By Kurt R. Karst –      

Representative Jo Ann Emerson (R-MO) has introduced a bill to amend the FDC Act that would prohibit the marketing of authorized generics during a generic applicant’s 180-day exclusivity period.  The bill, H.R. 573, is almost identical to the bill Rep. Emerson introduced during the 110th Congress – H.R. 806.  The Senate version of that bill was introduced by Senator Jay Rockefeller (D-WV) – S. 438, the Fair Prescription Drug Competition Act.  A Senate companion bill to Rep. Emerson’s latest bill has not yet been introduced. 

Interest in authorized generics has steadily increased over the past few years, particularly after FDA denied citizen petitions in 2004, concluding that “[t]he marketing of authorized generics during the 180-day exclusivity period is a long-standing, pro-competitive practice, permissible under the FDC Act,” and legal challenges upheld FDA’s determination.  (See an article we published on the topic in RAPS Focus.)  The Federal Trade Commission (“FTC”) is currently studying the competitive effects of authorized generics.  Some legislative action has already been taken with respect to gathering information on authorized generics.  As we previously reported, the FDA Amendments Act amended the FDC Act to create new § 505(t) – “Database for Authorized Generic Drugs” – that requires FDA to compile and publish a complete list of all authorized generic drugs identified in annual reports submitted to the Agency since January 1, 1999.  FDA has issued a direct final rule, as well as a companion proposed rule, to implement FDAAA § 920.  Among other uses, this list is intended to assist the FTC as the Commission moves ahead with its study.

Pundits have predicted that a large amount of FDA-related legislation will be introduced in the 111th Congress.  To help our loyal FDA Law Blog readers follow these legislative developments, we have decided to create a new tracker feature on the blog – the “FDA Legislation Tracker.”  The legislation tracker, along with our “FDC Act § 505(q) Citizen Petition Tracker,” appear on the right-hand side of FDA Law Blog.  We will update the legislation tracker as new bills are introduced.  To access the text and a summary of legislation identified in the tracker, press and hold the control key on your keyboard and click on the pdf icon.

Hyman, Phelps & McNamara, P.C. today posted on its website an updated version of its outline entitled “Application of Health Care Fraud and Abuse Laws to Pharmaceutical Marketing."  This 89-page outline, authored by Alan Kirschenbaum and Jeff Wasserstein,  provides a comprehensive overview of how the federal health care program antikickback law, the Federal False Claims Act, and other federal and state laws affect pharmaceutical marketing activities.  The outline focuses on the major problem areas for drug marketing under these laws, and, for each area, describes the pertinent safe harbors, OIG advisory opinions, and major enforcement actions.  The outline also provides general guidelines for evaluating marketing proposals. 

This outline was first published by Hyman, Phelps & McNamara, P.C. in 1996, and has been updated periodically.  The new version is current as of January 31, 2009.  Although the primary focus is on marketing of pharmaceuticals, much of the outline is equally applicable to the marketing of medical devices, and the major government actions against device companies are discussed.

By Anne Marie Murphy –

We previously reported on the Consumer Product Safety Improvement Act of 2008 (“CPSIA”), which makes sweeping changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”).  CPSIA Section 102(a), paragraph (1), amends the Consumer Product Safety Act (“CPSA”) to require each importer or domestic manufacturer of any product that is subject to any CPSC rule, ban, standard, or regulation to issue a certificate based on specific tests or a reasonable testing program that the product complies with such CPSC requirements.  CPSIA Section 102(a), paragraphs (2) and (3), require that certification of compliance for certain children’s products be based on third-party testing, and set forth a timeline for implementation of the third-party testing requirements.

On Friday evening, even as the regulated industry continued to scramble to comply, the CPSC announced a one-year stay of enforcement (with certain exceptions) of the certification and testing requirements.  The CPSC explained: 

The Commission is aware that there is substantial confusion as to which testing and certification requirements . . . apply to which products under the Commission’s jurisdiction, what sort of testing is required where the provisions do apply, whether testing is necessary for children’s products that may not by their nature contain lead, whether testing to demonstrate compliance must be conducted on the final product rather than on its parts prior to assembly or manufacture, whether manufacturers and importers must issue certificates of compliance to address the labeling requirements under the Federal Hazardous Substance Act (“FHSA”), and what sort of certificate must be issued and by whom.

In addition to substantial confusion over the requirements, the CPSC noted industry complaints concerning the expense of testing products that will ultimately be exempt by regulation and the Commission’s own lack of resources as reasons for the stay. 

The stay covers all testing and certification requirements except the following:

1. Any testing and certification requirements that were in place prior to CPSIA.
2. Four requirements (when they become effective) for third-party testing of children’s products for which the CPSC has already issued criteria for acceptance of third party testing laboratories:
• lead paint;
• cribs and pacifiers;
• small parts; and
• metal components of children’s metal jewelry.
3. Any certifications that are expressly required by CPSC regulation (e.g., bicycle helmets).
4. Certifications required by the Virginia Graeme Baker Pool & Spa Safety Act.
5. Certifications of compliance required for all terrain vehicles (“ATVs”).
6. Any voluntary guarantees provided for in the Flammable Fabrics Act (“FFA”).

The CPSC emphasized that the stay applies to testing and certification requirements.  Products must comply with the underlying safety requirements, including the upcoming CPSIA limits on lead and phthalates in children’s products.

By Kurt R. Karst –      

As a follow-up to our recent post on obtaining orphan drug designation and approval based on a major contribution to patient care – the so-called “MC-to-PC” orphan drug designation and approval – we thought we would post on another rarity in the orphan drug world: the “cost recovery” orphan drug designation and approval. 

The FDC Act, as amended by the Orphan Drug Act, and FDA’s orphan drug regulations at 21 C.F.R. Part 316 provide two routes for obtaining designation and approval of a drug for a rare disease or condition (i.e., an “orphan drug”).  Orphan drug designation and approval may be granted: (1) on the basis that a product is intended to treat a disease or condition that has a U.S. prevalence of less than 200,000 persons (FDC Act § 526(a)(2)(A)); or (2) if a disease or condition affects 200,000 or more individuals, then if a sponsor can show that there is no reasonable expectation that the costs of developing and making available the drug will be recovered from U.S. sales (FDC Act § 526(a)(2)(B)). 

An orphan drug designation request citing cost recovery as a designation basis must include certain documentation (with appended authoritative references) to demonstrate that “there is no reasonable expectation that costs of research and development of the drug for the indication can be recovered by sales of the drug in the United States.”    Such documentation must include the following information (from FDA’s orphan drug regulations at 21 C.F.R. Part 316):

• “Data on all costs that the sponsor has incurred in the course of developing the drug for the U.S. market,” including “nonclinical laboratory studies, clinical studies, dosage form development, record and report maintenance, meetings with FDA, determination of patentability, preparation of designation request, IND/marketing application preparation, distribution of the drug under a ‘treatment'’ protocol, licensing costs, liability insurance, and overhead and depreciation.”  In addition, the sponsor must “demonstrate the reasonableness of the cost data.  For example, if the sponsor has incurred costs for clinical investigations, the sponsor shall provide information on the number of investigations, the years in which they took place, and on the scope, duration, and number of patients that were involved in each investigation.” 

• “If the drug was developed wholly or in part outside the United States,” then the designation request must also include: (1) “[d]ata on and justification for all costs that the sponsor has incurred outside of the United States in the course of developing the drug for the U.S. market,” including an explanation of “the method that was used to determine which portion of the foreign development costs should be applied to the U.S. market, and what percent these costs are of total worldwide development costs,” and “[a]ny data submitted to foreign government authorities to support drug pricing determinations;” and (2) “[d]ata that show which foreign development costs were recovered through cost recovery procedures that are allowed during drug development in some foreign countries” (e.g., revenues from charging for investigational drug). 

• “[A] clear explanation of and justification for the method that is used to apportion the development costs among the various indications” where “the drug has already been approved for marketing for any indication or in cases where the drug is currently under investigation for one or more other indications (in addition to the indication for which orphan-drug designation is being sought).” 

• “A statement of and justification for any development costs that the sponsor expects to incur after the submission of the designation request.” 

• “A statement of and justification for production and marketing costs that the sponsor has incurred in the past and expects to incur during the first 7 years that the drug is marketed.” 

• “An estimate of and justification for the expected revenues from sales of the drug in the United States during its first 7 years of marketing,” which should “assume the total market for the drug is equal to the prevalence of the disease or condition that the drug will be used to treat.”    

• Information on “each country where the drug has already been approved for marketing for any indication,” including “the annual sales and number of prescriptions in each country since the first approval date.” 

• “A report of an independent certified public accountant in accordance with Statement on Standards for Attestation established by the American Institute of Certified Public Accountants on agreed upon procedures performed with respect to the data estimates and justifications submitted pursuant to [21 C.F.R § 316.21].” 

In addition to the above-referenced documentation, a sponsor requesting orphan drug designation pursuant to FDC Act § 526(a)(2)(B) must, “at FDA’s request, allow FDA or FDA-designated personnel to examine at reasonable times and in a reasonable manner all relevant financial records and sales data of the sponsor and manufacturer.” 

To our knowledge, of the more than 325 designated and approved orphan drugs, there are only three drugs have been designated and approved based on a showing that a disease or condition affects 200,000 or more U.S. individuals and where the sponsor showed that there is no reasonable expectation that the costs of developing and making available the drug will be recovered from U.S. sales: (1) SUBUTEX (buprenorphine HCl) Sublingual Tablets; (2) SUBOXONE (buprenorphine HCl; naloxone HCl dehydrate) Sublingual Tablets; and, most recently, (3) EVISTA (raloxifene HCl) Tablets.

FDA approved SUBUTEX (NDA #20-732) and SUBOXONE (NDA #20-733) on October 8, 2002 for the treatment of opioid dependence.  FDA designated SUBUTEX as an orphan drug for this indication on June 15, 1994, and designated SUBOXONE for this indication on October 27, 1994.  In each case, the sponsor put forth two arguments for designation – based on FDC Act § 526(a)(2)(A) (prevalence) and § 526(a)(2)(B) (cost recovery).  Although FDA did not agree with the sponsor’s prevalence figures, the Agency concluded that the economic analysis and supporting documentation submitted by the sponsor were sufficient to support a cost recovery designation.

FDA approved EVISTA (NDA #22-042) on September 13, 2007 for reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis and reduction in risk of invasive breast cancer in postmenopausal women at high risk for invasive breast cancer.  Despite some questions concerning the sponsor’s cost recovery analysis, FDA designated the drug as an orphan drug on July 14, 2005 pursuant to FDC Act § 526(a)(2)(B) for the reduction of the risk of breast cancer in postmenopausal women.  Interestingly, FDA notes in its designation recommendation that the sponsor should present certain information to the Agency post-approval to support the cost recovery designation.  FDA states that “[t]his information should be presented . . . after a certain period of postmarketing experience is available . . . .  At each of these time points, [FDA] will need to determine if the designation and/or marketing exclusivity should remain in place or whether the designation and/or exclusivity should be revoked as permitted under 21 CFR 316.29.” 

The latest issue of the Food and Drug Law Institute’s “Update” magazine features articles written by four Hyman, Phelps & McNamara, P.C. attorneys.  The first article, titled “Imported Products – FDA Is Not Fooling Around,”  was written by Dara Katcher Levy and John R. Fleder.  It provides background information on FDA’s regulation of imports, discusses inconsistencies in FDA’s enforcement actions against imported articles, and analyzes FDA’s increasing use of very broad import alerts and the adverse effects that these are having on importers. 

The second article, titled “FDA’s Implementation of FDAAA’s Food-Related Provisions: A Work In Progress,” was written by Ricardo Carvajal and Diane B. McColl.  It discusses sections 417 and 301(ll) of the FDC Act, which were added by the FDA Amendments Act of 2007.  Section 417 requires FDA to establish a reportable food registry and an electronic portal to which  responsible parties must submit instances of reportable food.  FDA is expected to implement the reportable food registry in Spring 2009.  Section 301(ll) makes it a prohibited act to market a food to which has been added a new drug, a licensed biologic, or a “drug” or “biological product” for which substantial clinical investigations have been instituted and their existence made public (with certain exceptions). 

By Wes Siegner & Ricardo Carvajal – 

Last August, FDA published data that the Agency had gathered on the content of lead in 324 vitamin products labeled for use by women or children. FDA made clear that its estimates of lead exposures for all of the products surveyed were below the safe/tolerable exposure levels for children, pregnant and lactating women, and adult women.  However, it appears that FDA’s estimates of lead exposures for some products fell above the safe harbor levels for lead established under California’s Proposition 65. 

Not surprisingly, California’s Attorney General, joined by a number of county district attorneys, has filed suit against dozens of dietary supplement manufacturers alleging that they marketed vitamin supplements containing lead “without first giving clear and reasonable warning,” as required under Proposition 65.  The complaint asks for civil penalties and injunctive relief, among other things.  It is easy to imagine that this scenario could repeat itself with other contaminants that are the focus of future FDA surveys or of FDA’s increased inspectional activities under the recently promulgated dietary supplement Current Good Manufacturing Practices regulation.

By John A. Gilbert & Larry K. Houck –

The Drug Enforcement Administration (“DEA”) has published advance notice of proposed rulemaking that solicits comments on the disposal of controlled substances by non-registrants.  This proposal for the first time could authorize DEA registrants to accept controlled substances back from patients for disposal.  It could also place additional burdens on registrants, particularly pharmacies, who may be inundated with requests to dispose of unused controlled substances. 

Under the Controlled Substances Act (“CSA”) and its regulations, controlled substances may be transferred only between DEA registrants, including manufacturers, distributors, pharmacies and practitioners.  Patients for obvious reasons, are exempt from DEA registration.  Long term care facilities such as nursing homes, retirement facilities and other institutions that provide extended health care to resident patients are also exempt because they hold prescribed controlled substances in a custodial capacity for their patient-residents.   

Because DEA registrants may not receive controlled substances from non-registrants, patients and long term care facilities cannot transfer unused or unwanted controlled substances to a DEA registrant.  For example, current law prohibits patients and long term care facilities from returning controlled substances to the dispensing pharmacies or transferring the drugs to reverse distributors, the registrants specifically authorized to receive and dispose of controlled substances.  Such prohibition would seem to contradict DEA’s mission to prevent the diversion of legitimate controlled substances because it could lead to non-registrants stockpiling unwanted drugs.

Under current law, patients and long term care facilities who wish to dispose or destroy controlled substances and do not want to just throw them away or flush them down the drain must submit a letter to the local DEA office for authorization.  The authorization may include transfer of the drugs to a registrant, delivery to a DEA agent or local DEA office, or destruction in the presence of a DEA agent.  Few consumers are aware of this regulation and the requirement can present a burden on long term care facilities who may need to dispose of controlled substances on a frequent basis.

On a case-by-case basis, DEA recently granted temporary permission to law enforcement agencies who have requested authorization to accept unwanted controlled substances from patients for disposal. 

The advanced notice of proposed rulemaking recognizes that there may be additional appropriate methods for disposing unwanted controlled substances held by non-registrants and DEA is requesting public comments on disposal options that minimize the risk of diversion, are consistent with the CSA and its regulations and which are environmentally sound.

Comments should be submitted to DEA on or before March 23, 2009.

By Jamie K. Wolszon –

On January 22, Senators Herb Kohl (D-WI) and Charles Grassley (R-IA) introduced the Physician Payments Sunshine Act of 2009, which would require drug, biologic, medical device, and other medical supply manufacturers to disclose to the Secretary of Health and Human Services the amount of payments or other transfers of value they provide to physicians.  The reporting requirement would apply to manufacturers of products for which payments are made under Medicare, Medicaid, or the State Children’s Health Insurance Program (“SCHIP”). 

We previously reported on a predecessor of this bill, the Physician Payments Sunshine Act of 2007.  We also previously reported that Representatives Peter DeFazio (D-OR) and Pete Stark (D-CA), Chairman of the Ways and Means Subcommittee, introduced a bill in the House similar to the Senate 2007 version in March of 2008. 

Some of the more significant changes between the 2007 and 2009 versions of the Senate legislation are as follows:
 
Frequency of Reports; Threshold for Reporting.  Unlike the 2007 legislation, which required quarterly reporting, the 2009 version requires manufacturers to submit the specified information about each transfer or payment to physicians in annual reports.  The annual reporting requirement is triggered by transfers of value or payments of $100 or more per year per “covered recipient.” Covered recipients include a physician, a medical practice or a group practice.  However, if the annual report requirement applies, the manufacturer must report each payment or transfer, regardless of how small the value.  Manufacturers would need to submit their first annual report to the Secretary of HHS on March 31, 2011 under the 2009 legislation.

No Exclusion for Small Businesses.  Whereas the 2007 legislation would have applied only to “an entity with annual gross revenues that exceed $100,000,000,”  the 2009 legislation contains no such annual gross revenue minimum. The Advanced Medical Technology Association (AdvaMed) has issued a statement which identifies the lack of an exemption for small businesses as a possible area of concern:

As we review this legislation, we also will be mindful of the unique needs of medical device companies, many of whom are small businesses that may lack the resources to meet the administrative requirements set forth in the bill, and the need to include physician-owned entities, distributors and a group purchasing organization (GPO) in the compliance requirements set forth in the legislation. 

Disclosure of Ownership Interests.  The 2009 legislation includes a new provision that would require drug, biologic and device manufacturers, and group purchasing organizations that purchase, arrange for, or negotiate the purchase of a covered drug, device, biologic or medical supply, to report information regarding certain ownership interests in the company that a physician or a physician’s immediate family member has in the manufacturer or GPO during that year.  The ownership interests that require reporting do not include interests in certain publicly held securities or mutual funds.

Exclusions.  The list of exclusions from reportable transfers has been considerably expanded in the 2009 bill.  Excluded from the reporting requirements are samples, educational materials for patients, trial loans of devices, items provided under a warranty, discounts and rebates, in-kind charity donations, returns on investments in a publicly traded security or mutual fund; and transfers of value to a physician who is a patient.

Preemption. Several states, including Minnesota, Massachusetts, Vermont, Maine, West Virginia, and the District of Columbia have existing gift disclosure laws.  Unlike the 2007 version, the 2009 legislation includes language, effective January 1, 2010, pre-empting state laws that require reporting of payments or other transfers of value to physicians.  However, the bill would not preempt state requirements for reporting of information not required under the bill.

Federal preemption was an important to concession to industry.  As stated by AdvaMed in its press release: “[I]t is important that any federal disclosure legislation create a uniform national standard to prevent a patchwork approach by all 50 states.”

Penalty Scheme Differentiates between Accidental and “Knowing” Failure to Report.  The 2007 version of the legislation subjected any manufacturer who fails to report to a civil monetary penalty of $10,000 to $100,000 for each offense.  The new legislation, however, levies greater penalties on the “knowing failure” to report.  A failure to report exposes the manufacturer to a civil monetary penalty of not less than $1,000, but not more than $10,000, for each payment or other transfer of value or ownership or investment interest that the manufacturer does not report, with a maximum penalty of $150,000 per annual report. By contrast, a knowing failure to report is subject to a civil monetary penalty of $10,000 to $100,000 for each offense, with up to $1 million in civil monetary penalties per annual report.

Delayed Reporting for Payments Under Product Development Agreements and Clinical Investigations.  The 2007 legislation included a provision that exempted payments made for the general funding of a clinical trial.  The 2009 legislation instead includes a provision that would delay the reporting requirement for payments that manufacturers make under product development agreements and in connection with clinical investigations.  The manufacturer would not have to report those payments until the earlier of: (1) FDA approval or clearance of the product; or (2) two calendar years after the date of the payment. 

By Diane B. McColl & Ricardo Carvajal –      

In an attempt to improve import safety and further implement its Food Protection Plan, FDA has issued a Guidance for Industry titled “Voluntary Third-Party Certification Programs for Foods and Feeds.”  The guidance recognizes that independent certification of a supplier’s compliance with food safety and security requirements has increasingly become a condition of doing business in the U.S. and elsewhere, and that ensuring the quality of certification programs could help FDA make more effective use of its resources and reduce the likelihood that businesses will be subject to multiple audits by different certification programs. 

The guidance is billed as a step toward “future recognition” of specific certification programs.   If and when FDA decides to recognize specific certification programs, then foods from an establishment certified by a recognized certification program would be looked upon favorably by FDA.  In FDA’s words, recognition would mean that “FDA has determined that certification may be a reliable reflection that the foods from an establishment certified by the certification body meet applicable FDA requirements,” among other criteria.

Although participation in a recognized certification program would be voluntary and would not affect the rights or obligations of an establishment, there are a number of potential carrots under consideration.  First, being certified could reduce the likelihood of inspection by FDA or expedite entry into the U.S.  Second, certified establishments could be acknowledged through inclusion in a public database.  Third, certified establishments might be excluded more quickly by FDA during outbreaks of foodborne illness.  Fourth, certification could aid removal of a product from an import alert.  Finally, although not explicitly mentioned in the guidance, we suspect that certification also could reduce the likelihood of inspection by state authorities.

Even if FDA does not go forward with recognition of specific certification programs, the criteria laid out in the guidance are likely to influence the operation and content of such programs.  In considerable detail, the guidance addresses a number of attributes of a “model” certification program, such as ensuring that the certification body has adequate authority, auditors are appropriately qualified and trained, audits are performed according to written policies and procedures, audits and auditors are monitored to provide quality assurance, appropriate steps are taken when there is noncompliance, and there is ongoing self-assessment of the certification program.

By Kurt R. Karst –      

Those following the subject of preemption of conflicting state laws have speculated for months whether the Obama Administration might undo the position FDA has advanced in Federal Register announcements and in court filings in which the Agency has generally staked out a pro-preemption position.  Earlier today, Inside Health Policy published a report that might offer some clue as to the Obama Administration’s plans. 

On January, 23, 2009, just three days after the White House issued a memorandum ordering that “no proposed or final regulation should be sent to the Office of the Federal Register . . . for publication unless and until it has been reviewed and approved by a department or agency head appointed or designated by the President after noon on January 20, 2009,” and just two days after the Office of Management and Budget issued a memorandum providing guidance on the White House memorandum, FDA’s advance display Federal Register feature of its website included a 96-page final rule – signed off on by FDA’s Associate Commissioner for Policy and Planning on January 15, 2009 – that would have required new organ-specific warnings and related labeling for Over-The-Counter (“OTC”) Internal Analgesic, Antipyretic, and Antirheumatic (“IAAA”) drug products.  The final rule included the following statements concerning preemption:

We have determined that the rule will have a preemptive effect on State law. Section 4(a) of [Executive Order 13132] requires agencies to “construe . . . a Federal statute to preempt State law only where the statute contains an express preemption provision or there is some other clear evidence that the Congress intended preemption of State law, or where the exercise of State authority conflicts with the exercise of Federal authority under the Federal statute.”  Section 751 of the Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 379r(a)) is an express preemption provision.  Section 751r(a)) provides that “no State or political subdivision of a State may establish or continue in effect any requirement– . . . (1) that relates to the regulation of a drug that is not subject to the requirements of section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or in addition to, or that is otherwise not identical with, a requirement under this Act, the Poison Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling Act (15 U.S.C. 1451 et seq.).” Currently, this provision operates to preempt States from imposing requirement related to the regulation of nonprescription drug products. Section 751(b) through (e) of the act outlines the scope of the express preemption provision, the exemption procedures, and the exceptions to the provision.

This final rule will require important new organ-specific warnings and related labeling requirements for OTC IAAA drug products. The new labeling informs consumers about the risk of liver injury when using acetaminophen and the risk of stomach bleeding when using [non-steroidal anti-inflammatory drugs].  Although this final rule would have a preemptive effect, in that it would preclude States from promulgating requirements related to these drug products that are different from or in addition to, or not otherwise identical with a requirement in the final rule, this preemptive effect is consistent with what Congress set forth in section 751 of the act. Section 751(a) of the act displaces both state legislative requirements and state common law duties. We also note that even where the express preemption provision is not applicable, implied preemption may arise (see Geier v. American Honda Co., 529 US 861 (2000)).

We believe that the preemptive effect of the final rule would be consistent with Executive Order 13132.  Section 4(e) of the Executive Order provides that “when an agency proposed to act through adjudication or rulemaking to preempt state law, the agency shall provide all affected State and local officials notice and an opportunity for appropriate participation in the proceedings.”

Curiously, the version of the final rule, which was approved prior to Inauguration Day, was reportedly taken down from the advance display Federal Register feature of FDA’s website late on January 23rd.  While the posting of the final rule on FDA’s Federal Register website might have been an error and its removal from the website might have been done by FDA simply in an effort to comply with the Obama Administration’s directive, it might also signal the new Administration’s intent to take a much closer look at the issue of preemption, and perhaps take an FDA position that is different from that supported by the Bush Administration. 

By Diane B. McColl & Ricardo Carvajal –

In response to a citizen petition filed on behalf of a pharmaceutical company, FDA has determined that products containing pyridoxamine (a form of vitamin B6) are not dietary supplements within the meaning of FDC Act § 201(ff) and “may not be marketed as such.”  Although pyridoxamine is a dietary ingredient within the meaning of § 201(ff)(1), FDA determined that pyridoxamine is excluded under § 201(ff)(3) because: (1) pyridoxamine is authorized for investigation as a new drug for which substantial clinical investigations have been conducted and their existence made public; and (2) there is no “independent, verifiable evidence” of prior marketing of pyridoxamine as a food or dietary supplement.  Among the conclusions reached by FDA:

• an “article authorized for investigation as a new drug” includes not only the active ingredient (i.e., pyridoxamine hydrochloride), but also the active moiety (i.e., pyridoxamine);
• consistent with the position taken by FDA in Pharmanex v. Shalala, 2001 WL 741419, the “mere presence” of a substance in the food supply, even at high levels in foods, does not alone constitute marketing within the meaning of § 201(ff)(3)(B);
• affidavits, without more, are insufficient to support a claim of prior marketing.

FDA further states that "the marketing of pyridoxamine in a dietary supplement is essentially equivalent to the marketing of an investigational new drug as a dietary supplement."  Thus, it appears that FDA regards products containing pyridoxamine as drugs subject the new drug provisions of the FDC Act.

The implications of FDA’s § 201(ff)(3) analysis could be significant for the agency’s interpretation of § 301(ll).  As we have discussed in prior postings, § 301(ll) was added to the FDC Act by the FDA Amendments Act of 2007.  In relevant part, § 301(ll) prohibits the addition to food of an approved drug or a “drug” for which substantial clinical investigations have been instituted and their existence made public, unless the “drug” was first “marketed in food.”  We have noted that there are differences between the text of § 201(ff)(3)(B) and that of § 301(ll).  Whereas the former refers to an “article” that is “marketed as a food or dietary supplement,” the latter refers to a “drug” that is “marketed in food.”  These differences are among the issues on which FDA requested comment to gauge the potential impact of alternative interpretations of § 301(ll). Notwithstanding these differences, the rationale expressed by FDA in support of its determination with respect to pyridoxamine suggests that FDA is likely to adopt an interpretation of § 301(ll) that is much more favorable to the pharmaceutical industry than what many food and dietary supplement manufacturers have advocated.

By Riëtte van Laack & Ricardo Carvajal –

On January 15, the Center for Veterinary Medicine ("CVM") published its final guidance on “Regulation of Genetically Engineered Animals Containing Heritable Recombinant DNA Constructs.”  The final guidance describes CVM’s application of the FDC Act’s new animal drug provisions and FDA’s related regulations to genetically engineered animals and foods derived from those animals. 

Under the FDC Act, an rDNA construct in a genetically engineered animal that is intended to affect the structure or function of that animal is a drug.  Consequently, the new animal drug provisions apply to such rDNA constructs.  Each new animal drug approval ("NADA") covers all animals that contain the same rDNA construct, so long as those animals are derived from the same transformation event (a transformation event is the introduction of an rDNA construct into the germline of an animal)  However, different transformation events are subject to separate NADA’s because animals derived from different transformation events are likely to have the rDNA construct present at different sites in the genome, which can affect the expression of the construct and the animal’s health.  Although the rDNA construct is the regulated article, the guidance refers to regulation of the construct as “regulation of the GE animal.” 

CVM’s final guidance also clarifies that the U.S. approach is consistent with the recommendations of the Codex Alimentarius Commission ("CAC").  The CAC, created by the Food and Agriculture Organization of the United Nations ("FAO") and the World Health Organization ("WHO"), published its Guideline for the Conduct of Food Safety Assessment of Foods Derived from Recombinant DNA Animals in July 2008.   [www.codex.alimentarius.net/download/standard/11023/CXG-068e.pdf]

CVM’s final guidance is a revised version of the September 2008 draft guidance.  Over 28,000 comments were submitted to CVM in response to the 2008 draft guidance.  The Agency’s responses to these comments are available here.  Simultaneous with the issuance of the final guidance, CVM updated its “Fact Sheet on Genetically Engineered Animals” and “Genetic Engineering Technology General Q&A.”

GE animals are developed for a variety of purposes, including production of pharmaceuticals and organs for transplantation (biopharming), hypoallergenic pets, improved disease resistance, increased performance characteristics, and animal models for human disease.  According to the final guidance, all GE animals are subject to premarket approval, but CVM intends to exercise enforcement discretion based on risk.  For example, CVM may decide not require a NADA for aquarium fish genetically engineered to fluoresce in the dark, or for GE engineered laboratory animals.  Moreover, CVM does not intend to take enforcement against “GE animals of non-food-species that are regulated by other government agencies or entities, such as GE insects” regulated by USDA’s Animal and Plant Health Inspection Service. 

Although the final guidance discusses the investigational new animal drug requirements for GE animals (meaning the rDNA constructs in such animals), its primary focus is the NADA requirements for GE animals.  See 21 C.F.R. Parts 511 and 514.  With the exception of the veterinary food directive, all NADA requirements apply. 

As with any NADA for food producing animals, CVM will not approve the rDNA constructs in a GE animal unless it has determined that any food derived from the GE animal is safe.  CVM’s evaluation is consistent with the CAC Guideline and includes assessment of direct toxicity, including allergenicity, and “potential indirect toxicity with both the [rDNA construct] and its expressed product.”  Only if “food from a GE animal is [materially] different from that of its [non-GE] counterpart” must the food from a GE animal be labeled to indicate that it originates from a GE animal.

Just like sponsors of other NADAs, sponsors of a GE animal must comply with the statutory registration and drug listing requirements and the requirements for adverse event and periodic reporting. However, CVM has yet to develop guidance as to how GMP requirements for GE animals can be met. 

Thus far, CVM has not approved any NADAs for GE animals.  The guidance repeatedly encourages developers to consult with CVM early and often about many aspects of the preparation and submission of a NADA, including the preparation of an environmental assessment that addresses issues and impacts related to “the use and disposal of the GE animal and its final product” (in the absence of a categorical exclusion, preparation of an environmental assessment is required under FDA regulations implementing the National Environmental Policy Act).  In addition, CVM intends to provide transparency of the GE animal review process by holding public advisory committee meetings prior to approval.  As with other NADA approvals, CVM will publish a detailed summary of the basis for its approval of a GE animal.  Language in the guidance suggests that a number of details have yet to be worked out, particularly with respect to coordination with other federal agencies, and that additional guidance documents on specific issues may be forthcoming. 

By Ricardo Carvajal –      

A report issued by Project on Emerging Nanotechnologies ("PEN"), a partnership between the Woodrow Wilson International Center for Scholars and the Pew Charitable Trusts, concludes that FDA is not prepared to effectively regulate dietary supplements that use “engineered nanomaterials” due to a lack of information, insufficient resources, and inadequate statutory authorities.  The report is especially critical of FDA’s apparent inability to take quick action against dietary ingredients for which manufacturers lack adequate substantiation of safety, and cites as an example FDA’s multi-year effort to get ephedrine alkaloids off the market. 

The report recommends that Congress authorize FDA to: (1) require registration of all dietary supplements that contain “engineered nanoparticles;” (2) establish safety standards for such supplements; (3) review, and require a demonstration of safety for, all such supplements on the market; (4) require premarket safety testing of such supplements; and (5) require reporting of all adverse events for such supplements.  The report asks that these additional authorities be coupled with adequate funding to enable their implementation.  The report references the National Nanotechnology Initiative's definition of nanotechnology, but does not explicitly define the terms "engineered nanomaterials" or "engineered nanoparticles," nor does it take on the question of how those terms should be defined for regulatory purposes.

The report follows closely on the heels of a statement by PEN urging FDA to issue guidance that addresses the question of how existing “generally recognized as safe” ("GRAS") and food additive regulations apply to nanomaterials.  That statement quotes Andrew Maynard (PEN’s chief science advisor) as saying that, “The time may come, when the body of scientific evidence demonstrating the safety of a nanoscale food additive is sufficient to meet the GRAS standard. But the science is not close to meeting that level of confidence now.”

Ricardo Carvajal of Hyman, Phelps & McNamara, P.C. will be moderating panels or speaking in two upcoming conferences that address dietary supplement and food regulatory issues.  The first is a Food and Drug Law Institute conference titled “What you Need to Know Now about Emerging Dietary Supplements Issues & Trends,” January 29-30, at the L’Enfant Plaza Hotel in Washington, DC.  For information and registration, click here. Conference sessions include: 

• Formulation and review of structure/function claims and health claims for dietary supplements
• Review of recent FDA enforcement actions concerning dietary supplements
• Handling an FDA Good Manufacturing Practice (GMP) inspection, visit and audit
• Review of recent Federal Trade Commission (FTC) enforcement actions
• Dietary supplement substantiation scientific perspective
• Codes of conduct and self-regulation
• Adverse Event Reporting (AER)
• New Dietary Ingredients (NDI’s) and GRAS status
• Emerging topics (e.g., FDAAA section 912)

The second conference is an American Bar Association Section of Litigation teleconference titled “Hot Topics in Food Law II,” February 10 from 1 to 2 p.m. ET.  For information and registration, click here.  Issues to be discussed include:

• Pervasiveness of melamine, current cases and preventive measures to stay out of the fray
• How BPA became an issue and what the real public health risk is
• Differences between FDA’s regulation of contaminants and unsafe food additives
• Differences in how products labeled “natural,” “organic,” or “sustainable” are regulated, current cases, and the growing importance of this issue
• Risk prioritization and risk management strategies
 

By Ricardo Carvajal –      

FDA has issued a proposed rule that would amend the standard of identity for yogurt and revoke the regulations on standards of identity for lowfat and nonfat yogurt.  Under § 401 of the FDC Act, FDA has the authority to establish a reasonable definition and standard of identity for any food to “promote honesty and fair dealing in the interest of consumers.”  Currently, there are separate standards of identity for yogurt, lowfat yogurt, and nonfat yogurt.  Under FDA’s proposal, there would be a single standard of identity for yogurt.  This standard of identity could be modified to produce lower-fat versions under 21 C.F.R. 130.10, which sets out requirements for foods named by use of a nutrient content claim (e.g., “low fat”) and a standardized term (e.g., “yogurt”).

In considering how to amend the standard of identity for yogurt, FDA reached a number of tentative conclusions, a few of which we highlight here.  First, the presence of live and active cultures would not be required, either at the time of manufacture or at the retail level.  However, yogurt that is not heat-treated after culturing and that contains a specified amount of live and active cultures could bear an optional labeling statement to that effect.  Second, reconstituted forms of cream and milk would be permitted as basic ingredients in the manufacture of yogurt, but whey protein concentrate would not be.  Third, the use of safe and suitable preservatives as optional ingredients would be permitted. 

FDA’s proposal states that, pending issuance of a final rule, FDA intends to consider the exercise of its enforcement discretion for yogurt products that comply with the proposed standard of identity.