An article published by Law360 and co-authored by H. Keeto Sabharwal and Dennies Varughese of Sterne Kessler Goldstein & Fox PLLC, and Kurt R. Karst of Hyman Phelps & McNamara PC, examines whether, and to what extent, a successful Inter Partes Review (“IPR”) challenge by a subsequent ANDA sponsor might cause a forfeiture of 180-day exclusivity under the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) added by the 2003 Medicare Modernization Act.

The IPR proceedings present a new wrinkle in patent litigation and were created with the September 16, 2011 enactment of the Leahy-Smith America Invents Act (“AIA”).  The U.S. Patent and Trademark Office (“PTO”) has already taken several steps to implement the new IPR procedures.  As Mr. Sabharwal and Mr. Varughese explained in a 2012 article, the IPR is an administrative patent challenge proceeding at the PTO that serves as a parallel or alternative to district court litigation to adjudicate patentability of issued patents.  (The IPR procedures replaced the old inter partes re-examination procedures.)  IPR petitions are filed with the PTO’s Patent Trial and Appeal Board (“PTAB”), which adjudicates the cases.  The PTAB has already received at least three relevant IPR petitions relating to Hatch-Waxman cases – two concerning patents on moxifloxacin (IPR2013-00012 and IPR2013-00015), and another concerning a patent on fosamprenavir (IPR2013-00024).

Under the failure-to-market 180-day exclusivity forfeiture provisions, there must be two events (i.e., “bookends”) to calculate a “later of” event between items (aa) and (bb).  The first bookend date under item (aa) is the earlier of the date that is 75 days after ANDA approval or 30 months after ANDA submission.  The (bb) part of the equation (i.e., the other bookend) provides that the (bb) date is “the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a [Paragraph IV] certification qualifying the first applicant for the 180-day exclusivity period,” one of three events occurs – two of which are relevant here:

(AA) In an infringement action brought against that applicant with respect to the patent or in a declaratory judgment action brought by that applicant with respect to the patent, a court enters a final decision from which no appeal (other than a petition to the Supreme Court for a writ of certiorari) has been or can be taken that the patent is invalid or not infringed.

(BB) In an infringement action or a declaratory judgment action described in [FDC Act § 505(j)(5)(D)(i)(I)(bb)(AA)], a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

The (AA) and (BB) court decision events under item (bb) can be triggered in patent infringement litigation by “the first applicant or any other applicant (which other applicant has received tentative approval).”

While a final, unappealed district court judgment of patent invalidity would operate to trigger forfeiture under the failure-to-market forfeiture provisions, it is unclear whether patent nullification by the PTAB in an IPR proceeding would similarly qualify to trigger forfeiture  According to the authors of the new paper:

Under a strict reading, one might argue that a PTAB decision would not qualify because the decision would not be from “an infringement action … or declaratory judgment action,” as recited in the statute. Instead, IPR is a post-issuance challenge to the patent, which necessarily does not involve claims of patent infringement.

And the same argument may apply to any Federal Circuit affirmance of a PTAB decision.  Although such a Federal Circuit affirmance would be a final court decision, it arguably would not be from “an infringement action … or declaratory judgment action.” Even so, a PTAB nullification decision may nevertheless form the basis for further district court action that could lead to forfeiture.  A Federal Circuit affirmance, at the very least, would be binding on a district court and would form the basis for a simple motion for entry of
judgment in a district court action that could then trigger forfeiture. And because this district court judgment would be based on a Federal Circuit ruling, it is unlikely to be appealed.

Once final, judgment would trigger the 75-day window period leading up to the forfeiture.

Of course, this is still all speculation; however, as the PTAB begins to make IPR decisions, it seems likely that the issue will ripen and need to be addressed.

By Kurt R. Karst –      

On Tuesday, February 26th, Representatives Henry Waxman (D-CA) and Louise Slaughter (D-NY) announced the introduction of H.R. 820, the Delivering Antimicrobial Transparency in Animals Act of 2013 (“DATA Act”).  Introduction of the DATA Act comes just as the U.S. Senate Committee on Health, Education, Labor, & Pensions is scheduled to hold a hearing on reauthorization of two animal drug user fee agreements – the third iteration of the Animal Drug User Fee Amendments (“ADUFA III”) (proposed statutory text and goals letter available here and here) and the second iteration of the Animal Generic Drug User Fee Act (“AGDUFA”) (proposed statutory text and goals letter available here and here) – and several months after Rep. Waxman first announced his intention to introduce the DATA Act and after gathering input on a discussion draft of the bill.  Representative Slaughter, who is a microbiologist, has shown a keen interest in antibiotic use in animal agriculture and has been a critic of FDA’s efforts to address the issue (see our previous post here).  She is the author of the 2011 Preservation of Antibiotics for Medical Treatment Act, which was intended to phase out the non-therapeutic use in livestock of medically important antibiotics, among other things.

The DATA Act would amend FDC Act § 512(l) to require drug manufacturers to obtain and provide to FDA enhanced information on how their antimicrobial drugs are used in the food-producing animals for which they are approved.  The bill is also intended to improve the timing and quality of the data that FDA publicly releases on antimicrobial drug use in food-producing animals.  According to a summary of the bill:

[T]he DATA Act will, for the first time, require large-scale producers of poultry, swine, and livestock to report data on the medicated feeds provided to their animals. The bill would require these producers to submit data to FDA detailing the type and amount of antibiotics and other antimicrobials contained in the feed they use. If the medicated feed is under a Veterinary Feed Directive (VFD), more detailed information must be provided to FDA, including the quantities, dosages, and duration of time the medicated feeds were provided to the animals.

The DATA Act would also require the HHS Secretary to coordinate with the Secretary of Agriculture to improve the collection of data and information on the use antimicrobial drugs in or on food-producing animals, and require the U.S. Government Accountability Office (“GAO”) to evaluate FDA’s antimicrobial data collection process and the Agency’s voluntary approach to reducing or eliminating injudicious use of antimicrobials in animals. 

ADUFA II directs FDA to prepare and publish annual summaries of antimicrobial animal drugs sold or distributed for use in food-producing animals.  The data are derived from information submitted by sponsors of antimicrobial new animal drugs who each year must submit to FDA a report regarding, among other things, their distribution data for antimicrobial animal drugs distributed domestically and exported for use in food-producing animals (see FDA’s annual reports here).  A September 2011 GAO report, titled Agencies Have Made Limited Progress Addressing Antibiotic Use in Animals, suggests that this information is insufficient to support a meaningful analysis of the possible relationship between antimicrobial resistance and the use of medically important antibiotics in food-producing animals.  In July 2012, FDA published an Advance Notice of Proposed Rulemaking requesting comments as to how the Agency might be able to obtain more detailed information about the use of antimicrobial animal drugs when the drugs are used in numerous species, including non-food producing animals (see our previous post here). 

The DATA Act would also require FDA to promptly finalize a guidance document issued in April 2012 in draft form, titled New Animal Drugs and New Animal Drug Combination Products Administered in or on Medicated Feed or Drinking Water of Food-Producing Animals: Recommendations for Drug Sponsors for Voluntarily Aligning Product Use Conditions with GFI #209.  The guidance is intended to provide sponsors with specific recommendations on how to supplement their approved marketing applications to align with FDA’s guidance on the judicious use of medically important antimicrobial drugs in food-producing animals.

In addition to activity on the legislative front, FDA is embroiled in litigation over the withdrawal of approval of certain uses of certain classes of antibiotics in food-producing animals.  As we previously reported, the National Resources Defense Council sued FDA in 2011 and initially sought to compel the Agency, by a court-ordered deadline, to withdraw approval of all subtherapeutic uses of penicillin in animal feed and nearly all subtherapeutic uses of tetracyclines (oxytetracycline and chlortetracycline) in animal feed and to issue final responses to two Citizen Petitions relating to hearing notices FDA issued in 1977 on the Agency’s withdrawal proposals.  FDA has not fared well in the litigation, which is on appeal to the U.S. Court of Appeals for the Second Circuit (Docket Nos. 12-2106 and 12-3607).

By Larry K. Houck –

The Government Accountability Office (“GAO”) has issued a report assessing the approaches states have taken to restrict the sales of pseudoephedrine (“PSE”), an ingredient commonly found in over-the-counter cold and allergy medications and a primary ingredient in clandestinely manufactured methamphetamine.  U.S. Gov’t Accountability Office, GAO-13-204, Drug Control: State Approaches to Control Access to Key Methamphetamine Ingredient Show Varied Impact on Domestic Drug Labs (2013).  The report concludes that electronic tracking systems help enforce sales limits but has not reduced “meth lab” incidents due to smurfing, the practice of recruiting individuals or groups to purchase up to the legal limit at multiple retailers, then aggregating quantities for meth production.  Meth lab incidents include law enforcement seizures of labs, dumpsites, chemicals and glassware.  The report finds that requiring PSE to be available by prescription appears to have helped reduce lab incidents but with unclear impact on consumers and limited impact on the health care system.

Beginning in about 2004, states and jurisdictions began taking efforts to regulate PSE at the point of sale.  Congress enacted the Combat Methamphetamine Epidemic Act of 2005 (“CMEA”), which set daily sales and monthly purchase limits, and requires retailers to keep PSE behind the counter and to maintain a written or electronic logbook of sales.  Nineteen states have implemented electronic reporting to track PSE sales and to determine if purchasers are in compliance with state purchase limits.  Two states, Oregon and Mississippi, and sixty-three Missouri cities and counties, require a prescription for PSE products.

The GAO analyzed data from the Drug Enforcement Administration’s (“DEA’s”) National Seizure System on lab seizure incidents from 2002 through 2011 to identify trends in domestic meth lab incidents.  To determine the impact of electronic tracking systems on meth lab incidents, the GAO analyzed data on the number of meth lab incidents reported in Kentucky, Missouri and Tennessee, where electronic tracking has been in place the longest.  The GAO assessed the impact of the prescription-only requirement in Oregon, Mississippi and their border states by analyzing data on meth lab incidents. 

Interestingly, as the GAO points out, meth lab incidents nationwide dropped to a low of 6,951 incidents in 2007, and has increased since, numbering 15,314 in 2010.  The 2010 incident total is more than twice the number of 2007 incidents.

Of the nineteen states that have implemented electronic reporting systems to track PSE sales, seventeen use the National Precursor Log Exchange (“NPLEx”) system and two states use a system developed in-house or by another vendor.  Under these systems, retailers report PSE sales to a centralized database that can determine whether a customer has or will exceed the federal or state PSE purchase limits.  Most of these systems query the database, notify the retailer if the sale would violate the daily or monthly limit and deny sales when a state or federal limit has been reached.  All sales in states using the NPLEx system are linked so the system blocks customers who try to purchase more than the permissible amount in another NPLEx state.  Electronic tracking systems make PSE sales information more accessible to law enforcement for investigation of potential PSE diversion, locating meth labs and prosecuting individuals.  Law enforcement officers in Indiana and Tennessee have noted that because NPLEx blocks customers from exceeding purchase limits, would-be purchasers associated with meth labs are not as readily identifiable and investigations take longer and are more labor intensive.

The GAO found that meth lab incidents in states that have implemented electronic tracking have not declined due in part to smurfing and the “one pot method” of methamphetamine manufacture.  Meth lab incidents in Oklahoma, Kentucky and Tennessee, the states that have been using electronic tracking the longest, are at their highest levels since implementation of federal and state PSE sales restrictions.  These states experienced initial declines in meth lab incidents from 2004 through 2006, but lab incidents have continued to rise since 2007.  While the systems block attempts by a customer with a single identification to purchase PSE in excess of the legal limits at one or more locations, smurfers have taken to using several different fake IDs to purchase above the legal limit without being detected or blocked. 

The number of reported meth lab incidents in Oregon and Mississippi declined followed by their prescription-only approach.  Reported meth lab incidents in Oregon had declined by 63 % in 2005 from 2004.  The number of reported meth lab incidents continued to decline in subsequent years after placement of PSE behind the counter and implementation of the CMEA and prescription requirements.  After adoption of the prescription requirements in Mississippi in 2010, the number of reported meth lab incidents declined by 66 % in 2011.  The report notes that declines were also observed in states neighboring Oregon and Mississippi because of regional or reporting factors.  State and local law enforcement officials in Oregon and Mississippi credited the reduction of meth lab incidents in those states to the prescription requirement.  Predictably, officials have reported observing related declines in the demand and utilization of law enforcement, child welfare and environmental cleanup services related to meth labs.

GAO notes that according to the Oregon High Intensity Drug Trafficking Area (“HIDTA”), while the number of reported meth labs there has declined, crystal meth remains “highly available” as Mexican traffickers import finished meth from labs outside the state.  The prescription-only approach in Oregon and Mississippi does not preclude residents from traveling to neighboring states to purchase PSE without a prescription.  However, in Arkansas it is now illegal to dispense PSE unless the customer presents a prescription or an Arkansas driver’s license or ID card, and Alabama requires individuals residing in a prescription-only state to provide a valid prescription for PSE.  Law enforcement officials in Oregon and Mississippi have reported no instances from their meth lab investigations in which PSE has been obtained through prescription forgery, illegal or improper prescribing or “doctor shopping” patients who obtain prescriptions from more than one doctor.  The prescription requirement appears to have reduced PSE sales in Mississippi (sales data is unavailable for Oregon), but the impact on customers is unknown.  Customers incur costs for traveling to and visiting a physician.  Customers may be able to obtain a PSE prescription via telephone.  The GAO observes that there has been no substantial healthcare workload increases required to issue PSE prescriptions and there has been no increase of medical appointments for patients seeking PSE products.  In addition, customers have not shifted from PSE to phenylephrine. 

The GAO report provides state lawmakers with a number of issues to consider about implementing electronic reporting systems, requiring a prescription to purchase PSE or weighing some other approach to further restrict sales of PSE used in the clandestine manufacture of methamphetamine.

By Jennifer D. Newberger –

FDA issued a proposed rule to amend its regulations on acceptance of data from medical device clinical studies.  The primary proposed changes include:

• Requiring that clinical studies conducted outside the United States to support any submission to FDA, including a 510(k) or IDE, be conducted in accordance with good clinical practices ("GCPs");
• Adopting a definition of GCPs;
• Amending the IDE and 510(k) regulations to address requirements for FDA acceptance of data from clinical studies conducted within the United States;
• For PMAs, updating standards for accepting data from outside the United States by replacing the requirement to be in compliance with the Declaration of Helsinki with compliance with GCPs;
• Amending Parts 807 and 812 to incorporate GCPs into the requirements for FDA acceptance of data from studies outside the United States to support a 510(k) or IDE; and
• Amending Part 812 to impose different requirements for nonsignificant risk versus significant risk studies conducted outside the United States, mirroring the current IDE regulations.

FDA believes that taking these steps will “help provide greater assurance of the quality and integrity of the data obtained from clinical studies conducted outside the United States and submitted in support of an application or submission to FDA.”  By eliminating the requirement to comply with the Declaration of Helsinki and replacing it with the GCP standard “provides a unifying approach, which may simply [trials outside the United States] and decrease the regulatory burden on sponsors.”  The GCP requirements also will make acceptance of foreign data for device studies more consistent with those for drugs and biologics. 

By Ricardo Carvajal & JP Ellison –

The U.S. Department of Justice ("DOJ") announced the indictment of former officials of the Peanut Corporation of America ("PCA") for their alleged role in the distribution of peanut products that were implicated in a 2008-2009 national outbreak of salmonellosis.  In part, the indictment charges PCA’s former president, vice-president, plant operations manager, and QA manager with conspiracy to defraud PCA’s customers, introduction of adulterated and misbranded food into interstate commerce with intent to defraud or mislead, and obstruction of justice.  Possible sanctions include fines, imprisonment, and forfeiture to the government of any property derived from proceeds that can be traced to the offenses.

The indictment alleges that defendants:

• shipped products prior to receiving test results and failed to inform customers when test results confirmed the presence of Salmonella;
• shipped products that had tested positive for Salmonella;
• retested products after initial tests confirmed the presence of Salmonella, and shipped products on the basis of subsequent negative test results;
• shipped products manufactured at plants not approved by customers;
• substituted imported products for the domestic products specified by customers;
• substituted non-organic products for the organic products specified by customers;
• falsified Certificates of Analysis ("COAs") in numerous ways; and 
• repeatedly lied to FDA inspectors during the course of their investigation.

As noted in DOJ’s press release, “an indictment is merely an allegation.”  Nonetheless, the indictment can be expected to refocus scrutiny on the adequacy of certain approaches to supplier verification and acceptance/rejection of ingredients.  As we noted in a prior posting, FDA did not include provisions that require supplier approval and verification in its proposed rule on preventive controls, which was recently issued under authority granted to FDA by the Food Safety Modernization Act ("FSMA").  However, FDA requested comment on that issue and might include related requirements in the final regulation.  The results of the PCA investigation could well influence FDA’s thinking on the issue, given the relative ease with which PCA is alleged to have defrauded a number of purchasers ranging from specialty manufacturers to multinational companies. 

By Kurt R. Karst –      

In a widely anticipated move, Momenta Pharmaceuticals, Inc. and Sandoz Inc. have petitioned the U.S. Supreme Court to review the August 3, 2012 judgment of the U.S. Court of Appeals for the Federal Circuit, in which a divided (2-1) Federal Circuit panel ruled that the scope of the Hatch-Waxman “safe harbor” provision at 35 U.S.C. § 271(e)(1) is broad and exempts from infringement any commercial activity where FDA requires that a record of that activity be maintained, even if no record is ever submitted to the Agency.  The Supreme Court case, Momenta Pharmaceuticals, Inc. v. Amphastar Pharmaceuticals, Inc., has been assigned Docket No. 12-1033. 

As we previously discussed, the case involves a generic version of LOVENOX (enoxaparin) and U.S. Patent No. 7,575,866 (“the ‘866 patent”) assigned to Momenta that generally relates “to methods for analyzing heterogeneous populations of sulfated polysaccharides” such as enoxaparin.  Momenta sued generic drug sponsor Amphastar in the U.S. District Court for the District of Massachusetts for patent infringement alleging that Amphastar infringed the ‘886 patent by manufacturing for commercial sale enoxaparin using the patented method.  Relying on the Federal Circuit’s decision in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057 (Fed. Cir. 2011), the District Court ruled that Amphastar’s activity fell outside of the “safe harbor” provision at 35 U.S.C. § 271(e)(1).  In Classen, which concerned whether a vaccine license holder was required to report to FDA certain adverse event information, the Federal Circuit held that 35 U.S.C. § 271(e)(1) “does not apply to information that may be routinely reported to the FDA, long after marketing approval has been obtained.” 

On appeal, the Federal Circuit disagreed with the District Court and vacated an injunction in the case.  The Federal Circuit explained that its decision is not inconsistent with Classen “because the information submitted is necessary both to the continued approval of the ANDA and to the ability to market the generic drug,” and that in this case, “the submissions are not ‘routine submissions’ to the FDA, but instead are submissions that are required to maintain FDA approval. . . ,” thereby bringing them within the scope of the 2171(e)(1) safe harbor.   

During the pendency of the Federal Circuit’s consideration of Momenta, the U.S. Supreme Court had been asked to review the Classen decision.  See GlaxoSmithKline v. Classen Immunotherapies, Inc. (Docket No. 11-1078).  Ultimately, the Supreme Court decided not to hear the case, but not before the U.S. Solicitor General filed an amicus brief urging the Court to deny certiorari.  According to the U.S., although the Federal Circuit “erred in stating that section 271(e)(1)’s safe harbor encompasses only activities undertaken to obtain the FDA’s pre-marketing approval of generic products . . . there is no longer any practical need for theis Court’s intervention in light of the Federal Circuit’s subsequent decision in Momenta.”  Moreover, states the U.S., if “postapproval studies involve the use of patented inventions solely for uses reasonably related to the development and submission of information to the FDA, the plain language of Section 271(e)(1) precludes any claim for patent infringement.”  (Thus, if the U.S. Solicitor General is asked to file a brief in the Amphastar/Sandoz appeal, it is not difficult to discern what that brief will say.)

Amphastar and Sandoz present the following question to the U.S. Supreme Court:

Whether the use of a patented invention in the course of post-approval manufacture of a drug for commercial sale, where the FDA requires that a record of that manufacturing activity be maintained, is exempted from liability for patent infringement under Section 271(e)(1) as “solely for uses reasonably related to the development and submission of information under a Federal law which regulates the manufacture, use, or sale of drugs.

According to Petitioners, the Federal Circuit’s Classen and Momenta decisions are irreconcilable and fundamentally wrong:

Both Classen and the ruling below give the wrong scope to the safe harbor provision and together they leave its meaning in an intolerable state of uncertainty.  The Federal Circuit has shown no willingness to correct its interpretation or to provide the needed certainty.  In the absence of guidance from this Court, future panels will have two purportedly binding precedents from which to choose.  District courts are left adrift with two conflicting compasses, each purporting to be definitive.  Companies attempting to chart their own courses have no idea whether they are free to use patented inventions or whether such use will subject them to infringement liability.  The pharmaceutical industry cannot wait for the Federal Circuit to get it right (or wrong) a third or fourth time.

Absent review, the ruling below will undermine pharmaceutical industry investment in life-saving and life-enhancing innovations.  Each drug the pharmaceutical industry brings to market requires enormous investment. That investment is predicated on the protection provided by the patent laws: protection for innovators, during a patent’s term, from unlicensed, commercial competition from their own invention.  The court of appeals’ sweeping interpretation of Section 271(e)(1) calls into question the value of a great many pharmaceutical patents.

Regardless of whether or not the U.S. Supreme Court decides to take up the Momenta case, a final decision could have significant implications on the budding biosimilars industry where method patents play an important role.  Indeed, it is possible that FDA could require, as a condition of approval, that all biosimlar sponsors for a particular product use a particular analytic method that is under patent by a reference product sponsor.  As the law currently stands, the Section 271(e)(1) safe harbor would appear to exempt infringement in such circumstances.

In a new Contemporary Legal Note published by the Washington Legal Foundation (“WLF”), titled “Federal Taint Teams And Attorney-Client Privilege In Corporate Criminal Investigations,” Hyman, Phelps & McNamara P.C. Director Douglas B. Farquhar explores issues surrounding privileged material and so-called “taint teams” when government investigators seize company materials that may be used to build a criminal case.  “Taint teams,” which are described in the U.S. Attorneys’ Manual (Section 9-13.420(E)) as “privilege teams,” are supposed to determine what material is privileged, and to ensure that agents and prosecutors working on an investigation and prosecution do not gain direct or indirect access to secrets (usually attorney-client privileged material).

Mr. Farquhar describes how “taint teams” operate, highlights some areas of concern about attorney-client privileged information, and recounts the skepticism that some courts have expressed about the ability of “taint teams” to provide a fair assessment of whether a privilege applies to certain seized company material.  “In an era with more frequent revelations of serious prosecutor conduct,” writes Mr. Farquhar, “defense counsel and courts are left to wonder what prosecutorial misconduct has not been discovered or disclosed.  Prosecutors tend to work pretty closely together within the Department of Justice, and, although aspersions are not intended to be cast on the vast majority of federal prosecutors, the author and many other defense counsel can recount incidents where prosecutors engaged in ethically questionable conduct to increase the likelihood of a successful prosecution, or to produce pressure to accept an offered plea bargain.”

By Jennifer D. Newberger –

The Food and Drug Administration Amendments Act of 2007 (“FDAAA”) amended the Federal Food, Drug, and Cosmetic Act (“FDC Act”) to require certain medical device submissions to include, “if readily available – (A) a description of any pediatric subpopulations that suffer from the disease or condition that the device is intended to treat, diagnose, or cure; and (B) the number of affected pediatric patients.”  (See our FDAAA summary and analysis here.)

To implement that requirement, on April 1, 2010, FDA published a proposed rule along with a direct final rule.  FDA ultimately withdrew the direct final rule because it received “significant adverse comment[s].”  After considering the comments, on February 19, 2013, FDA issued a supplemental notice of proposed rulemaking to implement the pediatric submission requirements.  It issued a draft guidance document the same day addressing how industry can comply with those requirements.

One aspect of the proposed rule that resulted in negative comments was FDA’s request for information on “potential” pediatric uses.  The comments noted that requiring information on potential uses was inconsistent with the language of the statute, and would require sponsors to speculate as to possible uses and subpopulations.  FDA agreed, and removed references to potential pediatric uses.

The proposed rule now requires sponsors to include “readily available” pediatric information in any HDE, PMA or PMA supplement, or PDP.  FDA does not interpret 30-day notices to be PMA supplements for purposes of the proposed rule.  Furthermore, it notes that an applicant submitting a PMA supplement need not provide previously submitted information, but may reference the previous application that contained that information.  If new addition has become “readily available” since the prior submission, the PMA supplement must include that information.

The proposed rule defines “readily available” as “available in the public domain through commonly used public resources for conducting biomedical, regulatory, and medical product research.”  The draft guidance expands on this by providing examples, including “bibliographic databases of life sciences and biomedical information (such as MEDLINE and PubMed) and online scientific and medical publishers (such as the Public Library of Science (PLoS) and the Cochrane Library).”

The draft guidance also clearly states that because the submitted pediatric use information will be available to the public as part of the annual report required by FDAAA to be submitted to Congress, the submitted information “should exclude proprietary, trade secret, and commercial confidential information about the device.”

The proposed rule and draft guidance also address the following important issues:

• Pediatric patients are defined as “patients who are 21 years of age or younger (that is, from birth through the 21st year of life, up to but not including the 22d birthday) at the time of the diagnosis or treatment.”
• Pediatric subpopulations include neonates, infants, children, and adolescents, and the draft guidance provides the age ranges included within each subpopulation.
• The information provided should come from a data source that has data only on U.S. subjects.  If there is no readily available information on U.S. subjects, or if the estimate of pediatric patients is considered unreliable, the sponsor may rely on information obtained from data on non-U.S. subjects.  In that case, the sponsor should include a discussion about the applicability of the non-U.S. data to the U.S. patient population.
• If no information about pediatric uses or subpopulations is readily available, the sponsor must indicate that it made a “reasonable effort” to provide the information, and must also provide documentation of the search performed, including the search engines used and key words searched.
• The draft guidance includes a table intended to serve as an example of how the information should be presented.  The table includes information on the approved or proposed device indication; pediatric incidence; pediatric prevalence; pediatric subpopulation/age range; specific device/component; and the source used to identify the information.

Perhaps the question of greatest importance to sponsors is what FDA will do with the pediatric device use information.  According to the draft guidance, “FDA would like to use this data to determine unmet pediatric needs in medical device development.  Once unmet needs are identified, FDA will be better able to coordinate efforts of stakeholders, device manufacturers and FDA staff to promote new device development and proper labeling of existing medical devices for pediatric use.”  It is not clear how FDA will use the pediatric information to meet this noble, if vague, intent.

By Carmelina G. Allis –

As reported in FTC Watch Issue No. 823 (Feb. 13, 2013), the Federal Trade Commission has plans to increase enforcement actions against mobile apps – including mobile medical apps.

During a Consumer Protection Conference sponsored by the American Bar Association earlier this month, FTC Commissioner Julie Brill and the former head of the agency’s Bureau of Consumer Protection, David Vladeck, discussed the agency’s renewed focus on advertising and consumer protection, and the need for more aggressive enforcement action against health claims, social media apps, and medical apps.

Commissioner Brill specifically referenced FTC’s action during the fall 2011 ordering a company to stop making claims that its mobile medical app could cure acne.  As we previously blogged, that was FTC’s first case targeting health claims related to a mobile medical app sold in Apple’s iTunes Store and Google’s Android Marketplace under the names “AcneApp” and “Acne Pwner.”  The mobile apps claimed that the colored lights emitted from the mobile devices could treat acne.

The marketers of the acne apps were fined and the FTC barred them from making any further claims on the mobile apps without competent and reliable scientific evidence.  As Commissioner Brill explained during the Conference, the laws that apply to traditional kinds of companies also apply to “cutting-edge social media apps,” because there “’isn’t any mobile ‘exceptionalism’ going on.’”

Despite FTC’s action against the maker of the acne apps, we are not aware of FDA initiating an enforcement action against that company.  As we previously blogged, FDA has proposed to exert regulatory authority over select mobile medical apps that meet the “device” definition in the Federal Food, Drug, and Cosmetic Act, and that are either used as an accessory to a regulated medical device, or transform a mobile platform into a regulated medical device.  The FDA regulatory landscape for these products, although somewhat defined, is still being carved out, and enforcement actions against mobile medical app developers do not appear to be at the top of FDA’s agenda.

The FTC, however, apparently has a different agenda on mobile apps.  So if you market a mobile medical app, bear in mind the FTC initiative.

By Kurt R. Karst – 

A recent report from the National Institutes of Health (“NIH”) Council of Councils Working Group on the Use of Chimpanzees in NIH-Supported Research leaves unanswered questions about the future utility of FDA’s so-called “Animal Efficacy Rule” for NIH-funded research intended to develop medical countermeasures. 

The NIH Working Group report is rooted in recommendations made by the Institute of Medicine (“IOM”) in a December 2011 report, titled “Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity,” in which the IOM concluded that most current biomedical use of chimpanzees is unnecessary.  The IOM also recognized, however, that chimpanzee use could still serve an important role in some research areas, but recommended that such use be governed by a set of principles and criteria.  The NIH, which accepted the IOM report, charged a working group with, among other things, developing a plan of action to implement the guiding principles and criteria identified in the IOM report.  In the interim, NIH implemented a policy of not funding new research projects involving chimpanzees, but currently funded research may continue.  The policy remains in effect until the NIH considers and issues policy implementing the IOM recommendations.

According to the NIH Working Group report, on which the NIH is seeking public comment:

For rare but serious diseases, product-driven studies may need to consider the FDA Animal Rule.  This greatly raises the expectations for the applicability of animal model studies and would raise expectations about the true value of data from chimpanzee experiments.  For example, the combination of animal and strain of pathogen used would likely be selected so that lethality occurred in untreated animals but not in treated animals.  If a decision were made to use chimpanzees, it might be necessary to use staged experiments with smaller numbers of animals per study along with data accumulated from multiple studies.  Whether the FDA Animal Rule would accommodate this is unknown.

FDA’s “Animal Efficacy Rule,” which was finalized in May 2002 (see here), provides that in certain circumstances, and where where human efficacy trials are not feasible or ethical, animal studies can be relied on to provide substantial evidence of effectiveness of a drug or biological product.  Specifically, FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of a drug or biological product when:

1. There is a reasonably well understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product;
2. The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well characterized animal model for predicting the response in humans;
3. The animal study endpoint is clearly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and
4. The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.

Evaluation of the drug or biological product for safety in humans is still required, and cannot be addressed by animal studies alone.  In addition, approval under the Animal Efficacy Rule is subject to certain postapproval commitments.

FDA has been working to address various elements of the Animal Efficacy Rule by issuing guidance on animal models and by developing an Animal Model Qualification Program (see here, here, and here).  Thus far, only a few products have been approved under the Animal Efficacy Rule.  In February 2003, FDA approved NDA No. 020414 for pyridostigmine bromide to increase survival after exposure to Soman "nerve gas" poisoning.  In December 2006, FDA approved NDA No. 022041 for CYANOKIT (hydroxocobalamin for injection) for the treatment of known or suspected cyanide poisoning.  In April 2012, FDA approved NDA supplements for LEVAQUIN (levofloxacin) Injection, Tablets, and Oral Solution for the treatment and prophylaxis of plague due to Yersinia pestis in adults and pediatric patients 6 months of age and older.  And in December 2012, FDA granted a license (BLA No. 125349) for raxibacumab injection to treat inhalational anthrax. 

The NIH Working Group report is not inconsistent with a 2011 consensus report from the National Research Council, titled “Animal Models for Assessing Countermeasures to Bioterrorism Agents.”  That report addresses the challenges stemming from developing and testing medical countermeasures against biothreat agents in animal models.  Among other things, the report recommends the development of a comprehensive strategy to reduce the dependency on nonhuman primates by maximizing the value of data derived from all research. 

By Riëtte van Laack –

On February 13, the Center for Science in the Public Interest (“CSPI”) together with a coalition of 10 public health departments, 20 national health organizations, and 41 health and nutrition experts, submitted a 55-page petition to FDA requesting that FDA review the generally recognized as safe (“GRAS”) status of caloric sweeteners (“added sugars”).  Although the Petition concerns all “added sugars,” that are “formally denominated GRAS,” including sugar, high fructose corn syrup, corn sugars, invert sugars, corn syrup, and others, the emphasis appears to be on high fructose corn syrup and sucrose.

According to Petitioners, unsafe levels of added sugar in soda and other sugar-containing beverages cause, among other health problems, obesity, diabetes, heart disease, the metabolic syndrome, tooth decay, and gout.  They claim that sugar-containing drinks are the single biggest source of added sugars and calories in the American diet.  Consumption data show that Americans, on average, consume 18 to 23 teaspoons of added sugars (the equivalent of 300 to 400 calories) per day.  Teens and young adults consume half again more than this average.  Moreover, about 14 million people of all ages consume more than one-third of their daily calories in the form of added sugars.

The Petition presents evidence to support its position that “added sugars” are no longer GRAS.  In fact, it claims that there is a current scientific consensus that added sugars are unsafe at the levels consumed.  Sugar-containing beverages provide 50% or more of the added sugars in the American diet and typically provide no other nutrients.  Moreover, the Petition asserts that liquid calories (from sugar-containing beverages) do not cause the normal satiety response, and as a result, people who consume liquid calories do not compensate for the increased caloric intake by reducing the calorie intake in subsequent meals. 

Rather than proposing a level at which “added sugars” are GRAS, the Petition leaves that determination to FDA.  However, the Petition does note that various health agencies have suggested 10 grams (or 40 calories) of added sugar per drink as a reasonable amount.

Although CSPI has previously questioned the safety of artificial sweeteners, it now appears to endorse the use of artificial sweeteners.  In a footnote, it explains that it has concluded that “the certain harm caused by the 15 teaspoons of sugar in a 20 oz. drink outweighs the speculative harm from artificial sweeteners.” 

In addition to the request to revisit the GRAS status of added sugars, the Petition suggests that FDA:

• encourage industry to voluntarily reduce added sugars in breakfast cereals, baked goods, and other foods;
• encourage reduced use and consumption of added sugars through limits on sale of sugar-containing over-sized beverages and development of means of reducing the use of added sugars;
• add a separate line for added sugars on Nutrition Facts labels (in 2012, a coalition of public health associations requested that FDA require “added sugars” in the ingredient statement – see our previous post here); and 
• launch education campaigns aimed at curbing consumption of added sugars.

Under 21 C.F.R. § 10.30, FDA has 180 days from receipt of the Petition to respond.  This response, however, is ordinarily a statement that the Agency has received the petition and needs more time to respond.  In light of the Agency’s past record and other priorities (including deadlines under the Food Safety Modernization Act), we do not anticipate a substantive FDA response for well over a year.

By Alexander J. Varond –

In response to FDA’s increasing reliance on Risk Evaluation and Mitigation Strategies (“REMS”) for the management of risks presented by certain drugs, the US Department of Health and Human Service’s Office of Inspector General (“OIG”) conducted an investigation into FDA’s REMS program.  Specifically, it sought to evaluate whether FDA was receiving the information it needed to evaluate the effectiveness of individual REMS programs.  OIG recently released its findings in a report entitled “FDA Lacks Comprehensive Data to Determine Whether Risk Evaluation and Mitigation Strategies Improve Drug Safety.”  The report makes it clear that, in many instances, FDA has not received adequate feedback about REMS programs.  Also, the agency has consistently failed to meet several statutory requirements to timely review sponsor feedback and independently evaluate REMS.

As our readers know, FDA requires REMS for certain drugs to ensure that the benefits from those drugs outweigh their risks.  REMS include medication guides, patient package inserts, communications plans, and, for drugs with the most serious risks, elements to assure safe use (“ETASUs”).  ETASUs may include restricted distribution plans, physician certification, patient registries, and other similar requirements.  REMS are often onerous and require drug sponsors to effectively implement and assess their programs.  Sponsors are required to submit assessments at predetermined times (typically 18 months, 3 years, and 7 years after approval of the REMS).  Under the Food and Drug Administration Amendments Act of 2007 (“FDAAA”), FDA is then required to review these assessments within 60 days. FDA is also required to assess one REMS with ETASUs each year to evaluate “whether the ETASUs (1) assure safe use of the drug; (2) are unduly burdensome on patient access to the drug; and (3) to the extent practicable minimize the burden on the health care delivery system.”

OIG reviewed “49 sponsors’ REMS assessments and FDA’s reviews of these assessments to determine the extent to which sponsors’ assessments were complete, were submitted to FDA within required timeframes, and indicated that REMS were meeting their goals.  [OIG] also determined whether FDA evaluated the ETASUs of one drug in each year of the program, as required by Federal law.”

The study found that nearly half of the 49 sponsor assessments reviewed were incomplete and 10 were not submitted to FDA within the required timeframes.  The study also found that FDA review memorandums indicated that only 7 of the 49 REMS met all of their goals and that 21 did not.  FDA review memorandums indicated that FDA could not determine whether 17 REMS were meeting their goals, and 4 review memorandums did not contain statements regarding whether the remaining 4 REMS were meeting all of their goals.  In addition, FDA’s own review time for sponsor-submitted assessments exceeded the goal of 60 days in all but one instance.  Lastly, despite the FDAAA requirement to review one REMS with ETASUs per year, FDA had only conducted one review since the program’s start in 2008.

The OIG report makes several key observations.  First, without comprehensive data, FDA “cannot ensure that the public is provided maximum protection from a drug’s known or potential risks.”  Second, because only 7 of 49 REMS were found to meet all of their goals and 21 were not, there were “questions about the effectiveness of REMS.”  Third, “FDA has limited data to demonstrate that the remaining [31] REMS with ETASUs [not reviewed by FDA] effectively ensure safe use of drugs or meet statutory requirements to minimize burdens on patients and the health care system.”  Fourth, “FDA has not identified reliable methods for evaluating REMS.”  And fifth, FDA’s inability to meet its 60-day review clock of sponsor-submitted assessments “may limit sponsors’ ability to implement suggested changes to the REMS before submitting the next assessment.”

Thus, the OIG report calls into question “the overall effectiveness of the REMS program.”  OIG concludes its report by offering seven recommendations to FDA:

• Develop and implement a plan to identify, develop, validate, and assess REMS components;
• Identify REMS that are not meeting their goals and take appropriate actions to protect the public health;
• Evaluate the ETASUs of one REMS each year as required by Federal law;
• Identify incomplete sponsor assessments and work with sponsors to obtain missing information;
• Clarify expectations for sponsors’ assessments in FDA assessment plans;
• Seek legislative authority to enforce FDA assessment plans; and
• Ensure that assessment reviews are timely.

FDA responded to OIG’s recommendations and agreed with all but one of the recommendations, choosing to abstain from whether it should seek legislative authority to enforce FDA assessment plans.

As FDA’s reliance on REMS grows, the effectiveness of the program must be carefully measured.  FDA must therefore fully collect and review data to judge whether its REMS program overburdens the health care system and modify REMS requirements accordingly.  The OIG report emphasizes that FDA’s REMS program should be practical, effective, and tailored.

By Jeffrey K. Shapiro –

We are seeing the first fruits of a new device reclassification procedure added last summer to the Federal Food, Drug, and Cosmetic Act (“FDCA”).  The new procedure modifies Section 513(e) of the FDCA to make it easier for FDA to reclassify devices (see Food and Drug Administration Safety and Innovation Act (“FDASIA”), Pub. L. No. 112-144, § 608(a); HP&M FDASIA Summary and Analysis at page 37).

As before, based on new information about a device, FDA may on its own initiative or after petition by an interested person reclassify the device and revoke any related regulation or requirement in effect under a PMA approval order. 

The difference is that previously FDA was required to issue a reclassification regulation, while now FDA can accomplish the same thing by administrative order.  The order is to be issued “following publication of a proposed reclassification order in the Federal Register, a meeting of a device classification panel … and consideration of comments to a public docket.”  FDASIA, § 608(a).

Why is issuing a proposed order for notice and comment less burdensome to FDA than issuing a proposed rule for notice and comment?  It may be simply that an agency order does not have to undergo the same level of internal Executive branch scrutiny prior to issuance as does an agency regulation.  Notably, the latest proposed orders lack the “analysis of impacts” section that can be found in FDA’s proposed rules.

In any event, the agency has issued four proposed orders to reclassify the following preamendment devices:

• Temporary mandibular condyle prosthesis, 78 Fed. Reg. 9010 (Feb. 7, 2013);
• Blade form endosseous dental implant, 78 Fed. Reg. 2647 (Jan. 14, 2013);
• External cardiac compressor, 78 Fed. Reg. 1163 (Jan. 8, 2013); and
• Membrane lung devices for pulmonary support, 78 Fed. Reg. 1158 (Jan. 8, 2013).

The fifth proposed order is a call for PMAs for metal on metal hip prostheses (cemented and uncemented).  78 Fed. Reg, 4094 (Jan. 18, 2013). 

These six device types are among the 25 preamendment Class III device types not yet subject to a final regulation reclassifying them to Class I or II or calling for PMA submissions.  FDA has been repeatedly urged to complete this process, which began about 37 years ago, in 1976. 

All 25 device types were subject to FDA’s April 9, 2009 order requiring manufacturers to provide information on safety and effectiveness (see our previous post here).  The information submitted in response to this order is the “new information” that FDA is relying upon to invoke Section 513(e). 

Interestingly, in all the proposed orders, FDA relied on panel meetings that have already taken place, even though the statute seems to contemplate a panel meeting after the proposed order is issued.

Hopefully, the streamlined Section 513(e) will allow FDA to promptly finish the classification process for preamendment devices.  Once that is done, FDA should use the amended Section 513(e) to more swiftly reclassify devices.  The greater use of reclassification will make FDA’s regulatory process more nimble and able to calibrate regulatory burden more appropriately on the basis of risk, which is what the statutory scheme requires.

By Jessica A. Ritsick –

This week, the Institute of Medicine (“IOM”) released its report, commissioned by the FDA, “Countering the Problem of Falsified and Substandard Drugs.”  The objective was to gain an understanding of the “global public health implications of falsified, substandard, and counterfeit pharmaceuticals.”  The lengthy report detailed twelve recommendations for international regulatory authorities as steps to combat the proliferation of falsified and substandard drugs throughout the world.  These recommendations, in brief, are:

• Adoption of universal definitions for “substandard,” “falsified ,” and “unregistered” drugs;
• Governmental establishment and strengthening of systems to identify substandard, falsified, and unregistered drugs;
• Creation of “investment vehicles” for manufacturers interested in “upgrading” their systems to international standards;
• Development of plans for procurement agencies to comply with the World Health Organization (“WHO”) Model Quality Assurance System;
• Use of a uniform document format for product registration by regulatory authorities in low- and middle-income countries, and creation of joint inspections, for harmonized procedures and reduced manufacturing costs; 
• Support by the governments in low- and middle-income countries for stronger international manufacturing and quality control standards; 
• Funding for public education campaigns on the dangers of falsified and substandard medicines; 
• Stronger licensing standards for wholesalers and distributors, including establishment of a public licensure database to be maintained by FDA; 
• Congressional authorization and funding of a “mandatory track and trace” system to be implemented by FDA; 
• Fostering, in low- and middle-income countries, environments incentivizing the private sector to supply underserved areas with quality medicines; 
• Funding of a national repository of technology used to detect substandard and falsified medicines; and
• Creation of a “code of practice” for the international problem of substandard medicines.

Substandard, falsified, and unregistered drugs are, as the IOM report acknowledges, a global problem, and there is no single solution to immediately fix the global issues involved, such as poor quality ingredients, lack of regulation, and drug diversion.  The IOM report’s suggestions for less-developed countries, if put into practice, would likely only provide a partial solution to the problem.  At a later date, we may post on the global recommendations provided by the IOM.  For now, we focus on the most noteworthy domestic-related issues raised by the report.

IOM recommended excluding the use of the term “counterfeit.”  There is disagreement in the international regulatory community as to whether “counterfeit” refers broadly to something that is “not what it claims to be,” or whether the narrower, legal definition, which focuses on trademark infringement, is applicable.  The IOM report forgoes the use of the term “counterfeit,” and instead encourages the use of the terms “substandard,” “falsified,” and “unregistered.”  “Substandard” drugs are “those that do not meet the specifications given in the accepted pharmacopeia or in the manufacturer’s dossier.”  However, what is considered “substandard” varies from country-to-country, despite the fact that many countries use standards provided by international pharmacopeias.  “Falsified” drugs are “those drugs that carry a false representation of identity or source or both,” and the report is clear to note that falsified drugs are often also substandard drugs.  Falsified drugs can range from a legitimate product in fake packaging, or a fake product in legitimate packaging.  Lastly, “unregistered” drugs are “those not granted market authorization in a country.”  Unregistered drugs, unsurprisingly, are often substandard and are distributed outside the normal, regulated distribution channels.  These definitions, if adopted domestically and internationally, will help regulatory agencies and industry alike characterize the specific problem when “bad drug” issues arise, and provide more clarity to this global problem.

The IOM also recommends creation of a centralized public database of suspended and revoked wholesale pharmaceutical licenses.  The report recommends that FDA create this national database in collaboration with existing state licensing boards.  While a “one stop shop” for this information could prove beneficial to industry, it is unclear how IOM expects FDA to implement such a large program, especially within IOM’s recommended two-year timeframe.  While Congress could allocate funds for the creation of such a registry, FDA would also require the necessary statutory authority.  While the Prescription Drug Marketing Act (“PDMA”) provides for creation of a state system of wholesale and manufacturer licensure, and tasked FDA with creating licensure guidelines, there is no federal licensure system.  See 21 C.F.R. Part 205.  Further, FDA would have to rely on the states to provide timely data.  Many states already have online resources to perform simple searches to determine whether a company is licensed, and if so, whether there are any violations or issues with that license.  A national database would be beneficial, but there currently does not appear to be a mechanism for FDA to manage this effort.  For example, there is federal funding for state-level prescription drug monitoring programs, but there is no national or FDA-regulated federal program.  Creation of a national wholesaler licensure database, whether or not in collaboration with state licensure boards, does not appear to be a task that FDA has either the resources or current authority to implement.

The IOM report also urges Congress to fund FDA and provide it with authority to create a mandatory track and trace system.  As our readers know, Congress has been kicking around this idea for some time (see here).  So far, however, there has been no real movement on the issue.  FDA has had its eye on a track and trace system for almost 10 years (see here and here).  Industry, too, would likely be receptive to a national “pedigree” system.  However, any sort of track and trace legislation proposed by Congress would likely be met with harsh resistance from industry absent a federal preemption provision.  IOM noted this concern, and the potential problems of a piecemeal approach.  We can only imagine the regulatory quagmire and backlash from industry trying to comply with a federal pedigree, along with myriad state pedigrees.  However, IOM recommends that FDA bring together “all industry stakeholders” to work together on the issue. 

For its part, FDA has already issued a public statement on the IOM report, and stated that it is “transforming from a predominantly domestically focused agency to one that is fully prepared to help ensure product safety and quality within a globalized world.”  How FDA will be able to meet these growing and changing needs, in addition to its many other functions, remains to be seen.  Stronger regulation and quality oversight in other countries can only benefit the quality of products coming into the U.S., and progress towards a global solution to an increasingly global problem would be encouraging. 

By Kurt R. Karst & Frank J. Sasinowski –

The Orphan Drug Act (“ODA”), which President Ronald Reagan signed into law on January 4, 1983, turned 30 years old in January.  The milestone came just days after the death of actor Jack Klugman, who has been credited as being an important driving force behind the passage of the law.  Klugman, the star of “Quincy, M.E.,” testified before Congress on the ODA, and two episodes of the show focused on the issue of rare diseases: “Seldom Silent, Never Heard” (1981) and “Give Me Your Weak” (1982). 

FDA celebrated the ODA’s 30th anniversary with a series of articles and interviews (see here and here).  And the National Organization for Rare Disorders (“NORD”) put out a great spread, including ODA milestones and 2013 events at which the anniversary will be celebrated, including at Rare Disease Day 2013 (February 28, 2013).  Representative Henry Waxman (D-CA), who was instrumental in the passage of the ODA, also commemorated the anniversary and Klugman’s passing (see here).  

We at Hyman, Phelps & McNamara, P.C. are celebrating the ODA’s 30th anniversary as well . . . . and here on the FDA Law Blog in our own special way.  For several years now we have taken stock of the year that was in orphan drug designations and approvals.  For example, in 2011, we noted that 2010 saw a record number of orphan drug designation applications.  Also in 2011, we saw the publication of a landmark report authored by former Chairman of the NORD Board of Directors and HP&M Director, Frank J. Sasinowski, on the flexibility in FDA’s review of potential treatments for patients with rare diseases (see our previous post here), as well as FDA’s publication of a proposed rule intended to clarify regulatory provisions and make minor improvements to address issues that have arisen since the Agency promulgated its orphan drug regulations in December 1992 (see our previous post here).  In 2012, we celebrated a record number of orphan drug approvals and orphan drug designations in 2011.   In 2013, we don’t have any new records to report on reached in 2012; however, there are some near records, showing that interest in orphan drug remains quite high.  And we’ve looked at some new orphan drug metrics based on information available from FDA’s searchable database for Orphan Designated and or Approved Products that we think readers will find interesting.

In 2012, FDA surpassed the 400 orphan drug approval mark, ending up with 25 orphan drug approvals – just one shy of the record 26 orphan drug approvals set in 2011.  Both orphan drug designations and orphan drug designation requests were down in 2012, with 188 orphan drug designations and 264 orphan drug designation requests.  Records for those metrics were set in 2011 and 2010, respectively, as shown in the table below.  Overall, FDA has granted designation to nealy 70% of the requests submitted to the Agency since 1983. 

The new metrics we decided to look at this year, as reflected in the last two columns of the table below, required some significant number crunching based on data from FDA’s database.  The first metric is the number of drugs designated in a particular year that ended up with an approval.  Thus, for example, in 1984, FDA designated 41 products as orphan drugs, and 24 of those designations ended up with an orphan drug approval.  The second metric is perhaps of greater interest.  It shows the number of days – expressed as an average, median, and range – between orphan drug designation and approval for products designated in that particular year.  Overall, it takes an average of about 4 years and a median of about 3 years from designation to approval.  Excluding the zeros in the table below, the quicked designation-to-approval was 2 days (for epirubicin as a component of adjuvant therapy in patients with evidence of axillary node tumor involvement following resection of primary breast cancer), and the longest designation-to-approval was 9,529 days (for factor XIII concentrate (human) for the routine prophylactic treatment of congenital factor XIII deficiency). It should be noted that the figures in the last column include a small percentage – about 2.9% – of products that were approved before designation was granted.  Those anomalies occurred in 1984, 1985, 1987, 1991, 2008, 2010, and 2011, and, in most cases, before the ODA was amended to require that a company request designation before submission of a marketing application for the orphan drug.  Instead of counting those days in the negative, we counted them towards the overall figures. 

Outside of the 2012 statistics, it is also worth noting that 2012 saw significant litigation involving the ODA, as well as the first ever rescission of orphan drug exclusivity – for  Octapharma USA, Inc.’s WILATE (von Willebrand Factor/Coagulation Factor VIII Complex (Human)) for von Willebrand disease (see our previous post here).  The first piece of litigation was brought against FDA by K-V Pharmaceutical Company to “restore” orphan drug exclusivity for the pre-term birth drug MAKENA (hydroxyprogesterone caproate) Injection.  As we previously reported, the case was dismissed in the DC District Court, but is on appeal to the DC Circuit (Case No. 12-5349).  The second piece of litigation was brought against FDA by Depomed, Inc., which, as we previously reported, filed a Complaint in the DC District Court challenging FDA’s denial of orphan drug exclusivity for GRALISE (gabapentin) Tablets.   In January, Depomed filed a Motion for Summary Judgment.  Last week, FDA filed a Motion to Dismiss/Motion for Summary Judgment in the case.