By Kurt R. Karst –      

Ever since FDA came up with the idea of a so-called “180-day exclusivity punt,” the Agency has taken a shine to using it with impunity, as a quick perusal of our 180-Day Exclusivity Tracker shows.  FDA’s recent approval of ANDAs for generic versions of Pfizer, Inc.’s GEODON (ziprasidone HCl) Capsules approved under NDA No. 020825 is one good case on point. 

Under FDC Act § 505(j)(5)(D)(i)(IV), one of the six 180-day exclusivity provisions added to the FDC Act by Title XI of the Medicare Modernization Act, 180-day exclusivity eligibility is forfeited if:

The first applicant fails to obtain tentative approval of the application within 30 months after the date on which the application is filed, unless the failure is caused by a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed.

The 2007 FDA Amendments Act clarified FDC Act § 505(j)(5)(D)(i)(IV), such that if “approval of the [ANDA] was delayed because of a [citizen] petition, the 30-month period under such subsection is deemed to be extended by a period of time equal to the period beginning on the date on which the Secretary received the petition and ending on the date of final agency action on the petition (inclusive of such beginning and ending dates) . . . .” (FDC Act § 505(q)(1)(G)).  FDA has applied and discussed this provision on many occasions, including in recent Citizen Petition responses – see, e.g., Docket No.  FDA-2011-P-0486 and Docket No. FDA-2010-P-0632.

FDA’s “punt” when a first applicant is eligible for 180-day exclusivity but does not obtain a timely tentative approval goes something like this:

[Generic Applicant] was one of the first applicants to submit a substantially complete ANDA with paragraph IV certifications to the [‘XXX] patents.  As a first applicant, therefore, [Generic Applicant] may be eligible for 180 days of generic drug exclusivity for [Drug].  This exclusivity, which is provided for under section 505(j)(5)(B)(iv) of the Act, would begin to run from the date of the commercial marketing by any first applicant. The agency notes that [Generic Applicant] failed to obtain tentative approval of this ANDA within 30 months after the date on which the ANDA was filed.  See section 505(j)(5)(D)(i)(IV) (forfeiture of exclusivity for failure to obtain tentative approval).  The agency is not, however, making a formal determination at this time of [Generic Applicant’s] eligibility for 180-day generic drug exclusivity.

FDA’s punt language has gone through some refinements and changes throughout the years since the Agency first introduced the concept when approving ANDA No. 076969 for Metoprolol Succinate Extended-Release Tablets on July 31, 2006 (see our previous post here).  FDA has also applied the punt concept to the failure-to-market forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) in at least one case (see our previous post here).  FDA has never, to our knowledge, issued a written decision that that there was a “punt return” – i.e., a formal decision after a punt decision that although a first applicant failed to obtain timely tentative approval, FDA has determined that there was “a change in or a review of the requirements for approval of the application imposed after the date on which the application is filed” and that 180-day exclusivity is saved.

In the case of generic GEODON, FDA punted on 180-day exclusivity for several ANDAs – seemingly unnecessarily.  According to FDA’s Paragraph IV Certification List, the first ANDAs for Ziprasidone HCl Capsules, 20 mg (base), 40 mg (base), 60 mg (base), and 80 mg (base), were submitted to FDA on February 7, 2005.  Only one ANDA was tentatively approved within 30 months of ANDA submission (i.e., on or about August 7, 2007): ANDA No. 077560 (approved on March 2, 2012) was tentatively approved on May 16, 2007).  Three other ANDAs (two of which have also received final approval) were not tentatively approved within 30 months of ANDA submission: ANDA No. 077561 (approved on March 2, 2012), ANDA No. 077565 (tentatively approved on December 29, 2008 and approved on March 2, 2012), and ANDA No. 077562 (tentatively approved on September 17, 2008).  

Thus, for generic GEODON, FDA was faced with a situation similar to that the Agency faced with generic STARLIX (nateglinide) Tablets in 2009.  There, FDA addressed for the first time the following question: “What is the effect of a forfeiture of 180-day exclusivity eligibility due to the failure of a first applicant to obtain tentative ANDA approval pursuant to FDC Act § 505(j)(5)(D)(i)(IV) when at least one other first applicant remains eligible for 180-day exclusivity?”  FDA ruled in a Letter Decision that a forfeited first applicant that “lawfully maintains” a Paragraph IV Certification to an Orange Book-listed patent is nevertheless a first applicant whose ANDA can be approved, who can trigger 180-day exclusivity for an eligible first applicant, and who can therefore enjoy the benefits of such exclusivity (see our previous post here).  FDA’s approval decision for a forfeited first applicant of generic STARLIX clearly states that 180-day exclusivity was forfeited because of a failure to obtain timely tentative approval. 

Fast forward 2.5 years later to generic GEODON and FDA, instead of ruling that a first applicant forfeited 180-day exclusivity eligibility because of a failure to obtain timely tentative approval, takes a more conservative approach and says that the Agency is punting on exclusivity for those ANDAs not tentatively approved within 30 months of application submission.  Perhaps there are particular facts surrounding generic GEODON that swayed FDA one way over the other.  Or perhaps (and we think more likely) FDA, as a general policy, has chosen to make as few final decisions on 180-day exclusivity as possible to avoid or otherwise stave off possible litigation.  Indeed, such avoidance pops up elsewhere.  Just last week, FDA issued a non-response denial to two citizen petitions concerning labeling carve-out issues for generic versions of SEROQUEL (quetiapine fumarate) and SEROQUEL XR (quetiapine fumarate).  The petitions, which FDA determined to be subject to the 180-day response timeframe under FDC Act § 505(q), were submitted a little more than six months before generic SEROQUEL might be approved.  Had FDA outright denied the petitions with a substantive response, that could open the door to a lawsuit and potentially delay or prevent the generic genie from coming out of its bottle.  Delaying a final, substantive response until ANDAs might be approved makes it more difficult to put the genie back in its bottle.

By Riëtte van Laack –

The United States District Court for the Southern District of Florida recently denied a motion by the Federal Trade Commission (“FTC”) to hold Garden of Life and its founder, Jordan S. Rubin (collectively “GOL”) in contempt for allegedly violating a court-issued consent decree.  GOL entered into a consent decree with the FTC in 2006 over claims linking supplements to cancer treatments.  Under the consent decree, GOL agreed not to make any health statements about its products without the support of “competent and reliable scientific evidence.” 

In August 2011, the FTC initiated a contempt proceeding claiming that GOL had violated the consent decree because GOL did not have competent and reliable evidence for its OceansKids and Vitamin Code RAW calcium supplements and the Grow Bone System.  In its defense, GOL claimed it had adequate substantiation for the claims according to an independent expert opinion that GOL’s products offered the claimed benefits.  FTC’s expert disagreed with GOL’s expert and claimed that the evidence was flawed and did not constitute competent and reliable evidence.  The Court held that competent and reliable evidence does not mean “uncontroverted proof” and denied the FTC’s motion.

Whether this decision means that FTC may need to reconsider what constitutes “competent and reliable” scientific evidence remains to be seen.  An important difference between contempt proceedings and FTC enforcement actions is that in the context of civil contempt of court, the evidentiary standard is “clear and convincing evidence” – a higher standard that is more favorable for the defendant than the “preponderance of the evidence” standard that applies in other FTC enforcement actions.  Moreover, in the context of contempt, all ambiguities are resolved in favor of the defendant.

Nevertheless, the Court’s ruling suggests that a company which hires an independent expert to testify that the expert earlier determined that there was competent and reliable scientific evidence to support certain claims may have a chance to beat the FTC.  Moreover, the ruling suggests that claims may be substantiated based on published research; companies do not need to perform their own clinical studies. 

The Court also rejected other arguments by the FTC regarding other product claims.  For instance, the Court refused to find GOL in contempt for allegedly violating a provision in the consent decree by making comparisons between its products and a competitor’s products.  The Court concluded that interpreting the consent decree in that fashion would be unlawful because it would make that provision of the consent decree into an “obey the law” provision, which courts cannot do.

Although the ruling does not say so specifically, this decision resembles the Lane Labs decision, i.e., it may have been a result of less than clear language in the consent decree (see our previous post here).  Since the Lane Labs decision in 2009, the FTC has included more specific substantiation provisions in some of its order reducing the likelihood of similar decisions. 

By Alex J. Varond - 

On March 5, 2012, the Department of Veterans Affairs ("VA") issued a final regulation on promotion of drug and drug-related products (i.e., supplies related to the use of a drug, such as insulin needles and inhalers) by pharmaceutical company representatives at VA medical facilities.  This rule was issued “to reduce or eliminate any potential for disruption in the patient care environment, manage activities and promotions at VA facilities, and provide pharmaceutical company representatives with a consistent standard of permissible business practice at VA facilities.”  We discussed the proposed rule from May 2010 here.  Issued nearly two years later, the Final Rule serves as an important guide for marketing drugs and drug-related products at all VA facilities.  The VA health system serves more than 5.3 million people at more than 1,300 sites of care, and operates the largest medical education and health profession training program in the United States.

The final rule, which becomes effective on April 4, 2012, includes limitations on the promotion of drugs and drug-related supplies, educational programs and associated materials, providing gifts, food, samples or other promotional items to VA employees or facilities, and the conduct of pharmaceutical company representatives.  It also details penalties and procedures in the case of non-compliance.

Promotion of drugs and drug-related supplies

VA National Formulary ("VANF") drug and drug-related products and non-VANF drug and drug-related products with criteria-for-use may be promoted only if: (1) the drug is discussed, displayed, and represented accurately; (2) the promotion has significant educational value; and (3) the drug is not classified as non-promotable.  Promotion of non-VANF drugs and drug-related supplies without criteria-for-use, and of new molecular entities, must meet the same criteria but additionally must be specifically permitted by the pharmacy management at the Veterans Integrated Services Network ("VISN") level.

Educational programs and associated materials

VA has defined an educational program as a pre-scheduled event or meeting with a pharmaceutical company representative in which information is provided about a drug or drug-related product.  Unless VA agrees otherwise, all educational programs and related materials require 60-day prior approval from the facility’s Chief of Pharmacy Services or another person with delegated authority.  Any material relating to a risk evaluation and mitigation strategy ("REMS") or other duty imposed by the FDA will be deemed suitable.  All other materials will be approved only if: (1) industry sponsorship is adequately disclosed; (2) industry-sponsored data is adequately compared with non industry-sponsored data; (3) the program does not solicit protected health information or patient participation in pharmaceutical company-sponsored programs; (4) patient education materials do not contain the name or logo of the drug manufacturer (with certain exceptions) and are not used for promotion of a specific medication; and (5) if the education program relates to non-VANF drugs and drug-related supplies without criteria-for-use, the drug must meet the requirements for promotion (see above).

Providing gifts, drugs or other promotional items to VA employees or facilities

Any gift to any VA employee is barred if it exceeds the value permissible under government ethics rules.  However, items such as continuing education materials, promotional materials, textbooks, and gratuities may be donated to a medical center library or individual department for use by all employees.  Gifts supporting official travel by VA staff can be accepted if cleared through prior legal review. 

Sales representatives may not provide food items of any type or value to VA staff (including volunteers and without compensation employees) or bring food items into VA medical facilities for use by non-VA staff (e.g., employees of affiliates).  The preamble notes that these limitations on food and gifts to VA employees are consistent with Standards of Ethical Conduct applicable to Executive Branch Employees.

The rule also states that all drug and drug-related product samples must be submitted for approval to the person at the medical facility with the responsibility to review samples, usually the Director.  All usage information pertaining to the samples must be sent to the VISN Pharmacist Executive or Formulary Committee, and the samples themselves must be delivered to the Office of the Chief of Pharmacy Services.  Samples may not be provided to VA staff for personal use.

Conduct of pharmaceutical company representatives

The rule considerably limits the extent of sales representative contacts with doctors and patients.  Pharmaceutical company representatives may initiate on-site, in-person contacts by appointment only, and may not attempt to contact individuals or departments designated by the facility on a no-contact list.  Representatives may not page VA employees via a public address (paging) system unless specifically requested by the VA employee, may not market to students, may not attend conferences where information regarding individual patients is discussed, may generally not wait in patient-care areas, and may not leave materials in patient-care areas.

Penalties for non-compliance

Visiting privileges of a pharmaceutical company representative or multiple representatives may be limited, suspended, or revoked for failure to comply with the rule.  VA will provide notice of interim action, a chance to respond, and a final written order according to a set timeline.  The actions may be applied to visiting privileges for one or more VA medical facilities.  The rule also provides an appeals process whereby the pharmaceutical company may request a review by the Under Secretary.

VA has expressed that it intends to maintain the amicable nature of interactions with pharmaceutical companies, and “does not intend to impose sanctions except as necessary to prevent future impropriety.”

By Jeffrey K. Shapiro –

We previously discussed the government’s brief in the Par case in the context of what it says about FDA’s draft Research Use Only guidance.  However, the government’s brief in Par is worth examining from another angle.  (Note:  the Par case involves promotion of a drug, but the discussion below applies equally to medical device promotion.)

Background.  Par sued for declaratory relief, seeking a ruling that FDA’s regulations prevent truthful and non misleading speech about the approved use of the drug Megace ES. (see our previous post here).  The drug Megace ES is approved to treat wasting in AIDS patients.  Par alleges that it wishes to speak about this approved use to physicians in long term care and oncology settings, but fears prosecution under FDA’s regulations.  The drug has not been approved to treat wasting in these settings.  Par alleges that the chilling of its truthful and non-misleading speech caused by FDA’s regulatory activities violates the First Amendment.

On Label Promotion in An Off-Label Setting.  The government contends that Par’s complaint does not present a ripe case or controversy because FDA’s longstanding application of its regulations would not prohibit the proposed conduct.  The government emphatically argues that FDA’s regulations do not prohibit the dissemination of on label information about a drug in an off label setting.  In particular, according to the government, the proposed speech would not establish an unapproved new intended use.  (Gov’t brief, pages 15-19.)

The government ridicules Par’s fear of prosecution as self inflicted and unnecessary, and even based upon a “fabricated” reading of FDA’s regulations.  Of course, in reality, there has been widespread uncertainty whether FDA might find that dissemination of on label information about a drug’s use in an off label setting creates an unapproved new intended use.  This clarification from the government – if it truly represents FDA policy – is very welcome.

Of course, the clarification comes with a major caveat.  The government indicates in its brief that there would never be a prosecution exclusively based upon on label speech about a drug in an off label setting, but that such speech could be cited as one element of an overall scheme and practice to promote an off label use.

By John A. Gilbert & Larry K. Houck –

On February 29, 2012, the Drug Enforcement Administration (“DEA”), exercising its emergency scheduling authority under 21 U.S.C. § 811(h)(2), extended the temporary scheduling of five synthetic cannabinoids: JWH-018, JWH-073, JWH-200, CP-47,497 and cannabicyclohexanol until August 29, 2012.  77 Fed. Reg. 12,201 (Feb. 29, 2012).  The temporary scheduling was extended while permanent scheduling is pending.  DEA published a Notice of Proposed Rulemaking the next day to permanently place the five chemicals in Schedule I of the Controlled Substances Act (“CSA”).  77 Fed. Reg. 12,508 (Mar. 1, 2012).

DEA stated that numerous products, marketed as “herbal incense” under names like “Spice” and “K2” as legal alternatives to marijuana, have been found to contain the chemicals.  77 Fed. Reg. 12,510.  DEA also noted that “these products are manufactured by spiking plant material with the synthetic cannabinoids and then distributed in a way that poses dangerous consequences to the consumer.”  Id.  DEA stated that the products are being abused for their psychoactive properties.

DEA Administrator Michele M. Leonhart stated in a related press release that “[o]ur efforts have clearly shown that these chemicals present an imminent threat to public safety.  This six month extension is critical and give us the time necessary to conduct the administrative scheduling process necessary to conduct the administrative process for permanent control.”

DEA published a Notice of Intent on November 24, 2010 to temporarily place the five cannabinoids in Schedule I (see our previous post here).  On March 1, 2011, DEA temporarily placed the cannabinoids in Schedule I (see our previous post here).  The temporary scheduling was set to expire February 29, 2012 when DEA extended temporary scheduling until August 29, 2012.

DEA explained in the March 1, 2011 Final Order that a cannabinoid “is a class of chemical compounds in the marijuana plant that are structurally related”, “[t]he cannabinoid Δ9-tretrahydrocannabinol (THC) is the primary psychoactive constituent of marijuana” and “[s]ynthetic cannabinoids are a large family of unrelated structures functionally (biologically) similar to THC, the active principal ingredient of marijuana.”  76 Fed. Reg. 11,075 (Mar. 1, 2011).

Health and Human Services (“HHS”) and DEA considered factors relating to the five cannabinoids that DEA in turn considered in its scheduling decision.  DEA found, based on its own eight-factor analysis, on consideration of the scientific and medical evaluations and recommendations of HHS, “that these facts and all relevant data constitute substantial evidence of potential for abuse” and proposes to place them in Schedule I.  77 Fed. Reg. 12,512.

Drugs and chemicals meet Schedule I criteria if they have a high potential for abuse, no currently accepted medical use in treatment in the United States and lack accepted safety for use under medical supervision.  21 U.S.C. § 812(b)(1).  Handlers of the five cannabinoids are subject to Schedule I regulatory controls that include DEA registration, security, labeling and packaging, quota, inventory, recordkeeping, reporting, and use of DEA-222 order forms.  Administrative, civil and criminal sanctions apply to the  manufacture, distribution, dispensing, importing and exporting of the five chemicals.

DEA noted that 48 states, numerous local jurisdictions and countries control at least one of the five cannabinoids.

Interested persons may submit electronic comments regarding scheduling on or before April 30, 2012; written comments must be postmarked on or before that date.  DEA must receive requests for hearing and waivers of participation on or before April 2, 2012.

By Ricardo Carvajal –

In a letter that includes fun facts about the function of the epiglottis, FDA has warned Breathable Foods, Inc. that its AeroShot product is misbranded.  The product’s labeling is alleged to be false and misleading because it contains contradictory statements regarding whether the product is intended for inhalation or ingestion.  The labeling also declares the product to be a dietary supplement, which – by definition – must be ingested.  The product is alleged to be further misbranded because the labeling fails to bear contact information that would enable third parties to notify the company of a serious adverse event.  In an accompanying press release,  FDA “encourages healthcare providers to report to FDA any adverse events in their patients that are associated with AeroShot,” but notes that no such reports have been received to date.

With respect to safety, the letter raises concerns with respect to the potential inhalation of caffeine, and questions whether the product is intended for use by adolescents.  In a prior posting, we noted the possibility that FDA might show interest in the manufacturer’s marketing practices, and in the product’s potential effects on consumer behavior.  Sure enough, the letter notes that the product’s website includes news videos and articles that reference the use of the product with alcohol.  The letter contends that such “publicity may have the effect of encouraging the combination of your product with alcohol – a scenario that raises safety concerns, as peer-reviewed studies show that ingesting these two substances together is associated with risky behaviors, such as riding with a driver who is under the influence of alcohol, which can lead to hazardous and life-threatening situations.”

By Kurt R. Karst –      

Last week, as Congress, FDA, and industry continue to ramp up debate on what changes or modifications should be made to the FDC Act and PHS Act as part of a user fee package of bills expected to be enacted later this year, three reports were issued discussing the various benefits of three long-standing areas of interest – pediatrics (under the Pediatric Research Equity Act (“PREA”) (FDC Act § 505B) and the Best Pharmaceuticals for Children Act (“BPCA”) (FDC Act § 505A)), orphan drugs (under the Orphan Drug Act), and generic drugs (as a result of the Hatch-Waxman Amendments).

After holding a series of meetings going back to December 2010, the Institute of Medicine (“IOM”) issued a 300-page report, titled “Safe and Effective Medicines for Children: Pediatric Studies Conducted Under BPCA and PREA.”  The report, which was called for by Congress, documents improvements in the availability of evidence about the safety and efficacy of drugs in children following the enactment and FDA’s implementation of the BPCA and PREA (and their predecessor policies).  The report also considers the incentives for pediatric studies of biologics under the Biologics Price Competition and Innovation Act of 2009.  The IOM reports follows a May 2011 U.S. Government Accountability Office report on the effects of the BPCA and PREA on the study and labeling of drug and biological products for pediatric use (see our previous post here), and a February 2012 House Energy and Commerce Committee hearing at which the reauthorization of both laws was a major topic of discussion. 

After reviewing and assessing a representative sample of labeling changes and other FDA actions related to BPCA-requested or PREA-required pediatric studies (for the period from July 1, 1998, through December 31, 2010) and considering other data and information, a committee appointed by the IOM reached several broad conclusions detailed in the report:

• Pediatric studies conducted under BPCA and PREA are yielding important information to guide clinical care for children.  Information from pediatric studies sometimes supports and sometimes runs counter to expectations about the efficacy, safety, and pharmacokinetics of a drug in children of different ages.
• Some studies requested under BPCA or required under PREA do not achieve their full potential.  Reasons vary and may include the inability of sponsors to recruit sufficient numbers of children, the use of weak study designs and underpowered samples, the lack of dose-ranging studies to guide efficacy trials, and the omission of relevant study information from labeling.  FDA has taken steps to address many of these problems.
• More timely planning, initiation, and completion of pediatric studies would benefit children. European requirements for the submission of plans for pediatric studies apply at a stage of drug development that may be somewhat premature, whereas U.S.  requirements apply later than may be warranted. Delays in sponsor completion of required studies also warrant further attention.
• Pediatric drug studies remain particularly limited in certain areas, including the use of medications with neonates and the long-term safety and effectiveness of drugs for all pediatric age groups.  The frequent lack of information about the long-term safety of drugs used with children is a special worry—both for drugs that may be used for decades for chronic conditions and for drugs for which short-term use may have adverse consequences on a child’s development months or years later.  Many drugs commonly used with premature and sick neonates are older drugs that have not been adequately evaluated in studies with this vulnerable age group.
• Congress has significantly expanded public access to information from recent pediatric studies conducted under BPCA and PREA and has thereby enhanced the value of these studies.  Limitations still exist, however, particularly for products with PREA-related labeling changes that occurred prior to September 2007.
• The reauthorization processes for BPCA and PREA have improved policies promulgated under both acts, but frequent reauthorizations create uncertainties for industry and FDA.
• Pediatric studies of biologics conducted under PREA have generated valuable information.  The 2010 expansion of BPCA to cover biologics has potential to expand knowledge further, but it is too early to assess its effects.  Almost 90 percent of biologics that the committee investigated have been the subject of some study with children.  Of the dozen biologics that have not been studied with children, most were approved for indications that are not diagnosed or very rarely diagnosed in children.  Given the applicability to biologics of long-standing policies such as the 1984 Orphan Drug Act and PREA and given the range of existing pediatric research on many biologics, the incentives of BPCA may have a valuable but more modest effect in encouraging studies of biologics than they did for small-molecule drugs.

Among the suggestions and options the IOM committee says Congress and FDA should  consider as the BPCA and PREA are debated during the 112th Congress are the following:

• Expand public access to information from pediatric studies conducted under BPCA and PREA;
• Improve the timeliness of certain pediatric studies;
• Strengthen pediatric studies requested under BPCA or required under PREA; 
• Address areas of limited pediatric investigation under BPCA and PREA, including neonatal studies and long-term safety studies;
• Increase the clarity and understanding of FDA judgments about pediatric studies; and
• Continue to encourage pediatric studies of biologics.

The American Academy of Pediatrics (“AAP”) applauded the IOM report in a press release, saying that many of the IOM committee’s findings, “including the need to plan pediatric studies earlier and promote these studies in younger age groups,” are consistent with AAP’s priorities for reauthorization of the BPCA and PREA. 

In a second report, this one titled “What the Orphan Drug Act Has Done Lately for Children With Rare Diseases: A 10-Year Analysis” and published in the journal Pediatrics (2012;129:516–521), the authors (Chandana Thorat, et al.) scoured data and information provided to them by FDA on orphan drug designations and approvals from January 1, 2000 to December 31, 2009 to discern what effect the Orphan Drug Act has had on improving drug availability for children with rare diseases.  According to the authors, the Orphan Drug Act has “led to increased product availability for [rare diseases] overall, with an increasing number of marketing approvals for children this past decade.”  Specifically, say the authors, from January 1, 2000 to December 31, 2009:

1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases.  The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second.  More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup.  The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972.  Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%).

In recent years, FDA’s Office of Orphan Products Development has developed a policy under which the Office has determined, for orphan drug designation purposes, “that pediatric patients constitute a unique population that is eligible for orphan designation if the prevalence of the pediatric population with the disease or condition is less than 200,000.”

In a third report, titled “Drug Pricing: Research on Savings from Generic Drug Use,” the GAO “summarizes the findings of peer-reviewed articles, government reports, and studies by national organizations, including trade and nonprofit organizations” on estimates of cost savings from the use of generic drugs in the United States.  The report research was undertaken in response to a request from Senator Orrin Hatch (R-UT). 

The GAO’s review identified various articles that used different approaches to estimate the savings associated with generic drug use in the United States and places them into three groups.  (The GAO did not independently assess the methodologies of the articles, including the reliability of data used as a basis for them.)  “One group of studies estimated the savings in reduced drug costs that have accrued from the use of generics. . . .  A second group of studies estimated the potential to save more on drugs through greater use of generics. . . .  A third group of studies estimated the effect on health care costs of using generic versions of certain types of drugs where questions had generally been raised about whether substituting generic drugs for brand-name drugs was medically appropriate.”   “Unlike the other two groups which focused on savings on drugs only” (and showed significant savings from generic drug use), the third group of articles, says GAO, “had mixed results regarding the effect of using these generics in that some found they raised health care costs, while others found they led to cost savings.”  The difference in findings of the third group of articles, comments GAO, may be attributable to the fact that the studies were generally limited to certain types of drugs, such as narrow therapeutic index drugs like Anti-Epileptic Drugs (“AEDs”).   As we previously reported, questions have been raised as to whether there are increased risks to patients who are switched from a brand-name AED to an approved, bioequivalent generic version.

By Riëtte van Laack & John R. Fleder –

After the Federal Trade Commission (“FTC”) entered consent orders against Nestle and Iovate (see here), prohibiting future claims for respondents’ food and dietary supplements unless they are supported by two well-controlled clinical studies, the industry has been uncertain about the FTC’s substantiation standard and a shift in the FTC’s policy.  We previously reported that on September 13, 2010, POM Wonderful LLC (“POM”) filed a complaint in court against the FTC, alleging that the FTC was applying a new and legally unwarranted substantiation standard to POM’s claims.  POM also challenged that the FTC could not requires that the FDA approve certain health- related claims for a food or dietary supplement, even if the claims are supported by two well-controlled clinical studies.  This requirement for approval by FDA was apparently first included in the recent consent order that the FTC entered against Nestle.

Shortly after POM sued the FTC, the FTC turned around and sued POM, charging it with false and misleading advertising.  The FTC filed this action in its own “court”, seeking an order from the FTC that POM should be prohibited from violating the FTC Act.  The FTC contends that POM’s claims that its products prevent, reduce the risk of, or treat heart disease, high blood pressure, prostate cancer, and erectile dysfunction (“ED”) are not supported by competent and reliable evidence.  The FTC filed a proposed cease and desist order that, among other things, included a requirement for FDA approval of certain claims.

Over the past six or so months, the case was tried before an FTC Administrative Law Judge (“ALJ”).  All parties were given the opportunity to present witnesses, including experts, and documents with regard to the FTC’s allegations in the case.

On January 11, 2012, the parties filed their respective post-trial briefs. On February 7, 2012, they filed their respective reply briefs.  The voluminous briefing materials are available here.

Based on the record generated during the FTC trial, POM maintains that no cease and desist order is warranted.  It also contends that for claims for foods and dietary supplements, the substantiation standard is not two randomized placebo controlled studies (“RCTs”), and that the FTC does not have the authority to require FDA approval before POM makes claims. We believe that this case will be the first time that the prior FDA approval issue has been litigated.

The FTC defines an establishment claim as an express or clearly implied statement that the advertising claim is supported by scientific or medical studies.  According to the FTC, establishment claims related to health benefits require RCTs.  In response to the oft-voiced position that substantiation of claims for foods does not require RCTs because RCTs are impractical, impossible, unethical, too costly, etc., the FTC asserts that it does not matter whether a claim is for a food, a dietary supplement, a cosmetic or a drug.  The FTC contends that the nature of the claim, not the nature of the product is central to the “deception” analysis.  The FTC further asserts that unqualified efficacy claims (i.e., claims that a product provides health benefits without a representation that the claim is supported by scientifically or clinically proven) also require RCTs.

Although under the FTC Act a claim is deceptive only if it is likely to mislead consumers acting reasonably under the circumstances, in a material respect, the FTC asserts in this case that it need not prove the materiality element of the FTC Act because there is a rebuttable presumption that advertising is material if it involves health related efficacy information important to the consumers.  As you can probably imagine, POM hotly disputes the FTC’s position regarding materiality.

With regard to the FTC’s proposed cease and desist order, POM has raised a number of challenges, including arguments that the proposed Order would violate the First Amendment.  According to the FTC, the proposed pre-approval requirement does not constitute an imposition of an unlawful prior restraint. Whether the FTC may prohibit truthful claims, even if such claims do not meet the approval of another agency such as FDA, remains to be seen when this case is finally resolved.

Closing arguments before the FTC’s ALJ are set for March 6, 2012, at 1:00 PM.

There was a recent piece on National Public Radio debating whether the golden age of blogging is over.  One commentator suggested that moving forward, only the most successful blogs thus far (i.e., those blogs with a history of good content and that are able to capture the reader’s attention) will enjoy continued success.  We think that the FDA Law Blog, which turns 5 years old on March 6th, is among that group of blogs.  Certainly our numbers, which continue to grow each month, supports this.  About 7,000 of you now receive our posts each day.  We also have a growing following on Twitter (@fdalawblog) where we tweet throughout the day.  Just last month, we topped 1,500 blog posts (assuming 260 working days in a year, that’s more than one post a day!), and the awards and accolades continue to roll in.

As we enter old age (in blog years), we don’t plan on slowing down.  In fact, we’ve heard from several seniors (real ones) that they are busier in old age than ever.  Old age has its benefits too – and we’re not just talking about all of the e-mail offers we get telling us where to find Rolex watches and Jimmy Choo shoes at bargain basement prices!  Recently the United States Library of Congress contacted us and told us that because the FDA Law Blog is now one of the Nation’s cultural artifacts, our blog was selected for inclusion in the historic collection of Internet materials related to Legal Blawgs.  We think that’s pretty cool!

Of course, none of our success would have been possible without our loyal readers and fan base!  We appreciate your support and thoughtful comments over the past 5 years (and look forward to more in the coming years).  We also thank our Hyman, Phelps & McNamara, P.C. colleagues for their time and dedication to writing interesting and informative posts.

By Ricardo Carvajal - 

Last November, we noted that FDA’s regulation requiring the display on cigarette packages of graphic warnings intended to dissuade would-be smokers appeared in jeopardy at the hands of U.S. District Judge Richard Leon in R.J. Reynolds et al v. FDA et al.  In an opinion hewing closely to his earlier analysis, Judge Leon has now granted plaintiffs’ motion for summary judgment and held that FDA’s regulation violates the First Amendment.  (In our discussion below, we refer to the graphic warnings as “graphic images,” in deference to the court’s conclusion that the characterization of the graphics as warnings “is inaccurate and unfair as they are more about shocking and repelling than warning.”)

Citing numerous statements made by FDA, the court concluded that the graphic images required by the regulation were not “purely factual and uncontroversial information” intended to prevent consumer confusion or deception.  Rather, the court found that the images “were crafted to evoke a strong emotional response calculated to provoke the viewer to quit or never start smoking.”  The regulation was therefore subject to strict scrutiny, which required FDA to show that the regulation was “narrowly tailored to achieve a compelling government interest.”  

The court allowed that “an interest in informing or educating the public about the dangers of smoking might be compelling” (emphasis in original).  However, advocating a change in consumer behavior (i.e., “advocating that the public not purchase a legal product”) is not.  Further, the court held that the regulation was not narrowly tailored, citing “the sheer size and display requirements for the graphic images,” and the existence of “several alternatives that are easily less restrictive and burdensome for plaintiffs.”

Although the ruling is important from a legal perspective, it’s not clear what the public health impact of the ruling would be if it stands.  As noted by the court, FDA’s analysis of the benefits of the regulation estimated that it would have a negligible impact on smoking rates (an estimated reduction of .088% – “not statistically distinguishable from zero”).  Nevertheless, in a brief statement issued shortly after the decision, HHS signaled its intent to fight: “We are confident that efforts to stop these important warnings from going forward will ultimately fail.”   

By Riëtte van Laack – 

A coalition of public health associations sent a letter to FDA encouraging the agency to amend its ingredient statement regulation to include the single food ingredient “added sugars” followed by a parenthetical listing of the specific sugars added in descending order of predominance by weight.  Earlier this month, Representative Rosa DeLauro (D-CT) sent FDA a similar letter.

The letter maintains that the requested labeling would better enable the consumer “to evaluate the foods they purchase.”  However, any consumer interested in the amount of sugars in a food can glean that information from the nutritional facts box, which is required to declare “sugars” per serving.  Furthermore, it is information on total sugars, not just “added sugars” that is relevant for weight management and management of diseases such as diabetes.  Finally, the ingredient statement regulation requires the listing of ingredients in descending order of predominance by weight, but does not require disclosure of the amount of an ingredient per daily serving. 

On February 29th, FDA Commissioner Margaret A. Hamburg, M.D. announced in an FDA-wide e-mail the permanent appointment of Elizabeth H. Dickinson as FDA’s Chief Counsel.  Ms. Dickinson has served as FDA’s Acting Chief Counsel since August 7, 2011 (see our previous post).  Prior to that role, she served as Associate Chief Counsel for Drugs in FDA’s Office of Chief Counsel for several years.  Ms. Dickinson’s storied FDA career and myriad accomplishments are extolled in Dr. Hamburg’s e-mail announcement below.  Congratulations!

Dear Colleagues,
 
I am thrilled to announce the permanent appointment of Elizabeth Dickinson as the Chief Counsel of the Food and Drug Administration, effective Monday, March 12, 2012.
 
As many of you know, Liz has had a long and distinguished history at the Agency; she joined the Office of the Chief Counsel in 1994.  Over the years, Liz has served as legal counsel to the Center for Drug Evaluation and Research and the Office of the Commissioner on innovator and generic drug review issues, orphan drug development, and biosimilars; has implemented pediatric exclusivity and pediatric drug development programs; has worked closely with the Department of Justice on dozens of cases addressing Waxman-Hatch issues and preemption; and has coordinated the development of the Office of the Chief Counsel’s flexible workplace program.
 
A graduate of the University of Massachusetts and Northeastern University School of Law, Liz is highly regarded by both her internal colleagues and those across the food and drug bar.  Over the years, Liz has received numerous awards for distinguished service, leadership and her outstanding legal skills.
 
Liz has been serving as Acting Chief Counsel since August 2011, and we have been grateful for her hard work and dedication each day that she has been on the job.  It is terrific to know that she will be serving the Agency in this role permanently as we move forward.  Please join me in congratulating Liz.
 
Sincerely,
 
Margaret A. Hamburg, M.D.
Commissioner of Food and Drugs

By Kurt R. Karst –      

Every few years, interest in the creation of a third category of drug products – something other than prescription or Over-the-Counter (“OTC”) status – is piqued by FDA, Congress, or by some other entity.  The most recent attempt to explore the creation of a new drug category is FDA’s announcement earlier this week of a March 22-23, 2012 public hearing for FDA to obtain input on a “new paradigm” the Agency is considering.  But before we get into FDA’s “new paradigm,” first some background and history . . . .

The FDC Act was amended in 1951 by the Durham-Humphrey Amendment, Pub. L. No. 82-215, 65 Stat. 648 (1951), to give FDA the authority to require that drugs be limited to prescription status when they cannot be used safely OTC.  The underlying presumption then and now is that prescription restrictions are the exception.  In other words, if a drug can be used safely and effectively OTC it should be.  FDA stated this principle clearly in the Agency’s overview of issues for a May 11, 2001 advisory committee meeting that considered whether three prescription antihistamines should be switched to OTC status.  According to FDA, the FDC Act “restricts drugs to prescription-only status if a learned intermediary is required for the proper use of the drug.  As written, the default assumption of the [FDC Act] is for drugs to be marketed OTC without a prescription unless a decision is made that consumers are not able to appropriately diagnose their condition nor able to correctly choose the remedy and safely use it based on OTC labeling.”

The FDC Act defines a prescription drug at FDC Act § 503(b)(1) as:

A drug intended for use by man which – 

(A) because of its toxicity or other potentiality for harmful effect, or the method of its use, or the collateral measures necessary to its use, is not safe for use except under the supervision of a practitioner licensed by law to administer such drug; or

(B) is limited by an approved application under section 505 to use under the professional supervision of a practitioner licensed by law to administer such drug . . . .

(As enacted in 1951, FDC Act § 503(b)(1) included three categories of Rx drugs: (1) habit-forming drugs under § 502(d); (2) drugs that are unsafe for use except with a doctor’s supervision; and (3) drugs limited to Rx use under an NDA.  The FDA Modernization Act of 1997 amended FDC Act § 503(b)(1) to repeal subparagraph (A) (habit-forming drugs) and redesignated former subparagraphs (B) and (C) as (A) and (B), respectively.)  The FDC Act does not define the term “OTC drug;” however, it does define a “nonprescription drug” at FDC Act § 760(a)(2) to mean a drug that is “(A) not subject to [FDC Act § 503(b)]; and (B) not subject to approval in an application submitted under [FDC Act § 505].”

Very few drugs straddle the line between prescription and OTC status.  The contraceptive drug PLAN B, which has been in the news as of late (see here), is one example – available without a prescription to women 17 years of age and older, but only with a prescription to younger women.  Another example is cold medicine containing pseudoephedrine, which, under the Combat Methamphetamine Epidemic Act of 2005, is limited to Behind-the-Counter (“BTC”) sales.

Previous explorations to create a third category of drugs have petered out.  In October 2007, FDA announced a November 14, 2007 public meeting to discuss the creation of a BTC class of drugs – i.e., a class of drugs available behind the counter at a pharmacy without a prescription but that require the intervention of a pharmacist before dispensing (see our previous post here).  Previously, FDA declined to create BTC drug status when the Agency denied, in April 2004, a citizen petition requesting that FDA “switch Nicotrol Inhaler (Nicotine Inhalation System) from prescription only to over-the-counter status TO BE SOLD ONLY UNDER A PHARMACIST’S SUPERVISION as a third class of drugs” (Docket No. FDA-2003-P-0289). 

FDA’s November 2007 public meeting was followed by a March 2009 report by the U.S. Government Accountability Office (“GAO”) discussing, among other things, arguments supporting and opposing the creation of a BTC drug category (see our previous posts here and here).  The report also updated a 1995 GAO report on the topic.  

Discussion of the creation of a third drug class then apparently went into hibernation until April 2011, when Center for Drug Evaluation and Research Director Dr. Janet Woodcock floated a trial balloon for reviving the idea at the Food and Drug Law Institute’s annual conference, according to trade press reports.  And that brings us to FDA’s latest action on the topic. 

FDA’s February 28, 2012 Federal Register notice announcing the March 22-23, 2012 public hearing restyles the third drug class not as a BTC class, but rather as a “new paradigm” under which FDA “would approve certain drugs that would otherwise require a prescription for nonprescription use . . . under conditions of safe use.”  These “conditions of safe use,” says FDA, “would be specific to the drug product and might require sale in certain pre-defined health care settings, such as a pharmacy.”  Why now?  FDA points to undertreatment of diseases and other effects on the health care system and suggests that a new system could address these issues:

The requirement to obtain a prescription for appropriate medication (and to make one or more visits to a practitioner) may contribute to undertreatment of certain common medical conditions including hyperlipidemia (high cholesterol), hypertension (high blood pressure), migraine headaches, and asthma.  For instance, some consumers do not seek necessary medical care, which may include prescription drug therapy, because of the cost and time required to visit a health care practitioner for an initial diagnosis and an initial prescription.  Some patients who obtain an initial prescription do not continue on necessary medication because they would need to make additional visits to a health care practitioner for a prescription refill after any refills authorized by the initial prescription have been used or the time during which they can be filled has expired.  Some prescription medications require routine monitoring through the prescribing practitioner such as blood tests to assist in the diagnosis of a condition, or to determine whether or how well the medication is working, or to adjust the dose.  FDA believes that some of these visits could be eliminated by making certain prescription medications available without a prescription but with certain other conditions of safe use that would ensure they could be used safely and effectively without the initial involvement of a health care practitioner.  In some cases, a visit to a practitioner would be required for the initial prescription, but a certain number of refills could be authorized beyond those that would normally be authorized without a return visit under specialized conditions of safe use.

Based on the common medical conditions FDA identifies, one can guess the types of drugs that might be considered under a new paradigm.  FDA also says that the paradigm laid out in the notice might be useful for certain rescue medicines, such asthma inhalers and drugs for allergic reactions (e.g., epinephrine).

FDA’s public hearing notice contains a series of questions grouped into three categories that the Agency hopes will define the scope of the hearing, including: (1) “Types of Technology and Conditions of Safe Use” (e.g., “What types of technologies (e.g., kiosks, computer algorithms) are currently in development that could assist in allowing drugs to be used safely and effectively in the nonprescription setting?”); (2) “Pharmacy, Consumer, and Health Care Provider Issues” (e.g., “How might various types of conditions of safe use on nonprescription drug products affect pharmacy business operations?”); and (3) “Other Related Issues” (e.g., “How would insurance coverage of pharmaceuticals be affected by approving nonprescription products with conditions of safe use for widely prescribed prescription drugs under this paradigm?”).

Interestingly, as part of FDA’s discussion of its “new paradigm,” the Agency indicates that it might be open to considering permitting the simultaneous prescription and OTC marketing of the same drug.  “FDA is also considering whether the same drug product could be simultaneously available as both a prescription and nonprescription product with conditions of safe use.  Dual availability could help ensure greater access to needed medications by making obtaining them more flexible,” says FDA in the public hearing notice.

FDA has relied on FDC Act § 503(b), generally, for the assertion that, absent a “meaningful difference,” the FDC Act does not permit the simultaneous prescription and OTC marketing of the same drug for the same indications, in the same dosage forms and at the same strength, and on FDC Act § 503(b)(4) specifically to contend that a product whose labeling contains the “Rx-only” symbol (legend) where the same drug is approved for OTC use is misbranded and may not be legally marketed.  (FDC Act § 503(b)(4) renders a prescription drug misbranded if it fails to bear the “Rx-only” symbol and an OTC drug misbranded if it does.)  FDA discussed its interpretation of what constitutes a “meaningful difference” in a September 2005 Advance Notice of Proposed Rulemaking concerning the approval of PLAN B for OTC use in certain women.  Historically, a “meaningful difference” exists if the Rx and OTC drug products differ in: (1) active ingredient; (2) indication; (3) strength; (4) route of administration; or (5) dosage form.  FDA’s approval of PLAN B added age as a sixth difference. 

To this day, FDA is grappling with simultaneous prescription and OTC marketing issues.  Following the Rx-to-OTC switch of PEG 3350 (MIRALAX), FDA objected to the continued marketing of approved generic prescription versions of the same drug.  FDA approved prescription MIRALAX on February 18, 1999 under NDA No. 020698 for the treatment of occasional constipation.  FDA subsequently approved several ANDAs for generic versions of prescription MIRALAX.  On October 6, 2006, FDA approved NDA No. 022015 for OTC MIRALAX for the relief of occasional constipation.  After the approval of OTC MIRALAX, FDA removed all Orange Book references to NDA No. 020698 (prescription MIRALAX), and in April 2007, FDA’s Office of Generic Drugs sent letters to ANDA sponsors of prescription PEG 3350 stating that the FDC Act “does not permit both Rx and OTC versions of the same drug product to be marketed at the same time.”  The letters clearly rely on FDC Act § 503(b)(4) to contend that prescription PEG 3350 products are “misbranded and may not be legally marketed.”  The letters also cite FDC Act § 503(b), generally, for the assertion that the FDC Act does not permit the simultaneous Rx and OTC marketing of the same drug. 

On October 24, 2008, FDA issued a Notice for an Opportunity for Hearing (Docket No. FDA-2008-N-0549) on a proposal to withdraw approval of prescription PEG 3350 ANDAs on the basis that the Durham-Humphrey Amendment prohibits the simultaneous marketing of the same drug as Rx and OTC.  Moreover, FDA determined “that there is no meaningful difference between the Rx and OTC PEG 3350 drug products.”  Several ANDA sponsors requested a hearing and submitted comments to FDA challenging both the Agency’s interpretation of the statute to preclude simultaneous prescription and OTC marketing of the same drug, and FDA’s determination that no meaningful difference exists between the Rx and OTC versions of PEG 3350.  FDA has not yet scheduled a hearing.  Whether FDA’s “new paradigm” will resolve the issue, or perhaps result in a new “meaningful difference” (e.g., conditions of safe use) remains to be seen.

UPDATE:

• CDER Director Dr. Janet Woodcock suggested during a February 29th speech at the International Conference on Drug Development (Austin, Texas) that the “new paradigm” discussed in FDA's Federal Register notice might be taken up by Congress and included as part of a PDUFA bill, instead of by FDA as a proposed rulemaking.  No specifics were provided by Dr. Woodcock.  

By Kurt R. Karst –      

Among the Warning Letters FDA posted on its website this week, one in particular caught our attention – a February 17, 2012 Warning Letter to Merck Sharp and Dohme Corp. (“Merck”) citing a violatation of FDC Act § 505(o)(3).  FDA’s enforcement action against Merck appears to be the first of its kind citing the new authority Congress granted FDA under the FDA Amendments Act of 2007 (“FDAAA”).

The products at issue in the Warning Letter are Merck’s antidiabetic drugs Januvia® (sitagliptin) Tablets, approved under NDA No. 021995 on October 16, 2006, and Janumet® (sitagliptin/metformin HCl) Tablets, approved under NDA No. 022044 on March 30, 2007.  Based on reports of pancreatitis associated with the use of sitagliptin in FDA’s Adverse Event Reporting System database, including two cases of necrotizing pancreatitis, FDA invoked its authority under FDC Act § 505(o) to require Merck to conduct a postmarketing study (“PMR”) to investigate the safety issue.  Specifically, as a condition of approving NDA supplements for Januvia® and Janumet®, Merck agreed to conduct PMRs 1602 and 1603, described as a “3-month pancreatic safety study in a diabetic rodent model treated with sitagliptin.”  FDA documented the agreement in approval letters (here and here) with the following timetable:

Final Protocol Submission: June 15, 2010
Study Completion Date: March 15, 2011
Final Report Submission: June 15, 2011

FDC Act § 505(o)(3) states that FDA may “require a responsible person for a drug to conduct a postapproval study or studies of the drug, or a postapproval clinical trial or trials of the drug, on the basis of scientific data deemed appropriate by the Secretary, including information regarding chemically-related or pharmacologically-related drugs.”  A PMR is intended to “assess a known serious risk related to the use of the drug involved,” “assess signals of serious risk related to the use of the drug,” and “identify an unexpected serious risk when available data indicates the potential for a serious risk.”  FDC Act § 505(o)(3)(E)(ii) requires sponsors to periodically report to FDA on the status of a PMR.  A violation of FDC Act § 505(o) is a basis for misbranding under FDC Act § 502(z), and may result in civil monetary penalties under FDC Act § 303(f)(4) of $250,000 per violation, with the potential for significant additional penalties for a continuing violation.  In April 2011, FDA issued guidance on the Agency’s implementation of FDC Act § 505(o)(3). 

Animal studies are not generally viewed as particularly onerous PMRs and, while Merck attempted to submit results of studies to address the PMR, none of those study designs had been agreed upon by FDA.  FDA implies that the conducted studies did not reach sufficient levels of exposure to properly evaluate the safety concern.  If FDA was looking to set out an example of its willingness to enforce 505(o), Merck’s failure to even submit a draft protocol and get FDA buy-in for a study that FDA likely views as a fairly simple 3-month rodent study made it easy for them.  After some wrangling between Merck and FDA that is laid bare in the Warning Letter, and a November 2011 Failure to Repond letter FDA issued to Merck, FDA had apparently had enough.  “You have not provided an adequate explanation for the cause of the delay of either of the milestones in the timetable for completion of the postmarketing requirement, nor did you propose to revise the agreed-upon timeline,” writes FDA in the Warning Letter.  “[Y]ou are more than 20 months late in achieving the June 15, 2010 final protocol submission milestone and more than 8 months late in achieving the final protocol submission milestone in the timetable, and you have not demonstrated good cause for these delays.”

As a result, FDA concludes that Merck’s products are misbranded and threatens the company with civil monetary penalties:

Under section 502(z) of the Act [21 U.S.C. 352(z)], your product is considered misbranded because you are in violation of a [PMR] established under section 505(o)(3) of the Act.  You have failed to comply with the approved timetable and periodic report submissions of section 505(o)(3)(E)(ii) of the Act and failed to show good cause for not conducting the additional testing required to further assess whether a signal of a serious risk of acute pancreatitis, including necrotizing forms, associated with the use of sitagliptin, represents a public health risk.

Failure to promptly correct this violation may result in regulatory actions by the FDA without further notice.  These actions include, but are not limited to, civil money penalties.  Other federal agencies may take this Warning Letter into account when considering the award of contracts.  In addition, civil money penalties under section 303(f)(4) of the Act [21 U.S.C. 333(f)(4)] could be levied for a maximum of $250,000 per violation, with the possibility of additional penalties if the violation continues uncorrected.

Is the Merck Warning Letter a sign of a new enforcement move by FDA?  Only time will tell.  Interestingly, just days after FDA issued the February 17th Warning Letter to Merck, the Agency issued what can now be viewed as a prescient “Notice to Industry” stating, among other things: “Once FDA notifies a drug sponsor of the need for a postmarketing study or clinical trial, the company is required to provide a timetable for completion, including study milestones, and periodic status reports on progress toward completion of the PMRs.  If a company fails to comply with the timetable, FDA is authorized to take enforcement action against the company, unless the company can demonstrate good cause for the failures.”

ADDITIONAL READING:

• News Release – Merck Provides Information on FDA Post-Marketing Requirement for Sitagliptin

Hyman, Phelps & McNamara, P.C., the nation’s largest boutique food and drug regulatory law firm, seeks an associate with one to five years experience in food, dietary supplement, and OTC drug laws and regulations to assist with a growing practice.  Experience in regulation of labeling and advertising, food safety, and cosmetics would be desirable. Candidates should have prior law firm or government agency experience.  Strong writing skills are required.  Compensation is competitive and commensurate with experience.  HP&M is an equal opportunity employer.

Please send your curriculum vitae, transcript, and a writing sample to Jeffrey N. Wasserstein (jnw@hpm.com).