Over the summer we posted on several preemption cases involving FDA-regulated products.  In July, we reported that the Supreme Court agreed to hear Riegel v. Medtronic, Inc., which concerns whether the FDC Act preempts state tort claims regarding medical devices that entered the market pursuant to the Premarket Approval process, and that the Supreme Court was petitioned to hear Wyeth v. Levine, which concerns whether prescription drug labeling preempts state law product liability claims.  (The Court still has not ruled on the petition.)  In August, we reported that the Federal Circuit affirmed a lower court ruling that a District of Columbia law prohibiting sales activities that result in a patented prescription drug being sold in the District of Columbia for an “excessive price” is preempted by federal patent law.  The list of preemption cases continues to grow.

In February 2005, the Pennsylvania Employees Benefit Trust Fund (“PEBTF”), which administers health care benefits to eligible Commonwealth of Pennsylvania employees, retirees, and their dependents, sued AstraZeneca alleging, among other things, that the company unlawfully advertised NEXIUM (esomeprazole magnesium) (i.e., the “Purple Pill”) in violation of the Delaware Consumer Fraud Act (“DCFA”).  Specifically, PEBTF alleged that “the large-scale promotional campaign for Nexium, which included both physician-directed marketing and direct-to-consumer advertising, was misleading because it incorrectly represented that Nexium was superior to Prilosec,” and that AstraZeneca “initially sold NEXIUM at a price below Prilosec in order to establish brand loyalty, but then raised the price of Nexium while the price of Prilosec dropped.”  (PRILOSEC [omeprazole] is an AstraZeneca drug that is similar to NEXIUM; both drugs are proton pump inhibitors.)  In November 2005, the U.S. District Court for the District of Delaware ruled that NEXIUM advertisements that complied with the FDA-approved labeling were not actionable under the DCFA.  PEBTF appealed the decision. 

The U.S. Court of Appeals for the Third Circuit upheld the district court decision in its August 17, 2007 opinion.  The appeal presented two principal questions: (1) whether the DCFA exemption for advertising regulated by the Federal Trade Commission applies to the facts of this case; and (2) whether federal law preempts the plaintiffs’ state consumer protection claims.  With respect to the issue of preemption, the court ruled that:

allowing these claims to proceed would unnecessarily frustrate the FDCA’s purpose and FDA regulations, as the extent of agency involvement in regulating prescription drug advertising is extensive and specific. . . .  An even stronger case for preemption occurs when FDA approved labeling is the basis for allegedly fraudulent representations made in prescription drug advertising. The essential affinity between advertising and labeling is clear in the composition of the FDCA and its associated regulations. . . .  Although labeling is often directed at medical practitioners, the rules that govern labeling form the basis for the advertising regulations. . . .  Accordingly, the purpose of protecting prescription drug users in the FDCA would be frustrated if states were allowed to interpose consumer fraud laws that permitted plaintiffs to question the veracity of statements approved by the FDA.

It is unclear whether PEBTF plans to appeal the decision.  Meanwhile, another case involving preemption is awaiting the Supreme Court’s decision on whether to hear the case. 

In 1995, Michigan enacted legislation immunizing pharmaceutical companies from products liability claims, provided FDA approved the drug product at issue.  The law contains an exception, however, that preserves liability if the drug company withheld or misrepresented information that would have altered FDA’s decision to approve the drug product (i.e., “fraud-on-the-FDA”). Specifically, the Michigan law states, in relevant part:

In a product liability action against a manufacturer or seller, a product that is a drug is not defective or unreasonably dangerous, and the manufacturer or seller is not liable, if the drug was approved for safety and efficacy by the [FDA], and the drug and its labeling were in compliance with [FDA’s] approval at the time the drug left the control of the manufacturer or seller.

This subsection does not apply if the defendant at any time before the event that allegedly caused the injury does any of the following: 

(a) Intentionally withholds from or misrepresents to the [FDA] information concerning the drug that is required to be submitted under the [FDC Act] and the drug would not have been approved, or the [FDA] would have withdrawn approval for the drug if the information were accurately submitted.

In 2001, the Supreme Court held in Buckman Co. v. Plaintiffs’ Legal Comm. that state “fraud-on-the-FDA” claims were impliedly preempted by federal law.

In March 2000, the sponsor of REZULIN (troglitazone), Warner-Lambert (a wholly-owned subsidiary of Pfizer), voluntarily withdrew the drug product from the market amid certain safety concerns.  Several Michigan consumers alleging injuries caused by REZULIN subsequently sued Warner-Lambert in state court alleging breach of implied and express warranties, negligence, negligent misrepresentation, negligence per se, fraud, defective design, defective manufacturing, and loss of consortium –specifically that Warner-Lambert “knowingly concealed material facts about the safety and efficacy of Rezulin from the FDA, which would have prevented its approval and/or resulted in its earlier removal from the market.”  The case was removed to federal district court, where the court granted Warner-Lambert’s motion for judgment on the pleadings on the grounds that Plaintiff’s could not establish under Michigan law that REZULIN was “defective,” and that that the immunity exception in Michigan law should be severed because it was preempted by the FDC Act and the Medical Devices Act under the reasoning of Buckman.  The district court reasoned that:

[i]f plaintiffs covered by the Michigan statute were able to litigate claims of fraud on the FDA in individual personal injury suits, whether in state courts or in federal courts, the potential would exist for the FDA’s personnel to be drawn into those controversies on a case-by-case basis over and over again, [thereby resulting in] enormous . . . interference with the proper discharge of the mission that Congress created the FDA to perform.

The case was appealed to the U.S. Court of Appeals for the Second Circuit to determine whether, under the rationale of Buckman, federal law also preempts traditional common law claims that survive a state’s legislative narrowing of common law liability through a fraud exception to that statutory limitation.  In vacating the district court’s ruling, the Second Circuit ruled in an opinion entered earlier this year that:

because Michigan law does not in fact implicate the concerns that animated the Supreme Court’s decision in Buckman, and because Appellants’ lawsuits depend primarily on traditional and preexisting tort sources, not at all on a “fraud-on-the-FDA” cause of action created by state law, and only incidentally on evidence of such fraud, we conclude that the Michigan immunity exception is not prohibited through preemption.  It follows that common law liability is not foreclosed by federal law, and Appellants’ claims should not have been dismissed.

Warner-Lambert and Pfizer recently appealed the Second Circuit’s decision to the Supreme Court. Warner-Lambert’s Cert. Petition presents two issues for the Court’s review:

1. Whether, under the conflict preemption principles in [Buckman], federal law preempts state law to the extent that it requires the fact-finder to determine whether the defendant committed fraud on a federal agency that impacted the agency’s product approval, where the agency—which is authorized by Congress to investigate and determine fraud—has not found any such fraud, and thus—as in Buckman—the state requirement would interfere with the agency’s critical functions.

2. Whether, under the conflict preemption principles in Buckman, federal law preempts the provision in a Michigan statute that allows a product liability claim to be maintained against a manufacturer of an FDA-approved drug where, without an FDA finding of fraud on that agency, the fact-finder is required to make a finding under state law as to whether the manufacturer committed fraud-on-the-FDA and whether, in the absence of that fraud, the FDA would not have approved the drug.

Warner-Lambert argues, among other things, that:

the Second Circuit’s holding will interfere with the FDA’s ability to perform its critical functions, which is precisely what this Court sought to avoid in Buckman.  Findings of fraud-on-the-FDA would inevitably disrupt the regulatory process by encouraging manufacturers to supply unnecessary information to the FDA for fear that the failure to do so will lead to state-law liability; by discouraging manufacturers from seeking approval for beneficial drugs that are not risk-free; by distorting the FDA’s decision-making process to anticipate potential state-law review of that process; and by burdening FDA personnel who are ordered to testify as witnesses in state-law products liability cases concerning the FDA’s decision-making process.

The Respondents’ brief opposing Cert. argues (not surprisingly) that:

The Second circuit properly distinguished Buckman on the grounds that the present case involves (i) state regulation of tort law affecting health and safety, as to which the presumption against preemption applies (rather than an attempted use of state law to police fraud on the FDA); (ii) alleged violation of state common law duties, rather than solely the federal duty of candor to the FDA; and (iii) invocation of fraud on the FDA to rebut an affirmative defense, rather than as an element of a claim.

The Washington Legal Foundation, the Pharmaceutical Research and Manufacturers of America, and the Product Liability Advisory Council have submitted amicus briefs.  The Supreme Court is scheduled to consider whether or not to grant Cert. during a September 24, 2007 conference. 

On August 27, 2007, FDA published its long-awaited proposed rule to amend the final monograph for Over-the-Counter (“OTC”) sunscreen drug products.  The rule, if finalized, would set standards for formulating, testing, and labeling OTC sunscreen drug products with Ultraviolet A (“UVA”) light and Ultraviolet B (“UVB”) light protection.  UVA light is responsible for tanning, and UVB light is responsible for sunburn.  FDA’s OTC drug sunscreen monograph was finalized in 1999 and discusses the ability of a sunscreen to protect against UVB light, but the effective date of the monograph was later stayed until reliable testing methods for protection against UVA light were developed.  (The rulemaking history for OTC sunscreens is available here.)  (As an interesting historical note, Congress ordered FDA to issue a final sunscreen monograph within 18 months of enactment of the FDA Modernization Act of 1997 [§ 129].  This led FDA to issue the final monograph on May 21, 1999, effective in two years with UVA testing and labeling deferred.  In December 2002, FDA stayed the effective date of the monograph – which stay is still in effect, pending the development of the UVA issues addressed in the Agency’s August 2007 proposal.)

The most significant aspects of FDA’s proposal are the development of a standard testing method to determine a sunscreen’s efficacy to protect against UVA light and the creation of a consumer-friendly rating system for  a product’s  protection against UVA light.  According to an FDA press release:

The FDA proposal provides a ratings system for UVA sunscreen products on a scale of one to four stars. One star would represent low UVA protection, two stars would represent medium protection, three stars would represent high protection, and four stars would represent the highest UVA protection available in an OTC sunscreen product. If a sunscreen product does not provide at least a low level (one star) of protection, FDA is proposing to require that the product bear a “no UVA protection” marking on the front label near the SPF value.

Ratings would be derived from two tests the FDA proposes to assess the effectiveness of sunscreens in providing protection against UVA light. The first test measures a product’s ability to reduce the amount of UVA radiation that passes through it. The second test measures a product’s ability to prevent tanning. This test is nearly identical to the SPF test used to determine the effectiveness of UVB sunscreen products.

Other proposed amendments to the monograph include:

• Revisions to the UVB labeling regulations, including: (1) the increase of the highest SPF value from SPF30+ to SPF50+; (2) use of the terms “low” and “medium” rather than “minimal” and “moderate” as category descriptors for protection against UVB; and (3) insertion of the term “UVB” before “SPF” and before “sunburn;”

• Renaming the rating for UVB protection (i.e., SPF) from “sun protection factor” to “sunburn protection factor;”

• Addition of avobenzone with zinc oxide and avobenzone with ensulizole as permitted combinations of active ingredients in OTC sunscreens;

• The following mandatory warning in the “Drug Facts” box on the product label: “UV exposure from the sun increases the risk of skin cancer, premature skin aging, and other skin damage. It is important to decrease the UV exposure by limiting the time in the sun, wearing protective clothing, and using a sunscreen;”

• A requirement for a statement to inform consumers about the importance of both UVB and UVA protection;

• Mandatory directions that consumers apply the sunscreen either “liberally” or “generously” and that the sunscreen should be reapplied at least every 2 hours; and

• Various modifications to the SPF testing procedures that are intended to increase protection of persons enrolled in the SPF test and to improve accuracy and reproducibility of the test results.

Although FDA’s proposal does not address nanosize particles, the Agency solicits comments on the safety and effectiveness of nanometer-size sunscreen particles and proposals for regulation of sunscreens containing nanosize particles.  Comments concerning this issue will be included in the docket for the proposed monograph, as well as in FDA’s nanotechnology docket. (See 8/1/2007 FDA Law Blog post.)

Timing of the publication of a final rule will largely depend on the number of comments FDA receives.  Comments are due by November 26, 2007.  With respect to implementation of a final rule, FDA commented that the Agency “understands the seasonal nature of the sunscreen industry and the time required for product testing and relabeling. FDA is also aware that more than 1 year may be needed for implementation. FDA is proposing an 18- to 24-month implementation date and will try to have it coincide with the June/July time period.”

By Riëtte van Laack

On August 1, 2007, the U.S. Court of Appeals for the Federal Circuit affirmed (errata) the U.S. District Court for the District of Columbia’s December 2005 ruling declaring that the District of Columbia’s Prescription Drug Excessive Pricing Act of 2005 (the “Act”) is preempted by the federal patent laws and enjoining its enforcement.  The Act prohibited sales activities that result in a patented prescription drug being sold in the District of Columbia for an “excessive price.”  If the wholesale price of a patented prescription drug in the District exceeded the price in any “high income country” (defined in the Act as the U.K., Germany, Canada, and Australia), the manufacturer was presumed to be in violation of the law.  The burden would then shift to the manufacturer to prove that the price of its drug is not “excessive,” in light of the “demonstrated costs of invention, development and production of the prescription drug, global sales and profits to date, consideration of any government funded research that supported the development of the drug, and the impact of price on access to the prescription drug by residents and the [D.C.] government.”  Specifically, the Act stated:

(a) A prima facie case of excessive pricing shall be established where the wholesale price of a patented prescription drug in the District is over 30 percent higher than the comparable price in any high income country in which the product is protected by patents or other exclusive marketing rights.

(b) [If a prima facie case is made, a defense is to show that the] given prescription drug is not excessively priced given demonstrated costs of invention, development and production of the prescription drug, global sales and profits to date, consideration of any government funded research that supported the development of the drug, and the impact of price on access to the prescription drug by residents and the government of the District of Columbia.

The case is an appeal of consolidated actions brought by the Pharmaceutical Research and Manufacturers of America (“PhRMA”) and the Biotechnology Industry Organization (“BIO”).  PhRMA and BIO argued that the Act is preempted by federal patent laws because it conflicts with Congress’s intention to provide such manufacturers with the monetary reward that derives from the right to exclude competitors from making, using, and selling the invention during the patent’s term. 

The District Court and the Federal Circuit agreed with the plaintiffs that Congress expressed that intention in the statutory incentive scheme it developed in the Drug Price Competition and Patent Term Restoration Act of 1984 (the “Hatch-Waxman Act”).  The Federal Circuit reasoned that “[b]y penalizing high prices—and thus limiting the full exercise of the exclusionary power that derives from a patent—the District has chosen to re-balance the statutory framework of rewards and incentives insofar as it relates to inventive new drugs.”  In short, the court found that the “Act stands as an obstacle to the federal patent law’s balance of objectives as established by Congress” and is thus preempted by federal patent law.

By Brian J. Wesoloski

Hyman, Phelps & McNamara, P.C. is pleased to announce that J.P. Ellison has joined the firm as Of Counsel.  Mr. Ellison joins HPM from the U.S. Department of Justice Office of Consumer Litigation (“OCL”).  By regulation, OCL has responsibility for representing the FDA, Federal Trade Commission, and Consumer Product Safety Commission in affirmative and defensive litigation.  Mr. Ellison handled litigation matters involving each of these agencies.  Mr. Ellison received his undergraduate degree from Princeton University’s Woodrow Wilson School of Public & International Affairs, and his law degree from the University of Virginia School of Law.  After law school Mr. Ellison served as a law clerk for the Honorable Diana Gribbon Motz on the U.S. Court of Appeals for the Fourth Circuit.

Hyman, Phelps & McNamara, P.C.’s Brian J. Donato cautioned companies about the dangers of “residual risk” while speaking at a recent conference on risk management sponsored by AdvaMed.  Medical Device & Diagnostic Industry reported on the speech in an August 2007 article.  Residual risk, which is “how much risk remains in a product after a company has conducted risk assessment,” can show up in many ways, including with respect to regulatory compliance, product liability, contractual obligations, marketing and sales, and company reputation.  As such, Mr. Donato cautioned companies not to ignore residual risk, and to minimize it as much as possible by conducting rigorous, upfront product risk assessments.

The U.S. District Court for the Southern District of New York is expected to decide soon whether a New York City regulation requiring restaurants to post calorie content values on menus and menu boards is preempted by the Nutrition Labeling and Education Act of 1990 (“NLEA”), a federal statute.  The regulation, which was scheduled to take effect on July 1, 2007, applies to restaurants that make the calorie content information of standardized menu items publicly available.  In June, the New York State Restaurant Association (“NYSRA”) filed a complaint and a motion for declaratory relief and a preliminary injunction arguing that the regulation is preempted by the NLEA and asking that the court preclude New York City from violating the First Amendment rights of NYSRA members by impermissibly compelling speech.       

The NYSRA takes the position that calorie content values constitute “nutrient content claims” under the subsection of the NLEA that governs such claims.  The preemption provision applicable to that subsection prohibits states and local governments from enacting any law regarding nutrient content claims “made in the label or labeling of food that is not identical to the requirement of” that subsection.  NYSRA argues that the requirements imposed by the New York City regulation are not “identical” to those of federal law and therefore are preempted.  The City takes the view that because disclosure of a calorie content value does not involve a characterization of calorie levels, such disclosure does not constitute a nutrient content claim.  The City argues that the NLEA’s preemption provision applicable to nutrient content claims does not apply to the City’s regulatory requirements at issue.

The NYSRA also maintains that the City’s regulation violates the First Amendment by compelling restaurants to voice a point of view with which they disagree; namely, that calories are the only nutritional criterion that customers should consider when selecting menu items.  New York City responds that the reasonableness standard governs commercial speech and that its regulation at issue meets that standard because it is reasonably related to the city’s legitimate interest in curbing obesity. 

An amicus curiae brief was filed in support of the City by Rep. Henry Waxman (D-CA), former FDA Commissioner David Kessler, Public Citizen Litigation Group, Center for Science in the Public Interest, several medical and public health organizations, and several professors of medicine, nutrition, and public health.  The City and County of San Francisco also filed an amicus brief in support of New York City and is joined by several other cities and the National League of Cities.   

ADDITIONAL READING:

• National Restaurant Association State Menu Labeling Legislation

By Brian J. Wesoloski

Earlier today, FDA announced that Tim Coté, M.D., M.P.H., a Captain in the U.S. Public Health Service, has accepted the position of Director of the Agency’s Office of Orphan Products Development (“OOPD”).  Dr. Coté is only the fourth OOPD Director since the office was created in the 1980s after the passage of the Orphan Drug Act.  He replaces Dr. Marlene Haffner, who held the position for many years and retired from public service earlier this year.  Dr. Coté plans to join FDA around September 1, 2007, and comes to the Agency from the Centers for Disease Control and Prevention, where he was the Country Director for Rwanda.  In that position, Dr. Coté  managed a staff of U.S. government direct hires, contractual employees, and locally employed staff and a budget of about $119 million directing programs in HIV/AIDS, malaria, and avian influenza. 

Since FDA announced its current enforcement policy for marketed unapproved drug products in a June 2006 Compliance Policy Guide (“CPG”), the Agency has taken various company- and product-specific enforcement actions.  We have previously reported on some of these enforcement actions (here, here, and here).   FDA has not, however, launched a whole-scale enforcement effort, as many companies had feared when FDA issued the CPG.  That may change.

We recently learned that FDA is in the midst of planning enforcement action against companies marketing and distributing unapproved prescription drugs that, according to one source, would seek to remove almost all such drug products from the market within the next few years.  We believe that the enforcement action FDA is planning is likely to be class-based.  For example, FDA might take enforcement action (through a Federal Register notice and/or Warning Letters) against all marketed unapproved prescription cough/cold drugs products. 

FDA’s anticipated enforcement initiative comes on the heels of the Agency’s January 2007 “Marketed Unapproved Drugs Workshop.”  The workshop was widely viewed as an effort by FDA to encourage companies to seek approval for their marketed unapproved drugs, rather than to explain the Agency’s CPG enforcement policies.  In what could be viewed as foreshadowing of anticipated future enforcement action, FDA Commissioner Dr. Andrew von Eschenbach commented during the workshop:

The FDA is seriously committed to resolving the problem of unapproved drugs and it is because the FDA is committed to assuring the patients that they are going to be able to obtain drugs for themselves and their children and their grandchildren not just on the hope that they are safe but based on the fact that FDA has reviewed the evidence and the labeling that defines the conditions under which that drug is safe and effective.  It is our responsibility and our mission to fulfill that commitment to the American people . . . .  Rather than working on a piecemeal basis, company or company or drug by drug, what we have wanted to do is to address this problem globally.  

Copies of the presentations made at the workshop are available here, and a transcript of the workshop is available here. 

We will continue to update our loyal FDA Law Blog readers as we learn more information.

ADDITIONAL READING:

• FDA Marketed Unapproved Drugs Website
• February 2007 RAPS FOCUS Article on Marketed Unapproved Drugs

Horace Scudder’s 1915 “The Book of Fables and Folk Stories” includes a story, titled “The Arab and His Camel,” that ends with the moral “It is a wise rule to resist the beginnings of evil.”  This is, of course, a parable of the Middle Eastern metaphor for the situation where allowing a small act will lead to a larger undesirable circumstance: “Do not allow a camel to put his nose under the edge of your tent, for soon you will have a camel in your tent.”  In 1992, when Congress passed the Prescription Drug User Fee Act (“PDUFA”) establishing user fees for the review of “human drug applications,” the proverbial camel’s nose came under the tent.  Although it can be debated (particularly given the substantial decrease in NDA review times in the post-PDUFA era compared to the pre-PDUFA era) whether PDUFA signalled the “beginnings of evil” (as certainly some people both in and out of FDA would contend), PDUFA has clearly provided a blueprint for the creation other user fees.

In the almost 15 years since the passage of PDUFA, not only have human drug application user fees increased substantially (FDA’s interpretation of the law has also resulted in more user fee revenue), but Congress has created PDUFA-like user fee systems for medical devices (under the Medical Device User Fee and Modernization Act of 2002) and animal drugs (under the Animal Drug User Fee Act of 2003).  FDA has also proposed, and Congress is considering as part of omnibus FDA reform legislation, a PDUFA-like user fee system as part of PDUFA IV to fund the review of direct-to-consumer advertisements. 

The most recent user fee proposal was made earlier this month by Representative John Dingell (D-MI). (And you thought the whole camel already entered the tent.)  Rep. Dingell issued discussion draft legislation, titled the “Food and Drug Import Safety act of 2007,” that would amend the FDC Act to, among other things, permit the assessment of two new types of user fees: (1) imported food inspection user fees; and (2) imported drug inspection user fees.  According to a press release and “Dear Colleague” letter issued by Rep. Dingell “[r]ecent reports of tainted imports including pet food, seafood, and cough syrup, have highlighted the need for legislative action.”  A summary of the draft bill is available here.

Rep. Dingell’s draft bill, if enacted, would authorize food import fees totaling $500 million and drug import fees totaling $300 million in each of fiscal years 2008 through 2012.  A fee of up to $50 would be assessed for each line item of food, and a fee of up to $1000 would be assessed for each line item of drug.  FDA would need to issue regulations defining what constitutes a “line item” of food and drug.  The draft bill would also amend the FDC Act to enhance civil monetary penalties for food importers that violate the FDC Act.  Specifically, the bill would amend FDC Act § 303 to permit civil monetary penalties of $100,000 in the case of an individual and $500,000 in the case of a company (not to exceed $1 million for all adjudications in a single proceeding).    

Rep. Dingell’s user fee proposal, although it serves an admirable purpose, begs the questions of how much more room there is in the proverbial user fee tent, and whether Congress’ increasing reliance on user fees to fund FDA activities (instead of substantially increasing FDA appropriations) will eventually cause that tent to collapse. 

In two previous posts (here and here), we reported on a trend in Warning Letters issued by FDA’s Division of Drug Marketing, Advertising, and Communications (“DDMAC”) that focuses on ensuring that promotional pieces contain substantial evidence to support advertising claims and proper presentations of safety data.  In an August 10, 2007 article published by the Washington Legal Foundation, and titled “Recent Warning Letters for Ads Reflect FDA’s Fixation on ‘Substantial Evidence,’” former FDA Associate Chief Counsel Arnold I. Friede drives home the point that to avoid problems with DDMAC, companies need to pay attention to providing substantial evidence to support all advertising claims, and in particular comparative claims.  Mr. Friede comments that:

The recent DDMAC compliance correspondence should be studied closely by companies and practitioners to provide a first hand sense of how FDA applies the “substantial evidence” standard to specific advertising and promotional claims for prescription drugs. But the overall message is simple relatively straightforward: If you want to avoid problems with DDMAC, insure that claims in prescription drug advertising and promotion are supported by “substantial evidence,” no matter how competent and reliable the supporting evidence might otherwise be to the company and to leading experts in the field. To put it bluntly, DDMAC doesn’t really care.  What DDMAC cares about is like “location,” “location,” “location” in the real estate purchase context. It’s about “substantial evidence,” “substantial evidence,” “substantial evidence”.

So whether we like it or not, or whether we think it is unconstitutional or violates the [Administrative Procedure Act] or is otherwise illegal or not, for those who seek to avoid an unpleasant compliance confrontation with DDMAC, “substantial evidence” should be the watchword.

As if to reinforce this conclusion, on August 13, 2007, DDMAC posted a Warning Letter issued to Pfizer on July 16, 2007 concerning certain promotional materials for GEODON (ziprisadone mesylate) Injection.  GEODON is approved for the treatment of acute agitation in schizophrenic patients for whom treatment with ziprasidone is appropriate and who need intramuscular antipsychotic medication for rapid control of the agitation, and includes a black box warning concerning increased mortality in elderly patients with dementia-related psychosis.

DDMAC’s Warning Letter objects to Pfizer’s omission of important risk information (e.g., the failure to communicate certain warnings and precautions associated with Geodon) and to an unsubstantiated superiority claim.  Specifically, with respect Pfizer’s claim that there are “[p]roven advantages over haloperidol [intramuscular] ―twice the improvement as measured on the [Brief Psychiatric Rating Scale],” DDMAC comments that:

This presentation is misleading because it implies that Geodon for Injection is more effective than haloperidol [intramuscular] when this has not been demonstrated by substantial evidence or substantial clinical experience. The single study cited for this claim was an open-label study, which is not an appropriate study design to evaluate subjective endpoints, such as those measured by the Brief Psychiatric Rating Scale anchored version (BPRS), because of the potential for evaluator bias. In fact, FDA is not aware of any substantial evidence to support this claim. If you have data, please submit them to FDA for review. Of interest, in the clinical trials submitted to the NDA for Geodon for Injection, the BPRS was not used and there were no active comparators.

Certainly “substantial evidence” is the DDMAC watchword for now and for the foreseeable future. 

Indeed, as we were drafting this post, DDMAC updated its Warning Letter webpage with a yet another Warning Letter objecting to ubsubstantiated superiority claims.  The letter, issued to Novartis last week, cites certain statements in promotional materials for EXELON (rivastigmine tartrate) Capsules and Oral Solution that are misleading “because, on the basis of an inadequate study, it suggests that Exelon is superior to donepezil [(ARICEPT)] in patients with mild-to-moderate Alzheimer’s Disease who have not responded to donepezil.”

We previously reported on some of the highlights of the most notable provisions of the final rule issued by the Centers for Medicare & Medicaid Services (“CMS”) on the Medicaid Drug Rebate Program.  Today, Hyman, Phelps & McNamara, P.C. issued a detailed memorandum summarizing the July 17th final rule.  The memorandum, among other things, notes where the final rule differs from the proposed rule and prior CMS policy or guidance, and identifies issues that would benefit from further CMS clarification.

In December 1992, FDA promulgated final regulations under which the Agency will accelerate the approval of certain new drugs and biologics for serious or life-threatening illnesses, and when such products provide a meaningful therapeutic benefit to patients over existing treatments. These regulations, which are commonly referred to as “accelerated approval,” are located in Subpart H (21 C.F.R. § 314.500) of FDA’s drug regulations, and in Subpart E (21 C.F.R. § 601.40) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based: (1) on a demonstrated effect on a “surrogate endpoint” and a sponsor’s commitment to complete with “due diligence” the required postmarketing studies to demonstrate the product’s clinical benefits; or (2) on restrictions to assure safe use (that is, when FDA determines that a drug can be used safely only if distribution or use is modified or restricted, e.g., THALOMID (thalidomide)).  (In clinical trials, a “surrogate endpoint” is an alternative measurement of the symptoms of a disease or condition that are substituted for measurements of observable clinical symptoms.)   Importantly, FDA may expedite the withdrawal of approval of an application approved under the accelerated approval regulations if a sponsor “fails to perform the required postmarketing study with due diligence,” or if “[a] postmarketing clinical study fails to verify clinical benefit.”   

Since 1992, FDA has approved scores of applications under the Agency’s accelerated approval regulations –primarily for products with a demonstrated effect on a surrogate endpoint.  FDA has never, however, withdrawn approval of an application for a sponsor’s failure to complete a required postmarketing study with due diligence or because a postmarketing study failed to verify clinical benefit (under either Subpart H or Subpart E).  That may be changing.  (FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit.  Instead, FDA approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment.)   

FDA approved Shire’s PROAMATINE (midodrine hydrochloride) Tablets under the Agency’s Subpart H (surrogate endpoint) regulations in September 1996 for the treatment of symptomatic orthostatic hypotension.  FDA also subsequently approved several generic versions of the drug.  The labeling for PROAMATINE includes the following warning: 

The indication for use of ProAmatine® in the treatment of symptomatic orthostatic hypotension is based primarily on a change in a surrogate marker of effectiveness, an increase in systolic blood pressure measured one minute after standing, a surrogate marker considered likely to correspond to a clinical benefit. At present, however, clinical benefits of ProAmatine®, principally improved ability to carry out activities of daily living, have not been verified.

To verify the drug’s clinical benefit to conclude that the drug is safe and effective, FDA required the sponsor of PROAMATINE to conduct certain Phase 4 studies.  According to FDA’s Postmarketing Study Commitments Database, the official status of the required postmarketing studies is “delayed.”  This makes PROAMATINE the accelerated approval with the longest outstanding commitment. 

On August 7, 2007, FDA sent a letter to companies marketing approved versions of midodrine hydrochloride.  The letter states: “To date, the holder of the midodrine hydrochloride [NDA] has failed to obtain approval for the required phase 4 studies verifying clinical benefit.  If those studies are not approved in a timely manner, that NDA (and all ANDAs referencing that NDA) will be subject to withdrawal . . . .”  It is unclear whether Shire plans to complete and obtain FDA’s approval of those studies.  If not, then FDA’s letter raises the possibility that companies currently marketing generic versions of midodrine hydrochloride might conduct those studies.  FDA’s letter states that “several holders of approved [ANDAs] for midodrine hydrochloride have considered whether to conduct the requisite studies and have requested FDA advice regarding the availability and potential scope of 3-year new clinical studies exclusivity if holders of approved midodrine applications were to collaboratively or individually complete the required post-marketing studies to verify clinical benefit for midodrine hydrochloride.”  FDA requests comment on several questions related to 3-year exclusivity and withdrawal of approval of certain applications, because the proposals to conduct the required midodrine hydrochloride postmarketing studies “raise issues of first impression and will affect more than one midodrine application holder.”   

On August 7, 2007, the U.S. Court of Appeals for the District of Columbia Circuit held in Abigail Alliance for Better Access to Developmental Drugs v. von Eschenbach in an 8-2 opinion “that there is no fundamental right ‘deeply rooted in this Nation’s history and tradition’ of access to experimental drugs for the terminally ill.”  The decision affirmed an August 2004 opinion from the U.S. District Court for the District of Columbia.  In May 2006, however, a divided court of appeals ruled that where there are no other FDA-approved treatment options, a terminally ill patient’s access to investigational new drugs is a “fundamental right” protected under the Due Process Clause of the U.S. 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 FDA’s Investigational New Drug (“IND”) regulations was “narrowly tailored” to serve a “compelling governmental interest.”  FDA appealed, and the D.C. Circuit agreed to hear the case en banc.

The case stems from a citizen petition Abigail Alliance and the Washington Legal Foundation submitted to FDA in June 2003 requesting that the Agency amend its IND regulations to create a policy “to grant Initial Approval for promising drugs, biologics, and devices intended to treat life-threatening diseases with unmet needs,” and to seek “regulatory changes to permit expanded availability of developmental lifesaving drugs following phase 1 clinical trials and at all subsequent stages of the trial and review process.”  Although FDA has not yet substantively responded to the petition, the Agency did respond to earlier Abigail Alliance submissions.  Specifically, in an April 2003 letter from FDA to Abigail Alliance, the Agency commented that accepting Abigail Alliance’s proposal “would upset the appropriate balance that [it is] seeking to maintain, by giving almost total weight to the goal of early availability and giving little recognition to the importance of marketing drugs with reasonable knowledge for patients and physicians of their likely clinical benefit and their toxicity.”

The question Abigail Alliance presented to the D.C. Circuit for consideration was:

Whether the liberty protected by the Due Process Clause embraces the right of a terminally ill patient with no remaining approved treatment options to decide, in consultation with his or her own doctor, whether to seek access to investigational medications that the [FDA] concedes are safe and promising enough for substantial human testing.

The court reviewed the issue under the due process framework established in Washington v. Glucksberg, in which the Supreme Court described its “established method of substantive-due-process analysis” as having “two primary features:”

First, we have regularly observed that the Due Process Clause specially protects those fundamental rights and liberties which are, objectively, deeply rooted in this Nation’s history and tradition and implicit in the concept of ordered liberty, such that neither liberty nor justice would exist if they were sacrificed.  Second, we have required in substantive-due-process cases a careful description of the asserted fundamental liberty interest.

Assuming that Abigail Alliance’s description of its asserted right met the second Glucksberg feature, the court focused on Abigail Alliance’s arguments with respect to the first feature; namely that:

the concepts of self-defense, necessity, and interference with rescue are broad enough to demonstrate the existence of the fundamental right they seek —a right for “persons in mortal peril” to “try to save their own lives, even if the chosen means would otherwise be illegal or involve enormous risks.” (citations omitted).

The court dismissed Abigail Alliance’s arguments, noting that:

The Alliance argues that its right can be found in our history and legal traditions because “the government never interfered with the judgment of individual doctors about the medical efficacy of particular drugs until 1962,” i.e., when major amendments were made to the [FDC Act]. . . .  The Alliance has little to say, however, about our Nation’s history of regulating the safety of drugs. The Alliance’s effort to focus on efficacy regulation ignores one simple fact: it is unlawful for the Alliance to procure experimental drugs not only because they have not been proven effective, but because they have not been proven safe. Although the Alliance contends that it only wants drugs that “are safe and promising enough for substantial human testing,” i.e., drugs that have passed Phase I testing, current law bans access to an experimental drug on safety grounds until it has successfully completed all phases of testing. (citations omitted; emphasis in original).

With respect to Abigail Alliance’s arguments that barring access to experimental drugs for terminally ill patients is inconsistent with the common law doctrines of necessity, the tort of intentional interference with rescue, and the right to self-defense, the court again dismissed these arguments, relying, in part, on the Supreme Court’s decision in United States v. Oakland Cannabis Buyers’ Cooperative.  The court stated that “the common law doctrine of necessity provides little support to the Alliance’s proposed right,” that “we cannot agree that the tort of intentional interference with rescue evidences a right of access to experimental drugs,” and that “[b]ecause terminally ill patients cannot fairly be characterized as using reasonable force to defend themselves when they take unproven and possibly unsafe drugs, the Alliance’s desire that the terminally ill be free to assume the risk of experimental drugs cannot draw support from the doctrine of self-defense.”

The court also commented, citing, among other Supreme Court cases, the decision in United States v. Rutherford, that:

[W]e find it highly significant that the Supreme Court has rejected several similar challenges to the FDCA and related laws brought on statutory grounds . . . [a]nd other courts have rejected arguments that the Constitution provides an affirmative right of access to particular medical treatments reasonably prohibited by the Government.  In keeping with those decisions, we conclude that the Alliance has not provided evidence of a right to procure and use experimental drugs that is deeply rooted in our Nation’s history and traditions. To the contrary, our Nation’s history evidences increasing regulation of drugs as both the ability of government to address these risks has increased and the risks associated with drugs have become apparent. Similarly, our legal traditions of allowing a necessity defense, prohibiting intentional interference with rescue, and recognizing a right of self-defense cannot justify creating a constitutional right to assume any level of risk without regard to the scientific and medical judgment expressed through the clinical testing process.

In affirming the district court’s decision, the circuit court held that Abigail Alliance’s claim of a right of access to experimental drugs is subject to rational basis scrutiny and that:

Although terminally ill patients desperately need curative treatments, as Rutherford holds, their deaths can certainly be hastened by the use of a potentially toxic drug with no proven therapeutic benefit. Thus, we must conclude that, prior to distribution of a drug outside of controlled studies, the Government has a rational basis for ensuring that there is a scientifically and medically acceptable level of knowledge about the risks and benefits of such a drug. We therefore hold that the FDA’s policy of limiting access to investigational drugs is rationally related to the legitimate state interest of protecting patients, including the terminally ill, from potentially unsafe drugs with unknown therapeutic effects.

The two dissenting judges (Chief Judge Ginsberg and Judge Rogers) strongly rebuked the majority opinion in a 29-page dissent.  In sum, the judges contend that:

The court’s opinion reflects a flawed conception of the right claimed by the Abigail Alliance for Better Access to Developmental Drugs and a stunning misunderstanding of the stakes.  The court shifts the inquiry required by [Glucksberg], by changing the nature of the right, by conflating the right with the deprivation, and by prematurely advancing countervailing government interests.  The court fails to come to grips with the Nation’s history and traditions, which reflect deep respect and protection for the right to preserve life, a corollary to the right to life enshrined in the Constitution.  The court confuses this liberty interest with the manner in which the Alliance alleges that the liberty has been deprived, namely by denying terminally ill patients access to investigational medications under the narrow conditions described by the Alliance.  The court conflates the inquiry as to whether a fundamental right exists at all with whether the government has demonstrated a compelling interest, when strictly scrutinized, rendering its restrictive policy constitutional. . . .

In the end, it is startling that the oft-limited rights to marry, to fornicate, to have children, to control the education and upbringing of children, to perform varied sexual acts in private, and to control one’s own body even if it results in one’s own death or the death of a fetus have all been deemed fundamental rights covered, although not always protected, by the Due Process Clause, but the right to try to save one’s life is left out in the cold despite its textual anchor in the right to life. This alone is reason the court should pause about refusing to put the FDA to its proof when it denies terminal patients with no alternative therapy the only option they have left, regardless of whether that option may be a long-shot with high risks. The court is on even weaker footing when it relies upon the risks entailed in medical procedures to wrest life-and-death decisions that once were vested in patients and their physicians. The court commits a logical error of dramatic consequence by concluding that the investigational drugs are somehow not “necessary.”  While the potential cures may not prove sufficient to save the life of a terminally ill patient, they are surely necessary if there is to be any possibility of preserving her life. (citation omitted; emphasis in original).

The immediate effect that this ruling might have on FDA’s plans to move forward with the Agency’s proposed treatment IND regulations and on Senator Sam Brownback’s (R-KS) efforts to pass legislation supported by Abigail Alliance is unclear at this time.  We will update you as we learn more information.   

Last week, the U.S. House of Representatives passed H.R. 3161, the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act for Fiscal Year 2008.  The bill, which, among other things, funds FDA’s discretionary spending for the upcoming fiscal year, “fully funds the [President’s request] for the FDA and provides targeted increases of $55 million,” according to the House report accompanying the bill.  These “targeted increases” are with respect to food safety activities, speeding up generic drug application reviews (with a $5 million increase to FDA’s Office of Generic Drugs), post-market drug safety reviews, and review of direct-to-consumer drug ads. 

The bill also includes a controversial provision that would allow the importation of certain prescription drugs into the United States.  Specifically, Section 726 of H.R. 3161 states:

None of the funds appropriated or otherwise made available by this Act for the [FDA] may be used under section 801 of the [FDC Act] to prevent an individual not in the business of importing a prescription drug within the meaning of section 801(g) of such Act, wholesalers, or pharmacists from importing a prescription drug (as defined in section 804(a)(3) of such Act) which complies with sections 501 [(adulteration)], 502 [(misbranding)], and 505 [(new drug approval)] of [the FDC Act].

Representative Jack Kingston (R-GA), who was unsuccessful in his attempt to get an amendment passed to strike the importation provision, commented in the House Report on H.R. 3161 that “[i]f this provision is going to remain in the bill, then there should be funding to ensure the safety and efficacy of those imported drugs.”

FDA explained its current importation policy in a February 2003 letter issued in response to inquiries about the liability of various parties involved in importing prescription drugs from Canada.  FDA’s letter states:

The reason that Canadian or other foreign versions of U.S.-approved drugs are generally considered unapproved in the U.S. is that FDA approvals are manufacturer-specific, product-specific, and include many requirements relating to the product, such as manufacturing location, formulation, source and specifications of active ingredients, processing methods, manufacturing controls, container/closure system, and appearance.  21 C.F.R. § 314.50.  Frequently, drugs sold outside of the U.S. are not manufactured by a firm that has FDA approval for that drug.  Moreover, even if the manufacturer has FDA approval for a drug, the version produced for foreign markets usually does not meet all of the requirements of the U.S. approval, and thus is considered to be unapproved.  21 U.S.C. § 355.

The U.S. Senate Appropriations Committee, which passed its version of the appropriations bill, S. 1859, on July 19, 2007, does not include a similar importation provision.  The Senate report accompanying the bill, however, includes an amendment, sponsored by Senator Byron Dorgan (D-ND) that would require FDA to:

issue a report, using available data sources, within 120 days of enactment of this act, that outlines the location of the manufacturer of all drugs approved since January 1, 2000; the location of the manufacturer of the active ingredient in each of those drugs, only as submitted in the original application; the extent to which drugs manufactured overseas and commercially distributed in the United States are subject to different regulation than drugs manufactured and distributed in the United States; and the procedures taken when a manufacturer changes the procurement of active ingredients for their drugs.  The Committee further directs that the FDA present this information in such as way as to not violate any commercial confidential, trade secret, or proprietary information.

Sen. Dorgan, who was unsuccessful in his attempt to add a provision to the FDA Revitalization Act (S. 1082) permitting prescription drug importation, issued a press release stating that the “action comes on the heels of an all out attack by the big drug makers on legislation sponsored by Dorgan and Senator Olympia Snowe to allow the importation of lower priced prescription drugs from other countries.  The drug makers argue prescription medicines imported from other countries are inherently dangerous and that there is no way to guarantee their safety.”  According to Sen. Dorgan, “I am not claiming that drugs made overseas are dangerous, but if that’s the argument drug manufacturers are going to make to block importation of lower priced medicines, then Americans have a right to know the origin of prescription medicines the drug companies are already selling here.”

The National Association of Manufacturers and the National Association of Chain Drug Stores, among other organizations, have voiced opposition to the inclusion of a provision permitting prescription drug importation in appropriations bills (and other legislation).  In addition, the White House has objected to the importation provision in H.R. 3161.  Specifically, the Office of Management and Budget (“OMB”) stated the following in a July 31, 2007 Statement of Administrative Policy:

The Administration strongly opposes the prescription drug importation provision, which does not include any protections to ensure that imported drugs are safe and effective and which will have a negative effect on incentives for beneficial innovation. In 2004, a Department of Health and Human Services Task Force found that there are significant safety and economic issues that must be addressed with respect to prescription drug re-importation. While the provision theoretically limits importation to only FDA-approved prescription drugs, it would be impossible for FDA to verify at the border that they are not counterfeit.

The White House has previously threatened to veto certain legislation permitting importation.  For example, OMB stated in a May 1, 2007 Statement of Administrative Policy with respect to Senate efforts to include an importation provision in S. 1082 that:

The Administration would also strongly oppose any provision that might be added on the Senate Floor regarding the importation of prescription drugs that does not address the serious safety concerns identified in the December 2004 Department of Health and Human Services Task Force Report on Prescription Drug Importation.  The Administration believes that allowing importation of drugs outside the current safety system established by the FDA without addressing these serious safety concerns would threaten public health and result in unsafe, unapproved, and counterfeit drugs being imported into the United States.  As a result, if any such importation provision were included in the final version of the bill presented to the President, the President’s senior advisors would recommend that he veto the bill.

Although drug importation legislation appears to be off the table as an item for consideration in pending omnibus FDA reform legislation, it appears that the House and Senate are headed for a showdown over the issue as a part of FDA appropriations legislation. 

Legislation that would permit the U.S. Patent and Trademark Office (“PTO”) to exercise discretion to accept untimely filed Patent Term Extension (“PTE”) applications has reportedly been added to the “Patent Reform Act of 2007” (S. 1145) by Senator Edward Kennedy (D-MA).  Representative William Delahunt (D-MA), who introduced a stand-alone bill earlier this year in the House, H.R. 1778, is trying to get the legislation added to the House version of the “Patent Reform Act of 2007” (H.R. 1908). 

The legislation, dubbed the “Dog Ate My Homework Act,” has been an agenda item for Massachusetts lawmakers for several years now, and is intended to help Massachusetts-based The Medicines Company, which submitted its PTE application for U.S. Patent #5,196,404 (“the ‘404 patent”) for ANGIOMAX (bivalirudin) 62 days after FDA approved its New Drug Application (“NDA”) .  The patent term extension law, 35 U.S.C. § 156, requires the submission of such an application “within the sixty-day period beginning on the date the product received permission under the provision of law under which the applicable regulatory review period occurred for commercial marketing or use” (i.e., within 60-days of the date of NDA approval). 

FDA Approved ANGIOMAX on December 15, 2000.  On February 14, 2001, The Medicines Company submitted a PTE application to the PTO for the ‘404 patent, which is currently scheduled to expire in 2010.  After confirming the NDA approval date with FDA, the PTO dismissed the application in March 2002.  The Medicines Company subsequently requested reconsideration on the basis that the date of approval of the ANGIOMAX NDA was in fact first effective as of December 18, 2000, and in January 2007 requested a stay of action on its PTE application.  In April 2007, after permitting the company to amend and supplement its application, the PTO denied the extension request.  Among other things, the PTO cited Unimed, Inc. v. Quigg, 888 F2d 826; 12 USPQ2d 1644 (Fed. Cir. 1989), in which the Federal Circuit addressed the timeliness of a PTE application submission and observed that “section 156(d)(1) admits of no other meaning than that the sixty-day period begins on the FDA approval date.”  A copy of the file history of the ‘404 patent, including the April 2007 PTO decision, can be found on the PTO’s Patent Application Retrieval Database by searching by patent number. 

While the PTO was considering The Medicine Company’s PTE application and request for reconsideration, the company was, according to Securities and Exchange Commission filings made as early as March 2003, “exploring an alternative to extend the term of the patent.”  (The company’s most recent annual report reiterates this.)  This alternative took the form of lobbying Massachusetts lawmakers to push for legislation that would provide the PTO with discretion to consider PTE applications filed late unintentionally.  Until recently, the closest such legislation came to becoming law was on December 6, 2006, when the House passed the Senate version of the “Vessel Hull Design Protection Amendments of 2006’’ (S. 1785), which included language similar to H.R. 5120, a bill that had been introduced in April 2006 and that was vetted during a September 2006 House Judiciary Committee hearing. The Senate adjourned on December 9, 2006 without further considering S. 1785.

The issue did not remain dormant long.  In March 2007, Representative Delahunt introduced H.R. 1778, and in April, both the Senate and House began debating patent reform legislation, which offered one vehicle to which to attach such legislation.  Although the House Judiciary Committee passed H.R. 1908 (“Patent Reform Act of 2007”) on July 18, 2007 without the Delahunt PTE provision, Representative Delahunt will reportedly try to get it added when the full House considers the legislation.  In the Senate, Senator Kennedy reportedly was successful in his attempt to add language similar to the Delahunt House bill when the Senate Judiciary Committee considered S. 1145 (“Patent Reform Act of 2007”) during a mark-up session held on July 18, 2007.  The Senate Judiciary Committee is still considering the legislation.

UPDATE:

• A copy of Sen. Kennedy’s amendment agreed to at the Senate Judiciary Committee Executive Business Meeting is available here.