In a July 3, 2007 filing with the Securities and Exchange Commission (“SEC”), Altus Pharmaceuticals Inc. announced that the company was notified by FDA’s Office of Orphan Products Development (“OOPD”) that the orphan drug designation granted in January 2002 to ALTU-135, also know as TheraCLEC, for the treatment of Exocrine Pancreatic Insufficiency (“EPI”) was being revoked.  OOPD only very rarely revokes orphan drug designation.  According to the Altus filing, “[t]he FDA based its decision on a finding that if one includes all patients with HIV/AIDS who suffer from fat malabsorbtion in this indication, the patient population in the United States appears to exceed 200,000 persons and is thus ineligible for orphan drug designation.”  A March 2007 Altus SEC filing noted that FDA first informed the company in December 2006 of the Agency’s plans to revoke the TheraCLEC orphan drug designation.

TheraCLEC is a Pancreatic Exocrine Product (“PEP”) in clinical development that contains the enzymes amylase, lipase, and protease to break down the complex carbohydrates, fats, proteins, respectively, that are deficient in EPI patients and that causes poor absorption of essential nutrients (thereby often leading to malnutrition, impaired growth, and reduced survival). OOPD’s decision to revoke the Altus designation comes less than one year before the date FDA established in 2004 requiring the submission of NDAs for PEPs for EPI.  In addition, OOPD’s decision avoids the possibility that TheraCLEC, if it were the first product to obtain FDA approval with orphan drug designation, would be granted seven years of exclusivity, during which FDA could not approve an application for the “same drug” for EPI, absent a showing of “clinical superiority.” 

PEPs have been marketed in the United States for EPI since before the enactment of the FDC Act in 1938.  In April 2004, FDA published a Federal Register notice announcing that all PEPs are “new drugs” under the FDC Act, and that sponsors of currently marketed PEPs must submit and obtain approval of an NDA by April 28, 2008, or be subject to FDA regulatory action.  FDA simultaneously published a guidance document to assist sponsors in submitting NDAs for their PEPs.  With regard to patient needs, FDA’s Federal Register notice states:

[T]here is a need for a range of products to remain available for patient use.  The dosage requirements of patients vary, and the appropriate daily dose of pancreatic enzyme supplements must be individualized and adjusted when clinically indicated.  Furthermore, physicians have identified and stabilized their patients on currently available products with different ratios of lipase, protease, and amylase that meet the patients’ needs.  Thus, to meet the dosing requirements and to maintain compliance with treatment, pancreatic supplements are needed with varied concentrations of lipase, protease, and amylase. 

This statement indicates that FDA anticipates the submission of multiple applications for different drugs to meet the varied needs of EPI patients.  By permitting a single applicant with orphan drug exclusivity to monopolize the PEP/EPI market, however, FDA would be unable to meet its stated public health need for “a range of [PEPs].”  FDA’s decision to revoke the Altus designation removes this impediment. 

Presumably the next exclusivity battle over PEPs will concern whether each PEP is a new chemical entity eligible for 5-year exclusivity or whether 3-year “new use” exclusivity applies.  An FDA determination that all PEPs are different and eligible for 5-year exclusivity is arguably consistent with recent FDA policy conferring 5-year exclusivity “to products about which the Agency has insufficient information to know whether they contain a previously approved active moiety.”  Moreover, FDA has indicated (pages 15-21) that such a policy might be applicable to PEPs.       

Positron Emission Tomography drugs, or PET drugs (not to be confused with drugs approved for companion animals), would be accorded more equitable user fee status under PDUFA IV if the Senate-passed version of the FDA Revitalization Act (“FDARA”) is signed into law.  (A similar provision is included in the House version of PDUFA IV, H.R. 2900, introduced late last month.)  FDARA, if enacted, would also address an issue raised by The Council on Radionuclides and Radiopharmaceuticals (“CORAR”) in an August 2005 citizen petition, in which the organization requested that “FDA establish a class waiver under which manufacturers of PET drugs are exempt from multiple establishment user fees, and are subject, at most, to a single establishment fee for each approved ‘human drug application.’” 

The FDC Act defines the term “compounded positron emission tomography drug” at § 201(ii) to mean a drug that “(A) exhibits spontaneous disintegration of unstable nuclei by the emission of positrons and is used for the purpose of providing dual photon positron emission tomographic diagnostic images; and (B) has been compounded by or on the order of a practitioner who is licensed by a State to compound or order compounding for a drug described in subparagraph (A), and is compounded in accordance with that State’s law, for a patient or for research, teaching, or quality control.”  The term includes “any nonradioactive reagent, reagent kit, ingredient, nuclide generator, accelerator, target material, electronic synthesizer, or other apparatus or computer program to be used in the preparation of such a drug.” 

A more practical description is provided in the CORAR petition:

PET drugs are produced by tagging (i.e., “labeling”) a substrate compound with a positron emitting isotope, which is produced in cyclotrons (i.e., devices that accelerate protons or deuterons to the high energies needed for a nuclear reaction to occur).  Once injected, the isotope travels through a patient’s bloodstream and is distributed in certain tissues.  Using a PET camera, nuclear physicians measure the different rates at which the isotope emits positrons, based, for example, on the different ways in which different types of tissue metabolize the drug’s substrate, and thereby produce computerized images of biochemical processes and tissue structures within the body.  Physicians use the resulting images to diagnose, stage, and monitor diseases (e.g., focal epilepsy, certain cardiac diseases, dementias, and lung, breast, prostate, and colorectal cancer).

The FDA Modernization Act of 1997 placed a moratorium on FDA’s regulation of PET products as “new drugs” until the Agency establishes procedures by which PET drugs are to be approved under the FDC Act’s new drug approval process, and establishes appropriate PET drug current Good Manufacturing Practices (“cGMPs”).  During this moratorium, FDA has encouraged PET centers to voluntarily submit marketing applications for approval, and issued proposed regulations in September 2005 to establish PET drug cGMPs. 

CORAR has been concerned that, because of the unique characteristics and properties of PET drugs, FDA will assess multiple establishment user fees for each approved PET drug.  The CORAR petition states that:

Because of the unusual characteristics of PET drugs, and once all PET drugs are regulated as “new drugs,” the assessment of establishment user fees, in particular, will significantly and unfairly burden commercial PET drug manufacturers.  Due to the short half-lives of PET drugs, a commercial manufacturer that supplies PET drugs nationally, or even regionally, requires multiple manufacturing establishments located throughout the U.S. or the region (as the case may be).  Each of these establishments must be identified in any marketing application submitted to FDA.  Because establishment fees are assessed annually for “each prescription drug [manufacturing] establishment listed in [an] approved human drug application,” PET drug applicants would be assessed multiple establishment fees.  Such multiple fee assessments would be patently unfair, particularly for an industry that will soon be saddled with numerous new and expensive legal and regulatory burdens. 

At a recent public meeting on PDUFA IV, CORAR provided the following example: “[O]ne PET drug manufacturer operates 44 cyclotron facilities nationwide.  If these were used to manufacturer and supply a particular PET drug under an NDA, this company would have to pay over $13 million annually in establishment fees (based on FY 2007 user fee rates).”

FDARA would amend FDC Act § 736(a) to create special establishment user fee rules for PET drugs.  Under the Senate-passed version of FDARA:

[E]ach person who is named as the applicant in an approved human drug application for a compounded [PET] drug shall be subject . . . to one-fifth of an annual establishment fee with respect to each such establishment identified in the application as producing compounded [PET] drugs under the approved application.

FDARA would also exempt from all annual establishment user fees those PET drug sponsors who certify to FDA that they are not-for-profit medical centers with only a single PET drug manufacturing establishment, and provided at least 95% percent of the total number of doses of each PET drug produced by that establishment will be used within the medical center itself.

Although FDARA does not place all PET drug sponsors on equal footing with therapeutic drug sponsors (in the example above, the PET drug sponsor would still have to pay the equivalent of almost 6 full establishment fees for its 44 establishments), it would, if enacted, provide significant relief for multi-establishment PET producers.   

From the New York Times: “China executed its former top food and drug regulator today for taking bribes to approve untested medicine as Beijing scrambled to show that it is serious about improving the safety of Chinese products.” 

On June 29, 2007, the U.S. District Court for the District of Columbia, in Mylan v. Leavitt, issued a memorandum opinion denying Mylan’s Emergency Motion for a Temporary Restraining Order that asked the court to order FDA to relist Pfizer’s U.S. Patent No. 4,879,303 covering NORVASC (amlodipine besylate) until the issue of Mylan’s claim to 180-day exclusivity is resolved.  FDA previously approved Mylan’s ANDA, but was prevented from approving subsequent generic applications due to various exclusivity issues. 

In an April 18, 2007 FDA Letter Decision, and pursuant to the district court’s April 30, 2007 opinion substantially agreeing with FDA, the Agency concluded (with respect to pending ANDAs for generic NORVASC) that “where an applicant has challenged a patent and has received a decision of invalidity or non-infringment, that applicant will not be subject to the NDA holder’s pediatric exclusivity once that decision becomes effective.” Accordingly, FDA approved Apotex’s ANDA once the Federal Circuit issued its mandate in Pfizer, Inc. v. Apotex, Inc.  FDA’s Letter Decision also states that “[i]f the remaining claims [of the ‘303 patent] do not provide a basis on which to list the patent, . . . the patent would no longer be eligible for listing in the Orange Book.  In such a case, the patent must be withdrawn by Pfizer and any pediatric exclusivity that attached to the patent will no longer serve as a barrier to ANDA approval.” FDA and the court also concluded that Mylan’s 180-day exclusivity period expired when the ‘303 patent expired (without pediatric exclusivity) on March 25, 2007.  Mylan sought reconsideration of this issue, which the court denied in a May 14, 2007 order.  Mylan then appealed the issue to the D.C. Circuit, where the case is being briefed.

On June 14, 2007, Pfizer notified FDA that the ‘303 patent no longer meets the Orange Book listing criteria with respect to NORVASC and requested that the Agency delist the patent from the Orange Book.  FDA delisted the patent on June 22, 2007 and notified ANDA applicants of this action on the same day.  FDA subsequently approved ANDAs submitted by Synthon and Teva on June 27 and June 28, 2007, respectively.  There are still several tentatively approved amlodipine besylate ANDAs awaiting final approval. 

On June 26, 2007, Mylan submitted an application for a preliminary injunction seeking to enjoin FDA “from taking any action to issue an approval of any [ANDA] for amlodipine besylate products in derogation of Mylan’s right to 180-day exclusivity until the issue is finally decided on appeal.”  In Mylan’s accompanying memorandum, the company states “[n]ow that the FDA has delisted the Pfizer patent, Mylan’s claim to 180-day exclusivity has moved to the forefront. . . .  Mylan is likely to prevail on its claim to 180-day exclusivity in the Court of Appeals, but its victory will be hollow unless the Court maintains the status quo until the appeal has been decided.”

FDA’s opposition memorandum states that “[u]nder the law of this Circuit, this Court has no jurisdiction to revisit [the 180-day exclusivity] issue at this time.  For this reason, Mylan’s application should be denied.  Even if the Court were to examine this issue, however, it has no merit and should be rejected.”  Teva’s opposition memorandum similarly states that “[b]eyond the fact that Mylan’s motion merely reiterates the same discredited arguments that this Court previously considered and rejected, its motion asks this Court to exercise jurisdiction it plainly does not possess.”  Mylan’s reply memorandum counters these arguments and states:

The FDA and Teva would prefer that this Court avoid the merits of Mylan’s motion for injunctive relief pending appeal by ruling that it does not have jurisdiction now that the Court’s denial of Mylan’s earlier motion for a preliminary injunction is on appeal. But both the Federal Rules of Civil Procedure and case law from this Circuit make clear that the Court may maintain the status quo while the case is on appeal. That is exactly what Mylan seeks here –no more and no less. On the merits, the FDA relies on cases holding that eligibility for 180-day exclusivity does not survive patent expiration, ignoring the fact that here Mylan’s 180-day exclusivity had vested before the ‘303 patent expired.

The district court, not persuaded by Mylan’s arguments, issued its memorandum opinion on June 29, 2007.  The court concluded that “[i]njunctive relief emanating from this court is wholly inappropriate.  [Mylan] has made no showing of irreparable harm.  The court maintains confidence in its substantive legal ruling regarding the 180-day exclusivity and its prior conclusion regarding the balance of harms to other parties and the public.  Moreover, its ruling is presently before the Circuit . . . .  Accordingly, the court denies the plaintiff’s request for a TRO and a stay pending appeal.”

The reasons for Pfizer’s decision to request that FDA delist the ‘303 patent are unclear, as the continued listing of the patent in the Orange Book could prevent additional generic competition until September 2007.  Unless the D.C. Circuit reverses the district court’s decision on the issue of Mylan’s claim to 180-day exclusivity, FDA may continue to grant final approval to tentatively approved amlodipine besylate ANDAs.

On June 25, 2007, the Supreme Court agreed to hear Riegel v. Medtronic, Inc., which concerns whether the FDC Act preempts state tort claims regarding medical devices that entered the market pursuant to the Premarket Approval (“PMA”) process.  In 1996, the Supreme Court held in Medtronic, Inc. v. Lohr that certain state tort claims involving medical devices cleared under the premarket notification (i.e., 510(k)) process are not preempted. 

In Riegel, the U.S. Court of Appeals for the Second Circuit joined a majority of circuits (i.e., the Third, Fifth, Sixth, Seventh, and Eighth Circuits) that have addressed this issue in holding that state tort claims regarding PMA-approved devices are preempted by the FDC Act.  Specifically, the Second Circuit decided that claims alleging liability despite adherence to the standards on which the PMA device was approved are preempted, but claims that are based on a manufacturer’s departure from such standards are not preempted. 

Charles Riegel and his wife sued Medtronic for injuries allegedly suffered by Mr. Riegel when a balloon catheter manufactured by Medtronic ruptured during an angioplasty operation.  The suit raised several state common law causes of action, including negligence, strict liability, and breach of warranty.  The trial court and the Second Circuit addressed the scope of FDC Act § 521, which states, in relevant part: 

[N]o State or political subdivision of a State may establish or continue in effect with respect to a device intended for human use any requirement –

(1) which is different from, or in addition to, any requirement applicable under this Act to the device, and

(2) which relates to the safety or effectiveness of the device or to any other matter included in a requirement applicable to the device under this Act.

The Second Circuit reasoned that because devices approved through the PMA process are subject to the standards set forth in their approved applications, such devices are subject to “a requirement applicable to the device under [the FDC Act].”  The court further held that the claims for strict liability, breach of warranty, and negligent design, testing, inspection, distribution, labeling, marketing, and sale would (if successful) impose state “requirements” that differed from, or added to, the PMA-approved standards for the device.  In contrast, the court held that the negligent manufacturing claim was not preempted to the extent that it was based on the allegation that the particular catheter used during Mr. Riegel’s angioplasty had not been manufactured in accordance with the PMA-approved standards.

The Second Circuit emphasized that the scope of its decision is “actually quite limited,” because many Class III medical devices (i.e., those medical devices that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury) enter the market through the 510(k) process rather than the PMA process (that is, those Class III medical devices that are substantially equivalent to devices legally marketed before the enactment of the Medical Device Amendments on May 28, 1976, and for which a regulation calling for PMA has not been published).  In addition, the Second Circuit did not hold that all state tort claims as to PMA-approved devices are preempted; rather, only claims that allege liability despite the adherence of the device to standards set forth in the PMA are preempted.  The Supreme Court is expected to hear the case in the fall. 

Riegel is the first of two preemption cases the Court may hear.  The second case, Wyeth v. Levine, concerns whether prescription drug labeling preempts state law product liability claims.  FDA asserted in the preamble to its January 2006 final rule (page 3934) on prescription drug labeling that “FDA approval of labeling under the [FDC Act] . . . preempts conflicting or contrary State law.”  The Supreme Court has not yet decided whether to hear the case and has requested the Solicitor General’s views. 

In a recent development, on July 3, 2007, the U.S. District Court for the Eastern District of Louisiana issued an order in ongoing VIOXX (rofecoxib) product liability litigation denying Merck’s motion for summary judgment on federal preemption grounds.  With respect to FDA’s January 2006 position on preemption, the court stated:

FDA’s current position on preemption is neither entitled to the deference suggested in Chevron, nor to the deference espoused in Auer.  The FDA’s current views on preemption were not promulgated pursuant to its rulemaking authority, nor do they seek to clarify any ambiguity in the FDA regulations.  Rather, the FDA added these views at the end of the rulemaking process in a preamble to the 2006 Final Rule, that is, “through the back door.”  Moreover, the FDA’s preemption statements in the preamble actually conflict with statements made in the original notice of proposed rulemaking out of which the 2006 Final Rule grew. At best, the preamble merely offers an opinion on the viability of the plaintiffs’ state-law claims given the existence of the federal regulatory scheme as a whole; it does not purport to interpret any specific statutory or regulatory provision, nor is it a regulation itself. (citations omitted).

ADDITIONAL READING:

• LawMemo post with case history and documents
• SCOTUSblog post
• HPM presentation on preemption

By Brian J. Wesoloski

A colleague of your trusted bloggers spoke with counsel for the Nevada Board of Pharmacy (“BOP”) and reports the following about the new law in our post from yesterday:

• A draft regulation will be posted on the BOP website next week. 
• BOP welcomes comments on the draft rule.  Companies should send them to Jeri Walter at jwalter@pharmacy.nv.gov
• The BOP will conduct a public workshop on the draft rule on July 26, 2007.
• Based on comments at the workshop, a final rule will be developed and presented to the BOP for a vote on September 6, 2007. 
• The rule will become effective 30 days after it is adopted.
• As the rule is currently drafted, the first submission to the BOP will be due on June 1, 2008, and subsequent submissions will be due annually thereafter.

On June 14, 2007, Nevada Governor Jim Gibbons signed into law Assembly Bill 128, which is similar to the drug marketing compliance law that went into effect in California in July 2005.  Nevada’s new law, which goes into effect on October 1, 2007, requires a manufacturer or wholesaler who employs a person to sell or market a drug or device in the state to adopt a marketing code of conduct establishing the practices and standards that govern the marketing and sale of their products.  The marketing code of conduct must be based on applicable legal standards and should guarantee that the manufacturer’s actions are “intended to benefit patients, enhance the practice of medicine and not interfere with the independent judgment of health care professionals.”

The new marketing code of conduct requirement can be fulfilled by adopting the most recent version of the Pharmaceutical Research and Manufacturers of America’s (“PhRMA’s”) “Code on Interactions with Healthcare Professionals,” which California currently requires drug companies to have adopted.  In California, companies must adopt new versions of the PhRMA Code within 6 months of any PhRMA Code update.  In Nevada, however, it is unclear whether a company that has adopted PhRMA’s Code is required to adopt subsequent revisions of PhRMA’s Code to remain in compliance and, if so, how long a company would have to do so.  The Nevada Board of Pharmacy may clarify this point in a future rulemaking.

Unlike California’s law, the Nevada marketing law does not require that any particular elements be included in a company’s marketing code of conduct.  For instance, the Nevada law does not require companies to specify limits on gifts or incentives to health professionals.  While California requires companies to adopt the Office of Inspector General’s April 2003 “Compliance Program Guidance for Pharmaceutical Manufacturers,” Nevada does not.  Nevada also does not currently require a company to post its marketing code of conduct on its website, as is required in California.

In addition to adopting a marketing code of conduct, each company marketing or selling drugs or devices in Nevada must take a number of complementary actions.  First, each company must adopt a training program to regularly train appropriate staff regarding the company’s marketing code of conduct.  All sales and marketing staff must receive this training.  Second, each company must conduct an annual audit to monitor compliance with its marketing code of conduct.  Third, a company must adopt procedures for investigating non-compliance with its code.  Finally, each company must identify a compliance officer responsible for developing, operating, and monitoring the code.

Each company subject to this law must also make an annual report to the Nevada Board of Pharmacy.  The report must contain: (1) a copy of the company’s marketing code of conduct; (2) a description of its training programs; (3) a description of its investigation policies; (4) the name and contact information of the responsible compliance officer; and (5) a certification that the company has conducted its annual audit and is in compliance with the law.  The legislation also directed the Board of Pharmacy to “adopt regulations providing for the time of the submission and the form of the information required.”  The date of the initial report was not specified in the statute.

By Bryon F. Powell

At long last, 13 years after the Dietary Supplement Health and Education Act (“DSHEA”) of 1994 authorized their creation, and four years after publication of the proposed rule, FDA issued its final current Good Manufacturing Practice (cGMPs) regulations for dietary supplements on June 25, 2007. FDA’s press release announcing the new regulations is available here.

The highly anticipated final rule establishes the minimum level of GMPs for the manufacturing, packaging, labeling and holding of dietary supplements. The regulations aim at ensuring the identity, purity, strength, and composition of a dietary supplement and at guaranteeing that a “dietary supplement is manufactured, packaged, held, and labeled in a consistent and reproducible manner.”  Requirements address identity testing for incoming dietary ingredients, quality control, design and construction of manufacturing plants, personnel qualifications, use of written procedures, record keeping, returned dietary supplements, and consumer complaints.

In response to the more than 400 comments FDA received in response to the March 2003 proposed rule, the Agency revised and reorganized the various regulatory provisions.  New 21 C.F.R. Part 111 now consists of 16 subparts rather than the original eight subparts.  The preamble to the final rule includes a chart of the reorganization and renumbering of various sections facilitating a comparison of the final and proposed rules. 

The most important and obvious change is that the final rule does not apply to dietary ingredient suppliers and manufacturers.  The burden of compliance with cGMPs fully lies with the dietary supplement’s manufacturer and requires dietary supplement manufacturers to test 100% of the incoming dietary ingredients.

Concurrent with the final rule, however, FDA published an interim final rule providing an alternative to the 100% identity testing requirement.  In the interim rule, FDA recognizes that under some circumstances “a system of less than 100 percent identity testing would [not] material[ly diminish the] assurance of the identity of the dietary ingredient.” Thus, the interim rule provides a petitioning process for exemptions to the100% testing requirement.  FDA requests comments on what type of information would satisfy the exemption. Comments are due by September 24, 2007.

Other notable differences between the proposed and final rules include:

• Increased requirements for written procedures for, among other things, manufacturing operations, quality control operations, training of personnel, laboratory operations, holding and distributing operations, and for the handling of returned dietary supplements.

• Reduced requirements for testing finished batches.  The final rule allows testing of a “subset of finished dietary supplement batches [identified] through a sound statistical sampling plan” rather than testing of all finished batches.

• Because validated testing methods for the identity of dietary ingredients often may not be available, the final rule allows use of a “scientifically valid method” instead of a “validated testing method.”

• The final rule replaces the proposed requirement for a “quality control unit” with “a requirement for quality control operations performed by quality control personnel.”  Quality control personnel must have “distinct and separate responsibilities related to performing [their] operation” and non-quality control activities by these designated individuals are not restricted.  Quality control personnel must supervise and monitor the testing and evaluate the results and need not perform the actual testing and examination.

• Increased flexibility regarding qualification of employees and design of manufacturing facilities.   For example, the final rule (unlike the proposed rule) does not exclude employees who are a potential source of microbial contamination from the premises, but excludes such individuals only from areas where contamination of the dietary supplement may occur. 

Both the final GMP regulations and the interim final rule take effect on August 24, 2007, with a three-year phase-in process to limit disruption of businesses. Companies with more than 500 employees must comply by June 2008; those with 20-500 employees by June 2009; and those with less than 20 employees by June 2010.  FDA will review petitions for an exemption from the 100% identity testing requirement only once the compliance date for a particular manufacturer has passed.

By Riëtte van Laack

On May 14, 2007, Representatives John Dingell (D-MI), Henry Waxman (D-CA), and Bart Stupak (D-MI) sent a letter to the Government Accountability Office (“GAO”) requesting that the office update its July 2000 report on the safety of dietary supplements and functional foods.  Congress’ increased scrutiny of dietary supplement regulation has been anticipated since the November 2006 election and the change in control of Congress.

In its July 2000 report, GAO identified three major weaknesses in the dietary supplement and functional food regulatory system: (1) a “lack of a clearly defined safety standard for new dietary ingredients;” (2) a “lack of safety-related information on [some product] labels;” and (3) FDA’s failure to investigate “reports [about] health problems potentially caused by” dietary supplements and functional foods.  Several changes have occurred since the report was issued.  For example, the congressional letter cites FDA’s 2004 ban on ephedra-containing supplements, the Bioterrorism Act of 2002 (requiring registration of dietary supplement manufacturers to improve traceability of products), and the enactment of the Dietary Supplement and Nonprescription Drug Protection Act of 2006 (introducing a mandatory adverse event reporting system for dietary supplements and non-prescription drugs) as significant improvements that may help FDA ensure the safety of dietary supplements.  Nevertheless, Congress continues to be concerned about the safety of dietary supplements, and the May 2007 letter asks GAO to determine “what challenges remain.”

Specifically, the letter requests that GAO examine three different aspects of FDA’s activities concerning dietary supplements.  First, based on the ephedra experience, the lawmakers question FDA’s ability to monitor emerging safety concerns associated with dietary ingredients.  Although the Dietary Supplement and Nonprescription Drug Protection Act of 2006 does not become effective until December 22, 2007, the letter asks GAO to determine FDA’s progress in implementing this law and to evaluate whether it provides FDA with adequate authority to prevent a repeat of the ephedra experience. 

Second, the letter raises a concern about the safety of the use of dietary ingredients in conventional food products (suggesting that such use is increasing), and requests that the GAO investigate FDA’s effectiveness in monitoring associated safety issues.

Finally, the letter expresses concern about consumer confusion which, according to the lawmakers, “has increased as the number of dietary supplement claims have proliferated.”  Although this is not a safety issue, the letter requests information about FDA actions to “ensure that consumers understand label claims and have adequate information about the safety and efficacy of dietary supplements.”

By Riëtte van Laack

The FDA announced it is postponing the annual registration of medical device establishments for 2008. The agency said this is a temporary action and it expects to resume annual registrations in October or November 2007.  Establishments that are already registered for 2007 are valid until Dec. 31.

The FDA said it is postponing registration because "upcoming changes may significantly change the way [device manufacturers] register . . . establishment[s] and list . . . devices," including the possibility of electronic registration and listing, simpler registration and listing requirements and provisions under the Bioterrorism Act and the Medical Device User Fee and Modernization Act.

FDA also said that it is working to revise its registration and listing regulations to help foreign establishments meet the statutory requirements of  the Public Health Security and Bioterrorism Preparedness and Response Act of 2002 (P.L. 107-188, the “Bioterrorism Act”), which requires each foreign establishment to provide, as part of its registration, the name of each known importer of the establishment’s devices and the name of each person who imports or offers to import the device into the United States.

Manufacturers with questions should call (240) 276-0111 or send an email to device.reg@fda.hhs.gov.

In a recently published white paper (registration required), Steven Richter, a former FDA official and President and Chief Scientific Officer of Microtest Labs, discusses the regulatory challenges facing combination products.  The market for combination products is growing such that it is estimated to reach approximately $9.5 billion in 2009, up from $5.9 billion in 2004, according to one analyst.  Another survey estimates that 30% of new products in development are combination products.  This increased interest is due in part to the unique therapeutic benefits of combining drugs and medical devices, which can, for example, deliver drug to specific areas of the body. 

FDA decides which center governs a combination product based on its primary mode of action (PMOA).  A product that has a pharmaceutical PMOA will be governed by the Center for Drug Evaluation and Research (CDER).  Likewise, a product with a device PMOA will be governed by the Center for Devices and Radiological Health (CDRH).  Different quality regulations, however, apply to each product:  good manufacturing practices (GMPs) (21 C.F.R. Parts 210, 211) apply to drugs, biologic product standards (21 C.F.R. Part 610) apply to biologics, and quality system regulations (QSR’s) (21 C.F.R. Part 820) apply to devices.  Richter maintains, however, that a combination product manufacturer’s “main regulatory foundation must be the drug GMP’s” and that the GMP system must “address[] some of the issues with the device QSR’s.”

Richter predicts that, as FDA continues to shift its regulatory focus from product to process, the largest challenge for combination product manufacturers will be “during the scale-up process.”  This is in part because “additional quality control (QC) measures are required to determine process scale-up parameter shift.”  Richter also expects FDA to issue guidelines specific to combination products that incorporate Process Analytical Technology (PAT) initiatives and design of experiments (DOE) requirements “regarding both small molecule and large molecule process design and scale-up.”  Moreover, Richter believes FDA will “increase[] cGMP regulatory action that affects both laboratory and manufacturing” as a result of its guidelines. 

By:  Carrie S. Martin

Earlier this month, the Supreme Court issued its unanimous decision in Long Island Care At Home, Ltd. v. Coke, a case concerning compensation for in-home caregivers and the Department of Labor’s (“DOL’s”) interpretation of the Fair Labor Standards Act (“FLSA”).  The Court’s decision, although anticipated, clarifies when an administrative agency’s “gap-filling” authority may be upheld as a permissible interpretation of the law.  FDA, like many federal agencies, frequently uses this authority to promulgate regulations.

Evelyn Coke, a 73-year-old home healthcare attendant, sued her employer, Long Island Care at Home, Ltd., alleging that the company did not pay her the minimum wage or overtime compensation.  The FLSA generally requires employers to pay the minimum wage and overtime, but has an exemption for “companionship services.” The DOL’s regulations (labeled as an “interpretation”) implementing the FLSA provide that the exemption applies to home health aides and similar employees who are “employed by an . . . an agency other than the family or household using the services” (i.e., third parties).  29 C.F.R. § 552.109(a).  The DOL’s “General Regulations” at 29 C.F.R. § 552.3, however, define the statutory term “domestic service employment” as “services of a household nature performed by an employee in or about a private home . . . of the person by or for whom he or she is employed.” 

The Supreme Court agreed to hear the case after the U.S. Court of Appeals for the Second Circuit overturned the DOL’s “interpretation” regulations.  (There, the court concluded that the regulations conflicted with congressional intent.)  The questions presented to the Supreme Court were:

1.         Whether the Second Circuit erred in refusing to give deference under Chevron, U.S.A., Inc. v. Natural Res. Def Council, Inc., 467 U.S. 837 (1984), to a thirty-year old [DOL] regulation –a regulation that has twice been upheld by the Tenth Circuit– on the ground that, even though it was promulgated under express grants of legislative authority and after full notice-and-comment rulemaking, the regulation was contained in a subpart headed “Interpretations.”

2.         Whether, in holding that a longstanding [DOL] regulation was not persuasive and thus undeserving of any deference under Skidmore v. Swift & Co., 323 U.S. 134 (1944), the Second Circuit erred by failing to address the governing provisions of the [FLSA] and by declining to give any weight to [DOL’s] interpretation of its own regulations.

Ms. Coke argued that “a thorough examination of the [third-party] regulation’s content, its method of promulgation, and its context reveals serious legal problems. . . .  In particular, . . . that the regulation falls outside the scope of Congress’ delegation; that it is inconsistent with another, legally governing regulation; that it is an ‘interpretive’ regulation not warranting judicial deference; and that it was improperly promulgated.”

In the Court’s decision (written by Justice Stephen Breyer) holding the regulation (i.e., 29 C.F.R. § 552.109(a)) valid and binding, the Court summed up the case as follows:

[T]he ultimate question is whether Congress would have intended, and expected, courts to treat an agency’s rule, regulation, application of a statute, or other agency action as within, or outside, its delegation to the agency of “gap-filling” authority. Where an agency rule sets forth important individual rights and duties, where the agency focuses fully and directly upon the issue, where the agency uses full notice-and-comment procedures to promulgate a rule, where the resulting rule falls within the statutory grant of authority, and where the rule itself is reasonable, then a court ordinarily assumes that Congress intended it to defer to the agency’s determination. . . .  The three contrary considerations to which the Court of Appeals points are insufficient, in our view, to overcome the other factors we have mentioned, all of which suggest that courts should defer to the [DOL’s] rule. And that, in our view, is what the law requires.

Although this decision is important to those (i.e., employers, states, municipalities, and insurers) in the home-care industry, the decision also has significant implications for all regulated industries, and in particular, FDA-regulated industries, as it signals, among other things, greater judicial deference to agencies’ interpretations of their own regulations.

RELATED READING:

• SCOTUSblog post
• LawMemo post with case history and documents

On June 20, 2007, the United States Court of Appeals for the Eighth Circuit issued a decision in Washington University vs. Catalona affirming the District Court for the Eastern District of Missouri’s holding that neither the medical researcher nor the contributing patients have any ownership or proprietary interest in biological tissue samples collected for research.  Rather, Washington University — the institution to whom patients consented to donate their tissue samples — retained ownership.

Pharmaceutical and biotech companies routinely use banked biological tissue specimens for product development and other purposes.  This court case involves a hotly-contested dispute among a leading medical research institution, Washington University, a well-established prostate cancer researcher and former employee of the University, Dr. William Catalona, and his patients.  At issue was who owns biological tissue specimens, such as prostate, blood, and DNA samples, collected by Dr. Catalona (and other medical researchers) from study subjects and patients for use in prostate cancer research.  The specimens at issue comprise a very large and valuable biorepository.  The repository includes more than 4,000 prostate tissue samples and more than 100,000 blood samples.  The Court of Appeals upheld the District Court’s holding in favor of the University – that research participants retained no ownership in the biological specimens they contributed to the University’s repository. 

The Court of Appeals narrowly framed the question presented, and limited its holding to the facts of this case.  The Court held that individuals who make a voluntary and informed decision to contribute their biological tissues to a particular institution for medical research do not retain an ownership interest that would allow them to direct or authorize that the specimens be transferred to a third party.

This holding is not new, and is consistent with what little legal precedent is available.  Still, this case appears to be the first to address the ownership of biological specimens themselves, as opposed to some improvement or attempt at commercialization (e.g., a cell line or patented gene).  The decision underscores the importance of having clear documentation of the intent of study subjects to contribute their tissues.  It remains to be seen whether Dr. Catalona and his patients will petition the Eighth Circuit for rehearing or petition the United States Supreme Court for certiorari.

By:  Anne Marie Murphy

Our “blogfather” over at the Orange Book Blog already has a preliminary post up about the recent victory in the district court by Bristol-Myers Squibb and Sanofi-Aventis over Apotex relating to the enforceability and validity of the patent on the active ingredient in Plavix.  Long story short:  The patent is valid and Apotex is enjoined from further infringing the patent.

Aaron Barkoff, the blogmaster at OBB, always does a nice job summarizing the patent cases for those of us with liberal arts degrees whose eyes glaze over at the intricacies of patent law.  We look forward to his forthcoming detailed post on the topic.

In chemistry, enantiomers are stereoisomers that are non-superimposable complete mirror images of one another.  Enantiomers may be either “right-handed” (dextro-rotary) S(+)-isomers, or “left-handed” (levo-rotary) R(-)-isomers.  A racemic mixture is one that has equal amounts of “left- and right-handed” enantiomers of a particular chiral molecule.  For example, omeprazole (PRILOSEC) is a racemic mixture; esomeprazole, the “right-handed” enantiomer of the racemate, is approved under the brand name NEXIUM.

FDA has for decades treated single enantiomers of approved racemates as previously approved active moieties not eligible for 5-year new chemical entity exclusivity (but rather 3-year exclusivity).  In the preamble to FDA’s July 1989 proposed regulations implementing the Hatch-Waxman Act, the Agency stated this position:

FDA will consider whether a drug contains a previously approved active moiety on a case-by-case basis.  FDA notes that a single enantiomer of a previously approved racemate contains a previously approved active moiety and is therefore not considered a new chemical entity.

The Senate-passed version of the FDA Revitalization Act (“FDARA”), however, would provide sponsors the opportunity to elect 5-year exclusivity under certain circumstances.  The FDARA provision would also apparently put to bed a 1997 FDA notice in which the Agency requested comment on whether granting a 5-year period of exclusivity to enantiomers of previously approved racemates would encourage medically significant innovation.

Specifically, FDARA § 264 would amend the FDC Act to add § 505(t) –“Certain Drugs Containing Single Enantiomers”– to provide that:

if an application is submitted under [§ 505(b)] for a non-racemic drug containing as an active ingredient a single enantiomer that is contained in a racemic drug approved in another application under [§ 505(b)], the applicant may, in the application for such non-racemic drug, elect to have the single enantiomer not be considered the same active ingredient as that contained in the approved racemic drug . . . .

Thus, if a single enantiomer is not considered to be the same active ingredient as that contained in the approved racemic drug, FDA may consider it to be a new chemical entity eligible for 5-year exclusivity.  There are, however, several provisos . . . .

The election of 5-year exclusivity can only be made if:

(A)(i) the single enantiomer has not been previously approved except in the approved racemic drug; and (ii) the application submitted under [§ 505(b)] for such non-racemic drug –

(I) includes full reports of new clinical investigations (other than bioavailability studies) – (aa) necessary for the approval of the application under subsections (c) and (d); and (bb) conducted or sponsored by the applicant; and

(II) does not rely on any investigations that are part of an application submitted under [§ 505(b)] for approval of the approved racemic drug; and

(B) the application submitted under [§ 505(b)] for such non-racemic drug is not submitted for approval of a condition of use— (i) in a therapeutic category [(as identified in the list referenced at 42 U.S.C. § 1860D-4(b)(3)(C)(ii))] in which the approved racemic drug has been approved; or (ii) for which any other enantiomer of the racemic drug has been approved.

In addition to these requirements, which essentially necessitate the submission of a “full” 505(b)(1) NDA, FDARA § 264 also includes two significant limitations that may offset the incentive for electing 5-year exclusivity. 

First, FDA may not approve a single enantiomer of a previously approved racemate granted 5-year exclusivity for any condition of use in the therapeutic category in which the racemic drug has been approved “[u]ntil the date that is 10 years after the date of approval of a non-racemic drug described in [proposed FDC Act § 505(t)(1)].” 

Second, “the labeling of a non-racemic drug described in [proposed FDC Act § 505(t)(1)] and with respect to which the applicant has made the election provided for by such paragraph shall include a statement that the non-racemic drug is not approved, and has not been shown to be safe and effective, for any condition of use of the racemic drug.”

Whether FDARA § 264 (if enacted) will encourage the development of single enantiomers for new therapeutic uses remains to be seen.  Perhaps for this reason, FDARA § 264 is a trial balloon that Congress would need to reauthorize after it sunsets in 2012 (and once Congress evaluates its costs and benefits).

RELATED READING:

• FDA policy document on stereoisomeric drugs