By Alexander J. Varond* & Kurt R. Karst –

Recently, the U.S. District Court for the District of Columbia dismissed a case brought by the Coalition for Mercury-Free Drugs (“Coalition”). Judge Reggie B. Walton ruled that the Coalition lacked standing to ask the court to ban vaccines containing the mercury-based preservative Thimerosal.

Background

Beginning on August 10, 2007, the Coalition pursued a Citizen Petition against the use of Thimerosal under the belief that it causes the onset of autism and other brain disorders in children.

Though the preservative has been used in vaccines in the United States since the 1930s and has been proven safe, FDA supports a policy to remove Thimerosal from vaccines that are commonly administered to children. Regardless, FDA denied the 2007 Citizen Petition citing its lack of a legal or scientific basis to support the Coalition’s proposition.

The Case: The Coalition for Mercury-Free Drugs v. Kathleen Sebelius

Following the denial of its Citizen Petition, the Coalition filed a petition for injunctive relief in the United States District Court for the District of Columbia. Specifically, the complaint sought to suspend all approval and licenses as well as recall the preservative unless manufacturers could positively prove that it did not cause neurological damage in susceptible populations.

The court first addressed whether the National Vaccine Injury Compensation Act (“Vaccine Act”) provided sufficient, independent standing. Judge Watson held that although the Vaccine Act contains a citizen petition clause which states that “[a]ny person may commence in a district court of the United States a civil action on such person’s own behalf against the Secretary where there is alleged a failure of the Secretary to perform any act or duty upon this part.” 42 U.S.C. § 300aa-31, “it does not dispense with the requirement that the plaintiffs must demonstrate that they have standing to bring such an action in federal court.” Opinion at 8.

Thus, to bring the action before the federal court, plaintiffs had to prove standing “which requires the presence [of]: (1) injury in fact, (2) causation, and (3) redressability.” Opinion at 6. The court noted that the group would have to prove that at least one individual in the group had “standing to sue in their own right,” as required under Hunt v. Wash. State Apple Advertising Comm’n, 432 U.S. 333 (1977).

First, Judge Walton ruled that fear of the effects of Thimerosal was an insufficient basis for standing since there was adequate availability of mercury-free vaccines. The court noted that these mercury-vaccines were ample alternatives for anyone fearing the potential harms of Thimerosal. Moreover, even if there was an increased burden for those people that preferred mercury-free vaccines, plaintiffs did not prove that the burden or delay caused sufficient harm.

The court also held that the potential for healthcare providers to become confused whether a vaccine contained Thimerosal was too abstract of a potential harm. This was particularly true because Thimerosal packaging clearly indicated the preservative’s presence. Moreover, the potential for mix-ups as a result of repackaging and  “blatant mislabeling and deception by a pharmacist cannot be deemed ‘fairly traceable’ to the actions of the named defendants . . . .” Opinion at 17 (citing Lujan v. Defenders of Wildlife, 504 U.S. 555, 560-61 (1992)).

Finally, the court rejected the coalition’s claim that doctors and other medical professionals would suffer a loss of reputation from an alleged inability to guarantee the safety of vaccines. In these terms, the court held that this potential harm to doctors merely constituted an insufficient and generalized grievance, not the concrete and imminent injury.  Thus, the Coalition’s suit was dismissed for a lack of standing because the Coalition was unable to prove adequate harm.

* Law Student

By Kurt R. Karst –   

Late Thursday, the U.S. House of Representatives passed a package of amendments (beginning on page 74) to the War Funding Bill (H.R. 4899) that included the “Preserve Access to Affordable Generics Act,” which is intended to curb patent settlement agreements (what opponents call “pay-for-delay” agreements).  The amendment appears to be identical to an amendment Senators Herb Kohl (D-WI), Charles Grassley (R-IA), and Susan Collins (R-ME) introduced during the Senate’s consideration of the Tax Extenders Act (H.R. 4213) (see our previous post here).

The bill, which will have to be passed by the Senate, would amend the Federal Trade Commission (“FTC”) Act to permit the FTC to “initiate a proceeding to enforce the provisions of [new Sec. 28] against the parties to any agreement resolving or settling, on a final or interim basis, a patent infringement claim, in connection with the sale of a drug product.”  Such agreements, if challenged, would be presumptively anticompetitive and unlawful unless it can be demonstrated “by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.”  In addition, “[e]ach person, partnership or corporation that violates or assists in the violation of [new Sec. 28] shall forfeit and pay to the United States a civil penalty of not more than 3 times the gross revenue of the NDA holder from sales of the drug product that is the subject of the patent infringement claim for the period of the violation, starting with the date of the agreement.”

The amendment was included in H.R. 4899 over the objection of some legislator who urged in a June 30, 2010 letter to House Appropriations Committee Chairman David Obey (D-WI) that the provision be eliminated.  According to those legislators:

From a substantive standpoint, the legislative language will achieve exactly the opposite of its intent. The two primary provisions of the legislative language will, in concert, remove current incentives for generic drug companies to challenge drug patents. Consequently, generic drug companies will wait until new drug patents expire before they bring a generic product to market. Consumers will then wait, on average, 5 to 9 years for access to cheaper generic medicines and consumer benefit will arguably be diminished.

According to a Dow Jones report, the measure was strongly backed by both House Speaker Nancy Pelosi (D-CA) and House Energy and Commerce Committee Chairman Henry Waxman (D-CA).

By Ricardo Carvajal –

The Supreme Court overturned a district court decision, affirmed by the 9th Circuit Court of Appeals, that enjoined the USDA Animal and Plant Health Inspection Service ("APHIS") from partially deregulating Roundup Ready Alfalfa ("RRA") and prohibited the planting of RRA until APHIIS completes an Environmental Impact Statement ("EIS") as required under the National Environmental Policy Act ("NEPA").  RRA is subject to regulation as a plant pest under the Plant Protection Act until APHIS decides that RRA does not present a plant pest risk and can be “deregulated.”  To do so, APHIS is required under NEPA to prepare an EIS unless a less burdensome environmental assessment ("EA") reveals that deregulation would have no significant environmental impact. 

APHIS’s decision to deregulate RRA on the basis of an EA was challenged by conventional alfalfa seed farms and some environmental groups on the ground that the EA did not adequately address the risks of gene transfer from RRA to conventional and organic alfalfa, or from RRA to weedy species, and that APHIS violated NEPA when it failed to conduct an EIS.  The district court agreed and the Court of Appeals agreed.  The Supreme Court did not address the merits of these issues, nor did it disturb the district court’s decision to vacate AHPIS’s deregulation of RRA.  Rather, the Supreme Court held that the district court abused its discretion in the remedies that it crafted for APHIS’s violation, and remanded the case to the district court for further proceedings which could yet result in a complete or partial deregulation of RRA.

Although the fate of RRA remains uncertain, the Supreme Court decision stirred action on the Hill, where several bills that address different aspects of the controversy over development, marketing, and labeling of bioengineered foods were immediately introduced (H.R. 5577, The Genetically Engineered Food Right to Know Act; H.R. 5578, the Genetically Engineered Safety Act; and H.R. 5579, the Genetically Engineered Technology Farmer Protection Act.

The legal jousting over bioengineered crops is certain to intensify as developers seek to market and perhaps deregulate varieties that are bioengineered to produce substances used in the chemical and pharmaceutical industries.  Those technological developments promise to accentuate the fault lines that have emerged between the biotechnology sector and those who seek to satisfy market demand for conventional and organic foods. 

As for the FDA, this case serves as a reminder that NEPA, although perhaps a paper tiger, is not entirely toothless.  Transgenic salmon, anyone?

By Kurt R. Karst –   

On the first day of FDA’s two-day public hearing (agenda here) regarding the Agency’s regulation of drugs, biological products, and devices for the treatment, diagnosis, and/or management of rare (i.e., orphan) diseases, the National Organization for Rare Disorders (“NORD”) called for FDA to issue a Statement of Policy expressing a more granular expression of the Agency’s historic commitment to exercise flexibility in its review of therapies for rare disorders and for an FDA expression of ways to reduce regulatory uncertainty in the development and review of orphan disorder therapies. 

NORD Board of Directors Chairman (and Hyman, Phelps & McNamara, P.C. Director) Frank J. Sasinowski stated during his testimony that FDA needs to “develop and issue a specific Statement of Policy on FDA’s role in regulating therapies for rare disorders, which includes an explanation and affirmation of the FDA’s historic position that FDA flexibly applies the standards of safety and effectiveness with respect to therapies for those with rare disorders.”  Although FDA’s rigorous safety and efficacy standards apply equally to orphan drugs, “the FDA interpretation and application of those same standards have historically been tailored by FDA to the unique facts of each particular medicine under FDA review,” according to Mr. Sasinowski.  Indeed, Mr. Sasinowski said that such a Statement of Poicy could stimulate orphan drug research: “the investment community and pharmaceutical industry may benefit from such a formal, explicit statement of policy that will encourage investment in, research of and development of medicines for those with rare disorders . . . for which there still is not a single FDA-approved therapy.”

NORD also commented on the need to increase regulatory certainty in the development of therapies for rare diseases/condition: 

It is axiomatic that the perfect is the enemy of the good.  In the world of rare disorders, there is much that is often not known or not known well, starting with the etiology and pathophysiology of the condition, including its natural history, and ranging to a lack of agreement among even a small handful of world experts on the most common clinical manifestations of some conditions.  Against this backdrop, it is entirely understandable that FDA on occasion will find it difficult to concur in advance with a development program, even the design of a registrational trial under a special protocol assessment.  However, researchers, industry and FDA, as well as most importantly, persons with the condition, may find that sometimes a study needs to proceed because patients are suffering and can not wait for the perfect trial design with the ideal primary endpoint to be eventually determined or developed and consensually accepted. . . .  [W]hen these trials are conducted, sometimes with designs with which all parties may not be in full concurrence, including the FDA, great deference should be afforded the design of these trials and flexibility applied in the interpretation of their results.

Other recommendations were included in a presentation given by NORD Vice President Diane Edquist Dorman. 

NORD’s stated need for greater certainty and predictability in the approval process was echoed in comments submitted to FDA by the Biotechnology Industry Organization, and will likely be stated again during the second day of FDA”s hearing.

The public hearing was held to assist FDA as the Agency implements § 740 of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Pub. L. No. 111-80), which, as we previously reported and as commented on by Office of Orphan Products Development (“OOPD”) Director Dr. Timothy Coté during his testimony at the hearing, requires FDA to convene a committee of expert Agency employees to consider the ways FDA reviews products to treat people with rare diseases, and consider policy improvements that might help people with rare diseases get better treatments faster.  The public hearing is FDA’s first hearing on rare diseases since the Orphan Drug Act (“ODA”) was enacted 27 years ago.  Since then, FDA has approved 350 products for rare diseases and has granted orphan drug designation for almost 2,200 products, according to OOPD’s database.  Although the ODA has been hailed as a resounding success, there remain approximately 5,800 rare diseases/conditions for which there are no FDA-approved therapies.

Earlier this year, FDA announced the newly-created position of Associate Director for Rare Diseases in the Agency’s Center for Drug Evaluation and Research’s (“CDER’s”) Office of New Drugs.  This orphan drug czar “will serve as CDER’s focal point to the rare disease drug development community and assist stakeholders and developers of drug and biologic products in navigating the complex regulatory requirements for bringing safe and effective treatments to patients in need.”  In addition, OOPD recently introduced the Rare Disease Repurposing Database (“RDRD”), which is a listing of products that have received orphan designation and that are already approved for the treatment of some other disease.  The RDRD is intended to push orphan drug research by providing sponsors with “a new tool for finding special opportunities to develop niche therapies that are already well-advanced through development.” 

Hyman, Phelps & McNamara, P.C. (“HP&M”) is pleased to announce that Frank J. Sasinowski has been elected by the the U.S. Pharmacopeial Convention (“USP”) as an At-Large Trustee of the USP Board of Trustees for the 2010-2015 cycle.  The Board of Trustees will guide the activities of the USP for the next five years and makes decisions that guide USP’s policies, finances, and strategic direction. 

By Susan J. Matthees –  

USDA and HHS have announced the availability of the final Report of the Dietary Guidelines Advisory Committee (“DGAC”).  The agencies are required by law to jointly update and publish the Dietary Guidelines for Americans at least every 5 years, and the final Report, along with public comments to the Report, will be used by the agencies to draft the 2010 Dietary Guidelines for Americans. 

A major focus of the Report is America’s “growing” problem with weight management and the great paradox of the American diet- we are eating more than enough food, yet are not getting adequate amounts of key nutrients, such as vitamin D, calcium, and dietary fiber.  The Report recommends that the Dietary Guidelines make reducing obesity a priority, explaining that the “DGAC considers the obesity epidemic to be the single greatest threat to public health in this century.”   

The Report reiterates what many nutrition experts and health advocates, including Mrs. Obama, have been suggesting: Americans should shift their diets to more plant-based foods, such as legumes, seeds, nuts, whole grains, vegetables and fruit,  reduce intake of foods that contain added sugar and solid fat, and increase their physical activity.  The 2010 DGAC opted to discontinue the term  “discretionary calorie allowance” to explain how much extra fat and sugar should be in the American diet.  The 2005 DGAC used this term, but the 2010 DGAC found that although it is still a scientifically valid concept, it is difficult to communicate to consumers.  Instead, the 2010 DGAC recommends using numerical limits, including a recommendation that added sugar be limited to 25% of total calorie consumption. 

Weight management was not the sole focus of the Report.  The Report also recommended a reduction in sodium intake to 1,500 mg per day or less, which is a decrease from the 2005 DGAC recommendation to limit sodium intake to less than 2,300 mg.  The Report acknowledged that this could be difficult and thus recommends a gradual reduction in intake with a nod towards the Institute of Medicine’s ("IOM’s") recent roadmap to reduce sodium intake. 

The Report also reviewed the consumption of alcohol, water, potassium, protein, and carbohydrates.  The Report concluded that there was no evidence that high protein, low carbohydrate diets are better for weight loss and weight maintenance than other diets.  Although there has been increased attention to the fact that many Americans are deficient in vitamin D, the DGAC opted not to conduct its own review because the IOM is currently reviewing the DRI for vitamin D.  Finally, although the Report notes that most Americans are deficient in some nutrients, it states that daily supplementation with a multivitamin/multimineral “does not offer health benefits to healthy Americans.”  
 
Interested parties are encouraged to submit written comments until July 15, 2010.  Written comments can viewed on the same website.  There will also be a public meeting on July 8, 2010, to solicit oral comments. 

By William T. Koustas –

Regenerative Sciences, Inc. (“Regenerative”) filed a complaint in the U.S. District Court for the District of Columbia against FDA on June 22nd in order to prevent FDA from essentially closing the business.  Regenerative owns a procedure by which physicians take bone marrow and blood samples from a patient, culture the stem cells, and place them back in the patient’s damaged joint in order to repair it (“Regenexx Procedure”).  Regenerative Sciences, Inc. v. FDA, United States District Court for the District of Columbia, June 22, 2010 (“Complaint”).  The Regenexx Procedure is exclusively licensed for use at the clinic where the inventors of the procedure practice.  Complaint at 2.  However, FDA appears to consider Regenerative a drug manufacturer and the stem cells it cultures in its Regenexx Procedure to be biological drugs, and thus claiming that Regenerative is manufacturing an unapproved drug.  Complaint at 8. 

FDA conduced an inspection of Regenerative’s facility in February and March of 2009, which culminated in FDA issuing a Form 483.  Complaint at 8.  Then, FDA returned to inspect Regenerative again earlier this month and again issued another Form 483.  According to the complaint, an FDA investigator threatened that FDA would issue a warning letter, cease and desist letter, civil penalties and seek an injunction if Regenerative did not correct the deficiencies found during the inspection.  Complaint at 7.  Regenerative claims that correcting the deficiencies found in the inspection would bankrupt it.  Complaint at 3. 

Regenerative argues that the Regenexx Procedure is the practice of medicine and is beyond the scope of FDA’s regulatory authority as provided in the U.S. Food, Drug & Cosmetic Act as well as the Public Health Service Act.  Complaint at 12.  Regenerative contends that the manipulation of stem cells occurs in the normal course of a medical practice which is regulated by Colorado.  Further, Regenerative stresses that the Regenexx Procedure occurs completely within the state of Colorado and is therefore not subject to FDA’s authority because it does not engage in the interstate sale of drugs.  Complaint at 14.  Regenerative also asserts a due process argument in that FDA’s actions violate the Due Process Clause of the Fifth Amendment as it will force Regenerative to go out of business.  Complaint at 17.  The complaint requests that the Court enjoin FDA from regulating the Regenexx Procedure, issuing a cease and desist letter and from ex-parte action by FDA to prevent the use of the Regenexx Procedure.  (A related case filed in the U.S. District Court for the District of Colorado was dismissed earlier this year and has been appealed to the U.S. Court of Appeals for the Tenth Circuit.)

By Carrie S. Martin –

The Office of Inspector General (“OIG”) recently issued a report detailing the inclusion of foreign clinical trial data in New Drug Applications (“NDAs”) and Biologics License Applications (“BLAs”) and FDA’s oversight of foreign clinical trial sites.  The OIG examined all NDAs and BLAs, and related documents, submitted in Fiscal Year (“FY”) 2008 with two questions in mind: (1) how much foreign data did sponsors submit in their marketing applications; and (2) to what extent did FDA monitor and inspect these foreign clinical trials.  The answers: (1) a lot; and (2) not enough.

OIG found that 80% of approved NDAs and BLAs in FY 2008 contained data from foreign clinical trials.  Although most subjects and sites were located in Western Europe, Central and South America accounted for the highest average number of subjects per site.  Usually, only one clinical investigator oversees a clinical trial site.  OIG also determined that FDA inspected only 0.7% of foreign clinical trial sites in FY 2008.  (That being said, FDA inspected only 1.9% of U.S. sites.)  Finally, the report noted that data limitations inhibited FDA’s ability to inspect foreign sites, including, for example, the failure of sponsors to submit complete information on site locations and subject enrollment.  Some of these data omissions may be understandable:  federal law does not require an Investigational New Drug (“IND”) application for clinical trials conducted exclusively outside the U.S.  INDs serve as FDA’s primary method of collecting information on clinical trials.

OIG acknowledged the perceived benefits of foreign trials – lower clinical trial costs, larger populations from which to collect patients, and the desire to obtain foreign marketing approvals.  The downside, according to critics, is the lack of patient protection due to inadequate monitoring and the ability to “generalize” foreign data to the U.S. population.

Based on its research, OIG made three recommendations to FDA: (1) require standardized electronic clinical trial data and create an internal database from which FDA can select sites for inspection; (2) monitor trends in foreign clinical trials not conducted under INDs and take steps as necessary to encourage sponsors to file INDs; and (3) explore additional ways to expand the Agency’s oversight of foreign clinical trials, including agreements with foreign regulatory bodies and inspections of clinical trial sites in countries not previously inspected. 

FDA generally agreed with OIG’s recommendations and is seeking to address each recommendation.  For FDA’s full response, see Appendix E of the report.  OIG predicts that the reliance on foreign data will grow in coming years; this will undoubtedly increase the pressure on FDA to adopt new ways to ensure patient protection and the integrity of foreign data.

By Kurt R. Karst –   

Earlier this week, FDA announced Pfizer’s voluntarily withdrawal (at least insofar as a voluntary withdrawal is truly voluntary when FDA requests it) of MYLOTARG (gemtuzumab ozogamicin for Injection) from the market after a required postmarketing study failed to demonstrate clinical benefit.  FDA approved MYLOTARG in May 2000 under the Agency’s Subpart H (“accelerated approval”) regulations as a single agent for patients with CD33 positive Acute Myeloid Leukemia (“AML”) in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy.  Pfizer announced that the company will withdraw the MYLOTARG NDA effective October 15, 2010. 

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 accelerated approval regulations are located in Subpart H (21 C.F.R. Part 314) of FDA’s drug regulations, and in Subpart E (21 C.F.R. Part 601) of the Agency’s biologics regulations.  If a product meets these criteria, then FDA may grant marketing approval based on a demonstrated effect on a surrogate endpoint reasonably likely to predict clinical benefit and a sponsor’s commitment to complete with due diligence the required postmarketing studies to confirm the product’s clinical benefits.  A surrogate endpoint is an alternative measurement of the symptoms of a disease or condition that is 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] postmarketing clinical study fails to verify clinical benefit” or if a sponsor “fails to perform the required postmarketing study with due diligence.”

FDA approved MYLOTARG based on the surrogate endpoint of response rate observed in 142 patients with AML across three clinical trials and required the applicant to conduct a postmarketing study designed to determine whether adding MYLOTARG to standard chemotherapy demonstrated an improvement in overall survival time (i.e., clinical benefit) of AML patients.  The required postmarketing study was initiated in 2004, but was stopped early when no clinical benefit was observed.  In addition, according to FDA, the study was also stopped “after a greater number of deaths occurred in the group of patients who received Mylotarg compared with those receiving chemotherapy alone.” 

The MYLOTARG withdrawal appears to be the first instance in which a product granted accelerated approval has been withdrawn from the market – either because a postmarketing study failed to verify clinical benefit or because of a sponsor’s failure to complete a required postmarketing study with due diligence.  Although FDA could have pursued withdrawing approval of IRESSA (gefitinib) when the sponsor’s postmarketing study failed to verify clinical benefit, FDA instead approved new labeling that limits IRESSA use to patients with cancer who are currently benefiting, or have previously benefited, from IRESSA treatment. 
 

By Kurt R. Karst –   

Earlier today, the U.S. Supreme Court declined to hear appeals in two separate cases of interest to the food and drug law bar involving the False Claims Act (“FCA”) – Hopper v. Solvay Pharms, Inc., 588 F.3d 1318 (11th Cir. 2009) and United States, ex rel. Mark Eugene Duxbury v. Ortho Biotech Products, L.P., 579 F.3d 13 (1st Cir. 2009).  The decision lets stand two circuit court rulings.

In Solvay, the U.S. Court of Appeals for the Eleventh Circuit ruled that a FCA action should be dismissed when, as in this case, the Relators are unable to present any evidence that the defendant company actually caused false claims to be submitted based on an alleged off-label marketing campaign.  As we previously noted (here and here), Solvay is an important ruling in the context of FCA litigation generally, but more specifically with regard to off-label use cases.  The Eleventh Circuit’s ruling is the first decision by a United States Court of Appeals concerning off-label use in which the court ruled that a complaint was deficient where there were no claims identified by the Relator.  Many off-label FCA actions have been initiated by company sales representatives who claim first-hand knowledge about an alleged off-label sales program, but do not have first-hand knowledge about the reimbursement practices of the company (usually because  those functions are handled by others in the company).

As we previously reported (here and here), the underlying case in Duxbury asserted qui tam claims under the FCA against Ortho Biotech that were based on certain of the company’s product promotion activities, alleging promotion of off-label use, marketing the “spread” and providing “kickbacks” to providers in the form, among others, of free product samples.  The District Court dismissed all of the claims, citing multiple grounds.  On appeal, the U.S. Court of Appeals for the First Circuit reversed in part, reviving only those claims attributable to Duxbury based on kickbacks.

The United States recommended in an amicus brief that the Supreme Court decline to hear the case, in part, on the basis that a recent amendment to the FCA’s definition of the term “original source” made one question posed in the Petition for a Writ of Certiorari “not of sufficient continuing importance to warrant this Court’s review.”

By Jamie K. Wolszon –

FDA is signaling that it is considering whether to fundamentally reshape how it regulates laboratories and laboratory-developed tests ("LDTs").  LDTs, which are diagnostic tests developed and performed by a laboratory, are widely used.  For example, virtually every genetic test is an LDT.  When new diseases emerge, the initial diagnostic tests are often LDTs. 

Starting in 1992, FDA asserted that it had authority over LDTs as devices.  FDA’s position is that all LDTs are devices subject to regulation under the Federal Food, Drug, and Cosmetic Act.  The legality of FDA’s position has been disputed, but not yet been the subject of a court challenge.

FDA has adopted a policy of “enforcement discretion” over laboratories and LDTs.  However, FDA now is considering jettisoning that enforcement-discretion approach and instead adopting a new, more forceful approach to regulation for LDTs.  FDA is seeking comment on a new-risk based premarket approach at a July 19-20 public meeting.

The meeting notice is one in a series of recent signs of a more activist approach to regulating LDTs.  Less than a week before the meeting announcement, on June 10, FDA sent letters to five companies stating that their genetic diagnostic tests were unapproved, a move seen as heralding increased interest in asserting regulatory power over LDTs. 

In addition, FDA commissioner Margaret A. Hamburg and National Institutes of Health Director Francis S. Collins recently authored an article in the New England Journal of Medicine that also suggested FDA interest in a more active role in LDT oversight.  The letters, article, and meeting appear to represent a coordinated effort to extend FDA regulation over LDTs.

The July 19-20 meeting notice, published in the Federal Register on June 17, 2010, stated that for years the agency has generally exercised enforcement discretion and not enforced the regulations it claims were applicable to devices.  The notice added that the agency generally has not actively regulated LDTs. 

There have been exceptions to the hands-off approach.  Over the years, FDA has occasionally challenged a test offered by a laboratory, e.g., asserting that the test was not a true LDT.  FDA also proposed regulating as devices a single, narrowly-defined subset of LDTs, In Vitro Diagnostic Multivariate Index Assays ("IVDMIAs"), which are tests where the results of multiple markers are combined to generate an “index score.”  As previously reported, it proposed premarket review requirements for those tests in a September 7, 2006, draft guidance, and a revised draft guidance issued July 26, 2007.  It has not proposed premarket review for other subsets of LDTs.

The IVDMIA approach was widely criticized.  One of the major criticisms was that it was not risk-based.  FDA has never finalized those IVDMIA draft guidances.  According to published reports, the agency will not issue the IVDMIA guidance, but instead will focus on the more comprehensive review of LDTs.
In its meeting notice, FDA states, “[T]he agency believes it is time to reconsider its policy of enforcement discretion over LDTs.”  Expanding on its goals, FDA added, “[a]t this time, FDA believes that a risk-based application of oversight to LDTs is the appropriate approach to achieve the desired public health goals….”  After the conclusion of the public meeting and the public comment period, “FDA will move forward expeditiously to develop a draft oversight framework for public comment to provide predictability as quickly as possible.  The FDA also intends to phase in such a framework over time based on the level of risk to the test.”

Discussing the factors that brought it to the conclusion that it should abandon its years-long policy of enforcement discretion, FDA said that in the past LDTs were simple, well-characterized and understood tests for rare diseases.  Now, according to the agency, LDTs often use unregulated components, assess high-risk but common diseases, and sometimes are marketed directly to consumers.  Whether FDA’s view of LDTs is correct, will certainly be the subject of comments at the meeting.

The agenda for the meeting includes sessions on patient and clinical considerations, clinical laboratory challenges, direct-to-consumer testing, and education and outreach.  The agency has posed the following questions for the patient and clinical considerations session:

• What would patients and clinicians like to see done by the FDA with respect to LDTs?  What is ideal?  What is practical?
• How might increased FDA oversight of LDTs affect patients and clinicians?  What might be the benefits?
• What are patient expectations with regard to results obtained by an LDT?  How might increased oversight of LDTs affect these expectations?
• What is the patient’s perspective regarding tests that are non-regulated versus regulated by the FDA?
• Are physicians aware that a given diagnostic test may not have been cleared or approved by FDA?  How might this knowledge affect clinical practice?
• What are the reasons that a patient or physician might choose an LDT over an FDA cleared/approved IVD?
• What are patient’s and clinician’s expectations regarding clinical validation of LDTs?
• Examples or case studies related to LDTs.

FDA has proposed the following questions as part of the clinical laboratory challenges session:

• What are the potential benefits of increased FDA oversight of LDTs?
• What would you like to see done with respect to FDA oversight of LDTs?  What is ideal?  What is practical?
• Suggested approaches of risk stratification of LDTs
• What might be some of the specific challenges faced by clinical laboratories in meeting FDA regulations?
• How might increased oversight of LDTs affect diagnostic test innovation?
• How could increased oversight of LDTs affect diagnostics used for rare conditions?
• How might increased oversight of LDTs affect reimbursement and/or the cost of diagnostic tests for the consumer?
• What are the challenges associated with validation of LDTs for clinical laboratories?
• What will the challenges be to clinical labs with respect to diagnostic test change control under greater oversight of LDTs?
• Should the clinical and analytical validation requirements be different between FDA regulated and non-FDA regulated diagnostic tests?   

The agency has proposed the following questions for the DTC session:

• What are the major concerns associated with DTC testing?
• What is the benefit of DTC testing?  What are the risks?  What is the cost?
• Are there concerns that DTC testing could lead to consumer fraud?
• Are patients taking medical action based upon preliminary diagnostic test claims?  What are the risks and benefits? 

FDA suggests the following topics for the education and outreach session:

• What resources or educational opportunities are currently available to assist clinical laboratories in meeting FDA regulations?  What would be needed?
• What specific support will be needed by clinical laboratories from the FDA given greater LDT oversight?
• How can physicians use new genetic information? 
• Whose responsibility is it to ensure that physicians can use the information provided to them by LDTs?

Given the increasingly important role in LDTs in health care in general, and in personalized medicine in particular, the meeting is almost guaranteed to provide FDA with diverse – and strongly expressed – viewpoints.

By Wes Siegner –   

On June 14, 2010, The University of Maryland School of Law hosted the first of a series of multidisciplinary meetings being held as part of a Human Microbiome Project ELSI (Ethical, Legal, Social Implications) grant to study federal regulation of probiotics.  The team that received the grant included:

• Diane E. Hoffmann, MS, JD, Associate Dean for Academic Programs and Director, Law and Health Care Program, University of Maryland School of Law (Principal Investigator)
• Claire M. Fraser-Liggett, Ph.D, Professor of Medicine and Director, Institute for Genome Sciences,  University of Maryland School of Medicine
• Frank Palumbo, Ph.D, JD, Professor and Executive Director, University of Maryland School of Pharmacy Center on Drugs and Public Policy
• Jacques Ravel, Ph.D, Associate Professor, Institute for Genome Sciences, University of Maryland School of Medicine

Participants in the conference included members of academia and the scientific research, business, legal and federal regulatory communities.  The National Institutes of Health and the Federal Trade Commission are participating in the study, and representatives from the Food and Drug Administration attended as observers.  The agenda for the first meeting, including speakers for the first day, can be found here.

The first all-day meeting focused on achieving a broad-based understanding of the science relating to probiotics and the current federal regulatory framework into which products containing probiotics fall.  As planned, this meeting was a question-generating session.  Subsequent sessions will focus more on attempting to find consensus answers to the complex regulatory questions that surround products containing probiotics.  The next meeting is being planned for January 2011.

By Kurt R. Karst –   

With all of the FDA-related amendments being introduced for consideration to the Tax Extenders Act (H.R. 4213), including the Preserve Access to Affordable Generics Act to address patent settlement agreements and an amendment to legislatively extend a patent covering The Medicines Company’s ANGIOMAX (bivalirudin), it was a fait accompli that Sen. Bill Nelson (D-FL) would reintroduce his Drug Price Competition Act by proposing it as an amendment to the bill.  That happened on June 15th, with the submission of SA4361.

SA4361, which is viewed by some as a complement to the Preserve Access to Affordable Generics Act, appears to be identical to Sen. Nelson’s S. 1315, which was introduced last June.  Rep. Alcee Hastings (D-FL) introduced a companion bill (H.R. 3777) in the House of Representatives.  Rep. Hastings also initially proposed his bill as an amendment to the House Health Care Reform Bill last November, but then withdrew it from consideration.  In January 2010, before the election of Scott Brown (R-MA) to the Senate, the American Antitrust Institute, among several other organizations, penned a letter to Senate Majority Leader Harry Reid (D-NV) and House Speaker Nancy Pelosi (D-CA) encouraging inclusion of the Drug Price Competition Act in the final Health Care Bill, along with a per se ban on patent settlement agreement payments. 

As we previously reported (here and here), Sen. Nelson’s legislation would amend the definition of “first applicant” at FDC Act § 505(j)(5)(B)(iv)(II)(bb) with respect to 180-day exclusivity eligibility so that certain subsequent ANDA applicants could trigger and also be eligible for such exclusivity.  Specifically, under SA4361, a subsequent applicant subject to a first applicant’s 180-day exclusivity eligibility could qualify as a “first applicant,” and could obtain approval and trigger 180-day exclusivity for all first applicants if there is no timely filed patent infringement lawsuit arising from its Paragraph IV certification, or if there is a timely filed lawsuit and there is a court decision (including a district court decision) of patent invalidity or non-infringement or a “substantive determination that there is no cause of action for patent infringement or invalidity.”  Curiously, SA4361 also provides that any subsequent ANDA applicant that submits a “section viii” statement to an Orange Book-listed patent would be considered a “first applicant” eligible for 180-day exclusivity.

SA4361 and its predecessors appear to be rooted in a paper Apotex issued early last year.  In that paper, Apotex recommends that Congress work for legislation “that gives shared (if not sole) exclusivity to a generic challenger who, although not first to file a paragraph iv certification, is first to succeed in addressing the listed patents.”

By Kurt R. Karst –   

Since shortly after the enactment of the Hatch-Waxman Amendments in 1984, FDA has recognized an NDA sponsor’s ability to relinquish or selectively waive exclusivity, such as 5-year new chemical entity exclusivity and 3-year new use exclusivity, even though  the statute does not specifically permit relinquishment or waiver.  However, as FDA stated in a 2004 citizen petition response, it was not until 1997 that the Agency first considered an ANDA sponsor’s ability to relinquish or waive 180-day generic drug exclusivity.  In that 1997 case, which concerned a request from Genpharm to waive its pre-Medicare Modernization Act (“MMA”) 180-day exclusivity for Ranitidine HCl in favor of Granutec, FDA determined that a waiver was permissible.  That decision was challenged in court, see Boehringer Ingelheim Corp. v. Shalala, 993 F. Supp. 1 (D.D.C. 1997), and the D.C. District Court upheld FDA’s interpretation of the statute as permissible.  FDA subsequently proposed regulations (in 1999) to codify its interpretation, but those proposed regulations were withdrawn in 2002.  

FDA’s 2004 citizen petition response provides a comprehensive discussion of waiver and relinquishment of 180-day exclusivity.  Under FDA policy: 

an ANDA applicant who has obtained 180-day exclusivity may relinquish its exclusivity entirely or selectively waive the exclusivity in favor of a single ANDA, or multiple ANDAs, containing a paragraph IV certification.  Before the exclusivity period has been triggered, an applicant may only relinquish its exclusivity; after the exclusivity has been triggered, it may be selectively waived.

FDA stated in its petition response that “allowing eligible applicants to relinquish or waive [180-day] exclusivity enables them to exercise the exclusivity as they deem most beneficial,” and that there are four general reasons supporting waiver and relinquishment of 180-day exclusivity.  Specifically, that the practice of permitting relinquishment and waiver of 180-day exclusivity:

(1)  is based on a permissible statutory construction as acknowledged by the courts,
(2)  is consistent with the Agency’s long-standing allowance of waiver and relinquishment of other forms of market exclusivity,
(3)  promotes marketplace competition among pharmaceuticals in furtherance of the objectives of the [Hatch-Waxman Amendments], and
(4)  is consistent with FDA’s role in regulating the public health as opposed to competitive business arrangements.  

Importantly, FDA notes in its 2004 petition response that the Agency’s interpretation is limited to 180-day exclusivity subject to the pre-MMA (i.e., pre-December 8, 2003) statute:

[T]his response does not provide[] an Agency interpretation of section 505(j)(5)(B)(iv) as amended by the [MMA]. . . .  [T]he MMA made a number of changes to the statutory scheme in section 505(j) governing 180-day exclusivity, including providing tor forfeiture of the exclusivity. . . . The Agency has not yet assessed whether the changes made by the MMA should result in a different approach to waiver or relinquishment for those applications subject to the new exclusivity provisions.

Given the first applicant approach under the post-MMA statute, under which multiple first applicants can qualify for and share 180-day exclusivity (or forfeit such exclusivity), relinquishment and waiver of 180-day exclusivity is more complicated.

We are unaware of a post-MMA case in which a first applicant has relinquished 180-day exclusivity eligibility; however, FDA’s 2009 Letter Decision concerning generic versions of STARLIX (nateglinide) Tablets could provide some insight as to how FDA might ultimately address this issue in the context of multiple first applicants.  (Where there is only a single first applicant, relinquishment does not appear to complicate a 180-day exclusivity analysis.)  In the generic STARLIX case (see our previous post here), there were multiple first applicants and at least one first applicant forfeited 180-day exclusivity eligibility under FDC Act § 505(j)(5)(D)(i)(IV) (failure to obtain tentative approval in 30 months of ANDA submission).  FDA ruled that “a first applicant that forfeits exclusivity may obtain [ANDA] approval . . . and that first commercial marketing by any first applicant (including a first applicant that forfeits exclusivity) will begin the 180-day exclusivity period.”  Insofar as forfeiture is considered to be effectively the same as relinquishment, a first applicant that relinquishes its 180-day exclusivity could arguably continue to be a first applicant and not be blocked by another first applicant’s 180-day exclusivity eligibility, and also trigger other first applicants’ 180-day exclusivity. 

A selective waiver of 180-day exclusivity post-MMA (both where there is only a single first applicant and especially where there are multiple first applicants) is more complicated than relinquishment, as it confers on a subsequent applicant the most important benefit of first applicant status – 180-day exclusivity. 

We are aware of only one instance post-MMA in which FDA has permitted a selective waiver of 180-day exclusivity.  That case involved Bupropion HCl Extended-Release Tablets, 300 mg, and a single first applicant – Anchen Pharmaceuticals, Inc.  FDA approved Anchen’s ANDA No. 77-284 on December 14, 2006 and noted in the approval letter that as a first applicant the company is eligible for 180-day exclusivity.  Just a few days later, on December 15, 2006, however, FDA approved ANDA No. 77-415 for Bupropion HCl Extended-Release Tablets, 300 mg.  FDA noted in the approval letter for ANDA 77-415 that the applicant was not a first applicant but that there was a “relinquishment or selective waiver” of 180-day exclusivity by Anchen.  Although the ANDA approval letter is not clear on its face whether there was a relinquishment or waiver of 180-day exclusivity, the notation of exclusivity in the Orange Book for both applications makes clear that there was, in fact, a selective waiver and not a relinquishment.  (The Orange Book showed a period of shared 180-day exclusivity for both ANDAs.)

There is not, to our knowledge, a post-MMA case in which FDA has permitted a selective waiver of 180-day exclusivity where there are multiple first applicants.  Given the fact that FDA has permitted a waiver where there is a single first applicant, however, it seems likely that FDA, when faced with the issue, will permit a waiver when there are multiple first applicants.  But there will certainly be some ground rules. 

Being a first applicant means that you are the member of an exclusive club.  So to allow a non-member to share in the benefits of club membership, it seems possible that FDA would require all first applicants (whether 1 or 10) to agree in writing that a subsequent applicant should be accorded the benefits of club membership.  Also, it seems likely that because a subsequent applicant does not become a first applicant by virtue of all club members agreeing to a selective waiver, a first applicant will first have to trigger the 180-day exclusivity period before a waiver is made and a subsequent applicant can take advantage of the 180-day exclusivity period.    

The issue of selective waiver post-MMA is certain to crop up at some point in time, and we will be interested to see the outcome. 

By Ricardo Carvajal –

June 22 looms large on the calendar for firms subject to the requirements of the Family Smoking Prevention and Tobacco Control Act (“FSPTCA”) and FDA’s final rule curbing promotion and sale of cigarettes and smokeless tobacco to underage consumers.  In anticipation of that date, FDA has issued the following guidance documents:

• Compliance with Regulations Restricting the Sale and Distribution of Cigarettes and Smokeless Tobacco To Protect Children and Adolescents – This draft guidance document addresses questions raised by retailers with respect to their obligation under FDA’s final rule to ensure that cigarettes and smokeless tobacco are not sold to underage consumers.  It also addresses questions with respect to the obligation of retailers, distributors, and manufacturers to ensure compliance with advertising, marketing, and promotion restrictions imposed by that rule.  According to the document, FDA intends to exercise enforcement discretion with respect to certain requirements that are the subject of litigation (e.g., the limitation of labeling and advertising to black text on a white background and the restriction on the use of trade names of nontobacco products).  Violation of the final rule’s many other requirements could subject a retailer, distributor, or manufacturer to a range of civil and criminal penalties.  The final rule takes effect on June 22.

• Use of “Light,” “Mild,” “Low,” or Similar Descriptors in the Label, Labeling, or Advertising of Tobacco Products – This guidance document addresses the statutory ban on the use of the cited descriptors in labeling and advertising unless FDA authorizes such use.  Products labeled or advertised as such may not be sold after July 22 unless they were manufactured before June 22 and introduced into domestic commerce before July 22.

• Enforcement Policy Concerning Rotational Warning Plans for Smokeless Tobacco Products – This guidance document states FDA’s intent to exercise enforcement discretion with respect to the requirement that smokeless tobacco manufacturers, distributors, importers, and retailers have a rotational warning plan that has been approved by FDA, as long as they submit such a plan to the agency by July 22.  However, industry must begin rotating the warnings on June 22.

In addition, FDA has published “Harmful and Potentially Harmful Constituents” in Tobacco Products as Used in Section 904(e) of the Federal Food, Drug, and Cosmetic Act.  This draft guidance document provides FDA’s interpretation of the phrase “harmful and potentially harmful constituents.”  The FSPTCA requires that FDA publish a list of such constituents within two years of the law’s enactment.  That list will partially guide subsequent submissions by manufacturers of information on constituents in their products.  In that same vein, FDA will announce in the June 15 Federal Register that the Tobacco Product Constituents Subcommittee of the Tobacco Products Scientific Advisory Committee will meet on July 7-8 to "finalize its proposed list of harmful or potentially harmful constituents, the rational for inclusion of each substance, validated methods for measuring the constituents and the ancillary and normalization standards for the identified constituents."