By Kurt R. Karst –

Last week, ViroPharma Inc. announced that the company filed a complaint in the U.S. District Court for the District of Columbia alleging that FDA has “wrongfully withheld agency records requested by [ViroPharma] by failing to comply with the statutory time limit for the processing of [ViroPharma’s] FOIA request, resulting in constructive denial of that request, and by continuing to withhold response records” in connection with the approval requirements for a generic version of the company’s antibiotic drug product VANCOCIN (vancomycin HCl) Capsules.  The lawsuit is the latest salvo in a long-running debate over the approval of generic VANCOCIN Capsules.

On March 17, 2006, ViroPharma submitted a Petition for Stay to FDA requesting that the Agency stay the approval of any ANDA or 505(b)(2) application citing VANCOCIN Capsules as the listed drug until certain requirements are met.  In particular, the petition requested that FDA not approve an application for a generic version of VANCOCIN Capsules based solely on in vitro bioequivalence testing.  According to ViroPharma, prior to March 16, 2006, FDA concluded that “in vivo clinical trials would be the basis for determining bioequivalence for generic vancomycin hydrochloride capsules,” and that on March 16, 2006, it became public knowledge that FDA “was modifying its bioequivalence standard for oral Vancocin capsules and would accept the submission of in vitro dissolution testing data as a surrogate measure of in vivo bioequivalence.”

ViroPharma submitted a FOIA request seeking the administrative record related to FDA’s March 2006 bioequivalence recommendations for generic VANCOCIN.  FDA did not immediately provide records in response to the FOIA request.  According to the ViroPharma complaint, when FDA was threatened with litigation earlier this month, an agency official noted that “FDA would soon be releasing information regarding Vancocin that could ‘vitiate the need’ for filing [a] FOIA action.” 

On December 16, 2008, FDA issued a Federal Register notice announcing the availability of a draft product-specific bioequivalence recommendation – “Bioequivalence Recommendation for Vancomycin HCl.”  Supporting documents for the draft recommendation are available here and here.  According to FDA, the draft recommendation “further clarifies its recommendations on the design of BE studies to support ANDAs for vancomycin HCl capsules.”  Specifically, FDA provides bifurcated bioequivalence testing recommendations based on the formulation of the proposed generic drug product:

If the test product formulations are qualitatively (Q1) (i.e., contain all of the same inactive ingredients) and quantitatively (Q2) the same as the reference listed drug (RLD) with respect to inactive ingredients, bioequivalence (BE) of all capsule strengths may be established based on comparative dissolution. . . .

If the test product formulations are not Q1 and Q2 the same as the RLD with respect to inactive ingredients, BE should be established by conducting an in vivo study with clinical endpoints in patients with Clostridium difficile Associated Diarrhea (CDAD). 

FDA’s bifurcated approach is similar to the approach the Agency announced in May 2008 for generic versions of PRECOSE (acarbose) Tablets.  Comments on FDA’s draft vancomycin HCl bioequivalence recommendations are due by February 17, 2009; however, ViroPharma has requested an extension of the comment period.

FDA’s December 16, 2008 Federal Register notice also alludes to a forthcoming (but don’t expect anything soon) response to ViroPharma’s 2006 petition: 

Comments on this draft guidance will also be considered by FDA as it addresses the complicated issues raised in Viropharma, Inc.’s PSAs.  FDA will carefully consider such comments before responding to the petition and finalizing its BE recommendation for vancomycin HCl.  Because of the lengthy history of FDA’s consideration of bioequivalence methodologies for vancomycin HCl capsules, the pendency of the PSAs, and the complexity of the issues involved, the availability of this draft guidance is being announced in a drug product-specific notice, and the recommendations include a significant amount of background information and explanation of the reasons for the bioequivalence recommendations.

Dissatisfied with FDA’s December 16, 2008 announcement, ViroPharma filed its complaint.  ViroPharma states that “the Draft Guidance does not include the administrative record for FDA’s March 2006 decision to change bioequivalence methods for vancomycin . . . or the data supporting that change,” and “in no way vitiates the need for FDA to respond to ViroPharma’s FOIA request.”  Moreover, ViroPharma alleges that the draft bioequivalence recommendation “confirms that FDA failed to engage in any public process before its 2006 decision . . . .”  ViroPharma alleges that the company has a statutory right to the FDA records it seeks, as well as a statutory right “that FDA not review ANDAs that seek to copy Vancocin based on FDA’s changed interpretation of its bioequivalence regulations. . . .”

Given the importance of VANCOCIN to ViroPharma and the company’s unhappiness with FDA’s December 2008 bioequivalence recommendations, it seems clear that the current FOIA litigation is intended to obtain information that could be used in future litigation in the event FDA denies ViroPharma’s 2006 petition and approves generic versions.  Stay tuned for more as this interesting story develops. 

By Jamie K. Wolszon –

FDA’s recent decision to require a Risk Evaluation and Mitigation Strategy (“REMS”) for two prescription oral sodium phosphate (“OSP”) products raises questions regarding the impact the agency’s evolving application of its new REMS authority will have in instances where both prescription and OTC products are available that contain the same active ingredient.

On Thursday December 11, FDA issued a press release announcing that it was adding a Black Box warning to two prescription OSP products, Visicol and OsmoPrep, to address the kidney injury, acute phosphate nephropathy.  FDA directed the companies to develop a REMS.  The Agency also required the firms to distribute a Medication Guide and to conduct a clinical trial to further assess the risk.   

FDA also observed that the Agency had similar concerns regarding OTC products used at higher dosages for bowel cleansing, but that “the available data show no risk of acute kidney injury when OTC products are used at the lower dosages as laxatives.”  FDA recommended “that consumers not use OTC OSP products for bowel cleansing,” and promised to amend the labeling conditions for OTC OSP products. The press release specifically mentioned Fleet Phospho-soda’s OSP product.      

Consistent with the press release, FDA also issued two responses on the same day to citizen petitions related to OSP products.  The agency denied C.B. Fleet of Lynchburg, Virginia’s (“Fleet”) 2003 petition requesting professional labeling for OTC sodium phosphates oral solution for bowel cleansing.  In the wake of FDA’s statement, Fleet announced that it would voluntarily cease marketing its product.

FDA also responded to a citizen petition submitted by food and drug attorney Natasha Leskovsek on behalf of an unnamed client.  FDA denied the petitioner’s request to remove all prescription OSP drugs from the market; however, the Agency granted the petition’s request to apply a black box warning to the prescription OSP products; and granted the petition’s request to amend the Tentative Final Monograph to remove the professional labeling for OSP products. 

Although not mentioned in the press release, along with the Black Box warning and Medication guide, the REMS requires the two makers of Visicol and OsmoPrep to develop a communication plan targeted at gastroenterologists, surgeons, primary care physicians, and other healthcare providers who are likely to prescribe or dispense OSP products or perform follow-up assessments of patients following bowel cleansing. 

In order to invoke its REMS authority, FDA must determine that, without a strategy, the benefit of the drug would not outweigh its risk.  Meanwhile, a product cannot be marketed OTC if the drug “because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such a drug.”  An OTC drug also must be safe and effective for use in self-medication. 

FDA’s new statutory REMS authority applies to new drugs that the agency approves under the new drug or abbreviated new drug approval provisions and that require a prescription.  FDA thus cannot impose REMS on OTC monograph drugs, but the agency has the means to address specific risks for OTC monograph drugs through labeling warnings or restrictions. 

There are multiple other examples of active ingredients that are marketed, albeit at different dosages or indications, both as a prescription and OTC product.  For instance, aspirin, while marketed OTC, also has professional labeling for the cardiovascular and rheumatologic indications. The professional labeling allows the maker of an aspirin product to detail the professional labeling to health care providers.  Prilosec OTC (omeprazole magnesium) is marketed with a shorter course of treatment than the prescription version and unlike the prescription version is solely marketed for treatment of heartburn. 
  

By John R. Fleder & Kurt R. Karst –

On December 10, 2008, the United States District Court for the Northern District of Illinois in Chicago dismissed a federal False Clams Act qui tam action in U.S. ex rel. Kennedy v. Aventis Pharmaceuticals, Inc. involving allegations of off-label use sales concerning the drug LOVENOX (enoxaparin sodium).  The plaintiffs (Relators) are former Aventis sales representatives.  The court had earlier allowed the Relators to take discovery in order to develop evidence to identify specific false claims that could be tied to Aventis’ supposed illegal scheme.

First, the court ruled that any claims filed as a result of the alleged off-label use scheme were not “material” to the amount the government paid for treatment of a given patient.  The government’s reimbursement was based on a diagnosis group code that was tied to a patient’s diagnosis and age, and was not dependent on the particular services rendered to a patient.  As a result, the court ruled the claims could not have been “false.”

Second, the court examined whether the Relators’ third amended complaint satisfied the requirement of Fed. R. Civ. P. 9(b) that the fraud be pleaded with particularity.  The court ruled that although it had allowed Relators the opportunity to take discovery, they had failed to identify any specific claim that was actionable.

This decision is yet another example in which a federal court has rejected a False Claims Act qui tam lawsuit against a drug manufacturer alleging unlawful off-label promotional practices.  As we previously reported, in September 2008, the United States District Court for the Middle District of Florida (Tampa Division) dismissed similar claims in United States ex rel Hopper and Hutto v. Solvay Pharmaceuticals, Inc.  The court in that case adopted a report and recommendation from a magistrate judge concluding that the relators had utterly failed to comply with the requirements set forth in Fed. R. Civ. P (9)(b) to include specific allegations of actual false claims that were submitted to the government.  We note, however, that where the government has intervened in qui tam suits alleging off-label promotion, the government has had a greater likelihood of success in extracting a settlement from the defendant than in those cases where the government has declined to intervene.

Hyman, Phelps & McNamara, P.C.’s John Fleder was recently featured in a Washington Legal Foundation YouTube video discussing qui tam actions involving off-label promotion allegations, and wrote an article for the Food and Drug Law Institute’s Update magazine on the same topic.

By Diane B. McColl & Ricardo Carvajal –

FDA has issued “no questions” response letters to the GRAS notices submitted by Cargill and Whole Earth Sweeter Company for rebaudioside A, described as “a highly purified component of the stevia plant.”  The letters (available here and here) note that the GRAS notices are for “use of a specific purified component of stevia” and that the agency’s response does “not necessarily apply to the uses of other stevia products.”  The letters also include a § 301(ll) disclaimer, such that the response letters can not be construed as “a statement that foods that contain rebaudioside A, if introduced or delivered for introduction into interstate commerce, would not violate section 301(ll).”

Cargill’s GRAS self-determination encompasses “use as a general-purpose sweetener in foods, excluding meat and poultry products, provided that food standards of identity do not preclude such use, at levels determined by current good manufacturing practices.”  Whole Earth Sweetener Company’s GRAS self-determination encompasses “use as a sweetener in a variety of food categories [cereals (oatmeal, cold cereal, cereal bars), ready-to-drink teas, fruit juice drinks, diet soft drinks, energy drinks, and flavored waters], as well as use as a table top sweetener….”

Contrary to characterizations in the popular press, the issuance of a “no questions” response letter does not constitute an “approval.”  As noted in such response letters, FDA does not make its own determination regarding the GRAS status of the substance at issue, and places on the notifier the “continuing responsibility” of ensuring the safety of the substance and its compliance with all applicable legal requirements.

By Riëtte van Laack –

On October 21, 2008, the National Resource Defense Council (“NRDC”) petitioned FDA to issue a regulation to prohibit the use of Bisphenol A (“BPA”) as a food additive.

Currently, BPA is approved as a chemical for use in the production of polycarbonate polymers and epoxy-based enamels and coatings.  See, e.g., 21 C.F.R. §§ 175.300(b)(3)(viii), 177.1440, 177.1580,and 177.2280.  The safety assessments concerning the use of BPA date from the 1960s.  These safety evaluations focused on carcinogenicity and on genetic toxicity as an indicator of carcinogenicity.  However, recent research has raised concerns about the potential effects of BPA on the endocrine system. 

The release, in 2007, of two government sponsored reviews of BPA has resulted in a debate about the safety of residues of BPA in food contact substances.  Based on its review of existing data, the National Toxicology Program (“NTP”) concluded that there was “minimal concern” about the reproductive and developmental effects of BPA. In contrast, in the “Chapel Hill” report, a group of 38 experts raised serious concerns about the safety of BPA.  In August 2008, based on these reports, amendments thereto, and additional sources of information, FDA determined in its draft safety assessment that “an adequate margin of safety exists for BPA at current levels of exposure from food contact uses.” 

NRDC disagrees with FDA’s draft safety assessment, which NRDC claims relied on two-industry funded studies.  According to NRDC, “in light of the data suggesting that BPA is harmful to human health, and in response to well-founded concerns of experts in the field, FDA must prohibit BPA from use in food and food packaging [and] revoke all regulations permitting the use of any food additive that results in BPA becoming a component of food.”

NRDC’s petition was submitted shortly before a subcommittee of the FDA Science Board Advisory Committee released its review of FDA’s draft safety assessment.  The subcommittee also disagreed with FDA’s draft safety assessment and concluded that the margins of safety for BPA are inadequate.  However, the subcommittee indicated that “this does not mean that exposures are not acceptable.”  According to the subcommittee, the acceptability of exposures is a question of policy, and this decision lies with FDA. 

In response to the subcommittee review, FDA acknowledged in a statement the existence of “uncertainties” about BPA and that “additional research would be valuable.”  The Agency is “moving forward with [additional] research to address the potential low dose effects of [BPA].”  FDA’s statement also pointed to “the present consensus among regulatory agencies in the United States, Canada, Europe, and Japan . . . that current levels of exposure to BPA through food packaging do not pose an immediate health risk.”

By Diane B. McColl & Ricardo Carvajal –

On December 15, Cargill issued a press release in which it announced a “broad-based national integrated marketing campaign” to promote its sweetener Truvia™ (Truvia™ is Cargill’s preparation of rebiana, or rebaudioside A, one of the sweetening components that can be extracted from Stevia rebaudiana). According to Cargill, “the tabletop version of Truvia™ natural sweetener is now available nationwide, wherever groceries are sold.”  Previously, Cargill had filed a voluntary GRAS notification with FDA (GRN #253) setting out Cargill’s determination that its rebiana is safe for use as a general purpose sweetener.  FDA has yet to respond to that notification.

Under § 201(s) of the Federal Food, Drug, and Cosmetic Act ("FDC Act"), many food ingredients are not subject to approval and regulation by FDA as food additives if the use of those ingredients in foods is generally recognized, among experts qualified by scientific training and experience to evaluate their safety, as having been adequately shown through scientific procedures or common use in foods, to be safe under the conditions of their intended use.  Self-determination that the use of an ingredient is GRAS can be made independent of FDA, and requires neither FDA approval nor FDA notification.  Use of a self-determined GRAS ingredient carries with it the risk that FDA will disagree with the self-determination of GRAS status and take action against the substance as an unapproved food additive.  For this reason, potential users often demand that ingredient developers voluntarily notify FDA of their GRAS self-determinations.  If FDA has no questions about the notifier’s GRAS determination, FDA issues a letter stating so (a so-called “no questions” letter).  A notifier can accept the risk that FDA will disagree with its notified GRAS determination, and proceed to market without first receiving a “no questions” response letter from the agency. 

In the case of Stevia-derived sweeteners, proceeding to market without a GRAS notice “no questions” letter from FDA may carry some added risks.  As recently as August 2007, FDA issued a warning letter to the manufacturer of a tea product in which the agency took the view that Stevia rebaudiana is an unapproved food additive that renders a food adulterated under FDC Act § 402(a)(2)(C).  Additionally, the Center for Science in the Public Interest ("CSPI") issued its own press release on December 15, the same day as the Cargill press release, in which it contends that additional tests are needed to demonstrate the safety of Stevia and rebaudioside A, and that “FDA should immediately order those products off the market until all the safety testing has been done.”  Also, there is pending before the agency a citizen petition contending that the addition of steviol glycosides (the sweetening components that can be extracted from Stevia) to food is prohibited by FDCA § 301(ll) (see Docket No. FDA-2008-P-0542).

By Ricardo Carvajal & John R. Fleder –

At the invitation of the U.S. Supreme Court, the federal government has recently filed a brief as amicus curiae in the case of Albertson’s, Inc. v. Kanter (No. 07-1327) in which the government argues against preemption of California law.  The case was brought by California consumers of farmed salmon who alleged that grocers engaged in false advertising and unfair and deceptive trade practices (among other things) when they failed to disclose the presence of color additives in their salmon, in alleged violation of California’s Sherman Food, Drug, and Cosmetic Law (“Sherman Law”).  The Sherman Law sets out food labeling requirements that are identical to those imposed under federal law.  Albertson’s argued that federal law preempts the private lawsuit brought by consumers under the Sherman law.  The trial court agreed and dismissed the lawsuit on preemption grounds.  That dismissal was upheld by the California Court of Appeal, but reversed by the California Supreme Court (see out previous post here).  Albertson’s then filed a petition for a writ of certiorari with the U.S. Supreme Court, which prompted a request by the Court for the Solicitor General’s views on the matter.

In part, the government’s brief argues that the language of FDC Act § 403A “strongly suggests” that States are free to adopt requirements identical to federal requirements, and notes that NLEA section 6(c)(1) explicitly limits the preemptive effect of the NLEA.  The federal government further argues that nothing in § 403A suggests Congressional intent to “limit the States’ authority to prescribe the remedies for violations of the state requirements permitted by [section 403A].”  For support, the brief draws on the Court’s prior holdings interpreting other FDC Act statutory provisions in Medtronic, Inc. v. Lohr, Riegel v. Medtronic, Inc., and Bates v. Dow Agroscience LLC.

The government also argues in its brief that the California action is not preempted by FDC Act § 310, which provides that proceedings for enforcement, or to restrain violations, of the FDC Act must be by and in the name of the U.S. (with the exception of certain actions brought by States in conformance with certain procedural requirements).  According to the government, “[a]ctions to enforce state laws that impose requirements identical to those under the FDCA are not actions to enforce the FDCA itself.”  The government’s brief further argues that this section does not preempt state law claims that “parallel” FDC Act requirements.  Moreover, the federal government stated that even when state-law claims are predicated on violations of the FDC Act, they remain state-law claims that are not preempted by federal law.

The accolades keep rolling on in . . . .  

USPharmD has named the FDA Law Blog one of the “Top 50 Medical Ethics Blogs.”  According to them, we will help you “[s]tay on top of current legal issues in the medical field.”  And all this time we were just trying to spell the big words correctly.

The USPharmD top blogs list is the second such list we’ve made in the past few months.  In September, RNCentral.com named FDA Law Blog to their “100 Best Health Care Policy Blogs.”

By Ricardo Carvajal –  

According to a recently-issued Letter to Manufacturers, FDA “feels it is imperative to remind its constituents that front-of-package symbols can at times constitute nutrient content claims” that are subject to FDA’s regulatory requirements at 21 C.F.R. 101.13 and Subpart D of Part 101.  A nutrient content claim is one that expressly or impliedly characterizes the level of a nutrient in a food (e.g., low fat, 100 calories).  Manufacturers are making increasing use of front-of-package symbols to convey information about the nutritional attributes of their products in a simplified, consumer-friendly format.  FDA has been aware of the trend, and held a public hearing on the subject in 2007.  But it appears that some manufacturers have been making express or implied nutrient content claims without adhering to the regulatory requirements that attach to such claims.  FDA states that it “will notify manufacturers when we see any front-of-package symbols that are explicit or implied nutrient content claims that are not consistent with current requirements or where such front-of-package symbols are used in a manner that is false or misleading.”  Although not noted in FDA's letter, it is permissible to include a statement in labeling about the amount or percentage of a nutrient present in a food if the conditions specified in 21 C.F.R. 101.13(i) are met. 

By Kurt R. Karst –      

Earlier today, by a five-to-four vote, the U.S. Supreme Court ruled against preemption in Altria Group, Inc. Good, the so-called “light cigarette” case.  Background on the case is available via the SCOTUS Wiki. 

The respondents in the case (i.e., Good et al) alleged that Altria violated the Maine Unfair Trade Practices Act by fraudulently advertising their cigarettes as “light” and “low in tar and nicotine.”  The U.S. District Court for the District of Maine dismissed the lawsuit on preemption grounds, finding the Maine law preempted by the Federal Cigarette Labeling and Advertising Act (“FCLAA”).  In August 2007, however, the U.S. Court of Appeals for the First Circuit reinstated the lawsuit, holding that the FCLAA neither expressly nor impliedly preempts the respondents’ fraud claim.  In ruling that neither the FCLAA, nor actions in this field by the Federal Trade Commission in Commission dating back to 1966 preempted respondents’ state law fraud claim, the Supreme Court has effectively cleared the way for smokers to file lawsuits to challenge deceptive cigarette marketing. 

This ruling could have an impact on the FDA preemption cases now before the Court; namely that small case everyone is watching – Wyeth v. Levine.

By Kurt R. Karst –      

We previously reported on concerns as to whether a company submitting an ANDA (or a 505(b)(2) application) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new Public Health Service Act (“PHS Act”) § 402(j), as added by Title VIII of the FDA Amendments Act (“FDAAA”), applies and that in vivo bioequivalence studies  have been registered at ClinicalTrials.gov.  Specifically, it has been unclear whether an in vivo bioequivalence study is an “applicable drug clinical trial” subject to the PHS Act § 402(j) databank registration requirements.  PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial” to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” (emphasis added).   In September 2008, the Generic Pharmaceutical Association (“GPhA”) sent a letter to Representative John Dingell (D-MI) expressing concern “that FDA will incorrectly interpret the statute to include bioequivalence studies as ‘applicable drug clinical trials,’” and strongly urging that Congress “amend the definition of ‘applicable drug clinical trial’ at PHS Act § 402(j)(1)(A)(iii) to specifically exclude bioequivalence studies.”

Earlier this month, a draft document was posted on the ClinicalTrials.gov FDAAA website elaborating on the applicability of the FDAAA Title VIII requirements to bioequivalence studies.  (The draft guidance also discusses the term “applicable clinical trial” generally as it applies to drugs – including biological products – and medical devices, and the term “responsible party” for purposes of the entity or individual responsible for registering and submitting clinical trial information to the clinical trials registry data bank.)  According to the draft guidance:

In the agency’s view, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) is considered to be a controlled clinical investigation. In this case, the control generally would be the previously approved drug product.

Although a bioequivalence study is a controlled clinical investigation, the draft guidance goes on to note that:

Under certain circumstances, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) will be considered to be a Phase 1 clinical investigation under 21 CFR § 312.21 for purposes of determining whether a particular clinical trial is an “applicable drug clinical trial” under Title VIII of PL 110‐85 (section 402(j)(1)(A)(iii) of the PHS Act).  Although Phase 1 clinical investigations are generally designed to fit sequentially within the development plan for a particular drug, and to develop the data that will support beginning Phase 2 studies, 21 CFR § 312.21(a) does not limit Phase 1 trials to that situation.  Bioequivalence or comparative bioavailability studies that fall within the scope of the studies described in 21 CFR § 320.24(b)(1), (2), and (3) share many of the characteristics of Phase 1 clinical investigations as described in 21 CFR § 312.21(a), and therefore will be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. However, bioequivalence or comparative bioavailability trials that fall within the scope of 21 CFR § 320.24(b)(4) do not share the characteristics of Phase 1 trials as described in 21 CFR § 312.21(a), and thus would not be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. [(emphasis added)]

Bioequivalence studies that fall within the scope of 21 CFR § 320.24(b)(4) and that are not exempt from reporting on ClinicalTrials.gov are generally clinical endpoint studies.  According to an FDA Manual of Policies and Procedures, such studies are typically “applied to dosage forms intended to deliver the active moiety locally, forms that are not intended to be absorbed, or drug products for which traditional pharmacokinetic studies are not feasible,” such as drug products in topical dosage forms. 

Although the draft guidance posted on the ClinicalTrials.gov FDAAA website would exempt most bioequivalence studies from reporting under federal requirements, under a Maine law that is still in effect (and that might not be preempted for a few years), a “covered clinical trial,” which includes a bioequivalence study, initiated on or after October 15, 2002 must be reported.  Under the Maine law and its implementing regulations, bioequivalence studies must be registered and the results posted if the generic drug is approved by FDA and is or has been “dispensed, administered, delivered or promoted in Maine.”

By Anne Marie Murphy –

We have previously reported on the Consumer Product Safety Improvement Act of 2008 (“CPSIA”) (here, here, and here), which makes a number of changes to the laws enforced by the Consumer Product Safety Commission (“CPSC”).  Section 102(a)(1) of the CPSIA amends the Consumer Product Safety Act (“CPSA”) to require each importer or domestic manufacturer of any product that is subject to any CPSC rule, ban, standard, or regulation to issue a certificate that the product complies with such CPSC requirements.  The certificate must be “based on a test of each product or upon a reasonable testing program.”  This certification applies to drugs and dietary supplements that require child-resistant packaging (“CRP”) under the Poison Prevention Packaging Act (“PPPA”).

Yesterday, the CPSC posted on its website new Frequently Asked Questions (“FAQs”) that address the certification as it applies to PPPA products.  The FAQs confirmed the following:

• The CPSC does not regulate drugs, including drugs intended for children, because such products are excluded from the definition of “consumer product” under the CPSA.  The CPSC does, however, regulate CRP for those products that are subject to the PPPA.

• The importer of a PPPA-regulated product already in CRP or the domestic party that packages a PPPA-regulated substance in CRP must issue the general conformity certificate.

• The child resistance and senior friendly testing data obtained with the procedures described at 16 C.F.R. § 1700.20 may be relied upon as the “reasonable testing program” to support the certification.  There is no expiration date for such testing, and the testing need not be repeated unless the packaging is changed.

• There is no requirement to provide certification for the following types of shipments:  bulk drug product provided to pharmacies; empty vials and caps; and clinical trial drugs provided to physicians. 
   

By Jeffrey N. Wasserstein, Alan M. Kirschenbaum & Bryon F. Powell –

On December 10, 2008, the Massachusetts Department of Public Health (Department) issued proposed regulations pursuant to Mass. Gen. L. § 111N, which requires the Department to promulgate regulations that adopt a standard marketing code of conduct (the Code) for all prescription pharmaceutical and medical device manufacturers.  The law also requires the Department to establish a public database of payments by such companies to health care practitioners, to collect fees associated with marketing cost disclosure, and to enforce the law’s marketing requirements.  We previously reported on the enactment of this statute (here and here).

The Department issued a unified Code that covers both pharmaceutical and medical device manufacturers.  However, recognizing the differences between the PhRMA Code and the AdvaMed Code, the Code includes some provisions that are applicable only to pharmaceutical manufacturers, and other provisions applicable only to device manufacturers (such as reimbursement for certain training costs, discussed below).  The Code mirrors the PhRMA Code to some extent, while also including specific prohibitions and permissions required by the statute. 

The Code’s discussion of specific marketing practices includes tight restrictions regarding the provision of meals, support for CME, and other payments to health care practitioners.  While the restrictions are similar to those in the revised PhRMA Code, which we previously reported on, there are some differences.  Notably, the PhRMA Code limits the in-office/in-hospital restriction on meals to health care professionals to sales representatives and their immediate supervisors.  Other business people may provide meals out of the office or hospital on occasion, and meals may be provided outside the office or hospital in connection with a health care speaker provided by the company.  The Code does not mirror the PhRMA Code in this respect and limits all meals to in-office or in-hospital.  Another difference is that the Massachusetts Code apparently prohibits funding of unaccredited CME programs, whereas the PhRMA and AdvaMed Codes permit such funding.  Yet another difference between the Code and industry standards is that the Code permits reimbursement for certain medical device training costs, provided the costs of the training are specified in the purchase agreement for the device.  The AdvaMed Code permits device companies to train health care professionals on medical devices even whether or not such training is provided for in a purchase agreement.  

Manufacturer/practitioner interactions permitted by the Code include, among other things, payments for genuine research projects or clinical trials; product samples or evaluation units; normal price concessions, such as rebates and discounts; provision of reimbursement-related information; and medication for patient assistance programs.  The proposed regulations also address the use of prescriber-identifiable data, in a manner similar to the PhRMA Code. 

The Code also requires companies to: adopt and comply with the Code by July 1, 2009; adopt a training program to ensure compliance with the Code; conduct annual audits to ensure compliance with the Code; adopt policies and procedures for investigating noncompliance; appoint a compliance officer responsible for compliance with the Code; submit a description of the training program, the company’s investigation policies, and the contact information for the compliance officer; certify annually that the company has conducted an annual audit and is in compliance with the Code; and submit an annual disclosure report, described more fully below.

Under the Code’s disclosure requirements, manufacturers must annually report all payments of at least $50 made “in connection with the company’s sales and marketing activities.”  The Department proposed a $2,000 fee to be paid by reporting manufacturers to fund the disclosure program.  The first disclosure report is due July 1, 2010, covering the period of July 1, 2009 through December 31, 2009. 

The Massachusetts Public Health Council  discussed the proposed regulations at its December 10th public hearing.  Public hearings regarding the proposed regulations will also be held in Boston on January 9, 2009 and in Worcester on January 12, 2009.  Comments are due by February 10, 2009. 

By Cassandra A. Soltis –

FDA has posted on its web site two revised draft guidance documents (here and here) concerning the labeling requirements of dietary supplements and over-the-counter (OTC) drugs under the Dietary Supplement and Nonprescription Drug Consumer Protection Act of 2006.  That Act requires the labels of dietary supplements and OTC drugs other than those approved through the NDA process to bear the domestic phone number or domestic address of the “responsible person” so that consumers can report serious adverse events. 

In its draft guidance documents issued in December 2007, FDA indicated that by “domestic address,” Congress meant the full address, which includes the street address or P.O. box.  However, Hyman, Phelps & McNamara, P.C. and industry trade associations disputed this narrow interpretation of “domestic address” in comments on the guidance documents, arguing that FDA’s current “place of business” requirement for the labels of dietary supplements and OTC drugs satisfies the “domestic address” requirement of the new law, provided that the place of business is domestic, not foreign.  FDA also stated in its December 2007 guidance that it would not begin enforcing the labeling requirements until January 1, 2009.

In notices to be issued in the Federal Register on December 11, 2008, FDA announces that the December 2008 revised draft guidance documents change the enforcement date to January 1, 2010, “[b]ecause the agency is still in the process of finalizing the guidance” documents.  Nevertheless, even if the final guidance documents continue to interpret “domestic address” as including either the street address or P.O. box, FDA’s interpretation is not binding on either FDA or industry.  As FDA’s own regulation makes clear, “[g]uidance documents do not establish legally enforceable rights or responsibilities” and “do not legally bind the public or FDA.”  21 C.F.R. § 10.115(d)(1). 

By Susan J. Matthees—

FDA and the Department of Health and Human Services Office for Human Research Protections (OHRP) recently announced the availability of two guidance documents intended to help investigators, researchers, sponsors, and IRBs understand how data already collected may be used after a subject discontinues participation in a clinical trial.                                                             

FDA’s guidance document, “Guidance for Sponsors, Clinical Investigators, and IRBs Data Retention When Subjects Withdraw from FDA-Regulated Clinical Trials,” explains that under the existing regulatory scheme, if a subject withdraws from a study, the data collected on that subject up to the point of withdrawal generally must remain in the study database.  FDA states that “[c]omplete removal of data, possibly in a non-random or informative way, raises great concerns about the validity of a study.”  However, once a subject withdraws, an investigator may only continue to gather data with the subject’s permission.  The “investigator may ask a subject who is withdrawing whether the subject wishes to provide continued follow-up and further data,” distinguishing with the subject the “study-related interventions and continued follow up of associated clinical outcome information.”  The subject must agree and provide informed consent before the investigator can continue to gather data. 
 
If the subject does not give permissions to the investigator to collect further data, the investigator may not access the subject’s medical record.  But, the guidance document makes clear that the investigator may consult public records, including death records, to obtain follow-up data.   
 
OHRP’s draft guidance document, “Guidance on Important Considerations for When Participation of Human Subjects in Research is Discontinued,” does not discuss whether an investigator should consult public records to obtain follow-up data.  However, like FDA’s guidance document, OHRP’s draft guidance document states that an investigator may continue to analyze data already collected from a subject even after the subject withdraws from participation in the research.  OHRP’s draft guidance document also provides details on both the meaning of “participation” and the types of data that can be collected.   

The OHRP draft guidance states that OHRP “interprets subject participation” to mean any of the following activities:  interviewing the patient, taking a blood sample, administering a drug, “collecting individually identifiable private information . . . collecting individually identifiable biological specimens” from the subject, or “using or testing individually identifiable biological specimens already collected by the investigator (e.g., performing a genetic test on a tissue specimen already collected from a subject).”  OHRP does not consider the following activities to be subject participation:  “[a]ny continued analysis by the investigator of individually identifiable private information about the subject that was obtained by the investigator prior to the subject’s decision to discontinue participation in a study” or “continued analysis . . . of data that was derived by an  investigator through a previous use or test of a subject’s individually identifiable biological specimens prior to the subject’s decision to discontinue participation.” 

The OHRP guidance document also recommends that whenever a subject decides to discontinue participation, the investigator document the circumstances.  The investigator should specify “[w]hether the discontinuation of the subject’s participation results from a decision by the subject or by the investigator,” whether the discontinuation is full or partial, and “[t]he reason for the discontinuation.”