadth of subject exposure, particular safety concerns), even if the premeeting communications seem sufficient to answer the sponsor’s or applicant’s questions.  If the division agrees that the meeting can be cancelled, the division will document the reason for cancellation and the premeeting communication will represent the final responses and the official record.

Id. at 7. One way to read this qualification is that while the sponsor’s questions must be “precise” and asked far in advance of any meeting, FDA can apparently reserve its blockbuster questions for the meeting itself.  If FDA doesn’t ask the questions before the meeting, the sponsor may not have the appropriate time or personnel available to respond to FDA during the meeting, thus generating another meeting request that is subject to another delay.  We understand that “broad discussion” during a meeting may generate additional questions for both parties, but if FDA has questions about “relevant matters,” it is not clear why such questions can not be asked in advance of the meeting.  Ideally, such questions would be communicated ad hoc throughout the development cycle (e.g., when “particular safety concerns” are first observed).  But even if FDA asked their questions in the context of FDA’s premeeting responses to the sponsor’s questions, that would be far better than if FDA held them until the meeting itself.  Our observation is that such issues usually are raised by FDA no later than the premeeting responses.  Moving away from such a practice would be disastrous for sponsors.

In assembling the meeting package, FDA advises sponsors to consult FDA and ICH guidances, and to consider them in planning and developing the meeting package:

If a product development plan deviates from current guidances, or from current practices, the deviation should be recognized and explained.  Known difficult design and evidence issues should be raised for discussion (e.g., use of a surrogate endpoint, reliance on a single study use of a noninferiority design, adaptive designs).

Id. at 8.  FDA discourages presentations by sponsors or applicants noting that they “generally are not needed because the information necessary for review and discussion should be part of the meeting package.”  Id. at 9.  If a sponsor or applicant nevertheless wants to make a presentation, it should be discussed ahead of time with FDA “to determine if a presentation is warranted."  Id.

The Revision draws on FDA’s experience in conducting meetings over the last several years.  FDA’s expectations are more clearly described and the consequences for not meeting those expectations are highlighted.  FDA’s minutes of a meeting are the “official record” of decisions following what may have been a series of conversations and negotiations with the agency.  Thus, companies need to be familiar with the policies and procedures that lead to the creation of those minutes.

By JP Ellison – 

On May 18, 2009 the U.S. Department of Justice and sixteen states announced that they had intervened in whistleblower (qui tam) lawsuits pending in federal district court in Massachusetts against  drug manufacturer Wyeth, alleging false claims act violations under federal and state law.  A Wyeth spokesperson insists that the company has done nothing wrong and will vigorously defend against the allegations. 

The cases concern Wyeth’s acid-reflux drug Protonix (pantoprazole sodium).  According to the allegations made by the government, Wyeth “bundled” IV and oral versions of its drug Protonix, and sold both versions to hospitals at a substantial discount, but only if both versions of the drug were placed on the hospital formularies and certain market share requirements were met.  According to the government, Wyeth’s motivation for bundling the drugs was to get hospitals to use the IV version on its inpatients, so that they would continue with the oral version of the drug as outpatients.  The government alleges that the outpatient market was much more lucrative than the inpatient market.

Under Medicaid law, and the Medicaid rebate agreement, a brand name drug manufacturer is required to report its “best price” to the federal government.  The federal government then uses that pricing information to calculate a rebate that drug manufacturers must pay to each state Medicaid program.  The government alleges that Wyeth failed to properly calculate best price, and as a result underpaid Medicaid rebates to the states.  The government’s theory is that in reporting its best price, Wyeth improperly excluded as “nominal” the discounted sales price for the oral version of the drug, knowing that the discounted sales price was contingent on bundled sales, and therefore not properly excluded.

The government’s intervention in these lawsuits indicates that it  believes it can prove that Wyeth acted with the requisite intent to prove false claims act violations.

According to the allegations, Wyeth engaged in this conduct between 2000 and 2006.  Congress, in the Deficit Reduction Act of 2005, and the Centers for Medicare and Medicaid Services (“CMS”) in implementing regulations that were finalized in 2007, modified or clarified various aspects of best price reporting, including but not limited to bundling.  

It is unclear whether the 2000-2006 timeframe for the allegations is a function of the statute of limitations for these causes of action, changes in the laws and regulations, or some combination of both.

In any event, according to press reports, the expectation is that Wyeth will resolve these cases before Pfizer takes over Wyeth later this year.

By JP Ellison –

We previously reported on the President’s FOIA Memorandum and the Attorney General’s FOIA Guidelines encouraging discretionary disclosure.  Today, the D.C. Circuit handed the Administration a FOIA win that shows the importance of such discretionary disclosures, given FOIA’s exemptions. 

In CREW v. Office of Administration, the court ruled that the Office of Administration (“OA”) within the White House, was not subject to FOIA because “it performs only operational and administrative tasks in support of the President and his staff and therefore, under our precedent, lacks substantial independent authority,” and thus is exempt from FOIA.

According to the plaintiff, historically OA had complied with FOIA requests until some point in the prior Administration.  The court found it legally irrelevant what OA had done in the past, stating “past views have no bearing on the legal issue whether a unit is, in fact, an agency subject to FOIA.”

Perhaps more interesting than the decision concerning OA itself is the listing of entities that have been found to be FOIA exempt historically, including the Council of Economic Advisors, the National Security Council, and President Reagan’s Task Force on Regulatory Relief.  All of those entities were found to be FOIA exempt because they did not have a substantive role separate from advising the President.

Given the FOIA precedent, it would seem that the Administration could argue that the newly created White House Office of Health Reform is FOIA exempt.  In addition to health reform, the Administration has tapped “czars” for energy and urban affairs, which similarly could be FOIA exempt. 

It will be interesting to follow the position of the Administration with respect to FOIA’s application to these entities.  It will be similarly interesting to see whether the Administration elects to make discretionary disclosures from these and similar entities regardless of its legal position.