By Kurt R. Karst –     

A recent report from Leerink Swann LLC analyst Howard Liang, Ph.D. suggests that what appears to be a recent increase in the number of Refuse-to-File (“RTF”) letters issued by FDA to NDA and BLA sponsors – some of which are large, experienced biotech companies – might signal both a greater willingness from FDA to issue such decisions, and therefore a higher filing threshold, and that filing decisions are no longer non-events.  

FDA’s regulations at 21 C.F.R. § 314.101 (drugs) and 21 C.F.R. § 601.2 (biologics) provide the bases for the Agency to RTF an application – generally because an application does not, on its face, contain information required under the FDC Act, under the PHS Act, or in FDA’s implementing regulations.  (Note that NDA/BLA deficiencies that serve as the basis for an RTF action are distinct from filing review issues, which pertain only to applications that have been filed.)  Over the years, FDA has issued guidance (here and here) on the Agency’s RTF policies, and has established a Clinical Hold/RTF Committee that since about 2008 is supposed to meet approximately 6 times a year. 

According to Dr. Liang’s analysis of 28 publicly known RTF actions since 1998 – 13 of which have been issued since 2009 and several of which have been issued to large, experienced companies – “[w]hile it is not possible to firmly conclude that the pace of RTFs has increased statistically due to a relatively small sample size and lack of disclosure of all RTFs, the fact that even the most experienced companies receive RTFs suggests a change at the FDA.”  (It is likely that FDA has, in fact, issued more than 28 RTF decisions since 1998, as FDA acknowledged in 2006 that although infrequent, about 5 RTFs had been issued per year.  RTF decisions are difficult to track as FDA does not disclose them; however, FDA has proposed as part of the Agency’s Transparency Initiative that “FDA should disclose the fact that the Agency has issued a refuse-to-file or complete response letter in response to an original NDA, BLA, or an efficacy supplement for an NDA or BLA at the time the refuse-to-file or complete response letter is issued, and should, at the same time, disclose the refuse-to-file or complete response letter, which contains the reasons for issuing the letter.”)  The breakdown of the types of issues that led FDA to issue the 28 RTF actions discussed in Dr. Liang’s analysis is provided below.

 
Source: Leerink Swann LLC “RTFs Suggest FDA Filing Decisions May Have Become More Meaningful Events,” April 25, 2011.  Reprinted with permission.

According to Dr. Liang, the apparent increase in RTF actions suggests a lower threshold for RTFs and “could be due to the agency's enforcement mentality under the new Commissioner.”  In addition, “the wave of RTFs may also be related to the recent FDA implementation of good review practices in an initiative called ‘21st Century Review’, says Dr. Liang.  “After a pilot program started in 2008, this process is being implemented to all BLAs and NDAs in FY2011,” says the analyst report.  According to FDA, the “21st Century Review Initiative,” which is based on the Agency’s Good Review Practices, “is a set of performance standards [CDER] follows when doing drug reviews that involve multiple offices” the goal of which “is to make the drug review process more organized and integrated, and ensure all decision makers are heard.” 

In addition to the issues identified by Dr. Liang in his report as contributing to more RTF actions, it is certainly possible that pressure put on FDA officials to meet PDUFA performance goals is causing some reviewers to more liberally use the RTF procedures to better manage the review queue.  It is also possible that the increase in RTF actions has been spurred by the apparent resurgence of FDA’s Clinical Hold/Refusal-to-File Committee, which is intended to, among other things, share divisional experiences as a means of teaching and learning.

Hat tip Pharmalot.

Hyman, Phelps & McNamara, P.C.’s Jeffrey K. Shapiro will be giving the state of the industry address at Q1 Productions’ 2nd Annual Clinical & Regulatory Strategies for Combination Products, which is slated to take place in Baltimore, Maryland from July 11-12, 2011.  The potential benefit of combination products is significant for companies looking to provide cutting edge healthcare solutions and maintain a competitive edge.  These complex products have been cause for much regulatory discussion and interpretation since their inception and have thus been surrounded by uncertainty.  The conference will bring together not only industry representatives that have successfully navigated FDA’s combination product approval processes, but will also bring the Agency to the table to discuss and clarify processes and procedures for obtaining regulatory approval for these challenging products.

Topics to be covered at the conference include:

• State of the industry address: recognizing the past, present and future of combination products
• Exploration of various FDA approval pathways available for combination products
• Comparison of drug vs. device vs. combination approval routes
• Question & answer period with FDA executives, roundtable discussion
• Understanding timelines for data submission and approvals
• Development of strong working relationships with the FDA and internal teams
• Trial design strategies that ensure clinical data will support regulatory clearance
• Securing optimal data from clinical sites and labs based on regulatory path
• Establishing safety and efficacy of combination products
• Case study presentations focusing on various types of combination products
• Utilization of clinical data to support reimbursement goals
• The use of combination products in furthering personalized medicine
• Differences in approval routes for products containing a cleared product
• Opportunities in comparing similar products and establishing precedents
• Post-market concerns in adverse event reporting and surveillance
• International regulatory considerations and clearance routes
• Strategies in conducting international combination product clinical studies
• Manufacturing and quality assurance considerations for combined products
• Creating meaningful partnerships to support combination product commercialization
• Understanding and utilizing guidance documents released by the FDA
• Deciphering and complying with current good manufacturing practices

Mr. Shapiro’s presentation will focus on overcoming clinical and regulatory hurdles for combination products.  In particular, Jeff’s presentation will focus on:

• A thorough definition of combination products
• Historically important combination products & impact on regulations
• Current state of the combination products industry
• Methods for furthering commercialization
• Strategies for clinical & regulatory teams to get products to market

Additional information about the conference, including registration information, is available here.

By Ricardo Carvajal –

The Senate has adopted legislation that would strengthen criminal penalties "for any individual or corporation that knowingly endangers American lives by contaminating the food supply by distributing misbranded or tainted food products" (see Sen. Leahy's press release here).  The legislation provides for fines and imprisonment for up to ten years for any person that commits certain prohibited acts "with respect to any food… knowingly and intentionally to defraud or mislead… and… with conscious or reckless disregard of a risk of death or serious bodily injury."  The bill will now be taken up by the House.  As we noted in a prior posting, this year's version of the legislation raises the bar for prosecutors.  That should enhance its chances of becoming law.

By John A. Gilbert, Jr. & Peter M. Jaensch –

In a press conference at the National Press Club on April 19, 2011, the Administration presented its action plan (“Plan”) to address concerns about the increase in prescription drug abuse.  The Plan is entitled: “Epidemic: Responding to America’s Prescription Drug Abuse Crisis.”  Representing the Administration were White House Director of National Drug Control Policy Gil Kerlikowske, FDA Commissioner Margaret A. Hamburg, Assistant Secretary for Health and Human Services Howard Koh, and DEA Administrator Michele M. Leonhart.  (In a separate post we discuss FDA's final Risk Evaluation and Mitigation Strategy the Agency will require for all extended-release opioid medications, which FDA announced when the Administration presented its Plan.)

The Plan focuses primarily on measures to combat the abuse of prescription opioid analgesics.  The Plan calls for coordinated efforts by federal and state authorities in four key areas: Education and Training; Tracking and Monitoring; Proper Medication Disposal; and Enforcement.  Among these would be changes to the federal Controlled Substances  Act (“CSA”) and possibly state controlled substances laws, requiring the support of Congress and state legislatures.

A principal feature of the Plan is a proposed new requirement that prescribers “be trained on responsible opioid prescribing practices” as a prerequisite to registration with the DEA. Given that a DEA registration is required for practitioners to prescribe controlled substances to their patients, practitioners would need to meet this requirement to be permitted to prescribe controlled drugs.   The Plan does not provide details concerning this proposed training, stating only that such “training would include assessing and addressing signs of abuse and/or dependence.”  Such action would require a legislative amendment to the CSA, as the Plan openly acknowledges.  In questioning at the announcement of the Plan, Administrator Leonhart appeared to anticipate Congressional cooperation would be forthcoming and not controversial.

The Plan also calls on those states that have not implemented Prescription Drug Monitoring Programs ("PDMPs") to do so.  Currently 35 states have such plans.  In addition, the Plan calls for efforts going beyond most currently existing state PDMPs by encouraging an exchange of information between state plans.  Such information-sharing would arguably permit state and federal authorities to prevent drug seekers from circumventing existing limits by doctor-shopping and filling prescriptions across state lines.

The Plan also anticipates DEA administrative actions around drug disposal and e-prescribing. In the short-term, such activities primarily involve increased frequency of events at which DEA and possibly other federal and state agencies will collect unused controlled substances from end-users for disposal.  The CSA contemplates a closed system of controlled drug distribution, thus the return of controlled substances by patients to a DEA registrant, such as a pharmacy, has been prohibited under DEA regulations, with limited exceptions.  In the long term, DEA has stated that this issue would be addressed through promulgation of new regulations on disposal of controlled substances dispensed to end-users.  The Plan further contemplates issuance by DEA of a long-awaited final rule on the e-prescribing of controlled substances.

By William T. Koustas –

On Tuesday, April 19, 2011, after years of debate and several public meetings, FDA released the final Risk Evaluation and Mitigation Strategy ("REMS") it will require for all extended-release opioid medications.  The final REMS was issued as part of the White House’s multi-agency plan to reduce prescription drug abuse.  FDA has been working on a class-wide opioid REMS since at least February 2009, when it invited sponsors of extended-release opioid products to a private meeting.  Seventeen months later, in July 2010, FDA released its draft of a REMS for extended-release opioid products. 

In a letter to sponsors of extended-release opioid products, FDA states that it has “become aware of substantial numbers of postmarketing reports of abuse, misuse, addiction and overdose resulting in fatalities associated with [extended-release] opioid drugs.”  Letter from Bob A. Rappaport, M.D., Post-Approval REMS Notification, April 2011.  FDA considers this “new safety information,” which allows it to require sponsors to implement REMS under section 505-1 of the Federal Food, Drug, and Cosmetic Act. 

The REMS consists of a Medication Guide, elements to assure safe use ("ETASU"), and a timetable for submission of assessments.  The ETASU includes an education program for prescribers and materials that the prescribers can use to educate patients regarding the safe use, storage, and disposal of extended-release opioids.  Part of this program appears to include educating prescribers about the potential use of a “Patient Provider Agreement.”  The education program should be conducted through a continuing medical education provider and include information on opioid prescribing, product specific information, and patient counseling.  Prescribers must also obtain proof that they have successfully completed the education program.  The patient education materials must include, among other things, a Medication Guide and information on how to properly take an opioid, report adverse effects, and store opioids.  The materials released by FDA also mention a  “Patient Treatment Agreement,” although its use by the prescriber appears to be optional.

The timetable for submission of assessments is at least six months, 12 months, and annually after the REMS is approved.  Assessments should include the following:  the number of prescribers having completed the education program; an independent audit of the quality of the education materials used to train prescribers; an evaluation of patient and prescriber awareness of the risks associated with extended-release opioids; a surveillance plan to monitor misuse and abuse of opioids, including surveillance in various risk groups and settings; and evaluations of drug utilization and prescribing behaviors.  The FDA recommends that the sponsors of extended-release opioids cooperate to establish a single system for monitoring these assessments across all extended-release opioid products.

Sponsors must submit a proposed REMS based on the requirements described above within 120 days of the date of the notification letter.  Interestingly, FDA notes that prescriber education is not mandatory under the REMS, but FDA is working with other federal agencies and Congress to make it mandatory by linking prescriber education to training required by the Drug Enforcement Administration.  FDA expects the REMS to become effective by early 2012. 

By Kurt R. Karst –      

A recent amendment to the America Invents Act (H.R. 1249) introduced by Representative John Conyers (D-MI) and passed by voice vote during a markup of the bill last week by the
House Committee on the Judiciary would give The Medicines Company (“MDCO”) some legislative assurance of a Patent Term Extension (“PTE”) for U.S. Patent No. 5,196,404 (“the ‘404 patent”) covering the company’s ANGIOMAX (bivalirudin) as the the drama in the decade-old fight over a PTE continues to unfold in court. 

As we reported earlier this year, in February the U.S. Court of Appeals for the Federal Circuit denied MDCO’s Motion to Dismiss or, in the Alternative, to Bifurcate and Stay in Part APP Pharmaceuticals, LLC’s (“APP’s”) appeal related to Judge Claude M. Hilton’s August 3, 2010 decision in which he ordered the U.S. Patent and Trademark Office (“PTO”) to consider timely filed MDCO’s PTE application for the ‘404 patent under a next business day interpretation of the PTE statute.  (As folks might recall, FDA approved ANGIOMAX at 5:18 PM on Friday, December 15, 2000, and MDCO submitted its PTE application to the PTO on February 14, 2001 – 62 days after NDA approval, including the December 15, 2000 date of approval.  Under the PTE statute at 35 U.S.C. § 156(d)(1), the submission of a PTE application must occur “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.”)  The Federal Circuit’s February decision was precipitated by Judge Hilton’s September 13, 2010 decision denying APP’s Motion to Intervene in the litigation without addressing standing (on the basis that APP should have sought intervention earlier, and that allowing intervention at that point would unfairly prejudice MDCO).  APP appealed the decision to the Federal Circuit challenging not only the district court’s September 13th intervention decision, but also the underlying merits decision.  ANDA sponsor PLIVA recently filed an amicus brief in the Federal Circuit case in support of APP. 

Now back to the legislative front . . . .

Rep. Conyers’s amendment to H.R. 1249 would amend 35 U.S.C. § 156(d)(1) to add at the end of that section the following flush sentence:

For purposes of determining the date on which a product receives permission under the second sentence of this paragraph, if such permission is transmitted after 4:30 P.M., Eastern Time, on a business day, or is transmitted on a day that is not a business day, the product shall be deemed to receive permission on the next business dy.  For purposes of the preceding sentence, the term "business day" means any Monday, Tuesday, Wednesday, Thursday or Friday, excluding any legal holiday under section 6103 of title 5.

The “applicability” section of the amendment states that language above “shall apply to any application for extension of a patent term under section 156 of title 35, United States Code, that is pending on, that is filed after, or as to which a decision regarding the application is subject to judicial review on, the date of enactment of this Act.”  The language seems to match up pretty well with the current situation surrounding a PTE for the ‘404 patent.

Rep. Conyers’s amendment to H.R. 1249 – language that is not in the Senate-passed version of the bill, S. 23 – is not the first attempt to amend the PTE statute to accommodate the ‘404 patent; nor is it the first time that Rep. Conyers has been involved in what has come to be known as “The Dog Ate My Homework Act.”  In Securities and Exchange Commission filings made as early as March 2003, MDCO said that the company was “exploring an alternative to extend the term of the patent.”  Legislation was introduced in Congress in 2006, 2007, 2008, 2009, and 2010 (see our previous posts here, here, here, and here) reflecting the changing circumstances of the ‘404 patent PTE saga.  In June 2008, Rep. Conyers urged the House to pass the Responsive Government Act of 2008, which would have amended 35 U.S.C. § 156 to permit the PTO to accept late PTE submissions . . . for a fee ($65,000,000 for MDCO).

Although some industry support for H.R. 1249 seems to be fading – the Biotechnology Industry Organization issued a statement last week opposing House floor consideration of the bill due to a non-PTE issue – a legislative fix to MDCO’s ‘404 patent issue still appears to be alive and could ultimately be included in a final, enacted version of the America Invents Act. We’ll keep you posted.    

By Wes Siegner & Cassandra A. Soltis –

There has been a buzz in the trade press and industry over when a company is required under the Federal Food, Drug, and Cosmetic Act ("FDC Act") to submit to the Food and Drug Administration ("FDA") a 75-day premarket notification for a new dietary ingredient ("NDI").  Although parts of section 413 of the FDC Act are certainly confusing, the law is clear that an NDI does not need to be notified if it is “present in the food supply as an article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  Contrary to what has been reported in the press, to qualify for this alternative to the notification requirement, it is not necessary that the NDI be present and marketed in the food supply as an article used for food prior to October 15, 1994.  Presence in the food supply at any time, in any part of the world, is sufficient under the terms of § 413(a)(1).

Section 413 of the FDC Act defines an NDI as “a dietary ingredient that was not marketed in the United States before October 15, 1994 and does not include any dietary ingredient which was marketed in the United States before October 15, 1994” (emphasis added).  In other words, dietary ingredients that are first marketed in the United States on or after October 15, 1994 are, by definition, new dietary ingredients. 

A new dietary ingredient may be marketed immediately—that is, without FDA notification—if it is “present in the food supply as an article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  If there is no such evidence, however, the new dietary ingredient may still be marketed provided that a 75-day premarket notification is submitted to FDA and the notification contains, among other things, evidence that the dietary supplement containing the new dietary ingredient will “reasonably be expected to be safe.”  FDC Act § 413(a)(2).  In contrast, dietary ingredients marketed in the United States before October 15, 1994 are generally referred to in industry as “old dietary ingredients.”  Old dietary ingredients may be immediately marketed in dietary supplements; there is no notification required. 

Unlike § 413(c), which specifies that to be an old dietary ingredient, an ingredient must have been marketed in the United States prior to October 15, 1994, § 413(a) makes no such specification; the text “present in the food supply” is not qualified and, therefore, applies to any country’s food supply.  Thus, for example, if oat extract is eaten in Scotland (and assuming oat extract is not an old dietary ingredient), then oat extract is “present in the food supply”—the Scottish food supply—and is an “article used for food in a form in which the food has not been chemically altered.”  FDC Act § 413(a)(1).  Therefore, no NDI notification would need to be submitted. 

By Kurt R. Karst –      

On April 15th, Judge Ellen S. Huvelle of the U.S. District Court for the District of Columbia granted FDA’s Motion to Dismiss a Complaint filed last September by ViroPharma Incorporated (“ViroPharma”) in connection with the approval of ANDAs for generic versions of the company’s antibiotic drug of last resort, VANCOCIN (vancomycin HCl) Capsules.  The Washington Legal Foundation, in an amicus brief, joined ViroPharma in its opposition to FDA’s Motion to Dismiss.  ANDA sponsor Akorn, Inc. (represented by Hyman, Phelps & McNamara, P.C.) filed an amicus brief supporting FDA.

As we previously reported, ViroPharma’s Complaint alleges that FDA violated the Administrative Procedure Act (“APA”) when the Agency failed to engage in notice-and-comment rulemaking “before effectively amending its [ANDA] regulations to permit a waiver of the in vivo bioequivalence requirement based on 21 C.F.R. § 320.24 even when none of the waiver criteria of 21 C.F .R. § 320.22 are satisfied.” ViroPharma requested declaratory relief from the court, including “that the plain reading of FDA’s regulations requires an ANDA applicant seeking a waiver of the in vivo bioequivalence testing requirement to first meet one of the criteria set forth in 21 C.F.R. § 320.22,” and that a May 2008 FDA decision concerning generic PRECOSE (acarbose) – that 21 C.F.R. § 320.24 provides an independent basis for waiving the in vivo testing requirement even when none of the criteria of 21 C.F.R. § 320.22 is satisfied – constitutes an amendment to FDA’s ANDA bioequivalence regulations.

In her 11-page opinion, Judge Huvelle ruled that ViroPharma lacks standing.  Will Judge Huvelle’s decision help to clear the way for FDA approval of ANDAs for generic VANCOCIN for which there are, according to ViroPharma, 11 pending applications?  And will FDA now wrap-up consideration of ViroPharma’s citizen petition (detailed in Akorn’s amicus brief) and issue a response?  We patiently await answers to these questions.

Hyman, Phelps & McNamara, P.C. is pleased to announce that Linda S. Carter will join the Firm as a Regulatory Scientist on April 19th.  Linda, who will primarily assist HP&M’s drug development group, brings significant experience and expertise in shaping regulatory policies, particularly Comparative Effectiveness Research, Personalized Medicine, and Evidence-Based Medicine. 

“I have had the pleasure to have worked alongside of Linda while we were both at FDA and have always been impressed with her sophisticated understanding of the FDA drug review system.  We are thrilled to welcome Linda to our HP&M family in order to even better enhance our services to our drug sponsor clients, and through them, to patients,” said Frank J. Sasinowski, Director.

From 1984-2002, Linda worked for FDA, during which time she served as Associate Director of Regulatory Affairs in the Office of Drug Evaluation I in the Center for Drugs Evaluation and Research, and as Regulatory Policy Advisor in the Office of Review Management (now the Office of New Drugs), CDER.  During her tenure at FDA, Linda received many awards, including the FDA Award of Merit and the Commissioner’s Special Citation. 

Prior to joining HP&M, Linda served in several pharmaceutical industry positions, including as Senior Director, Global Regulatory Policy and Intelligence, Janssen Pharmaceutical Companies of Johnson & Johnson, Executive Director, FDA Liaison, Drug Regulatory Affairs, Novartis Pharmaceuticals Corporation, and Director, Global Regulatory Affairs, Legislative Policy and Regulatory Liaison, Pharmacia Corporation. 

By Nisha P. Shah –

On April 13, 2011, FDA issued a proposed rule that would expand the scope of clinical investigator disqualification.  76 Fed. Reg. 20575, Apr. 13, 2011.   The proposed changes are in response to a September 2009 report by the Government Accountability Office (“GAO”) on FDA’s Oversight of Clinical Investigators, which recommended that FDA extend the disqualification to include ineligibility to receive any FDA-regulated investigational products, regardless of what type of FDA-regulated product was being investigated by the clinical investigator when the serious misconduct occurred.  Comments to the proposed rule are due on July 12, 2011. 

Under the draft rule, a clinical investigator, including a sponsor-investigator, disqualified pursuant to 21 C.F.R. Parts 312 (drugs and biologics), 511 (animal drugs), or 812 (devices) will be ineligible to receive “any test article.”  Specifically, the investigator will be disqualified from conducting any investigation that supports an application for a research or marketing permit for FDA-regulated products, including “drugs, biologics, devices, new animal drugs, foods, including dietary supplements, that bear a nutrient content claim or a health claim, infant formulas, food and color additives, and tobacco products.”

Several changes are intended to harmonize the drug, biologic, animal drug, and medical device clinical investigator disqualification regulations.  For instance, similar to the device regulations, FDA is proposing to add to 21 C.F.R. Parts 312 (drugs and biologics) and 511 (animal drugs) a requirement that the applicable FDA Center notify the investigator in writing of the alleged violations when the Center has information indicating that a clinical investigator has “repeatedly or deliberately” failed to comply with the relevant requirements or has “repeatedly or deliberately” submitted to FDA or to the sponsor of the investigation false information in any required report.  For purposes of the disqualification rules, the Agency is also clarifying that an investigator includes a sponsor-investigator. 

The proposed rule also will add a notification to the reviewing institutional review board (“IRB”) about the investigator’s disqualification, in addition to the current notification requirements to the investigator and sponsor.  The notification to all parties will explain the basis for FDA’s determination.  For example, the notification to the sponsor will list the investigator’s violations and include instructions concerning ongoing studies and any approved products containing the investigator’s data. 

Another change is to add that when the Agency “determines that an investigation may not be considered part of a research or marketing application, or a notification or petition submission, this determination does not relieve the sponsor of any obligation under any other applicable regulation to submit to FDA the results of the investigation.”  Further, FDA is proposing to harmonize the regulations and clarify that if the Commissioner determines, after the unreliable data submitted by the investigator are removed from the application, that the continued approval of the FDA-regulated product cannot be justified, “the Commissioner will proceed to withdraw” approval or clearance of the product in accordance with applicable provisions of the Federal Food, Drug & Cosmetic Act (FFDCA).  Finally, to harmonize the regulations, FDA is proposing that an ineligible investigator may be reinstated when the investigator has presented adequate assurances to the Agency that the investigator will conduct any clinical investigation in compliance with the applicable regulations.

By John A. Gilbert & Karla L. Palmer –

On Wednesday, April 13, 2011, the Drug Enforcement Administration (“DEA”) published an Interim Final Rule with a request for comments on the “Self-Certification and Employee Training of Mail-Order Distributors of Scheduled Listed Chemical Products.”  See 76 Fed. Reg. 20,518 (Apr. 13, 2011).  The Interim Rule implements the Combat Methamphetamine Enhancement Act of 2010 (“CMEA”), which President Obama signed into law on October 12, 2010, and we blogged about here.

Although retail distributors of these products have been subject to self certification and training requirements since 2006, the 2010 law establishes new requirements for mail-order distributors of scheduled listed chemical products (“SLCPs”), which are defined in the Controlled Substances Act (“CSA”) as products containing ephedrine, pseudoephedrine or phenylpropanolamine, and are marketed in the United States as non-prescription drugs, see 21 U.S.C. § 802(45). 

The new federal law requires mail-order distributors to self-certify to DEA in order sell SLCPs at retail if those retail sales are intended for personal use.  The DEA defines a “mail-order distributor” as a person who makes sales at retail of SLCPs for personal use, and uses the U.S. postal service or a private or commercial carrier to deliver the product to the customer.  The mail-order distributor’s required self-certification must include a statement that the distributor understands the regulatory requirements, and that its employees will receive the appropriate training prior to self-certification. 

After April 10, 2011, which is the date of the implementation of the CMEA, a mail-order distributor cannot sell SLCPs at retail unless it has self-certified through DEA’s website (and paid a $21.00 fee).  The self-certification requires the distributor to confirm the following: (1) The distributor understands that under federal law it can sell no more than 3.6 grams of SLCPs per day, or 7.5 grams in a thirty-day period, to each customer (versus a 9 gram monthly limit for face-to face sales); (2) the distributor’s employees have undergone DEA-required training prior to self-certification; and (3) the distributor is maintaining employee training records.  The distributor must submit a self-certification for each place of business where it sells the products at retail, which, for a mail-order distributor means, “at each location that prepares or packages products for distribution to customers, and each location where employees accept payment for such sales.”  Id. at 20,520.  The interim rule sets forth (in table form) a summary of requirements for mail-order sellers of SCLPs now in effect since the enactment of the CMEA.  Id. at 20,521  

The required content of the employee training has been developed by DEA and is available at its website, (http://www.deadiversion.usdoj.gov).  DEA states that employers “must use the content of this training in the training of their employees” who sell SLCPs.  An employer may supplement the required DEA training with its own content as well.  Id. at 20,520.  Starting on or after April 10, 2011, each employee of a mail order distributor who is responsible for delivering SLCPs directly to purchasers, or “who deals directly with purchasers by obtaining payment for the [SLCPs]” must undergo the training, and must sign an acknowledgement that he or she has received training prior to selling SLCPs. The record must also be kept in the employee’s personnel file. 

The interim rule implementing the law further provides that when a mail-order distributor files its initial self-certification, the DEA will assign it to one of twelve groups.  The expiration date of the self-certification for all regulated persons within any one group will be “the last day of the month designated for that group.”  The first certification period will run for a period of not less than 12 to not more than 23 months from the date of self-certification.  After this initial certification period expires, distributors must update their regulated persons must update their self-certification on an annual basis.  Id. at 20,521.

The interim rule’s preamble notes that “a mail-order distributor that knowingly or willfully self-certifies to facts that are not true is subject to fines and imprisonment by virtue of 18 U.S.C. § 1001.”  Id. 20,520. In addition, it is unlawful for mail-order distributors to “negligently fail to self-certify” under 21 U.S.C. § 830 (by an amendment to 21 U.S.C. § 842(a)(10)).

The interim rule is effective April 13, 2011.  Note, however, that the law requiring self-certification became effective on April 10, 2011 (180 days after its enactment on October 10, 2010).  DEA is soliciting comments on the interim rule, due on June 13, 2011.  The DEA found “good cause” to exempt this rule from notice and comment rulemaking that is normally required under the Administrative Procedure Act, because DEA asserts that the “requirements addressed by the [CMEA] in this rulemaking are self-implementing and changes in this rulemaking provide conforming amendments to make the language of the regulations consistent with that of the law.”  Id. at 20,519.

By Jennifer D. Newberger –

After more than fifteen years of related cases in the larger matter of The First Amendment v. Dietary Supplement Health Claims, FDA mostly won one.  And its winning card?  Knowing that the courts will not, and cannot, independently assess whether the scientific evidence provided to FDA to support a health claim for a dietary supplement constitutes “credible evidence.”  So, FDA drafted Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims (Jan. 2009), in which the Agency laid out the types of studies it believed may provide credible evidence of a health claim – including the way those studies should have been conducted and the data that should have been collected –and those that will not provide credible evidence.  Then, all a court has to do is ask if FDA followed the guidance document, without considering whether the standards the Agency put forth in the guidance document are a reasonable means of assessing credible evidence.

This appears to be the theory upon which the decision was reached in the case of Alliance for Natural Health US v. Sebelius (“Alliance II”).  In this case, plaintiffs challenged FDA’s decision declining to approve several health claims concerning the relationship between vitamins C and E and the risk for certain types of cancer.  Plaintiffs had submitted seventeen qualified health claims linking vitamins C and E with a reduction in the risk of certain types of cancer.  FDA denied thirteen of the claims entirely and permitted four others to be made as qualified claims with modified language.  In Alliance II, plaintiffs challenged FDA’s ruling on six of these claims – four that were denied outright, and two that FDA agreed to permit as qualified claims with modified language.

As a preliminary matter, the court stated that FDA need not conduct an empirical study on the efficacy of a disclaimer before an outright banning of a claim if there is either no evidence to support the claim, or the evidence in support of the claim is qualitatively weaker than evidence against the claim.  Such claims would qualify as unprotected commercial speech and are therefore not protected under the Central Hudson analysis.  However, empirical evidence of the inefficacy of disclaimers is required for FDA to ban a health claim that is based on some credible evidence.

Enter the guidance document.  At its core, the opinion indicated that if FDA properly applied the process outlined in the guidance document, and, based on that process, determined that no credible evidence existed to support the claim, or the evidence in support of the claim was qualitatively weaker than that against it, FDA’s decision would stand.  The court found this to be the case for each of the four claims that FDA banned outright, and therefore upheld FDA’s denial of these health claims.  (These claims were:  (1) Vitamin C may reduce the risk of lung cancer. The scientific evidence supporting this claim is convincing, but not conclusive. (2) Vitamin C may reduce the risk of colon cancer. The scientific evidence supporting this claim is persuasive, but not conclusive. (3) Vitamin E may reduce the risk of lung cancer. The scientific evidence for this claim is convincing, but not conclusive. (4) Vitamin E may reduce the risk of gastric cancer. The scientific evidence for this claim is persuasive, but not conclusive.)

The reason that FDA only “sort of” won this one is because the court remanded to FDA the two claims that FDA was willing to allow with additional modifications.  The court stated that the modifications “replaced plaintiffs’ claim[s] entirely” and were not sufficiently precise, concluding:  “Where the evidence supporting a claim is inconclusive, the First Amendment permits the claim to be made; the FDA cannot require a disclaimer that simply swallows the claim.” In other words, if FDA allowed a qualified health claim, the qualification cannot be so limiting as to essentially erase the relationship between a substance and the specified disease or health-related condition.

So where does this leave us?  By drafting the guidance document, FDA regained some of the control that it lost over the years regarding health claims and allowable disclaimers.  It has laid out the studies that it considers to constitute credible evidence, and no court is likely to question those determinations.  If a dietary supplement manufacturer intends to support a health claim with a study on FDA’s black list, it does so at its own risk.  But, if FDA approves a qualified health claim, it cannot modify the substance/condition relationship out of existence.  Only one thing is certain — this is not the last we will hear of The First Amendment v. Dietary Supplement Health Claims.

By Peter M. Jaensch - 

In the latest installment in the criminal prosecution of Lauren Stevens, an attorney formerly employed by GlaxoSmithKline ("GSK"), the U.S. Department of Justice announced on April 14, 2011, that a grand jury in the U.S. District Court for the District of Maryland has reindicted Ms. Stevens on six counts alleging that she obstructed an official proceeding, concealed and falsified documents to influence a federal agency, and made false statements to the FDA.

As we previously reported, Ms. Stevens was originally indicted on November 8, 2010 on what the Justice Department states were essentially the same charges. The earlier charges arose in connection with an FDA investigation of alleged off-label promotion of drugs by GSK.  The government alleged that, among other things, Ms. Stevens falsely denied that GSK engaged in any activity promoting off-label use, that she falsely denied that attendees at company promotional speaker events had been provided gifts and entertainment, and that evidence of these gifts as well as other documentary evidence were not included in the documents provided by the company to FDA.

However, that indictment was dismissed without prejudice by District Judge Roger W. Titus on March 23, 2011, citing concerns that the prosecutors had incorrectly explained the advice of counsel defense to grand jurors such that the instruction raised “grave doubts about the grand jury’s decision to indict.”  The absence of actual misconduct by the prosecutors was cited by the Judge in his determination that dismissal with prejudice was unwarranted.

The Government was not to be dissuaded from continuing to pursue this case.  Judge Titus has tentatively scheduled a new trial date for April 26, 2011.

By Kurt R. Karst –      

Since the U.S. Court of Appeals for the Federal Circuit issued its December 2009 decision in Forest Group, Inc. v. Bon Tool Co. concerning the maximum $500 per violation penalty for intentionally falsely marking a product (in that case, spring-loaded parallelogram stilts) with a patent in violation of 35 U.S.C. § 292, setting off a barrage of hundreds of false patent marking qui tam lawsuits (including challenges to the Constitutionality of the statute), we have followed with some passing interest the various legal (and legislative) twists and turns of the issue, because scores of lawsuits involve FDA-regulated products – see our previous posts here and here.  Although the Gray On Claims Blog recently reported that the number of false marking qui tam lawsuits appears to have slowed since the Federal Circuit’s March 15, 2011 decision in In re BP Lubricants USA Inc., in which the Court held that the particularity requirement of Fed. R. Civ. P. 9(b) applies to false marking cases, that did not stop Pharmaceutical Technologies, LLC (“PharmaTech”) from lodging a Complaint last week in the U.S. District Court for the District of Arizona (Phoenix Division) against Eisai, Inc. and Eisai Medical Research, Inc. (collectively “Eisai”) for allegedly falsely marking ARICEPT (donepezil HCl) Tablets.

What makes the Eisai/ARICEPT case of particular interest to us is PharmaTech’s use of FDA’s Orange Book and the allegation of false Orange Book “advertising.”  Although the Orange Book has be raised in some false marking cases (see, e.g., Hollander v. Ortho-McNeil-Janssen Pharmaceuticals, Inc., No. 2-10-cv-00836 (E.D. Pa.), it has not, to our knowledge, previously been used as the primary basis for filing a false marking complaint. 

ARICEPT Tablets is listed in the Orange Book with four unexpired patents – U.S. Patent Nos. 5,985,864 (“the ‘864 patent”), 6,140,321 (“the ‘321 patent”), 6,245,911 (“the ‘911 patent”), and 6,372,760 (“the ‘760 patent”) – and one expired patent – U.S. Patent No. 4,895,841.  The ‘760 patent is listed with a “delist requested” flag, indicating that the NDA sponsor requested that FDA remove the patent from the Orange Book, but that the Agency would not do so because of a Paragraph IV certification to that patent.  On November 26, 2010, FDA approved Ranbaxy’s ANDA No. 76-786 with a period of 180-day exclusivity that expires on May 28, 2011 based on Ranbaxy's Paragraph IV certifications to the ‘864, ‘321, ‘911, and ‘841 patents.  Waiting in the wings for the expiration of Ranbaxy’s 180-day exclusivity is Teva’s tentatively approved ANDA No. 77-344.

PharmaTech alleges in its false marking Complaint that Eisai has violated 35 U.S.C. § 292 by falsely advertising ARICEPT in the Orange Book as patented by the ‘864, ‘321, ‘911, and ‘760 patents with the purpose of deceiving the public, and that such alleged false marking has been a part of the reason for the delay in FDA’s approval of ANDA No. 77-344.  Specifically, PharmaTech states that Eisai statutorily disclaimed the ‘864 and ‘321 patents, but that they continue to be “advertised” in the Orange Book, and that “not one claim in either of the ‘911 patent or the ‘760 patent reads on Aricept® tablets.”  Thus, according to PharmaTech:

By maintaining its false Orange Book advertisings/listings for each of the ‘864 patent, the ‘321 patent, the ‘911 patent, and the ‘760 patent for Aricept® tablets – despite actual knowledge that none of those patents cover Aricept® tablets – Defendant(s) have, in the past and present, engaged in conduct that violates the false marking statute.  By way of that unlawful conduct, Defendants are also quelling competition in the United States market for Aricept® tablets, at least by manipulating the Hatch-Waxman Act in a manner that effectively and substantially delays the generic drug manufacturer, Teva Pharmaceuticals USA, Inc., from bringing its generic version of Aricept® tablets, which has been tentatively approved by the FDA, to market in the United States.

If PharmaTech is successful in its false marking lawsuit, it’s possible that other potential plaintiffs will be scouring the Orange Book for allegedly false Orange Book patent “advertisements” on which to hang a complaint.  Watch out!

Thanks to Sean Mahoney for bringing the PharmaTech Complaint to our attention.

By Kurt R. Karst –      

FDA has responded to requests included in two reports accompanying the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80) – House Report No. 111-279 and Senate Report 111-39 – requesting information from FDA on generic Anti-Epileptic Drugs (“AEDs”), and in particular, whether there are increased risks to patients who are switched from a brand-name AED to an approved, bioequivalent generic version.  FDA concludes in the Agency’s 9-page report recently submitted to Congress that small analyses conducted by FDA do not show that generic AEDs are less effective than their brand-name counterparts, but that further study is necessary.

We initially reported on the Congressional requests in November 2009, and have been closely following the issue.  In November 2010, we reported that FDA responded to a request from New Jersey State Senator Joseph F. Vitale (D) concerning legislation that would require pharmacists in New Jersey to dispense epilepsy drugs from the same manufacturer as previously dispensed for certain patients, unless otherwise prescribed, and noted that FDA’s response seemed to give some foreshadowing as to what conclusions the Agency would include in its report to Congress.  That appears to be the case.

The report to Congress notes that:

Several small analyses conducted by FDA using data available in its Adverse Event Reporting System (AERS) do not provide evidence that generic anti-epileptic drug products are less effective than brand name products.  However, it is difficult to draw reliable conclusions about therapeutic equivalence from the AERS data because the adverse event reports are not necessarily representative of a random sampling of the patient population, nor can they be corrected for the relative market share of the various brand and generic products to determine if there is actually a difference in the incidence of adverse events for generic products.

In particular, FDA analyzed post-marketing surveillance reports of two AEDs for which safety and efficacy concerns were reportedly raised by stakeholders – Levetiracetam and Lamotrigine – for evidence of therapeutic inequivalence.  Based on FDA’s analyses, the Agency notes that the so-called “Weber effect” – a phenomenon that states that the number of reported adverse reactions for a drug increases until about the middle to the end of the second year of marketing – is likely “a factor contributing to increased patient complaints following switches from brand name to newly-approved generic anti-epileptic drugs.”  In addition, FDA says that “it is possible that the wide publicity given to negative literature about generic anti-epileptic drugs, much of which is disseminated by various epilepsy societies, may influence patients that recently switched to generics.”  Thus, according to FDA, “background breakthrough seizure and adverse event rates may be comparable whether the same patient is being treated with a generic drug or the brand drug, but because of the generic switch, the patient may be more likely to complain of adverse events and breakthrough seizures.” 

To better evaluate differences between brand and generic AEDs, FDA says in the report that some studies are in the works, including a study by the National Institutes of Health’s National Institute of Neurological Disorders and Stroke intended to determine whether  some epilepsy patients respond differently to AEDs from different manufacturers, and a similar study designed by the Office of generic Drugs that will be performed under FDA’s Critical Path Program and that is intended “to evaluate bioequivalence of an ‘older’ generic AED, such as carbamazepine, and a ‘newer’ generic AED, such as zonisamide, versus their respective reference products.” 

With respect to AED bioequivalence testing, FDA states that the Agency “is currently exploring the pros and cons of narrowing the acceptance criteria for the 90 percent confidence interval for AUC for certain drugs.”  In April 2010, FDA’s Pharmaceutical Science and Clinical Pharmacology Advisory Committee held a meeting and discussed, among other things, tightening bioequivalence standards (e.g., from the current 80%-125% standard to 90%-111%) for drugs whose dosing must be carefully adjusted to avoid adverse events, including Narrow Therapeutic Index (“NTI”) drugs.  Although the advisory committee was supportive of tightening the bioequivalence standards for NTI drugs, FDA’s report to Congress notes that “not all anti-epileptic drugs are considered NTI drugs based on their efficacy and toxicity profiles.  Therefore, other selection criteria would need to be established as a basis for changing the current bioequivalence standards for the AEDs.”