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.