By Kurt R. Karst –      

A recent article published in Roll Call, titled “Hatch-Waxman Act’s Interpretations Threaten Lives, Jobs,” caught our attention.  The article was penned by Delegate Donna Christensen (D-VI) (who is chairwoman of the Congressional Black Caucus Health Braintrust) and expresses the strong support of members of the Congressional Black Caucus for Section 37 of the House-passed version of the America Invents Act (H.R. 1249).  As we recently reported, Section 37 was sponsored by Representative John Conyers (D-MI) and would amend the Patent Term Extension (“PTE”) law at 35 U.S.C. § 156(d)(1) to effectively codify Judge Claude M. Hilton’s August 3, 2010 decision in The Medicines Company v. Kappos, 731 F. Supp. 2d 470 (E.D. Va. 2010), in which Judge Hilton ordered the Patent and Trademark Office (“PTO”) to consider timely filed The Medicines Company’s (“MDCO’s”) PTE application for U.S. Patent No. 5,196,404 covering ANGIOMAX (bivalirudin) under a next business day interpretation of the PTE statute.  Although H.R. 1249 includes the PTE provision, the Senate version of the bill (S. 23) does not.  (According to IPO Daily News, some Senators are objecting to a few provisions in the House bill, including Section 37.) 

Section 37 (also dubbed the “MedCo amendment” or the “Dog Ate My Homework Act”) has been controversial, but we will not get into that here.  What is of particular interest to us is a statement in Del. Christensen’s article that Judge Hilton’s “decision benefited not only the Angiomax innovator but also another company with a lifesaving drug that this month applied for patent term restoration based on Hilton’s decision.” 

We did some digging and there appear to be two candidates out there that fit Del. Christensen’s description. 

The first is the PTE application for U.S. Patent No. 6,441,168 (“the ‘168 Patent”) (currently set to expire on April 17, 2020) covering BEYAZ (drospirenone/ethinyl estradiol/levomefolate calcium and levomefolate calcium) Tablets.  FDA approved BEYAZ under NDA No. 022532 on September 24, 2011, and a PTE application was submitted to the PTO on November 23, 2010 – or 61 days after NDA approval, including the date of NDA approval.  Under 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.”  But does the next business day rule from The Medicines Company decision apply to the PTE application for the ‘168 Patent?  That is, was notice of the approval letter for NDA No. 022532 received after business hours (i.e., after 4:30 P.M., Eastern Time), thereby making November 23, 2011 day 60 instead of day 61?  (The BEYAZ approval letter does not include a time stamp.)

In March 2011, the PTO issued an Order to Show Cause with respect to the PTE application for the ‘168 Patent citing The Medicines Company decision and saying:

Here, no evidence has been made of record indicating that Applicant received notice of its NDA approval from FDA after FDA’s close of business, i.e., after 4:30 PM EST.  Therefore, without any such evidence, the USPTO presumes that the notice of NDA approval was transmitted to Applicant on September 24, 2010 during FDA’s normal business hours.  Thus, Applicant filed its PTE application one day late, and the eligibility requirement set forth in section 156(d)(1) does not appear to be satisfied and the ‘168 patent appears ineligible for patent term extension for this reason.

The applicant recently responded to the Order to Show Cause providing the requested evidence to the PTO, stating:

[T]he facts are the same as described in The Medicines Company v. Kappos.  Applicant received notice of their NDA Approval from FDA after the close of FDA's business, i.e., after 4:30 PM EST, on September 24, 2010.  Thus, the time period set forth in 35 USC §156(d)(1) started on the next business day, i.e., September 25, 2010.  Thus, the sixty day period set forth in 35 USC §156(d)(1) ended on November 23, 2010, the date that applicant fIled the instant PTE application. Therefore, the application was filed "within" the sixty day period set forth in 35 USC § 156(d)(1).

In this case, the FDA provided notice of the approval in an email received at 4:45 PM on September 24, 2010.

The second candidate is the PTE application for U.S. Patent No. 5,674,860 (“the ‘860 Patent”) covering SYMBICORT (budesonide; formoterol fumarate dihydrate) Inhalation Aerosol, which we have previously reported on (here and here).  FDA approved SYMBICORT under NDA No. 021929 on Friday, July 21, 2006, and a PTE application for the '860 Patent was submitted to the PTO on September 19, 2006 – or 61 days after NDA approval, including the date of NDA approval.  According to a recent submission to the PTO, however, FDA approved NDA No. 021929 at 4:36 PM (Eastern) on July 21, 2006.  Therefore, says the applicant, "in accordance with The Medicines Company, Applicant's period to file the PTE application did not begin to run until the first business day following the FDA's after-hours transmission," or Monday, July 24, 2006, "thus rendering the submission of the PTE application on September 19, 2006, timely within the meaning of § 156(d)(1)." 

By Jamie K. Wolszon –

FDA announced earlier this week the publication of a much-anticipated draft guidance on in vitro companion diagnostic devices.  In the draft guidance, FDA stakes out a policy position that if safe and effective use of a therapeutic depends on a diagnostic, then FDA generally will require approval or clearance of the diagnostic at the same time that FDA approves the therapeutic.  Companion diagnostics are key to the advancement of personalized medicine.  Some well-known companion diagnostics are the tests used to identify patients who will benefit from cancer therapy Herceptin.

FDA outlines two exceptions to this general rule: For new therapeutics, FDA may approve the therapeutic even though the companion diagnostic has not been approved or cleared if the therapeutic product is “intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared IVD companion diagnostic device.”

As for the second exception to the general rule, for therapeutic products that are currently on the market, FDA would be willing to approve a supplement for new labeling even without a cleared or approved companion diagnostic under the following limited circumstances: (1) The “labeling for an already approved therapeutic product must be revised to address a serious safety issue”; (2) the change made to address this issue requires use of a diagnostic test that is not yet approved or cleared; and (3) “the benefits from the use of the therapeutic product with an unapproved or uncleared IVD companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared IVD companion diagnostic device.”

The guidance did not provide examples of types of therapeutics or diagnostics that would qualify for these exceptions from the general rule.

The guidance defines IVD companion diagnostic as “an in vitro diagnostic device that provides information that is essential for the safe and effective use of a corresponding therapeutic product.” 

FDA provides as an example of an IVD companion diagnostic tests that “identify patients who are most likely to benefit from a particular therapeutic product.”  Companion diagnostics also include tests that “identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic product” and “monitor response to treatment for the purpose of adjusting treatment (e.g., schedule, dose, discontinuation) to achieve improved safety or effectiveness.”

Companion diagnostics do not include tests intended to provide “information that is useful to the physician regarding the use of a therapeutic product, but that are not a determining factor in the safe and effective use of the product.”  For instance, biochemical assays (e.g., serum creatinine tests) used to monitor organ function are not companion diagnostics.

Ideally, according to FDA, a “therapeutic product and its corresponding IVD companion diagnostic device would be developed contemporaneously, with the clinical performance and clinical significance of the IVD companion diagnostic device established using data from the clinical development program of the corresponding therapeutic product.”  However, FDA states that it recognizes that this will not always be possible.  This expectation that the therapeutic and the companion diagnostic would be developed contemporaneously may be viewed as unrealistic.

The guidance also notes that studies of companion diagnostics generally will be significant risk devices that will require an IDE.  Most studies of other IVDs are non-significant risk.

FDA will use a risk-based approach to regulate companion diagnostics.  FDA says that in its experience to date, companion diagnostics generally will be Class III devices requiring a PMA, but there could be instances where 510(k) would be sufficient.

The guidance recommends that sponsors consult with both the device center, for a pre-IDE meeting, and the center in charge of regulating the therapeutic component.  FDA notes that it is “developing appropriate internal policies and procedures to ensure effective communication among the relevant centers and to promote consistent and efficient product review.”  FDA also states that there could be instances where viewed as combination product and thus only one application but did not state what such instances would be. 

The guidance also discusses FDA’s view of the need for cross-labeling between the therapeutic and the companion diagnostic.

The guidance has been long-awaited by industry, which has sought guidance in this area – an area that has been marked by ambiguity.  Years ago, FDA issued a draft guidance on the topic, which received criticism from industry.  FDA stated last year that it would promulgate two guidances to provide clarity that would address issues including when FDA would require simultaneous approval and what data requirements the agency would require. 

The comment period for the draft guidance will close within 60 days of issuance, which occurred July 14.

By Nisha P. Shah –

Under a bill titled, “An Act to Make Certain Prescription Drug Disclosure Laws Consistent with Federal Law,” the State of Maine repealed three laws related to the reporting of marketing costs, price reporting, and the disclosure of clinical trials by manufacturers and labelers of prescription drugs dispensed in Maine. 

One repealed law, Me. Rev. Stat. Ann. tit. 22, § 2698-A, required manufacturers and labelers that employed or used marketing representatives in Maine to submit an annual report of certain marketing costs, including, but not limited to, (1) expenses associated with food, entertainment, gifts valued at more than $25, trips, and travel in connection with all licensed health care professionals and entities, and (2) costs associated with advertising, marketing, and promotion of prescription drugs as they pertained to Maine residents (unless the costs were for a regional or the national market).  The Maine legislature also repealed the $1,000 annual fee that was associated with the marketing report.  Note that the repeal does not affect the annual report and fee for CY 2010 that were due July 1, 2011.  The Maine reporting requirement was similar to marketing reporting laws in the District of Columbia and West Virginia.  Massachusetts and Vermont also have reporting requirements for marketing practices, though these laws extend to both pharmaceutical and medical device manufacturers.  Another rescinded law, Me. Rev. Stat. Ann. tit. 22, § 2698-B, required disclosure, on a quarterly basis, of the average manufacturer price and best price for all drugs subject to the Medicaid Drug Rebate Program. 

Finally, Me. Rev. Stat. Ann. tit. 22, § 2700-A was amended to revoke the requirement that manufacturers and labelers of prescription drugs post information on clinical trials that they conducted or sponsored on a publicly accessible website.  Such information included a summary of the purpose of the clinical trial, the dates during which the trial has taken place, and the results of the clinical trial (including potential or actual adverse effects of the drug).  Manufacturers of prescription drugs that are provided through MaineCare (Maine’s Medicaid program) were required to pay an annual fee of $1,000, in part, for the posting of clinical trial results and the monitoring of adverse event reports.  Because this fee also was used to fund the state’s academic detailing program, the Maine legislature amended the bill to cut the annual fee to $500 beginning April 1, 2012. 

The repeal provisions are effective September 28, 2011, 90 days after the Maine legislature adjourned on June 29, 2011. 

By Larry K. Houck –

The Drug Enforcement Administration (“DEA”) published a Notice of Proposed Rulemaking (“NPRM”) on July 6, 2011 seeking to raise initial registration and renewal fees for all registrants.  76 Fed. Reg. 39,318 (July 6, 2011).  Citing increased diversion control activities, DEA justified increasing fees for the second time in five years.  DEA also explained the different fee-setting methodologies it considered, including the one selected, that would increase fees for each category of registrants.  The proposed fees for all registrants would increase by 33%.

The Controlled Substances Act authorizes DEA “to charge reasonable fees relating to the registration and control of the manufacture, distribution, and dispensing of controlled substances and to listed chemicals.”  21 U.S.C. § 821.  DEA is required to set registration fees “at a level that ensures the recovery of the full costs of operating the various aspects of” the Diversion Control Program.  21 U.S.C. § 886a(1)(C).  Thus, registration fees must be “reasonable” but must cover all costs of the Diversion Control Program.

DEA listed its historical diversion control activities in the NPRM in addition to salary and other costs related to the Diversion Control Program’s expanded mission since the last fee adjustment in 2006.  DEA cited a number of factors justifying the fee increase including:

• Expansion and use of Tactical Diversion Squads comprised of DEA diversion investigators and special agents, state and local law enforcement and regulatory officers conducting criminal investigations.  (There were 37 operational Tactical Diversion Squads as of March 2011, and since 2006, DEA added 161 special agent positions, the majority assigned to Tactical Diversion Squads.  76 Fed. Reg. 39,324);
• Increased frequency of scheduled cyclic regulatory investigations of registrants;
• Increased drug and chemical scheduling initiatives;
• Improved information technology capabilities for the Controlled Substances Ordering System (“CSOS”), Automated Reports and Consolidated Orders System (“ARCOS”) and the Drug Theft/Loss database; and
• Implementation of the Combat Methamphetamine Epidemic Act of 2005, the Methamphetamine Production Prevention Act of 2008 and the Combat Methamphetamine Enhancement Act of 2010 requirements.

DEA asserts in the NPRM that it “will be unable to continue current operations” without increasing fees, and will violate the requirement that it set fees at a level that ensures the recovery of the full costs of operating the Diversion Control Program.  To that end, DEA considered four different fee-setting methodologies, explaining the benefits and disadvantages of each.  DEA selected a weighted-ratio methodology to determine the reasonable fee for each category of registrant that would increase future registration fees for all registrants by 33%.

Current and Proposed Fees for Three-Year Cycle Registrants

Current and Proposed Fees for Annual Cycle Registrants

The deadline for submitting comments is September 6, 2011. 

FDA Law Blog has learned that Elizabeth H. Dickinson, who currently serves as Associate Chief Counsel for Drugs in FDA’s Office of Chief Counsel, will serve as FDA’s Acting Chief Counsel effective on August 7th.  As we previously reported, FDA’s current Chief Counsel, Ralph Tyler, recently gave word that he will be leaving FDA effective as of August 5th.  Ms. Dickinson is very well known to the Food and Drug Bar, and in particular among the Hatch-Waxman community.  Ms. Dickinson received her B.A. in Economics from the University of Massachusetts, and her J.D. from Northeastern University.  She was law clerk to the Honorable William B. Bryant of the U.S. District Court for the District of Columbia, and has been with FDA since 1994.  Ms. Dickinson was awarded the Food and Drug Law Institute’s Distinguished Service and Leadership Award in 2009, the National Organization for Rare Disorders’ Public Health Leadership Award in 2005, and has received several FDA and Department awards for legal services.

By Dara Katcher Levy –

On July 5, 2011, seven pharmaceutical companies submitted a joint Citizen Petition requesting that FDA clarify its policies for industry about four distinct types of manufacturer-communications that often deal with off-label information – Manufacturer Responses to Unsolicited Requests; "Scientific Exchange"; Interactions with Formulary Committees, Payors, and Similar Entities; and Dissemination of Third-Party Clinical Practice Guidelines. 

The first three types of communications have been addressed by FDA over the years, with FDA acknowledging, conceptually, that these communications are permissible and recognizing certain mechanisms for dissemination as appropriate.  The Citizen Petition is requesting that FDA further clarify and formalize its policies in these areas through rule-making.  The fourth area, Dissemination of Third-Party Clinical Practice Guidelines, has been a subject of much debate within industry.  Although several DDMAC Warning and Untitled Letters have confirmed that promotional claims based on such Guidelines may be inappropriate, it is unclear whether these Guidelines can currently be disseminated in their original published state pursuant to FDA's Guidance on Good Reprint Practices.      

As part of the request, the Citizen Petition makes clear that notice and comment rule-making is strongly preferred over FDA issuance of guidance documents.  And as the Pink Sheet notes, although rule-making, and not guidance, is requested, there is hope that FDA will respond as the issues raised in the Citizen Petition are likely issues for which FDA, at least internally, already has policy and can better iterate its position.  Some in the industry speculate that this Citizen Petition may help even if (or especially if) FDA takes no action on it – to the extent the government attempts to take enforcement action against a company on the basis of a communication subject to the Citizen Petition, it is possible that FDA's failure to clarify its position can be used as part of its defense.

By Kurt R. Karst –      

A recent article in The RPM Report concerning the apparent fate of the only Priority Review Voucher (“PRV”) issued to date by FDA caught our attention.  Kudos to The RPM Report team, which took note of some statements made during a recent meeting of FDA’s Arthritis Drugs Advisory Committee to discuss Novartis Pharmaceuticals Corporation’s (“Novartis’”) supplemental Biologics License Application (“sBLA”) for ILARIS (canakinumab) for the treatment of gouty arthritis attacks in certain patients.  According to The RPM Report, during the panel discussion, FDA disclosed that the ILARIS sBLA was granted 6-month priority review status instead of the standard 10-month review: “As part of the explanation, an FDA reviewer noted the distinction between a priority and standard review, adding that Ilaris was an expedited sBLA but not because it was originally designated a priority review by the agency: ‘this one was not necessarily a priority for any unmet need.  It was a voucher the sponsor is redeeming.’”

PRVs were established by § 1102 of the 2007 FDA Amendments Act, which created  FDC Act § 524.  Under the statute, sponsors of certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  FDA has granted only a single PRV – in connection with the April 2009 approval of Novartis’ NDA No. 22-268 for COARTEM (artemether; lumefantrine) for the treatment of acute, uncomplicated malaria infections in adults and children weighing at least five kilograms (see our previous post here).  

PRVs are transferable and led some people to initially speculate that there would be a PRV market where the value of a PRV would be somewhere between $50 million and $500 million.  However, the paucity of PRVs, the mere prospect of saved approval time, and the often unpredictable market for a new drug have not led to the fruition of that speculation.  Moreover, FDA has set a high PRV redemption price of  $4,582,000 for Fiscal Year 2011.  That figure is in addition to the Fiscal Year 2011 full application fee of $1,542,000 that must accompany the submission of an NDA (see our previous post here). 

Novartis was apparently willing to pay the PRV redemption fee and roll the dice that FDA would approve the ILARIS sBLA within 6 months of its February 28, 2011 submission.  The Arthritis Drugs Advisory Committee voted 11-1 against approval of the ILARIS sBLA.  Although FDA is not bound by the advisory committee vote, “[a]ssuming FDA follows that advice, the first [PRV] will end up translating into a faster ‘complete response’ letter—not an earlier launch date for a new product,” says The RPM Report.  While such an outcome “does not by itself prove that the voucher incentive is flawed . . . .  it will reinforce the concerns of advocates for tropical disease research that the incentive isn’t really doing much to help drive development.”

The case of ILARIS “may be another trigger for a fix to the priority voucher program as part of the PDUFA V reauthorization negotiations on Capitol Hill,” says The RPM Report.  Last week, the House Energy and Commerce Committee Health Subcommittee held a hearing on PDUFA V.  CDER Director Dr. Janet Woodcock testified at the hearing and identified several proposed enhancements to PDUFA in her prepared testimony, but her prepared remarks did not touch on PRVs.  Nevertheless, there is already pending legislation that would change the PRV program, but probably not to the extent needed to address perceived program shortcomings.  Earlier this year, the Creating Hope Act of 2011 was introduced in the U.S. Senate (S. 606).  The bill, like its nearly identical 2010 version (S. 3697), would, among other things, amend FDC Act § 524 to extend the PRV program to applications for a “rare pediatric disease,” and amend the PRV eligibility requirements for tropical disease applications (see our previous post here).  

Finally, we note that on July 11th, David Ridley of the Duke University Fuqua School of Business (and one of the authors to have first proposed in a 2006 Health Affairs article the idea of stimulating tropical disease drug development by offering a voucher system) presented on PRVs (and other issues) at the 8th World Congress on Health Economics in a session titled “The Priority Review Voucher and Other Incentives for Neglected Diseases.”  Details on the presentation are not yet available. 

By Riëtte van Laack –

Last week, Senator Richard Durbin (D-IL) introduced “the Dietary Supplement Labeling Act of 2011” (S. 1310).  The bill proposes to amend the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to “improve the safety of dietary supplements.” Durbin’s bill includes a requirement that dietary supplements manufacturers register with FDA their dietary supplements, a list of dietary ingredients contained in these supplements, and copies of the label and labeling of these dietary supplements.  Failure to register a dietary supplement or keep the information up to date causes that product to be misbranded. 

In addition, Durbin’s bill would mandate FDA and the Institute of Medicine (“IOM”) to identify (based on review of the literature) dietary ingredients that cause potentially serious adverse events, drug interactions, contraindications, or potential risks to subgroups such as children and pregnant women, and establish warning statements for dietary supplements containing these potentially unsafe ingredients.  If a potentially unsafe dietary ingredient is part of a proprietary blend, the product label must disclose the amount of that dietary ingredient per serving.  The bill further proposes to require that a dietary supplement label includes a batch number, and that FDA establish a definition of “conventional foods.”

If passed, the Dietary Supplements Labeling Act of 2011 will significantly increase the administrative burden for dietary supplement manufacturers.  Particularly the requirement to disclose the amount of certain dietary ingredients in proprietary blends is cause for concern as the quantitative composition of a proprietary blend is generally considered a valuable trade secret. 

Durbin’s bill also will impose a significant burden on FDA and IOM without an apparent benefit.  FDA currently has ample authority to address safety issues of dietary supplements and remove unsafe dietary supplements from the market.  Moreover, FDA has the authority – and has used that authority – to take enforcement action against dietary supplements that are conventional foods marketed as dietary supplements. 

By Kurt R. Karst –      

Earlier this week, Judge Joel A. Pisano of the U.S. District Court for the District of New Jersey issued a 19-page decision in Nostrum Pharmaceuticals, LLC. v. FDA denying the injunctive relief sought by Nostrum in a Complaint and a Motion for a Preliminary Injunction filed last month.  The case stems from FDA’s decisions on pre-Medicare Modernization Act (“MMA”) 180-day exclusivity with respect to Nostrum’s ANDA No. 76-697 for a generic version of CARBATROL (carbamazepine) Extended-release Capsules, 300 mg, which FDA approved on May 20, 2011.  As we previously reported, at issue in the case is FDA’s application of the so-called “holding-on-the merits” standard with respect to one Orange Book-listed patent on which Nostrum qualified for 180-day exclusivity (U.S. Patent No. 5,912,013 (“the ‘013 Patent”)), and FDA’s interpretation that 180-day exclusivity terminates with the expiration of another patent on which Nostrum qualified for 180-day exclusivity (U.S. Patent No. 5,326,570 (“the ‘570 patent”)).  Lerner, David, Littenberg, Krumholz & Mentlik, LLP and Hyman, Phelps & McNamara, P.C. represent Nostrum in the lawsuit.

In a May 20, 2011 Letter Decision, FDA says that Nostrum’s exclusivity with respect to the ‘013 patent was triggered by a June 14, 2009 ruling in Shire Labs, Inc. v. CorePharma, LLC, C.A. 06-2266 (D.N.J.), in which the court entered a final judgment of its previous order granting a Motion for Summary Judgment of Non-infringement of the ‘013 patent filed by CorePharma (another ANDA sponsor).  According to FDA, this “holding is adequate as a basis to trigger the running of exclusivity as to the '013 patent,” and thus “Nostrum's exclusivity with respect to the '013 patent has expired.”  According to Nostrum, however, “the holding in CorePharma was a decision on the ground of judicial estoppel, not a decision on the merits of infringement,” and therefore, “there was no decision on the merits that could trigger Nostrum's exclusivity . . . and FDA's decision to the contrary in the Approval Letter, characterizing the ruling as a finding on the merits, was incorrect as a matter of law.”

On the ‘570 patent, FDA ruled that Nostrum is eligible for 180-day exclusivity, which was triggered on May 20, 2011 when Nostrum began commercial marketing.  The ‘570 patent, however, expires on July 23, 2011, several months before the November 16, 2011 date that is 180 days from May 20, 2011.  (Previously, the Orange Book showed the ‘570 patent expiring on July 5, 2011.  After Nostrum filed its lawsuit, the Orange Book was updated to reflect a July 23, 2011 expiration.  The ‘570 patent was filed on July 23, 1991, and issued on July 5, 1994.  For patent applications that were pending on and for patents that were still in force on June 8, 1995, the patent term is the longer of either 17 years from the date of issuance or 20 years from the filing date.  So it appears that the NDA sponsor switched from the issued plus 17 years date to the filed plus 20 years date.)

Judge Pisano was not convinced that FDA incorrectly applied its holding-on-the merits standard with respect to the triggering of 180-day exclusivity associated with the ‘013 patent, saying in his opinion that:

As an initial matter, the FDA has never interpreted the court decision trigger provision to require a court to compare the claims of the asserted patents to the accused generic product.  Rather, the FDA has interpreted the statute’s express requirement of a court decision “holding the patent which is the subject of the certification to be invalid or not infringed” as resolution of the issues of validity, infringement and enforceability “on the merits.”  Nothing suggests that the only way a court can reach a decision “on the merits” of an infringement claims is in the manner suggested by Nostrum.  Indeed, in the context of a motion for summary judgment a court is called upon to examine evidence, weigh substantive arguments and perform legal analysis.  The court must determine whether there exists a genuine dispute of material fact and whether the undisputed facts entitle a party to judgment as a matter of law.  Addressing such a motion, the CorePharma court concluded that there were no facts from which infringement could be found and entered judgment of noninfringement of the ‘013 patent as a matter of law.  The FDA need not look any further than that. [(Internal citation omitted)]

With respect to 180-day exclusivity stemming from the ‘570 patent, Nostrum argued, among other things, that the plain language of the statute does not limit 180-day exclusivity to the term of a patent.  Judge Pisano disagreed, however:

The statutory provision entitling Nostrum to exclusivity, by its terms, applies only to paragraph IV certifications, “which cease to exist upon patent expiration.”  Applying step one of Chevron, the Court finds the FDCA unambiguously supports the FDA’s determination that it is not prohibited by 21 U.S.C. § 355(j)(5)(B)(iv) (2002) from approving later-filed ANDAs upon expiration of the ‘570 patent.

Within hours of the district court issuing its decision, Nostrum filed a notice to appeal Judge Pisano’s decision to the U.S. Court of Appeals for the Third Circuit (Case No. 11-2837).  Nostrum also says in a filing that the company intends to ask the Third Circuit for an injunction pending appeal.

By Anne K. Walsh & John R. Fleder –

Companies must proactively prepare for the strong arm tactics the government employs to investigate companies regulated by FDA.  A recent case demonstrates that the federal government can act with little regard to companies seeking to represent themselves by defending against such aggressive tactics.   As a result, without certain procedures in place, a company’s employees could disclose otherwise privileged documents, or make statements on behalf of the company without the company’s knowledge.

In In re Amgen, Inc., No. 10-MC-0249(SLT) (E.D.N.Y. Apr. 6, 2011), Amgen sought a protective order to stop the government from interviewing its current employees without coordinating through Amgen’s legal counsel.  Amgen argued that such communications violated the “no contact” rule of New York’s Code of Professional Responsibility.  The magistrate judge recommended that the court deny Amgen’s motion on the ground that it was non-justiciable, or in the alternative, without merit.  The district court later entered an Order in accordance with that recommendation on June 14, 2011.

The “no contact” rule provides that a lawyer shall not communicate (or cause another to communicate) about the subject of the representation with a party the lawyer knows to be represented by another lawyer in the matter, unless the lawyer has the prior consent of the other lawyer or is authorized to do so by law.  N.Y. Rule of Prof’l Conduct 4.2(a).  This rule applies to all federal government attorneys practicing within the State of New York by virtue of 28 U.S.C. § 530B(a).  Most states have a similar rule of professional conduct preventing lawyers from communicating with represented parties.

In its report and recommendation, the magistrate judge analyzed application of the rule to the relevant facts of the case.  The report merits review by anyone interested in the nuances of the rule of professional conduct governing these communications.  One interesting highlight is the list of alternative remedies the magistrate judge identifies for Amgen, in lieu of granting the injunctive relief it seeks: 1) seeking professional disciplinary action against the prosecutors before the relevant state bar authorities; 2) seeking disciplinary action before the court’s Committee on Grievances; 3) seeking internal disciplinary action by the U.S. Department of Justice for violating its policies; and 4) seeking to suppress in litigation any evidence resulting from a violation of the “no contact” rule.

We want to highlight that the federal government makes no apologies in purposefully and systematically directing its agents to interview employees of represented companies.  The result in this case likely will increase the number of interviews conducted in this manner.

As described in Amgen’s memorandum in support of its motion, for two years the government had coordinated with Amgen’s counsel to interview its current employees.  There appears to have been some discussion between the company and the government about this coordination, but obviously the discussions did not lead to a meeting of the minds.  The coordination ended without notice, and the government conducted interviews of several current employees at their homes.  In at least one of those interviews, government agents sought to obtain documents belonging to Amgen.  According to Amgen, the government “was looking to interview current Amgen employees outside of the presence of counsel and to attempt to obtain statements binding against Amgen about activities that might have occurred exclusively, or at least primarily, in past years.”

Given the increasing likelihood of “at home” visits to current employees, companies must have procedures for employees to respond to inquiries from federal law enforcement agents.  These procedures should require employees to immediately notify in-house counsel of any contacts made by the federal government.  In addition, employees should be instructed about the confidentiality and potential privileged status of certain documents and information, and the prohibitions on their disclosure outside the company without prior approval.  Employees should be trained about these issues.

By Riëtte van Laack –

The Food Safety Modernization Act ("FSMA") required that FDA, within 180 days of enactment of the FSMA, publish guidelines clarifying the definition of a new dietary ingredient ("NDI") and requirements for NDI notifications.  FDA just made that deadline when it released the “Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues” on Friday July 1, 2011 (the Federal Register notice of availability was published on July 5, 2011).  It will take some time to distill the information contained in this long-awaited draft guidance.  However, from an initial read it appears that FDA’s interpretation of the statutory requirements applicable to NDIs is more restrictive than the statutory language contemplates and would create substantial hurdles for manufacturers. 

The FDC Act defines a NDI as one not marketed in the U.S. before October 15, 1994.  The manufacturer or distributor of an NDI (or a dietary supplement that contains an NDI) must notify FDA at least 75 days before the marketing of the product, unless the NDI has “been present in the food supply as an article used for food in a form in which the food has not been chemically altered.”  The notification must provide the basis for the manufacturer’s conclusion that its product “will reasonably be expected to be safe.” 

FDA estimates that there are more than 55,000 dietary supplements on the market and, annually, another 1000 new dietary supplements introduced.  Yet, since 1995, FDA has received only approximately 700 NDI notifications.  FDA has pointed to these numbers as evidence that NDI notifications are not being submitted in cases when they should be.  Further, FDA has indicated many of the 700 notifications that FDA has so far received did not provide the information required by FDA’s regulations.  In part, the guidance is intended to address these issues.  The draft guidance consists of more than 120 Q&As regarding the determination of whether a dietary ingredient is an NDI, and, if it is, whether a notification is required and what information should be included in the notification.  FDA’s draft guidance also includes a decision tree to help determine whether an NDI notification is needed, as well as an NDI Notification Form providing a template that a manufacturer may use for submission of its NDI notification.

As is clear from the high percentage of NDI notifications that FDA regards as deficient and the more than 70 Q&As that address the contents of a notification, preparing an NDI notification is no small task.  Smaller companies may not be able to afford a notification, and larger companies should be prepared to devote substantial resources to the effort.  Consequently, the determination of whether an NDI needs a notification, or whether the NDI is present in the food supply in a form in which it has not been chemically altered, is a critically important issue when deciding whether to incorporate a dietary ingredient in a supplement.  Under FDA’s proposed interpretation of the NDI requirements, one or more notifications could be required for the majority of NDIs. According to the draft guidance, circumstances under which a notification may be required include:

• a change in the manufacturing process resulting in a change of the specifications of the NDI that previously has been notified to FDA;
• an NDI for which another manufacturer already submitted an NDI notification;
• use of solvents other than water or aqueous alcohol;
• preparation of an extract by removal of some components of a solution in water; and
• use of a different fermentation medium to grow a microorganism.

The requirement that a notification be submitted even where an NDI is the subject of a previous notification appears especially problematic for the inefficiencies it would generate – and for the lack of statutory authority upon which to base such a requirement.   FDC Act § 201(ff) specifically states that a dietary supplement is a food, with certain exceptions not applicable here.  Given that provision, isn’t a previously notified NDI “present in the food supply as an article used for food,” and therefore exempt from notification?

The determination of whether a dietary ingredient is an NDI must be preceded by a determination of whether the substance in question qualifies as a dietary ingredient within the meaning of FDC Act § 201(ff).  On several occasions, FDA has objected to NDI notifications because, according to the Agency, a substance did not qualify as a dietary ingredient.  In the draft guidance, FDA asserts that a substance does not necessarily qualify as a dietary ingredient merely because it occurs in food.  Instead, a substance that is not a vitamin, mineral, botanical or amino acid, qualifies as a dietary ingredient only if it is consumed as a component of the diet.  Therefore, contaminants of food products (including pathogenic microorganisms), food contact substances and other indirect food additives usually do not qualify as dietary ingredients.  According to FDA, whether and when a synthetic substance qualifies as a dietary ingredient depends on the nature of the substance and the particular provision of the dietary ingredient definition under consideration.  Although the draft guidance rejects the proposition that a synthetic substance can be a “constituent” or “extract” of an herb or other botanical, the guidance states that the “enzymatic or synthetic processing of cysteine or any other dietary ingredient would be an appropriate method for the manufacture of a metabolite of a dietary ingredient like taurine for use in a dietary supplement.”

As noted above, the requirements for the contents of the NDI notification are addressed in 71 Q&As.  The purpose of the NDI notification is to provide FDA with information that forms the basis on which the manufacturer has determined that the dietary supplement(s) containing the NDI will reasonably be expected to be safe.  Therefore, it is not surprising that 43 of these 71 Q&As address what FDA believes constitutes “history of use or other evidence of safety” to support the safety of the NDI.  The guidance provides a table with FDA recommendations regarding safety testing for an NDI depending on the proposed level of use and the documented historical use levels.  This table includes references to the specific Q&A for further discussion of FDA’s recommendation. 

Comments on the draft guidance are due by October 3, 2011.

By Kurt R. Karst –    

Over the Independence Day holiday, in between the family BBQ and fireworks, we had a few minutes to reflect on what a hectic month June was for FDA and the regulated industry.  There were the decisions handed down by the U.S. Supreme Court in Mensing and Sorrell (here and here), and the Court’s decision to hear Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S (Docket No. 10-844).  June also saw a host of new lawsuits and appeals, including the ReGen and PREVOR Complaints filed against FDA.  The U.S. Government Accountability Office issued a bevy of reports on issues including antibiotic resistance, the influenza pandemic, medical device recalls, and a late May report on pediatric research. 

FDA, of course, had its hands full with the AVASTIN (bevacizumab) hearing, but the Agency still found time to issue myriad guidance documents, reports, rules and regulations, and other decisions on issues including Research Use Only and Investigational Use Only products, 505(q) citizen petitions, OTC sunscreen drug products, nanotechnology, and global product safety and quality.

Things were particularly busy on Capitol Hill where a flurry of bills were introduced in June, and several missives to FDA and the regulated industry were generated (see, e.g., here, here, here, and here).  Below is a sampling of the FDA-related bills recently introduced in Congress.

• Dietary Supplement Labeling Act of 2011 (S. 1310)
• Preservation of Antibiotics for Medical Treatment Act of 2011 (S. 1211)
• Medicare Drug Savings Act of 2011 (S. 1206)
• Pandemic and All-Hazards Preparedness Reauthorization Act of 2011 (H.R. 2405)
• Safe Cosmetics Act of 2011 (H.R. 2359)
• America Rx Act of 2011 (H.R. 2296)
• Preserving Access to Life-Saving Medications Act of 2011 (H.R. 2245)
• Medical Gas Safety Act (H.R. 2227)
• Skin Cancer Prevention, Education, and Consumer Right-To-Know Act (H.R. 2132)
• Ryan Creedon Act of 2011 (H.R. 2119)

There are no signs of activity letting up for the rest of the year and into 2012.  Reauthorization of the Prescription Drug User Fee Act (“PDUFA”) – PDUFA V – will likely begin to take center stage.  The House Energy and Commerce Committee Health Subcommittee will hold a hearing on PDUFA on July 7th.  According to a hearing background memo, “[o]n September 1, 2011, FDA will publish the details of the agreement recommendations on its website.  A public meeting on the recommendations will follow in October 2011. By January 15, 2012, FDA must send its final recommendations to the Committee and the Senate HELP Committee as required by statute.”  As with previous iterations of PDUFA, PDUFA V will likely act as a vehicle to which other FDA-related measures are added, including perhaps generic drug user fees and biosimilars user fees.  As always, your intrepid bloggers will be there to report on these and other events.  

By Peter M. Jaensch –

On June 29th, 2011, the Washington Legal Foundation (“WLF”) filed an amicus curiae brief in Friedman v. Sebelius, currently pending in the U.S. Court of Appeals for the D.C. Circuit.  WLF argues that excluding executives convicted of misdemeanor offenses under the strict liability Responsible Corporate Officer Doctrine (“RCO or Park Doctrine”) from participation in federal healthcare programs violates the Due Process Clause of the Constitution.

Although we have previously covered this case in more detail, some background is helpful.  The appellants are three former Purdue Frederick Co. (“Purdue”) executives.  In 2007, Purdue pled guilty to a felony based on the promotion of one of its painkiller products by lower-level employees.  The three appellants were company executives at the time of the underlying offenses, and entered misdemeanor guilty pleas under the RCO doctrine. This doctrine creates strict liability for corporate officers for the company’s violations – that is, a company executive may be found guilty of a misdemeanor without having had any part or even awareness of the wrongdoing. And, in fact, in this case, the government’s charges against the executives were based solely on the fact that they were executives during the period in which the improper promotion occurred. The executives were sentenced to probation and fines were imposed.

As a result of these convictions, however, the Department of Health and Human Services (“HHS”) determined that these executives should be excluded from participation in federal healthcare programs for 12 years. Such an exclusion is effectively a career-ender. As a function of this exclusion, any company that employs these executives would also be subject to HHS exclusion, and their products would be ineligible for medicare or medicaid reimbursement. Thus, such executives become essentially unemployable for at least the period of the exclusion.

WLF’s brief takes this issue up on Due Process grounds and argues that the enormous impediment of HHS exclusion is unconstitutional in connection with an RCO doctrine conviction because in such cases the executive has not been convicted of any wrongdoing.  In making its argument, WLF also notes that the Supreme Court established the RCO doctrine as an exception to the general rule that criminal liability requires culpability.  The government will likely argue that exclusion is not a criminal penalty but an administrative act. FDA has repeatedly said that it intends to increase the use of the RCO doctrine in prosecuting violations of the FDC Act, and that it will seek to prosecute more individuals.

By Kurt R. Karst & Jeffrey K. Shapiro –      

French company PREVOR has filed a Complaint in the U.S. District Court for the District of Columbia  challenging FDA’s determination that PREVOR’s Diphoterine® Skin Wash (“DSW”) is a drug-device combination product with a “drug” primary mode of action.  Hyman, Phelps & McNamara, P.C. represents PREVOR in the lawsuit.

DSW consists of a liquid substance contained inside a canister.  It is intended to help prevent and minimize chemical burn injuries that occur due to accidental exposure to chemicals and is intended to be used in the industrial setting as a “first response” method.  DSW is sprayed onto the skin to physically and mechanically remove or wash away the offensive chemical from the skin.  A secondary purpose is to neutralize the acids and bases that are washed off the skin.  The Complaint alleges that uncontradicted data show that over 90% of the overall intended purpose of the product comes from a physical washing effect, and that less than 10% of the intended purpose comes from a chemical neutralization effect. 

Under the FDC Act and FDA’s implementing regulations, a product that is a “device” is generally subject to the regulatory authority of FDA’s Center for Devices and Radiological Health (“CDRH”), while a product that is a “drug” is generally subject to the regulatory authority of FDA’s Center for Drug Evaluation and Research (“CDER”).  Some products, termed combination products, contain both drug and device components. 

In October 2009, OCP issued a Letter of Designation to PREVOR in response to the company’s August RFD.  OCP concluded that DSW is a drug-device combination in which the liquid is the “drug” constituent part and the canister is the “device” constituent part. OCP further concluded that DSW has a “drug” primary mode of action and assigned primary jurisdiction of the product to CDER for regulation.  In March 2010, PREVOR requested that FDA’s Office of Special Medical Programs (“OSMP”) reconsider OCP’s October 2009 determination.  More than a year later, however, on April 25, 2011, FDA’s OSMP issued a letter affirming OCP’s October 2009 determination. 

The Complaint states that DSW is a liquid that meets the statutory definition of a “device,” because its primary intended purpose is not chemical, but physical/mechanical, and alleges that FDA’s jurisdictional determination is arbitrary, capricious, and contrary to law under the Administrative Procedure Act.  PREVOR also alleges, among other things, that FDA “erroneously ruled that a product does not meet the definition of a device if there is any chemical action within or on the body of man in achieving its primary effect,” and that FDA’s decision “conflicts with numerous prior decisions by FDA to regulate products as devices because their primary effect is physical, despite having some chemical effect.” 

PREVOR is seeking injunctive relief and a Declaratory Judgment that would vacate FDA’s finding that DSW’s solution is a “drug” and not a “device” and designation of DSW as a drug-device combination product with a “drug” primary mode of action, and that DSW is a “device,” or, in the alternative, that DSW is a drug-device combination product with a “device” primary mode of action.

About 18 months after coming to FDA to serve as Chief Counsel, Ralph Tyler will be leaving the Agency, according to an FDA-wide e-mail sent out on June 30th by FDA Commissioner Margaret Hamburg.  Prior to joining FDA, Mr. Tyler served as Insurance Commissioner of the State of Maryland (see our previous post here).  Mr. Tyler's last day at FDA will be August 5, 2011.  We understand that an Acting FDA Chief Counsel has not yet been named.