The Washington Legal Foundation (WLF), a public-interest law and policy center, has challenged FDA’s authority to regulate laboratory developed tests (LDTs), as well as FDA’s proposed method of changing its regulations governing analyte specific reagents (ASRs), which are components of LDTs.  LDTs are commonly referred to as "home brew" assays. 

At the center of debate are two draft guidance documents FDA issued on September 7, 2006: (1) Draft Guidance for Industry, Clinical Laboratories, and FDA Staff: In Vitro Diagnostic Multivariate Index Assays (the IVDMIA Draft Guidance); and (2) Draft Guidance for Industry and FDA Staff: Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions (the ASR Draft Guidance).  Earlier this month, WLF filed comments pointing out the illegalities of both draft guidance documents. 

Laboratories are regulated by the Centers for Medicare & Medicaid Services under the Clinical Laboratory Improvement Amendments of 1988.  LDTs, which are developed by and used in a particular laboratory, have not been regulated by FDA.  In the IVDMIA Draft Guidance, however, FDA creates a new category of LDTs, and declares that IVDMIAs are medical devices subject to FDA regulation.  At a Febryary 2007 FDA public meeting, WLF asserted that FDA’s regulation of IVDMIAs as medical devices is contrary to law.  Independent of the IVDMIA Draft Guidance, in September 2006, WLF filed a citizen petition requesting that FDA not regulate LDTs as medical devices.  The petition raises many legal issues not addressed in the IVDMIA Draft Guidance.

In response to the ASR Draft Guidance, WLF argues that FDA’s proposed regulatory activity violates the Administrative Procedure Act and the First Amendment.  The ASR Draft Guidance introduces new characteristics that products must have in order to be considered an ASR. WLF’s comments point out, however, that these characteristics are not included in, and actually conflict with, FDA’s existing regulations.  WLF argues that the ASR Draft Guidance represents a substantive change to FDA’s regulations, and that these changes can only be made through notice and comment rulemaking.  Additionally, WLF asserts that the ASR Draft Guidance violates the First Amendment rights of ASR manufacturers by restricting commercial speech. 

WLF and numerous other stakeholders have submitted comments on both draft guidance documents. 

RELATED READING:

• Medical Device Link article on the draft guidances

By Christine P. Bump

Earlier today, FDA announced the availability of a draft guidance document “that would implement a more stringent approach for considering potential conflicts of interest for its advisory committee members and for recommending eligibility for meeting participation.”  The new guidance document, once finalized, will replace a guidance document FDA issued February 2000 on how the Agency manages conflict of interest issues concerning special government employees who serve as advisory committee members, consultants, or experts to the Agency.  The Federal Register notice announcing the guidance document will be published on March 23, 2007.

According to FDA, because of the complexity of the February 2000 guidance document “FDA officials found it difficult to achieve consistent results that the public could readily understand.”  The new draft guidance document, however:

would reduce the likelihood that the process for recommending waivers would vary from meeting to meeting.  In addition to a more streamlined approach for considering who may participate in meetings, FDA would tighten its policy for considering eligibility for participation.  If an individual has disqualifying financial interests whose combined value exceeds $50,000, after applying certain exemptions, the person would generally not be considered for participation in the meeting, regardless of the need for his or her expertise.  If the financial interests are $50,000 or less, after applying certain exemptions, the individual might be recommended to participate as a non-voting member.  Only individuals with no potential conflicts would be eligible to fully participate in meetings as voting members.

FDA’s issuance of the draft guidance is part of the Agency’s broader efforts to improve the advisory committee process.  In February 2007, FDA issued a draft guidance document on the preparation and public availability of information given to advisory committee members.  A third guidance document will reportedly address when conflict of interest waivers will be publicly released.

RELATED READING:

• FDA January 2007 Announcement on Establishing an Advisory Committee on Communication 
• FDA Advisory Committee Webpage
• AP News Article

On March 12, 2007, Greenberg Traurig submitted a citizen petition to FDA to switch four prescription antihistamine and antihistamine-decongestant drugs from prescription to OTC status.  The four drugs are ALLEGRA (fexofenidine HCl), ALLEGRA D (fexofenidine HCl; pseudoephedrine HCl), ZYRTEC (cetirizine HCl), and ZYRTEC D (cetirizine HCl; pseudoephedrine HCl).  The petition cites several bases justifying the forced switches –all of which are related to FDA’s previous discussion and actions concerning the OTC status of CLARITIN (loratadine). 

Interest in the issue of forced Rx-to-OTC switches has waxed and waned over the past several years.  In July 1998, Wellpoint Health Networks submitted a petition requesting that FDA switch CLARITIN and the other drugs mentioned in the Greenburg petition to OTC status.  In May 2001, FDA held a joint meeting of the Nonprescription Drugs and Pulmonary-Allergy Drugs Advisory Committees to consider the issue.  Although the committees recommended the Rx-to-OTC switches of ALLEGRA, ZYRTEC, and CLARITIN, FDA took no formal action on the recommendation.  FDA has not yet responded to the Wellpoint petition, and may never do so.  Wellpoint has reportedly lost interest in pursuing the issue because the company’s petition stimulated enough discussion to assure the company that FDA and the pharmaceutical industry are actively considering Rx-to-OTC switches.  Indeed, in November 2002, FDA approved the Rx-to-OTC switch of several CLARITIN drug products. 

FDA attempted to force an Rx-to-OTC switch over the objections of the product’s sponsor once –in 1982, FDA proposed the Rx-to-OTC switch of metaproterenol sulfate metered-dose inhalers– but did not carry through with the switch after extensive adverse comment.  Since the switch of CLARITIN, FDA has indicated its preference to “stimulate” switches rather than force them.  The Greenberg petition, however, places the issue front and center once again.  With respect to FDA’s legal authority to force Rx-to-OTC switches, the Greenberg petition includes an 8-page legal memorandum analyzing the issue.  Three primary legal arguments are made: 

First, the [FDC Act] expressly authorizes [FDA] to switch a drug from prescription to OTC following rulemaking.  There is no statutory provision that even suggests, let alone requires, that rulemaking in this setting must give way to adjudication, i.e., formal trial-like proceeding.

Second, unless there is a statutory provision to the contrary, the courts have consistently held that an agency is free to undertake any type of rulemaking it deems appropriate.  Here, there is nothing that would interfere with that agency prerogative.

Third, there is nothing in the [FDA Act], [FOIA], or any other federal law that would preclude the agency from making regulatory decisions about a drug based on drug-specific data submitted to it by the drug’s sponsor.  While the [FDC Act] and FOIA may limit public disclosure of these data, they in no way affect the ability of the FDA to use the data as part of a rulemaking.  One cannot equate “use” of data by the agency with public disclosure.  In short, a decision concerning whether to switch a product from prescription to OTC is committed to agency discretion and should be based on the scientific merit of the petition and not hindered by artificial legal constraints that nowhere appear in federal law.

Reacting to a February 2007 FDA safety alert on the off-label use of erythropoietic stimulating agents (ESAs), Noridian Administrative Services (Noridian), a Medicare Administrative Contractor for 13 states in the west and midwest, announced that, effective March 5, 2007, Medicare will deny payment for the off-label use of darbepoetin alpha (ARANESP or DPA).  Other Medicare contractors are likely to follow Noridian’s lead in the coming weeks.  Three ESAs –ARANESP, EPOGEN, and PROCRIT– are FDA approved to treat anemia in patients with chronic kidney failure and cancer patients undergoing chemotherapy.  However, these drugs are also used off-label to treat anemia and fatigue in surgical patients and patients with HIV.  Noridian’s revised Local Coverage Decision (LCD) revoking payment for ARANESP noted several important developments.  FDA’s February 16, 2007 alert states that “ESAs are not FDA approved to treat anemia in cancer patients not receiving chemotherapy.”  The United States Pharmacopeia-Drug Information (USP-DI), a Medicare-recognized drug compendium, described the treatment of cancer-related anemia with DPA as “unaccepted.”  Additionally, Amgen, the manufacturer of ARANESP, recently issued a letter to health professionals stating that DPA “should be used only in accordance with its approved product labeling.”  Amgen issued the letter after observing increased mortality in patients treated with DPA for cancer-related anemia.

Noridian’s policy revision is noteworthy and may be used by other contractors to revoke payment for ARANESP and other ESAs.  The Medicare contractor used a provision in the Medicare Program Integrity Manual (PIM) to revise its LCD on ARANESP without notice and comment.  Chapter 13, section 13.7.3 of the PIM allows Medicare contractors to revise coverage policy immediately when there are safety concerns about a product or procedure.  Based on the safety concerns raised by FDA’s alert combined with the actions of the USP-DI and Amgen, Noridian decided that sufficient safety concerns existed to immediately revoke Medicare payment for the off-label use of ARAESP.  However, the revised policy does not affect ARAESP used on-label to treat anemia caused by chemotherapy.  Noridian also plans to review Medicare coverage of ESAs in the coming weeks and requests public comment and peer-reviewed literature on their use.  FDA, on March 9, 2007, approved a "black box" warning and other labeling revisions for both DPA and epoetin alpha (EPOGEN/PROCRIT).  CMS, on March 14, 2007, announced that it will review the use of ESAs in all non-end-stage renal disease applications.  CMS also took a step toward generating a National Coverage Decision (NCD) by opening a National Coverage Analysis (NCA) with a 30-day public comment period on ESAs in all non-renal applications.  CMS will use the NCA to analyze clinical studies, medical literature and other medical evidence submitted in public comments to determine whether the agency’s coverage and reimbursement policies on ESAs should be revised.

Considering Medicare’s heightened review and recent FDA action, manufacturers should monitor updates to the Medicare Coverage Database and contractor websites for updates to coverage and reimbursement for ESAs in the coming weeks.  Manufacturer submission of public comments on the NCA may also be effective to ensure that CMS’s review of its ESA coverage and reimbursement policies and any ensuing NCD are based on sound medical evidence.

By Kirk L. Dobbins

In a case that may have wider implications for the data on which FDA bases its decisions, a medical marijuana rights group, Americans for Safe Access (ASA), has sued HHS and FDA for violating the requirements under the Data Quality Act, 44 U.S.C. § 3516 (the DQA).  The DQA, which was enacted in 2001, requires federal agencies to ensure and maximize the “quality, objectivity, utility, and integrity of information” disseminated to the public.  The information quality guidelines implemented by HHS requires that the agency ensure and maximize the “quality, objectivity, utility, and integrity of information” that it disseminates, as well as administrative mechanisms that allow affected persons to seek and obtain correction of information disseminated by HHS that does not comply with the guidelines. 

According to the ASA, since implementing its information quality guidelines under the DQA, HHS has stated that marijuana “has no currently accepted medical use in treatment in the United States.”  ASA alleges that this statement and the findings underlying it are inaccurate, and has identified numerous peer-reviewed scientific studies confirming the medical efficacy of marijuana, including a National Institute of Medicine report which was commissioned by the White House’s Office of National Drug Control Policy.  ASA complied with HHS’ administrative mechanisms and filed a petition and an appeal to correct what ASA believes to be erroneous statements.  According to the ASA, HHS’ responses were nonsubstantive and not timely. 

ASA filed suit in United States District Court for the Northern District of California on February 21, 2007.  ASA’s complaint requests, in part, that the court enjoin HHS and FDA from continuing to disseminate statements that marijuana “has no currently accepted medical use in treatment in the United States.”  If successful, this lawsuit may provide a precedent for challenging agency actions if the parties believe that the data on which the action is based is flawed, if the data is disseminated to the public.

By Christine P. Bump

On March 1, 2007, the District of Columbia Circuit Court of Appeals heard an oral argument in Abigail Alliance v. von Eschenbach.  Previously, a divided court of appeals had ruled that where there are no other FDA-approved treatment options, a terminally ill patient’s access to investigational new drugs was a “fundamental right” protected under the Due Process Clause of the Constitution.  The appeals court remanded the case to the district court to determine whether FDA’s policy of restricting access to post-Phase 1 investigational new drugs under the IND regulations was “narrowly tailored” to serve a “compelling governmental interest.”  The FDA appealed, and the D.C. Circuit agreed to hear the case en banc.

All 10 judges on the D.C. Circuit participated in the oral argument.  Both sides faced lively questioning.  The plaintiff’s lawyer was asked, for example, to identify the “fundamental right” to access of drugs for terminally ill patients.  The court also asked many questions regarding how that right would be defined, including what is a terminal illness, how is it defined, and who decides whether there is a therapeutic option.  The plaintiff was also challenged as to how it could be a fundamental, deeply rooted right when it is based on a very specific regulatory scheme.  There were also questions relating to how far this right would extend and what implications it might have in other situations, such as a request to access a drug by a “sick” patient instead of a terminally ill patient, and how the court should rule in cases where a patient demanded a right to investigational stem-cell therapy.

The government’s counsel faced some probing, albeit less intense, questioning.  The government’s counsel repeated that fundamental rights were very limited, excluding even a right to access a drug that was agreed to be safe and effective, but had not yet been approved.  Somewhat surprisingly, counsel asserted that FDA did consider efficacy even before the 1962 amendments, which added the efficacy requirement to the FDC Act.  When asked if a rule enacted by a “Pol Pot administration” that prohibited people from eating would affect a fundamental right, counsel said that while this might be a bad law, it did not implicate a fundamental right.

The Abigail Alliance case is but one component in the early access debate.  In December 2006, FDA issued a proposed rule to amend its regulations on access to investigational new drugs for the treatment of patients.  On the legislative front, Sen. Sam Brownback (R-KS), in November 2005, introduced S. 1956, the Access, Compassion, Care, and Ethics for Seriously Ill Patients Act, or ACCESS Act.

RELATED READING:

• Washington Legal Foundation Case Detail
• Abigail Alliance Webpage

FDA’s highly anticipated PDUFA IV proposal, if enacted by Congress, would eliminate any possibility that a 505(b)(2) application might not be an application subject to PDUFA user fees. 

Among various technical changes included in the Agency’s PDUFA IV proposal, FDA recommends that Congress “[s]implify the definition of ‘human drug application’ to include all new drug applications under section 505(b) of the [FDC Act].”  Currently, FDA collects user fees for each “human drug application.”  This term is defined to mean, with respect to 505(b)(2) applications, either an application requesting approval of a new molecular entity or a new “indication for a use” of a previously approved drug.  In a guidance document issued in February 2007, FDA finalized its interpretation of a new “indication for a use.”  In that document, FDA articulates a broad interpretation of that term:

[B]ecause only certain 505(b)(2) applications are exempt [from user fees], it is important that potential applicants who do not want to be assessed fees be advised to . . . not seek any new indications for a use.  It is particularly important that they strictly follow the approved labeling for the individual ingredients.  If, for example, applicants seek a different use of the drug, a different dosing regimen or route of administration, use in a new population, or if they compare their product to others in the labeling, they will not qualify for the 505(b)(2) exemption from fees.

FDA’s interpretation of a new “indication for a use” has been criticized as overbroad and contrary to Congressional intent.  Such criticism will disappear, however, if Congress implements FDA’s PDUFA IV recommendation to treat all applications as “human drug applications.”

In July 2004, the Coalition for Mercury-Free Drugs (the Coalition) filed a citizen petition with FDA requesting that the agency prohibit the use of thimerosal and other mercury compounds in vaccines and drugs.  In August 2006, the Coalition went to court claiming that FDA had unreasonably delayed responding to the Coalition’s petition.  Shortly thereafter, in September 2006, FDA denied the petition, thereby effectively mooting the Coalition’s claim.  To prevent dismissal of the case, the Coalition amended its complaint to challenge the substance of FDA’s decision.  However, one day earlier, the Coalition had filed a petition with FDA requesting a stay of action, asking FDA to reconsider and modify its response to the original petition.  The Coalition’s petition for a stay of action contained new information and documents that FDA had not reviewed.  Although the Coalition styled the petition as a petition for a stay of action, in reality it was a petition seeking reconsideration of FDA’s response to the original petition.

By filing a petition for a stay in which the Coalition presented new information, the Coalition essentially transformed FDA’s decision into a non-final agency decision, thereby resulting in the dismissal of the court case.  By filing the petition for a stay, the Coalition effectively sought FDA reconsideration, as well as judicial relief of the substantive decision.  As the United States District Court for the District of Columbia noted in its March 1, 2007 memorandum opinion, “plaintiffs cannot simultaneously seek administrative consideration and judicial review of the same order.”  In essence, the Coalition was asking the court to review FDA’s decision regarding certain materials that the agency did not have an opportunity to review. 

By Riëtte van Laack

In Late February 2007, FDA announced in the Federal Register the withdrawal of approval of 128 suitability petitions in accordance with the Pediatric Research Equity Act of 2003 (“PREA”).  FDA’s notice states:

[T]hese approval decisions are being withdrawn because ANDAs were never submitted and PREA requires that all applications submitted on or after April 1, 1999, for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration contain an assessment of the safety and effectiveness of the drug for the claimed indications in relevant pediatric subpopulations unless the requirement is waived or deferred.

Under PREA and new FDC Act § 505B, Congress granted FDA the authority to require pediatric studies in certain defined circumstances.  Specifically, FDC Act § 505B states that an applicant “that submits an application (or supplement to an application) under section 505 [of the FDC Act] for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration . . . shall submit with the application” the results of pediatric studies assessing “the safety and effectiveness of the drug . . . for the claimed indications in all relevant pediatric subpopulations; and to support dosing and administration for each pediatric subpopulation for which the drug . . . is safe and effective, [unless FDA] concludes that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients,” or unless FDA defers or partially or fully waives this requirement. 

An ANDA requiring an approved suitability petition for a change to the Reference Listed Drug (“RLD”) in an active ingredient, route of administration, or dosage form meets the PREA criteria triggering a pediatric assessment.  (The only RLD change permitted by a suitability petition that does not trigger PREA is a change in strength.)  However, because of the statutory exception mandating FDA’s denial of a suitability petition requiring clinical studies, FDA can no longer approve suitability petitions for PREA changes unless the Agency fully waives the pediatric assessment requirement.

Because PREA is retroactive to applications submitted on or after April 1, 1999, any suitability petition for a PREA change granted prior to that date can no longer be relied upon today to provide a basis for FDA to approve an ANDA.  To grant such a petition, FDA would have to reassess the change pursuant to a new suitability petition in light of PREA.  FDA’s Federal Register notice concerns only suitability petitions for which ANDAs were never submitted, and is non-controversial.  However, FDA could arguably go one step further in its PREA clean-up efforts and identify post-April 1, 1999 ANDA submissions and approvals that relied on an approved suitability petition no longer valid in light of PREA.  Such a move, while it would be highly controversial and invite intense criticism of FDA, might not be out of the question. 

On February 27, FDA announced a draft guidance, titled Guidance for Industry on Complementary and Alternative Medicine Products and Their Regulation by the Food and Drug Administration (CAM Guidance).  The CAM Guidance was prepared by the Office of Policy and Planning within FDA’s Office of the Commissioner with assistance from the Center for Biologics Evaluation and Research, the Center for Drug Evaluation and Research, the Center for Devices and Radiological Health, and the Center for Food Safety and Applied Nutrition.  The CAM Guidance is FDA’s attempt to clarify within which FDA regulatory schemes (i.e., food, drug, device, biologic, cosmetic, or dietary supplement) the wide range of complementary and alternative medicine products might fall.  The areas addressed in the CAM Guidance include biologically-based practices, energy therapies, manipulative and body-based methods, and mind-body medicine.

The trade press has noted FDA’s statements that probiotics could be regulated as dietary supplements, foods, or drugs.  In its CAM Guidance, FDA also suggests that “the bacteria used in a probiotic could make the product a ‘biological product’ subject to the [Public Health Service Act].”  This statement appears to relate to the potential for probiotics to contain bacteria that might cause communicable disease.  However, the guidance should be clarified on this point to make sure it is consistent with other statements in the CAM Guidance that recognize the longstanding principle of intended use as the determining factor in the regulatory status of a product.

Companies developing complementary and alternative medicine products should read carefully the CAM Guidance, as it is not directed solely at probiotics and other foods.  For example, the CAM Guidance suggests that FDA may regulate equipment used and products applied in manipulative and body based-practices, such as massage devices, lotions, creams, and oils.

Comments regarding the CAM Guidance must be submitted to FDA by April 30, 2007.

By Bryon F. Powell

On March 1, 2007, FDA announced that it issued 20 Warning Letters to companies marketing and distributing unapproved drug products containing ergotamine tartrate, a drug used to treat vascular headaches, including migraines. According to FDA’s press release announcing the enforcement action:

In addition to marketing these products without FDA approval, most of the companies receiving warning letters have omitted from their drugs’ labeling critical warnings regarding the potential for serious, possibly fatal, interactions with certain other drugs. Based on recent scientific information, the five marketed, approved versions of ergotamine-containing products have updated their labeling to include a box warning (the strongest agency warning) against using such products when also taking potent CYP 3A4 inhibitors, including some antifungal agents, protease inhibitors, and certain antibiotics.  CYP 3A4 is a metabolic enzyme that helps the body eliminate drugs or other chemicals.  Serious and life-threatening ischemia (a restriction in blood supply), including death and gangrene, have resulted when such products are used together.  Most unapproved versions of the drug do not carry these warnings.

FDA’s enforcement action is another example on a growing list of such actions taken to implement the risk-based enforcement approach described in the Agency’s June 2006 Compliance Policy Guide.  Moreover, it is the opening salvo this year for FDA to make good on its promise “to further accelerate its enforcement efforts against marketed unapproved drugs in 2007.”  As we recently reported in RAPS FOCUS, FDA’s stepped-up enforcement effort might be due to pressure from Congress and the threat of legislation addressing marketed unapproved drugs.

Welcome to the FDA Law Blog, the blog of Hyman, Phelps & McNamara, P.C.  We’ll be covering topics of interest to FDA-regulated companies, fellow food and drug and healthcare lawyers and regulatory personnel, as well as people just generally interested in FDA law.

First and foremost, this blog will bring you timely updates on FDA enforcement actions, proposed rules, personnel changes, new and improved policies, along with related issues such as healthcare fraud and abuse, drug and device reimbursement, HIPAA, and other topics of interest. We encourage you to email us (Jeff Wasserstein or Kurt Karst) with your comments and suggestions.