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. 

By Riëtte van Laack –

On January 16, 2009, FDA announced the availability of its final guidance for industry, titled “Evidence-Based Review System for the Scientific Evaluation of Health Claims” (“2009 guidance”).  At the same time, the Agency withdrew the 2003 “Guidance for Industry and FDA: Interim Evidence-based Ranking System for Scientific Data” and its 1999 “Guidance for Industry: Significant Scientific Agreement in the Review of Health Claims for Conventional Foods and Dietary Supplements.”  FDA’s new guidance includes the Agency’s 1999 interpretation of “significant scientific agreement,” but omits the ranking of claims from the 2003 guidance.  The Agency “intends to reexamine [this] ranking systems and issue appropriate guidance once [its] studies are completed.”

The 2009 guidance is substantially similar to the draft guidance which was issued in June  2007.  The evaluation criteria and approach described in the guidance are not new and have been used in the evaluation of more recent qualified health claim petitions. 

Since FDA started evaluating health claim petitions, its approach has evolved with the two primary results being that approval has been harder to achieve and, given the expense and low probability of success, that industry is submitting very few petitions.  The most significant development appears to be FDA’s requirement for an intervention study to support a health claim.  Referencing examples of situations in which results from intervention studies contradict results of observational studies, such as the finding of a positive association between beta-carotene and reduced risk of lung cancer in observational studies and a negative association in later intervention studies, FDA has taken the position that observational studies alone are insufficient to support a health claim.  In addition, as has become evident in the evaluation of qualified health claim petitions concerning the effect of a food or substance on cancer, FDA will evaluate the evidence to support a substance disease relationship for each form of cancer individually, rather than cancer generally.  FDA’s approach recognizes that cancer is a “constellation of more than 100 different diseases” each with a unique mechanism, “risk factors, treatment options, and mortality risk.”

Compared to the 2007 draft guidance, the 2009 final guidance includes a new paragraph in which FDA further explains its requirement that the specific disease that is the subject of the claim be measured as a primary endpoint in supporting intervention studies.  In addition, the final guidance includes more examples of the type of factors that FDA will consider when evaluating the methodological quality of studies to support the proposed claim.  FDA’s position regarding validated biomarkers or surrogate endpoints had not changed.

By Anne Marie Murphy –

As we have reported previously, Title VIII of the Food and Drug Administration Amendments Act of 2007 (“FDAAA”) amended the Public Health Service Act (“PHS Act”) by adding new section 402(j), 42 U.S.C. § 282(j), which greatly expands the types of clinical trials that must be registered as well as the information on such trials that must be submitted to the clinical trials data bank, www.ClinicalTrials.gov.  One of the provisions requires that a certification of compliance accompany certain human drug, biological, and device applications and submissions to FDA:

(B) CERTIFICATION TO ACCOMPANY DRUG, BIOLOGICAL PRODUCT, AND DEVICE SUBMISSIONS. –  At the time of submission of an application under section 505 of the Federal Food, Drug, and Cosmetic Act, section 515 of such Act, section 520(m) of such Act, or section 351 of this Act, or submission of a report under section 510(k) of such Act, such application or submission shall be accompanied by a certification that all applicable requirements of this subsection have been met.

PHS Act § 402(j)(5)(B), 42 U.S.C. § 282(j)(5)(B).

The certification requirement went into effect on December 26, 2007.  Failure to submit a required certification or knowingly submitting a false certification are now prohibited acts under section 301(jj) of the Federal Food, Drug, and Cosmetic Act (“FDC Act”). 

Instead of identifying submissions that do not need a certification (as was done in the earlier draft guidance), in the final guidance FDA has identified those submissions that do require a certification.  FDA expects that the following application/submissions (including resubmissions) will be accompanied by a certification:

• Initial investigational new drug applications (“INDs”) and new protocol submissions to existing INDs;
• New drug applications (“NDAs”) and efficacy supplements to approved NDAs;
• Biologics license applications (“BLAs”) and efficacy supplements to approved BLAs;
• Abbreviated new drug applications (“ANDAs”);
• Premarket approval applications (“PMAs”);
• PMA panel track supplements;
• Humanitarian device exemptions (“HDEs”); and
• 510(k)s that refer to or include information on a clinical trial.

FDA takes the position in the final guidance that the plain language of the statutory requirement to submit a certification applies to all NDAs, BLAs, ANDAs, PMAs, PMA panel track supplements, HDEs, 510(k)s, and supplements or resubmissions of any such applications or reports.  FDA explains, however, that amendments to such pending applications are not “independently ‘applications’” and therefore need not be accompanied by a certification.  In addition, FDA indicates that it intends to exercise its enforcement discretion and not require that supplements to approved applications, other than efficacy supplements, be accompanied by a certification.

FDA’s explanation for its position that INDs and new protocol submissions to existing INDs must be accompanied by a certification is less cogent.  FDA’s reasoning is that an IND is authorized under section 505(i) of the FDC Act and defined by regulation as “an investigational new drug application.” 21 C.F.R. § 312.23(a) (emphasis added).  With regard to new protocol submissions to existing INDs, the guidance indicates that such a submission is “the investigational stage analog to an efficacy supplement to an NDA or BLA.” 

The final guidance leaves open the following question:  What is the meaning of a certification that accompanies a new IND or a new protocol submission to an existing IND?  The statutory requirement to register a clinical study does not take effect until 21 days after the first study subject has been enrolled, PHS Act § 402(j)(2)(C)(ii), 42 U.S.C. § 282(j)(2)(C)(ii), but a clinical study protocol must be submitted to an IND before the study begins.  Indeed, a new IND must be submitted to FDA at least 30 days before any clinical study is initiated.  Thus, the IND sponsor has to certify compliance with a requirement that has not yet taken effect.  PhRMA’s comments on the earlier draft guidance make this point, but it is not addressed in the final guidance. 

By Ricardo Carvajal –      

The Center for Science in the Public Interest ("CSPI") and a New York firm have filed a class action lawsuit against Coca-Cola and Energy Brands, Inc. over allegedly fraudulent marketing of Glaceau VitaminWater.  The complaint contends that defendants “deceptively promote VitaminWater as a healthy alternative to soft drinks,” notwithstanding the fact that “the amount of sugar in a bottle of VitaminWater is roughly equal to a can of soda.”  The complaint does not suggest that defendants failed to disclose the amount of sugar present in the product as required by FDA regulations.  But in plaintiffs’ view, “[r]easonable consumers should not be forced to look beyond the misleading representations on VitaminWater labels and in other marketing, advertising and promotional materials to discover the truth from the ingredients listed in small print on the back of the bottle.”  As evidence that Coca-Cola knows that VitaminWater is not a healthy alternative to soda, the complaint cites statements in the Form 10-K that Coca-Cola filed with the Securities and Exchange Commission for 2007, which acknowledge that “obesity and other health concerns” could affect the company’s profitability. 

By Kurt R. Karst -     

FDA has issued a draft guidance document, titled "Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act," explaining the Agency's interpretation of this new statutory provision.  FDC Act § 505(q) was added to the FDC Act by § 914 of the FDA Amendments Act ("FDAAA").  FDA's guidance document affirms some of the aspects of FDC act § 505(q) on which we previously reported.  The most recent version of our "FDC Act § 505(q) Citizen Petition Tracker," which tracks such petitions, is now available (and is updated on a regular basis).

Briefly, FDC Act § 505(q) provides that FDA shall not delay approval of a pending ANDA or 505(b)(2) application as a result of a citizen petition submitted to the Agency pursuant to 21 C.F.R. § 10.30 (citizen petition) or § 10.35 (petition for stay of action), unless FDA "determines, upon reviewing the petition, that a delay is necessary to protect the public health."  Under FDC Act § 505(q), "[FDA] shall take final agency action on a petition not later than 180 days after the date on which the petition is submitted."  FDA may not extend the 180-day period "for any reason," including consent of the petitioner.  FDC Act § 505(q) does not apply to all citizen petitions.  Excluded from the new law are petitions that relate "solely to the timing of the approval of an application pursuant to subsection (j)(5)(B)(iv)" (i.e., 180-day exclusivity), and petitions that are made by an ANDA or 505(b)(2) sponsor "that seeks only to have [FDA] take or refrain from taking any form of action with respect to that application."  Petitions subject to FDC Act § 505(q) must include a specific certification identified in the new law, and petition supplements and comments must include a specific verification statement.

FDA's new guidance document describes the Agency's interpretation of FDC Act § 505(q) on how FDA determines if FDC Act § 505(q) applies to a particular petition, and whether such a petition would delay approval of a pending ANDA or 505(b)(2) application.  In addition, the guidance describes how FDA interprets the certification and verification statement provisions, and "addresses the relationship between the review of petitions and pending ANDAs and 505(b)(2) applications for which the Agency has not yet made a decision on approvability."  Some important aspects of FDA's draft guidance are highlighted below.

*       FDC Act § 505(q) does not apply to pre-FDAAA petitions – i.e., those petitions that were submitted to FDA before September 27, 2007 – "because section 505(q) does not state that it applies retroactively to petitions submitted before the effective date."

*       Communications "regarding a citizen petition should be filed as comments in the appropriate docket, not to the NDA, ANDA, or 505(b)(2) application."

*       FDA interprets FDC Act § 505(q) "to apply only to petitions for which, at the time the petition is submitted, at least one ANDA or 505(b)(2) application related to the subject matter of the petition is pending.  If there is no related ANDA or 505(b)(2) application pending at the time that the petition is submitted, then we will not consider the provisions of section 505(q) to apply to the petition."  FDA encourages "all petitioners challenging the approvability of a possible ANDA or 505(b)(2) application to include the certification required in section 505(q)(1)(H)."

*       FDA interprets FDC Act § 505(q) "to apply only to petitions that request an action that could delay approval of a  pending ANDA or 505(b)(2) application.  If the action requested by the petition could not delay  approval of the application under any reasonable theory, we will not consider the provisions of section 505(q) to apply to the petition."

*       Under FDC Act § 505(q)(1)(E), FDA may summarily deny a petition submitted with the primary purpose of delaying approval of an application and does not on its face raise valid scientific or regulatory issues.  According to FDA, "[i]f we do not find that the petition may be summarily denied, we will determine if the petition would be the cause of a delay in an approval of an ANDA or 505(b)(2) application by using a but for test.  In other words, would the ANDA or 505(b)(2) application be ready for approval but for the issues raised by the petition?  If, regardless of the petition, the ANDA or 505(b)(2) application would not be ready  for approval, then section  505(q)(1)(A) would not be implicated.  If the ANDA or 505(b)(2) application would be ready for approval but for the petition, then we would next determine if a delay of approval is necessary to protect the public health."

*       Under FDC Act § 505(q)(1)(A), FDA "shall not" delay ANDA or 505(b)(2) application approval because of a petition unless the Agency determines that a delay is necessary to protect the public health.  According to FDA, "[w]e determine if a delay of approval is necessary to protect the public health based on our preliminary evaluation of the issues raised in the petition. The Agency considers the following: If the application were approved before the Agency completed the substantive review of the issues in the petition and, after further review, the Agency concluded that the petitioner's arguments against approval were meritorious, could the presence on the market of drug products that did not meet the requirements for approval negatively affect the public health?  If, after undertaking this analysis, we conclude that the public health could be negatively  affected, the Agency will conclude that a delay "is necessary to protect the public health" and will delay approval of the pending application."  Issues identified by FDA that could implicate the public health include bioequivalence and labeling "carve-out" issues.

*       With respect to the certification requirement, FDA states that "if a petition is missing the complete certification, we will not permit a petitioner to cure the deficiency by submitting a supplement to  add the certification to the petition.  Instead, "the petitioner should (1) submit a letter withdrawing the deficient petition pursuant to § 10.30(g) and (2) submit a new petition that contains the certification."  Of particular note, FDA states that "we consider the 180-day timeframe for FDA to respond to the petition to begin from the date of submission of the new, complete petition and not the original, deficient petition."

*       "The review of applications that may be affected by the petition is governed by a separate review process, which will not necessarily be completed by the date the petition response is due.  If a petition requests that the Agency take an action related to a specific aspect of a pending application, we will consider the review status of the affected application(s) in determining whether it would be appropriate for the Agency to respond to the request to take the action requested in the petition within the 180-day timeframe."

*       "[R]esponses to citizen petitions, including petitions subject to section 505(q), constitute final Agency action and are subject to immediate review by the courts. They therefore carry with them none of the procedural rights for the affected applicants that attach to a decision to deny approval of an application.  If we were to respond substantively a petitioner's request regarding the approvability of a certain aspect of a pending application before we have taken a final action on the approvability of the application as a whole, such response could interfere with  the statutory and regulatory scheme governing the review of applications and related procedural  rights of applicants."  Examples of such "certain aspects" include the acceptability of a proposed trade name and specific claims proposed in a drug product's labeling.  FDA further notes that "[i]n such a situation, we would expect to deny a petition without comment on the substantive approval issue."  Indeed, this is precisely what FDA has done on several recent FDC Act § 505(q) petition (non-) responses.

By Carrie S. Martin & Anne Marie Murphy –

As we have previously reported, the Consumer Product Safety Improvement Act of 2008 (“CPSIA”) makes a number of changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”).  Among those changes are new limits on the amount of lead allowed in consumer products designed or intended primarily for children 12 years old and younger (i.e., children’s products).  (Note that the statutory definition of consumer products, and hence children’s products, excludes drugs, devices, or cosmetics.)  Specifically, Section 101 of the CPSIA states that a children’s product will be considered a banned hazardous substance under the Federal Hazardous Substances Act unless it contains no more than 600 ppm of lead as of February 10, 2009; no more than 300 ppm of lead as of August 14, 2009; and no more than 100 ppm of lead as of August 14, 2011 (if such a low level is technically feasible).  The law also allows the CPSC to exempt certain products from the lead requirements on its own initiative or upon the request of an “interested person.”  If the CPSC determines a children’s product is not subject to the lead requirements, it is exempt from the mandatory testing requirements in Section 102 of the CPSIA.

In order to implement certain provisions, the CPSC recently published in the Federal Register the following four notices of proposed rulemaking:  

(1)  Notice of proposed rulemaking regarding proposed lead content limits on certain materials or products (74 Fed. Reg. 2433 (Jan. 15, 2009));

(2)  Notice of a proposed interpretative rule on inaccessible component parts (74 Fed. Reg. 2439 (Jan. 15, 2009));

(3)  Notice of proposed rulemaking regarding exemptions for certain electronic devices (74 Fed. Reg. 2435 (Jan. 15, 2009)); and

(4)  Notice of proposed procedures and requirements regarding a CPSC “determination” or “exclusion” (74 Fed. Reg. 2428 (Jan. 15, 2009)).

In the first proposed rule, the CPSC exercises its authority to identify material or products that inherently do not contain lead or that do not exceed the 600 ppm or 300 ppm limits set forth in Section 101(a).  Among those materials identified are certain precious and semi-precious gemstones, wood, natural fibers (e.g., cotton, silk, wool, linen), and other “natural material” such as feather, fur, and untreated leather.  The materials do not qualify, however, if they have been treated with materials or chemicals such as pigments, dyes, coatings, or have undergone any processes that could add lead to the product. 

The second proposed rule provides guidance on how the CPSC will assess whether a component part of a children’s product is “inaccessible” and therefore exempt from testing requirements in Section 101(a) of the CPSIA.  The Agency proposes to use tests currently in CPSC regulations, including the “sharp points or edges” test in 16 C.F.R. §§ 1500.48-1500.49 and the “use and abuse tests” under 16 C.F.R. §§ 1500.50-1500.53, with some exceptions.   

In the third proposed rule, the CPSC explains that it has determined, after public comment, that it is not technologically feasible for certain electronic devices to comply with the lead limits in Section 101(a).  These devices include components of electronic devices that are removable or replaceable, such as batteries or light bulbs, and that are inaccessible when the product is assembled in functional form.  The proposed exemption also includes any electronic devices exempted under the Annex to the European Union Directive 2002/95/EC.  In addition, the proposed rule explains how to minimize the exposure to and accessibility of lead in such electronic devices and provides a schedule for achieving compliance. 

In the fourth proposed rule, the CPSC sets forth how an interested person may request a determination that a product or material either (1) does not have lead levels over 600 ppm, 300 ppm, or 100 ppm or (2) should be excluded from the lead limits altogether.  Both requests may be sent electronically or in paper form and must include supporting data.  In addition, for a request for exclusion, the request must be based on the “best-available, objective, peer-reviewed, scientific evidence” that any lead in the product or material would not be absorbed by the body or have an adverse effect on public health or safety.  The request for exclusion must also include unfavorable evidence if it is “reasonably available to the requestor.” 

While none of these efforts provides immediate relief to the regulated industry, they evidence the CPSC’s willingness to take action to lessen the regulatory burden of the CPSIA.  These efforts are encouraging given that certain companies would likely struggle to comply with the new requirements and remain solvent.

Comments on these notices must be received by February 17, 2009.  They may be submitted via mail, e-mail, or fax.