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The 2009 guidance is substantially similar to the draft guidance which was issued in June  2007.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Compared to the 2007 draft guidance, the 2009 final guidance includes a new paragraph in which FDA further explains its requirement that the specific disease that is the subject of the claim be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. 

By James P. Ellison –

The Department of Justice announced a $1.415 billion settlement with Eli Lily and Company (“Lilly”) to resolve allegations of off-label promotion of the antipsychotic drug Zyprexa (olanzapine).  The criminal component of this global settlement is a $515 million fine and a $100 million forfeiture.  The charge to which Lilly agreed to plead guilty is 21 U.S.C. § 333(a)(1), i.e., the misdemeanor provisions of the FDC Act.  As these provisions impose strict liability (there is no intent requirement), it does not bode well for the regulated industry if $615 million is the going rate in 2009  for an FDC Act misdemeanor.

According to the criminal information, to which Lilly has agreed to plead, “ELI LILLY'S management created marketing materials promoting Zyprexa for off-label uses, trained its sales force to disregard the law, and directed its sales personnel to promote Zyprexa for off-label uses.”  .  The information goes on to allege that sales representatives executed a “company plan” to target the long term care market and primary care physicians, even though Lilly knew that there was little on-label use in these markets.

The remaining $800 million of the settlement payment resolves Lilly’s civil liability under the False Claims Act and related state claims.  The qui tam relators, all of whom are former Lilly sales representatives, will share in $78.8 million, which represents 18% of the federal government’s civil share.  State Medicaid programs can opt into the settlement and share in up to $361.8 million. 
 
You may recall that Alaska settled with Lilly in March of last year for $15 million.  It was reported that Alaska was motivated to settle, at least in part, based upon concerns that a Supreme Court decision in Wyeth v. Levine would undercut its (and others) suits.  .

As is typical in connection with these settlements, Lilly also entered into a Corporate Integrity Agreement with the HHS OIG, which agreed to refrain from exercising its permissive exclusion authority. 

By Riëtte van Laack –

The United States Department of Agriculture (“USDA”) finalized its rulemaking concerning Country of Origin Labeling (“COOL”) mandated by the 2002 and 2008 Farm Bills.  The final rule requires that retailers notify customers of the country of origin of covered commodities (meat cuts and ground beef, veal, lamb, pork chicken, and goat meat, fish and shellfish, perishable agricultural commodities (fresh and frozen fruits and vegetables), peanuts, pecans, ginseng, and macadamia nuts).  The final rule amends and incorporates the interim final rule for fish and shellfish, and the interim final rule for the remaining covered commodities.  

USDA’s COOL requirements apply only to retailers as defined by section 499a(b) of the Perishable Agricultural Commodities Act of 1930 (“PACA”), i.e., persons engaged in the business of selling any fresh and frozen fruits and vegetables with an invoice cost of more than $ 230,000 per year.  Thus, USDA’s COOL regulations do not apply to retailers that do not sell fresh or frozen fruit or vegetables, such as butcher shops.  Food Service Establishments, such as restaurants, lunchrooms, cafeterias, food stands, bars, and lounges are also exempt.  USDA has determined that approximately 37,000 retail stores will be subject to its COOL regulations. 

The COOL regulations do not apply to “processed food items,” defined as a retail item derived from a covered commodity that “has undergone specific processing resulting in a change in the character of the covered commodity, or that has been combined with at least one other covered commodity or other substantive food component.”  A frozen vegetable medley, dried fruit, smoked salmon, and peanut butter are examples of processed food items. However, “the addition of a component . . . that enhances or represents a further step in the preparation of the product for consumption  [does] not in itself result in a processed food item.”  Thus, meat injected with salt or phosphate solution is not a processed food item, whereas cured ham is.

As USDA notes repeatedly in the final rule, an imported product that is exempt from USDA’s COOL regulations may still be subject to country of origin marking requirements of the Tariff Act of 1930 enforced by Customs and Border Protection.

The final rule becomes effective on March 16, 2009, which is 60 days after the date of publication.  USDA has published various guidance documents to aid retailers in understanding and complying with the COOL regulations. 

By Ricardo Carvajal –      

Several federal agencies, including FDA, have jointly issued a draft guidance for comment purposes only that recommends a wide range of practices intended to help ensure that imported products comply with applicable federal laws.  The action was taken pursuant to a recommendation in the Action Plan for Import Safety: A Roadmap for Continual Improvement, which was released in November 2007 by the Interagency Working Group on Import Safety (which was established by Executive Order 13439).  Although primarily directed at importers, the draft guidance states that retailers and manufacturers also should “carefully consider” the draft guidance.  Furthermore, “the principles and the non-customs related recommendations” that it sets forth “are also applicable to helping ensure the safety and security of products that are domestically produced.” 

The practices in the draft guidance are organized under four “guiding principles.”  The first of these is “Establishing a Product Safety Management Program.”  This principle focuses on establishing an organizational structure to facilitate implementation of the recommended practices and to ensure corporate responsibility.  That structure would provide for the establishment of appropriate policies, specifications, and procedures, training of personnel, effective communication within and outside the organization, and establishment of a formal quality assurance program. 

The second principle is “Knowing the Product and Applicable U.S. Requirements.”  This principle calls for importers to understand which regulatory requirements apply to a product and its producer, know the risks and compliance history associated with a product and any firms involved in that product’s life cycle, and be alert to information that suggests fraudulent activities, such as prices that are significantly below market value. 

The third principle is “Verifying Product and Firm Compliance with U.S. Requirements Throughout the Supply Chain and Product Life Cycle.”  This principle calls for importers to make significant efforts to ensure that products and their producers comply with applicable requirements, and contains the most extensive recommendations of all of the principles addressed in the draft guidance.  In general, importers are expected to take numerous steps to “control, monitor, and verify” product and producer compliance prior to the arrival of the product, during the product’s entry, and afterward when the product is in distribution. 

The fourth principle is “Taking Corrective and Preventive Action When the Imported Product or Firm Is Not Compliant with U.S. Requirements.”  Importers are expected to establish procedures for the development of corrective action plans, engage in root cause analysis when there is non-compliance by products or producers, and take steps to prevent recurrence.

The draft guidance acknowledges that importers may be using other practices that ensure that products comply with applicable federal laws.  Nonetheless, it offers a potential carrot to those who adhere to the recommended practices: such adherence “may, in some cases, facilitate admissibility determinations.”  Comments on the draft guidance should be submitted by April 12, 2009 to Docket No. FDA-2009-D-0675 at www.regulations.gov.

By Alan M. Kirschenbaum –

Today’s Federal Register announces FDA’s issuance of a final “Guidance for Industry on Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices.”  We previously reported on FDA’s issuance of the draft guidance in February 2008.  

The draft guidance elicited comments reflecting widely divergent views on this issue.  Members of Congress and industry critics objected that draft guidance was more permissive than the forerunner FDAMA § 401 “safe harbor” regulations, and would encourage drug and device companies to promote off-label and forego rigorous studies needed for FDA approval.  The industry, on the other hand, commented that certain provisions in the guidance were too restrictive and would violate First Amendment protection of commercial speech or pure scientific speech.  Between these two poles, FDA has stuck to the middle ground, issuing a final document that contains surprisingly few substantive changes from the draft. 

The few changes that have been made represent concessions to both sides.  Where industry objected to a requirement that reprints be limited to reports on adequate and well controlled studies, the final guidance retained the requirement, but added that these can include historically controlled studies, pharmacokinetic studies, pharmacodynamic studies, meta-analyses in some cases, and, for devices, articles on significant non-clinical research.  Where critics of the industry objected that the requirement for an article to be accompanied by reports of contrary studies should be strengthened, the final guidance expanded the requirement to all instances where such studies exist, not just those where the disseminated article has been specifically called into question.  As advocated by industry, the final guidance retains a “safe harbor”-type statement that FDA will not consider reprints and texts distributed in accordance with the guidance as evidence of an intent that the product be used for an unapproved use, but adds a cautionary statement that compliance with the guidance will not save a manufacturer from enforcement if it engages in other unlawful off-label promotion.  (Note also that, where a manufacturer engages in other unlawful off-label promotion, the guidance does not promise that FDA won’t consider reprints disseminated in accordance with the guidance as additional evidence of intent.) 

The heart of the guidance sets forth FDA’s recommendations for the content, type, and manner of distribution of reprints and texts, which are largely unchanged from the draft.  According to the guidance, the types of permissible journal articles are those that:

• Are published by an organization with an independent, expert editorial board and a publicly stated policy on conflicts of interest.
• Are peer reviewed.
• Are not false or misleading.  Examples of false or misleading articles are those that have been withdrawn by the journal or disclaimed by the author, or that report on studies that are inconsistent with the weight of credible evidence.
• Do not pose a significant health risk, if relied upon.
• Are not special supplements funded by the manufacturer, letters to the editor, abstracts, or reports of phase 1 studies in healthy subjects.

FDA’s recommendations for distribution, which also remain largely unchanged from the draft, are that the journal article or text should:

• Be unabridged and not marked, highlighted, summarized, or characterized by the manufacturer in any way.
• Be accompanied by the approved labeling.
• Be accompanied by a comprehensive bibliography of publications discussing studies on the unapproved use, when such information exists.
• Be disseminated with a representative publication (if any) that reaches contrary conclusions on the unapproved use.
• Be distributed separately from promotional information.
• Not be distributed in a promotional exhibit.
• Not be the subject of discussion between a sales rep and a physician during a visit.  A footnote explains that sales reps should refer questions to company medical staff, which should be separate from the sales or marketing departments.

Under the final guidance (as under the draft), the reprint or text should be accompanied by a prominently displayed statement disclosing that the uses discussed have not been approved or cleared, and disclosing the manufacturer’s interest in the product discussed,  and any author known to have a financial interest in the product or manufacturer or known to be receiving compensation from the manufacturer. Going beyond the draft, the final guidance adds that the amount of the financial interest or the compensation and the affiliation of the author should also be disclosed, if known.

It remains to be seen whether this “middle-ground” guidance satisfies stakeholders on both sides of the issue.  It is possible that the Washington Legal Foundation, which has long challenged FDA policies restricting dissemination of journal reprints, could target the guidance on Constitutional grounds.  It is also possible that Representative Waxman or other Congressional opponents of the policy reflected in the guidance could intervene with legislation.  It also remains to be seen what effect this guidance will have on enforcement against drug and device companies by the Department of Justice, which is not bound by the guidance, but presumably would take FDA’s views into account in making prosecutorial decisions. 

By Ricardo Carvajal –      

The Supreme Court has denied certiorari in the case of Albertson’s, Inc. v. Kanter (No. 07-1327).  As we previously reported, the California Supreme Court ruled against federal preemption of plaintiffs’ lawsuit alleging false advertising and unfair and deceptive trade practices in violation of California law, and remanded the case to the appellate court for further proceedings.  Defendants then filed a petition for certiorari with the U.S. Supreme Court, which led the Court to ask the federal government for its view on the question of preemption.  As we discussed in a prior posting, the Solicitor General and FDA argued against preemption in an amicus curiae brief that appears to have been persuasive.

By Ricardo Carvajal & Colleen M. Brown –      

Purified water is at the heart of a recently decided case in which the Federal Food, Drug, and Cosmetic Act ("FDC Act") was found to expressly preempt state law claims alleging unfair and deceptive trade practices in violation of state consumer protection laws. Plaintiffs in the case, In re: PepsiCo, Inc. Bottled Water Marketing and Sales Pratices Litigation (MDL No. 1903), sued PepsiCo for fraudulently marketing Aquafina based on label graphics and statements that allegedly give the false impression that the water is from a mountain source when it is sourced from public drinking supplies. PepsiCo filed a motion to dismiss, in part on the grounds that the claims are expressly preempted by section 403A of the FDC Act. 

Aquafina’s label depicts a mountain range and a rising or setting sun. The label also includes the phrases “Pure Water – Perfect Taste” and “Purified Drinking Water.” The back of the label includes the statement “BOTTLED AT THE SOURCE P.W.S.” In 2007, PepsiCo disclosed that the water used in Aquafina is public drinking water (tap water) that has been purified, but did not change the Aquafina label to explicitly say so. Plaintiffs contended that PepsiCo should disclose the source of Aquafina in its labeling.

Under the authority of section 401 of the FDC Act, FDA has established standards of identity for various types of water, including “purified water.” (See 21 CFR 165.110(a).) Section 403A of the FDC Act states that no state or subdivision of a state may directly or indirectly establish “any requirement for a food which is the subject of a standard of identity established under section 401 that is not identical to such standard of identity. . ..” 21 U.S.C. sec. 343-1(a)(1).  Thus, the key question presented in this case was whether “the duties imposed by Plaintiff’s state law claims are ‘identical’ to those imposed by the standard of identity for purified drinking water.”

The federal standard of identity for bottled water from a “community water system” provides that such water must be labeled as “from a community water system” or “from a municipal source,” but explicitly exempts water that meets the definition of purified drinking water from this disclosure requirement. 21 CFR 165.100(a)(3)(ii).  Notwithstanding this exemption, plaintiffs argued that PepsiCo could be held liable under state law for failing to disclose the source of Aquafina because of the misrepresentations as to source made on its label.  The court drew on preambles to the 1993 proposed rule and the 1995 final rule establishing the standard of identity to find that FDA “specifically addressed the disclosure of source information and determined, in its expert opinion, that representations of source are immaterial in the context of purified water.”  The court concluded that plaintiffs’ claims “are expressly preempted. . . because: (1) federal law is not silent on the subject of implied labeling misrepresentation regarding the municipal source of bottled water, and (2) given that the Aquafina fits within the exception for purified water and thus complies with the FDCA’s requirement, Plaintiff’s state law claims by necessity are premised on requirements that are not parallel to those imposed by federal law.” In its decision, the court drew on the Supreme Court’s prior holdings in Bates v. Dow Agroscience LLC, Medtronic, Inc. v. Lohr, and Riegel v. Medtronic, Inc.

By John A. Gilbert & Larry K. Houck  –      

The Drug Enforcement Administration (“DEA”) published a final rule on December 29, 2008 setting annual self-certification fees at $21 for “regulated sellers.”  “Regulated sellers,” persons and entities who sell scheduled listed chemical products at retail locations, must self-certify with DEA that they comply with certain requirements of the Combat Methamphetamine Epidemic Act of 2005 (“CMEA”).  The final rule is effective February 1, 2009.

Still left unanswered is what responsibility will suppliers or customers of these regulated entities have to determine whether the entity has submitted self-certification to DEA. For example, it is likely that DEA could hold suppliers accountable if there is a diversion issue and it turns out the purchaser has not self-certified.

The final rule states that regulated sellers cannot sell nonprescription products containing ephedrine, pseudoephedrine and phenylpropanolamine (“scheduled listed chemical products”) unless they have self-certified.  This certification must state that:

• Their employees have undergone training about CMEA requirements;
• They maintain records of that training;
• They understand that they cannot sell more than 3.6 grams of such products in a calendar day;
• Nonliquid products are packaged as required under the law;
• Scheduled listed chemical products are stored behind the counter or in a locked cabinet;
• They maintain a written or electronic logbook with required sales documentation; and
• They will disclose logbook information only to law enforcement authorities or to facilitate a product recall.

The Appropriations Act of 1993 requires DEA to set registrant fees to ensure the recovery of the full costs of operating the various aspects of the Diversion Control Program.  DEA determined that self-certification is one of the “various aspects” of its diversion control program.  DEA therefore calculated the Fiscal Year 2006 self-certification set-up costs, and operating and maintenance costs in Fiscal Year 2007 and 2008 to arrive at $2,240,496.  DEA divided the total cost by double the anticipated population of 55,000 affected regulated sellers (110,000) to reflect the initial self-certification and one renewal by each during the period.  DEA rounded the fee up to $21.00 per regulated seller.  DEA could not determine the cost of enforcement activities and subsequent proceedings and promised to recover their costs through fees revised by future rules. 

DEA waived self-certification fees for regulated sellers who hold current registrations to dispense controlled substances as pharmacies, rationalizing that “the retail sale of scheduled listed chemical products is essentially the same activity as dispensing (that is, sale at retail) of controlled substances.”        

By Ricardo Carvajal –    

On December 10, 2008, FDA issued a warning letter contending that the Coca-Cola Company’s Diet Coke Plus product violates FDC Act section 403(r)(1)(A) because it fails to comply with regulations that govern the use of the nutrient content claim “plus.”  Nutrient content claims characterize the level of a nutrient in a food, and typically are authorized via FDA's issuance of a regulation.  According to the agency, use of the term “plus” in conjunction with the phrase “Diet Coke with Vitamins & Minerals” constitutes a nutrient content claim that must meet the regulatory requirements in 21 CFR 101.54(e).  Among other criteria, that regulation requires that the fortification be “in accordance with the policy on fortification of foods in 21 CFR 104.20.”  Section 104.20 states in part that FDA “does not encourage indiscriminate addition of nutrients to foods, nor does it consider it appropriate to fortify. . . snack foods such as candies and carbonated beverages.”  To our knowledge, this is the first time that FDA has included a citation to section 104.20 in a warning letter. 

As noted in section 104.20, the rationale for the fortification policy rests on FDA’s concern that “random fortification of foods could result in over- or under-fortification in consumer diets and create nutrient imbalances in the food supply.”  Such fortification “could also result in deceptive or misleading claims for certain foods.”  As further explained by FDA in the preamble to the final rule on general principles for nutrient content claims, when FDA authorizes a nutrient content claim, “the agency is making a finding that the claim will assist consumers in maintaining healthy dietary practices. . . .  The agency cannot make such a finding for nutrient additions that are not consistent with the fortification policy.”  

The warning letter to Coca-Cola may have been presaged by agency statements in the preamble to the 1997 final rule on “high potency” nutrient content claims:

FDA has previously stated that fortifying a food of little or no nutritional value for the sole purpose of qualifying that food for a health claim is misleading for several reasons. First, there is great potential to confuse consumers if foods like sugars, soft drinks, and sweet desserts are fortified to qualify for a claim, when, at the same time, dietary guidance as contained in the U.S. Department of Agriculture's (USDA's) and U.S. Department of Health and Human Services' (DHHS') 1995 Dietary Guideline for Americans, for example, states that these foods provide calories and little else nutritionally. Indiscriminate fortification of such foods with one nutrient would not make such foods consistent with dietary guidelines and may encourage overfortification of the food supply (e.g., vitamin or mineral addition to soft drinks).

FDA’s warning letter begs the question of which types of snack foods (other than candy and soft drinks) could run afoul of its fortification policy.  Presumably, if FDA intends to issue similar warning letters for fortified snack foods other than candy and soft drinks, the agency will first provide more detailed guidance on its fortification policy.  Notably, the current Dietary Guidelines for Americans embrace the concept of “discretionary calories” (e.g., for a 2, 000-calorie diet, if you meet your recommended nutrient intake by consuming 1,800 calories, the remaining 200 calories would be your "discretionary calories").  The Guidelines state that “[y]ou can use your discretionary calorie allowance to. . .  [e]at or drink items that are mostly fats, caloric sweeteners, and/or alcohol, such as candy, soda, wine, and beer.”

By Ricardo Carvajal –      

FDA has announced the availability of a guidance for industry titled “Substantiation for Dietary Supplement Claims Made Under Section 403(r)(6) of the Federal Food, Drug, and Cosmetic Act.”  Under certain conditions, section 403(r)(6) permits manufacturers of dietary supplements to make nutritional deficiency, structure/function, or general well-being claims in the labeling of dietary supplements, provided those claims are truthful and not misleading.  The guidance issued by FDA is very similar to a draft guidance that FDA issued under the same name in 2004, but there are some interesting differences that suggest a possible tightening of FDA's standards with respect to the types of evidence that constitute adequate substantiation. 

In addressing animal and in vitro studies, FDA has eliminated qualifying language that was present in the draft guidance.  For example, the draft guidance stated that, "Generally, without any data from human studies, the results of animal studies alone are not sufficient to substantiate a claim."  The recently-issued guidance omits the qualifier "generally."  Also, the draft guidance stated that, "The strongest in vitro evidence would be based on data that have been reproduced in different laboratories, but this evidence alone would ordinarily not be adequate to substantiate a claim."  The recently-issued guidance changes the last phrase in that sentence to state that "this evidence alone would not substantiate a claim."  These two omissions suggest that FDA is likely to demand data from one or more human studies for substantiation (but note that FDA does not address structure/function claims that include qualifying language, a point briefly addressed further below). 

As to the weight that can appropriately be given to a single study, Example 20 in the draft guidance stated that a single positive study involving a small number of subjects likely would be insufficient to substantiate a claim in the face of several high-quality studies that produce negative results.  The recently-issued guidance omits any reference to the number of subjects as a relevant factor.  This suggests that, in the absence of explanatory circumstances, FDA may view a single positive study as insufficient to substantiate a claim in the face of several unfavorable studies, even if that study involved a substantial number of subjects.

There is additional material of interest in the footnotes of the guidance.  First, FDA responds to comments raising First Amendment concerns by concluding that the statutory substantiation requirement in section 403(r)(6) is constitutional under the analysis governing commercial speech in Central Hudson Gas & Electric Corp. v. Public Service Commission of New York (447 U.S. 557 (1980)).  The guidance states that the "misleading nature of a claim made under section 403(r)(6) that is not substantiated cannot be cured by a disclaimer stating that the claim lacks support."  However, FDA sidesteps the question of whether a claim made under section 403(r)(6) that includes qualifying language can be substantiated.  Second, FDA takes the position that a study using a conventional food or a multi-nutrient supplement would not substantiate a single ingredient dietary supplement claim, and that a disclaimer wouldn’t work in such situations.  In support of its position, FDA notes that “recent scientific studies have shown that nutrients in food do not necessarily have the same beneficial effect when taken in the form of a dietary supplement,” and may either have no benefit or show “an increased risk for the very disease the nutrients were predicted to prevent.”

By Kurt R. Karst –      

FDA’s recent approval of Antisoma Research Limited’s orphan drug, oral fludarabine phosphate, with 7 years of orphan drug exclusivity for the treatment of certain adult patients with B-cell chronic lymphocytic leukemia got us thinking about the unusual case of the major contribution to patient care – the so-called “MC-to-PC” – orphan drug designation and approval. 

The FDC Act (§ 527) provides a 7-year period of exclusive marketing to the first sponsor who obtains marketing approval for a designated orphan drug.  The scope of orphan drug exclusivity is broad; it prevents FDA approval of ANDAs, “full” 505(b)(1) NDAs, and 505(b)(2) applications.  Orphan drug exclusivity begins on the date that a marketing application is first approved for the designated orphan drug. 

Once FDA approves a marketing application for a designated drug, the Agency may not approve another firm’s version of the “same drug” for the same disease or condition for seven years, unless the subsequent drug is “different” from the approved orphan drug, or because the sponsor of the first approved product either cannot assure the availability of sufficient quantities of the drug or consents to the approval of other applications.  (FDA may, however, approve a second application for the same drug for a different use.)  A drug is “different” from an approved orphan drug if it is either demonstrated to be chemically or structurally distinct from an approved orphan drug, or “clinically superior” to the approved orphan drug. 

FDA’s orphan drug regulations (21 C.F.R. Part 316) define a “clinically superior” drug as “a drug . . . shown to provide a significant therapeutic advantage over and above that provided by an approved orphan drug (that is otherwise the same drug)” in one of three ways:

(a) greater effectiveness as assessed by effect on a clinically meaningful endpoint in adequate and well controlled trials;
(b) greater safety in a substantial portion of the target population; or
(c) demonstration that the drug makes a major contribution to patient care.

To support a claim of “clinical superiority” based on a demonstration of a major contribution to patient care, FDA has acknowledged that it will do so only in “unusual circumstances.”  In the preamble to FDA’s final orphan drug regulations, the Agency commented that:

convenient treatment location; duration of treatment; patient comfort; improvements in drug efficiency; advances in the ease and comfort of drug administration; longer periods between doses; and potential for self administration . . . when applicable to severe or life threatening diseases, might sometimes be legitimately considered to bear on whether a drug makes a major contribution to patient care.  However, this determination will have to be made on a case-by-case basis. 

As to how much superiority could constitute a “major contribution to patient care,” FDA also remarked that:

There is no way to quantify such superiority in a general way.  The amount and kind of superiority needed would vary depending on many factors, including the nature and severity of the disease or condition, the quality of the evidence presented, and diverse other factors. . .  While comparative trials are, of course, preferred and will usually be required, it is possible that, in some circumstances, a demonstration of a major contribution to patient care can be made without such trials. 

Other than the recent oral fludarabine phosphate designation and approval (see FDA’s orphan drug designation list here, which identifies the oral fludarabine phosphate designation as a MC-to-PC precedent based on a change from an intravenous to oral dosage form), we are aware of only two instances in which FDA has designated and approved an orphan drug based on a MC-to-PC demonstration: 

• In 1998, FDA determined that Novartis’ reformulated SANDOSTATIN LAR (octreotide) was “clinically superior” to a previously approved subcuteaneous dosage form of SANDOSTATIN, because “patients can be managed with one injection per month instead of sixty to ninety injections.”  
• In 2007, FDA determined that Indevus’ histrelin acetate implant drug product, SUPPRELIN LA, was “clinically superior” to SUPPRELIN on the basis that “a single histrelin subcutaneous implant could provide therapeutic blood levels for a period of 1 year versus 365 daily injections of Supprelin.” 

A MC-to-PC counter-precedent is found in Fisons’ attempt to obtain FDA approval for PNEUMOPENT (pentamidine isethionate).  On June 15, 1989 (before FDA’s orphan drug regulations were proposed), FDA approved American Pharmaceutical Partners’ aerosolized NEBUPENT (pentamidine isethionate) for primary and secondary prophylaxis of Pneumocystis Carnii Pneumonia (“PCP”).  NEBUPENT was approved for administration (300mg once every four weeks) through a nebulizer using compressed air by trained medical personnel.  Fisons subsequently sought FDA approval for PNEUMOPENT, also an aerosolized pentamidine product for the prevention of PCP.  However, PNEUMOPENT could be self-administered through a small ultrasonic nebulizer.  Fisons (and several AIDS groups) urged FDA to approve PNEUMOPENT despite NEBUPENT’s orphan drug exclusivity, arguing that PNEUMOPENT made a “major contribution to patient care” because: (1) PNEUMOPENT could be self administered at home whereas NEBUPENT required administration in an institutional setting; (2) PNEUMOPENT required about half the time per treatment as NEBUPENT; and (3) Fisons developed a unit-dose ampule for PNEUMOPENT that avoided the use of a syringe and sterile water to reconstitute NEBUPENT.  FDA reportedly did not accept that these differences established a sufficient MC-to-PC rationale.