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).

By Jennifer D. Newberger –

In September 2009, FDA engaged IOM, a member of the National Academy of Sciences ("the Academy"), to review the 510(k) medical device premarket review process and answer the following questions: (1) Does the current 510(k) clearance process protect patients optimally and promote innovation in support of public health; and (2) if not, what legislative, regulatory, or administrative changes are recommended to achieve the goals of the 510(k) clearance process optimally? 

The IOM formed a committee to research and respond to these questions.  As a member of the Academy, the committee formed by IOM was required to comply with the Federal Advisory Committee Act of 1972 ("FACA"), which states that an agency “may not use any advice or recommendation provided by [the Academy]” unless the membership of the committee is “fairly balanced as determined by the Academy to be appropriate for the functions to be performed.” 

During the committee’s consideration of the 510(k) process, many interested parties claimed that the committee’s make-up was not “fairly balanced” as required by FACA, in that it did not include anyone from the medical device industry familiar with 510(k) submissions, innovators affected by the pace of review of devices cleared through the 510(k) process, or consumers who have benefited from devices cleared through the process.  Nevertheless, the IOM committee refused to expand its representation.

Building on these stakeholder concerns, in June 2011, the Washington Legal Foundation ("WLF") submitted a Citizen Petition to FDA requesting that FDA issue a determination that it is barred from using any advice or recommendation from the IOM advisory committee, on the grounds that the committee is not fairly balanced and therefore violates the FACA.  The petition also requested that FDA issue a guidance document describing when a committee’s composition is sufficiently balanced to allow FDA to rely upon its advice and recommendation. 

On February 21, 2012, FDA denied the petition on two grounds.  First, it stated that “FDA is not required to make an independent determination concerning whether the membership of the convened advisory committee satisfies the FACA fair balance standard.”  Rather, FDA may rely on the representations of the IOM that the committee was fairly balanced “for the functions to be performed.”  Second, FDA stated that, even if FDA could determine whether the committee was fairly balanced, FDA believes that it was.  FDA also stated that it would not issue the guidance document requested because it is the responsibility of the IOM, not FDA, to determine fair balance.

FDA’s response does not come as a surprise, but its denial of the petition is not likely to have much impact on whether FDA adopts any of IOM’s recommendations.  FDA has clearly stated that it will not adopt IOM’s most controversial recommendation, to do away with the 510(k) process in its entirety (see our previous post here).  Many of the other IOM recommendations have faded into the background and are not expected to substantively influence FDA’s modifications to the 510(k) process.  Thus, WLF may be getting what it wants with regard to this particular issue, even if by different means.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Ricardo Carvajal –

Researchers report that in vitro and in vivo experiments conducted with polystyrene nanoparticles indicate that nanoparticle exposure can disrupt iron transport in the gut, and may possibly disrupt absorption of other minerals, as well as vitamins.  The in vivo experiments, which were conducted in chickens, further indicate that chronic exposure can result in remodeling of intestinal villi to increase surface area so as to increase absorption, thereby compensating for the disruption in nutrient transport.   Chickens were chosen for the experiments in part because of similarities between their gastrointestinal tract and that of humans. 

The significance of these findings may be difficult to assess until additional studies on the effects of nanoparticle exposure on the gut have been conducted.  Nonetheless, they should be of interest to food ingredient developers, given the researchers’ observation that dietary particles in certain food additives have been thought to potentially have adverse health effects.   The findings should also be of interest to drug developers, given the utility of nanoparticle carriers for drug delivery.

By Jamie K. Wolszon & Jeffrey N. Gibbs –  

On February 15, 2012, Hyman, Phelps & McNamara, P.C. (“HPM”) submitted supplemental comments to FDA’s June 1, 2011 draft guidance (see our previous post here) that would limit the sale and distribution of Research Use Only (“RUO”) products.  HPM’s supplemental comments highlight FDA’s discussion of the draft guidance in a recent government brief submitted in federal court in a case related to drug off-label information.  The government’s description to the court of the draft guidance is inconsistent with the position in the draft guidance itself that RUO manufacturers should cease sales to a customer if they have knowledge of that customer’s diagnostic use.

On October 14, 2011, Par Pharmaceutical, Inc. (“Par”) sued FDA for allegedly violating the First Amendment by improperly restricting the flow of truthful information (see our previous post here).  The government filed its brief opposing Par on January 11, 2012. 

In its brief, the government states that mere knowledge that an RUO is to be used diagnostically is insufficient to establish a new intended use. 

Looking beyond § 201.128 for proof that FDA equates knowledge that a drug is being prescribed for unapproved uses with intent to create a new intended use, Par quotes selectively from a draft FDA guidance document regarding in vitro diagnostic devices approved for investigational and research uses.  Compl. ¶ 69.  The draft guidance says that “FDA may consider a manufacturer’s knowledge of the purposes for which its customers offer and use its IVD [in vitro diagnostic] product, and the manufacturer’s provision of technical support for those activities, to be evidence that the IVD product is intended to be used for such purposes” (emphasis added).  The emphasized language, which Par omits, makes clear that it is the combination of manufacturer knowledge “and” technical support for the customer’s use, not bare knowledge by itself, that may be taken as evidence of the device’s intended use.

Government’s Brief at 28-29. (Emphases in original.)

HPM previously submitted comments to FDA on the Draft Guidance on August 30, 2011, and supplemental comments on September 22, 2011.

By Kurt R. Karst – 
 
Following the Federal Circuit’s recent precedential decision in AstraZeneca Pharms. v. Apotex et al. (Case No. 2011-1182) (in which the Court held that an ANDA sponsor who submits a “section viii” statement with respect to an Orange Book-listed method-of-use patent and does not seek approval for the patented use cannot be found liable under 35 U.S.C. § 271(e)(2) for patent infringement – see Orange Book Blog and Patent Docs posts), and as we all patiently await a decision from the U.S. Supreme Court in the patent use code counterclaim case, Caraco Pharmaceutical Laboratories, Ltd. v. Novo Nordisk A/S (Docket No. 10-844) (see our previous post here), we thought we’d tee up another case, pending before the Federal Circuit, that represents a middle ground of dispute of sorts between AstraZeneca and Caraco: Bayer Schering Pharma AG v. Lupin, Ltd. et al. (Case No. 2011-1143; Oral Argument held Dec. 7, 2011).  

The case involves U.S. Patent No. 5,569,652 (“the ‘652 patent”), which is listed in the Orange Book for the contraceptive drug YASMIN (drospirenone 3 mg/ethinyl estradiol 0.03 mg) Tablets (NDA No. 021098; approved on May 11, 2001) with a “U-1” patent use code defined as “PREVENTION OF PREGNANCY.”  

Depending on who you ask, Bayer Schering Pharma AG v. Lupin, Ltd. et al. is either a run-of-the-mill Hatch-Waxman patent infringement dispute under 35 U.S.C. § 271(e)(2), or a high-stakes case with significant implications for future Hatch-Waxman infringement litigation concerning method-of-use patents.  The question before the Federal Circuit is whether the U.S District Court for the Southern District of New York erred when it granted, in September 2010, a Judgment on the Pleadings in favor of the ANDA sponsors (Defendants-Appellees) determining that the ‘652 patent does not claim an FDA-approved use for YASMIN because the patented use does not appear in the “Indications and Usage” section of the YASMIN labeling, but rather in the “Clinical Pharmacology” section of the labeling. 

Claim 11 of the ‘652 patent, which is at the center of the dispute, asserts the following method-of-use claim for YASMIN:

A method of simultaneously achieving, during pre-menopause or menopause, a contraceptive effect, an anti-androgenic effect, and an antialdosterone effect in a female patient in need thereof comprising administering an effective amount of dihydrospirorenone and an effective amount of an estrogenic compound, wherein said effective amount of dihydrospirorenone is effective to simultaneously achieve a gestagenic effect, anti-androgenic effect, and an anti-aldosterone effect in said female patient.

Plaintiffs-Appellants argue that FDA approved the ‘652 patent’s claim of simultaneous gestagenic, anti-androgenic, and anti-aldosterone effect, and that that approval is found in the “Clinical Pharmacology” section of the YASMIN labeling, which states in relevant part:

Drospirenone is a spironolactone analogue with antimineralocorticoid activity.  Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, and antiglucocorticoid activity.  Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.

Based on Federal Circuit precedent – i.e., Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003) and Allergan Inc. v. Alcon Labs., 324 F.3d 1322 (Fed. Cir. 2003), which have been used to support the proposition that a method-of-use patent infringement claim against an ANDA sponsor cannot stand where that use is not approved by FDA – district court precedent – i.e., Alcon Labs. v. Allergan, Inc., 256 F. Supp. 2d 1080 (C.D. Cal. 2003) – and FDA’s labeling regulations at 21 C.F.R. § 201.57(c), which state in part that “[i]ndications or uses must not be implied or suggested in other sections of the labeling if not included in this section,” the New York District Court determined that “the FDA-approved use of a drug is governed by the “Indications and Usage” section of its label. . . .”

In their briefs (here and here), Plaintiffs-Appellants argue that the district court ignored basic principles of administrative law in coming to its September 2010 decision.  Citing FDA’s Hatch-Waxman patent listing regulations, Plaintiffs-Appellants argue that the court’s ruling is in direct conflict with those regulations.  Those regulations “confirm that a patented method need not appear just in the Indications section.”  Moreover, write Plaintiffs-Appellants, “[c]onsistent with these regulations, the Orange Book contains numerous [patent] use codes sourced outside of the Indications section.  The district court’s holding would render unenforceable in Hatch-Waxman proceedings the method of use patents underlying these use codes.”  Plaintiffs-Appellants also argue that the district court ignored other evidence of FDA approval of the ‘652 patented method, including DDMAC’s pre-clearance of certain promotional pieces “featuring the ‘652 patented method,” and a declaration from a former FDAer responsible for the clinical review of YASMIN. 

Defendants-Appellees argue in their brief that the district court got it right when it concluded that the only approved use for YASMIN included in the product’s labeling is contraception.  They counter that Plaintiffs-Appellants go too far in characterizing the scope of the district court’s decision.

Bayer repeatedly mischaracterizes the District Court’s opinion as going far beyond its actual holding that the FDA approved Yasmin for contraception only. . . .  Bayer insists that the District court held, far more broadly, that “a patentee can only assert method patents if those methods appear in the Indications section of the approved labeling.”  Bayer does not even attempt to cite to specific language in the District Court’s opinion in order to support its mischaracterization of the breadth of the court’s holding.  Rather, it simply sets up a straw man argument, and then devotes many pages of briefing to knocking it down.  In fact, the District Court’s holding was appropriately limited to the ‘652 patent claims, the scope of the FDA’s approval of Yasmin, and the consequences vis-a-vie Appellees’ ANDAs for their respective generic versions of Yasmin.  The court’s decision from which Bayer appeals . . . is a straightforward, narrow ruling, and is amply supported by the record.

Hatch-Waxman junkies will surely be watching this case closely.  Clearly, the Federal Circuit’s decision will be an important one regardless of how the Court ultimately rules.  Indeed, the case is so important that even PhRMA filed an amicus brief. 

By Ricardo Carvajal –

According to press reports, Senator Charles Schumer (D-NY) has prevailed on FDA to examine the regulatory status of Aeroshot, a product labeled as a dietary supplement that claims to contain “a unique blend of caffeine and B vitamins in a fine powder that dissolves quickly in your mouth.”  According to the manufacturer, each Aeroshot provides 100 mg of caffeine (roughly equivalent to a large coffee) and delivers 4 to 6 “puffs,” which users are directed to swallow.  Sen. Schumer first attacked the product last December, describing it as “nothing more than a club drug.”

Although readers might be reminded of FDA and FTC’s joint action against caffeinated malt beverages (see our previous post here), those products raised the question of whether the intended use of caffeine was generally recognized as safe, or GRAS – the standard applicable to the use of an ingredient in conventional foods when that use of the ingredient has not been the subject of a food additive approval.  Because Aeroshot is marketed as a dietary supplement, it will be evaluated under the definitions and safety standards applicable to those products.  That said, it bears watching whether FDA takes account of the manufacturer’s marketing practices, and of whether the product is associated with “adverse behavioral effects” – factors that the agency cited in support of its conclusion that the use of caffeine in caffeinated malt beverages such as Four Lokos is not GRAS.

Given that Aeroshot appears intended to dissolve in the mouth and be swallowed, it’s not clear what makes it “breathable.”  In any case, the concept of “breathable” food has been on the table for at least 10 years, albeit in a more rarified form.  Intriguing, but no substitute for a good bowl of gumbo.

By Kurt R. Karst –

Following a long court battle in which a three-judge panel of the U.S. Court of Appeals for the Tenth Circuit affirmed a November 2010 decision from the U.S. District Court for the District of Wyoming granting FDA’s Motion to Dismiss a lawsuit brought by Cody Laboratories, Inc. and Lannett Co., Inc. (collectively “Lannett”) concerning the alleged grandfather status of Lannett’s marketed unapproved Morphine Sulfate Solution, Lannett has submitted a citizen petition to FDA seeking the Agency’s determination on the subject.  As FDA Law Blog readers might recall, the Lannett lawsuit came about as a result of FDA’s March 2009 Warning Letters to Cody and Lannett (among other companies) to stop manufacturing certain unapproved narcotic drugs, including morphine sulfate oral solutions.  At that time, FDA concluded that marketed unapproved morphine sulfate products are “new drugs [under the FDCA] and not grandfathered and that manufacturing and marketing of these products without an approved application constituted a violation of the Act.”  Lannett ultimately submitted and obtained approval of a marketing application (NDA No. 201517) for Morphine Sulfate Oral Solution, 100 mg per 5 mL (20 mg per mL), which is subject to PDUFA user fees.

Although the Tenth Circuit agreed that the approval of NDA No. 201517 did not moot Lannett’s grandfather drug claim, because “[b]y prevailing on its grandfathering claim, Cody could still obtain meaningful relief in the form of freedom from [certain user fee and labeling]  burdens,” the Court refused to reach the merits of Lannett’s grandfather drug claim.  Importantly, the Court stated:

Mootness aside, we cannot reach the merits of [Lannett’s] grandfathering claim unless the FDA has engaged in “final agency action” under the APA. . . .  [Lannett’s] failure to avail itself of available administrative remedies [(i.e., use of the citizen petition process)] defeats its claim even if we were inclined to hold that the FDA’s action [(i.e., Warning Letters)] were otherwise final. . . .  Given that grandfathering status hinges on the fact-intensive history of the drug’s marketing and use, we do not anticipate that the agency will blindly refuse to consider evidence submitted by [Lannett].  Accordingly, we decline to consider [Lannett’s] grandfathering claim prior to exhaustion of the company’s administrative remedies.

The recent Lannett citizen petition would appear to be an attempt to obtain final agency action, perhaps on which to base a future lawsuit.  The citizen petition requests that FDA affirm, pursuant to the 1938 “grandfather clause” of the FDC Act, the grandfather status of morphine sulfate, which is marketed for the relief of severe acute and severe chronic pain.  In addition, FDA is asked to acknowledge that, in light of a grandfather affirmation, Lannett’s Morphine Sulfate drug product is not a “new drug” subject to premarket approval and PDUFA user fees.

Under the 1938 “grandfather clause,” a drug “shall not be deemed a ‘new drug’” requiring FDA approval if: (1) the drug was subject to the 1906 Food and Drugs Act at any time prior to June 25, 1938, when the FDC Act was enacted; and (2) “if at such time its labeling contained the same representations concerning the conditions of its use.”  The 1938 “grandfather clause” is different from the 1962 “grandfather clause,” which exempted manufacturers of pre-1962 drugs from the requirement to demonstrate effectiveness, in addition to safety under the 1938 FDC Act.

Lannett contends in its petition that morphine sulfate meets both of the 1938 “grandfather clause” requirements.  Along the way, Lannett addresses certain interpretations of the 1938 and 1962 “grandfather clauses” that might otherwise lead FDA to conclude that Lannett’s Morphine Sulfate drug product is not a grandfather drug.  For example, Lannett argues that:

The fact that a specific manufacturer’s morphine sulfate drug product was not introduced into interstate commerce in the United States prior to the enactment of the Act in 1938 does not disqualify its drug product from “grandfather” status.  The language of the first prong of the “grandfather clause” requires only that a drug be subject to the 1906 Act, not a specific manufacturer’s drug.  A more restrictive reading would preclude any other entity from marketing a drug that was on the market prior to 1938, with the same conditions of use, and claim that it was “grandfathered.” (Emphasis ion original)

Moreover, acknowledging that the labeling for its Morphine Sulfate drug product is not identical to that of pre-1938 product labeling, and that FDA and some courts have narrowly (and perhaps incorrectly) interpreted the 1938 “grandfather clause,” Lannett argues that the correct inquiry under the 1938 “grandfather clause” is whether the drug product contains “the same representations concerning the conditions of its use.”

The 1962 “grandfather clause” calls for a comparison of the drug products’ conditions of use, 
composition and labeling, while the 1938 clause focuses only on a comparison of their conditions of use.  Any attempt by FDA to impose the same requirements with respect to the applicability of the 1938 “grandfather clause” and the 1962 “grandfather clause”— despite the clear differences between the language used in the two provisions—is unsupported by the statutory language and is contrary to the above mentioned canons of statutory construction.

In that connection, says Lannett, FDA has incorrectly relied on its grandfather drug hearing regulations at 21 C.F.R. § 314.200(e) to establish the burden of proof necessary to qualify for grandfather status under the 1938 “grandfather clause.”  Those regulations, which Lannett says are related to the 1962 “grandfather clause,” state, in part, that “[a] contention that a drug product is exempt from part or all of the new drug provisions of the act under the exemption for products marketed before June 25, 1938, contained in section 201(p) of the act, or under section 107(c) of the Drug Amendments of 1962, is required to be supported by evidence of past and present quantitative formulas, labeling, and evidence of marketing.”  According to Lannett, however, the text of the FDC Act “sets forth the standard for when a drug product is not subject to the new drug requirements, and does not require FDA approval of such a claim before such old drugs can be marketed.  FDA cannot override or add to the unambiguous requirements of the statute. . . .  FDAs continued reference to §314.200(e) is misplaced and beyond its regulatory authority.”  For one example of where FDA has raised the Agency’s hearing regulations when faced with a 1938 “grandfather clause” issue, see FDA’s December 2000 response to a citizen petition concerning cannabis-containing drugs.

By Kurt R. Karst –      

Just days after FDA announced the release of three draft guidances on biosimilar product development (see our previous post here), and on the same day FDA officially noticed their availability in the Federal Register (here, here, and here) (as well as a proposed collection on § 351(k) biosimilar applications), FDA denied the outstanding requests in two citizen petitions submitted to the Agency in April 2003 (Docket No. FDA-2003-P-0003) and April 2004 (Docket No. FDA-2004-P-0214) by the Biotechnology Industry Organization (“BIO”) and Genentech, Inc. (“Genentech”), respectively.  Both petitions were submitted to FDA well before the March 2010 enactment of the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”), which amended the Public Health Service Act (“PHS Act”) to, among other things, create an approval pathway for biosimilar and interchangeable versions of reference products (§ 351(k) biosimilar applications).  As such, the petitions primarily pertain to the submission and approval of 505(b)(2) applications under the FDC Act for “biotechnology-derived products” (i.e., therapeutic drug or biological products developed by biotechnology methods) or “follow-on therapeutic proteins” (i.e., polypeptide therapeutic products, including recombinant versions of therapeutic protein products, not submitted to FDA with a full complement of clinical data).

FDA had previously addressed most of the issues raised in the petitions in the Agency’s October 2003 and May 2006 petition responses (here and here); however, two outstanding requests remained:

(1) that FDA decline to publish a draft guidance regarding the “similarity” or “sameness” of a “biotechnology-derived product” or “therapeutic protein” that relies on confidential or trade secret information; and

(2) that FDA provide advance notice and a pre-deprivation hearing if FDA does decide to issue such a guidance using trade secret or confidential information.

Genentech broadly requested in its petition that FDA “refrain from publishing a draft guidance document setting forth standards for the ‘similarity’ or ‘sameness’ of biotechnology-derived products. . . that relies, directly or indirectly, on Genentech’s trade secret and confidential commercial data.”  FDA says in its 2012 petition response that Genentech “suggests that any guidance document FDA creates on this subject impermissibly will be infused with protected confidential and trade secret information.”  Any such argument must fail, however, says FDA, because the Agency’s “mandate is to protect the public health in the areas within its purview – including biotechnology-derived products – and it may, among other things, create guidance to industry regarding the laws it administers.”  With respect to the draft biosimilars guidances issued on February 9, 2012, FDA comments that they “do not violate any protections available to applicants by relying, either ‘directly or indirectly,’ on Genentech’s or any other entity’s confidential information. . . [,] do not disclose any trade secret or confidential information, and [that] FDA did not impermissibly use or rely upon any such information in developing them.”

BIO more specifically requested in its 2003 citizen petition that FDA “refrain from preparing, publishing, circulating, or issuing any new guidance for industry, whether in draft or final form, concerning follow-on applications for therapeutic proteins, particularly human growth hormone or insulin, under [FDC Act § 505(b)(2)] which was intended simply to codify FDA’s earlier ‘paper NDA’ policy.”  Insofar as BIO’s request is limited to guidace involving 505(b)(2) applications for therapeutic proteins, FDA comments in the Agency’s February 2012 response that FDA has general authority to issue guidance and notes that “if FDA deems such an exercise of its authority appropriate or necessary, the Agency may prepare, publish, circulate, or issue new draft or final guidance for industry concerning applications for therapeutic proteins (or any other subset of products) eligible for approval under [FDC Act § 505(b)(2)].”  Insofar as BIO’s petition more generally requests that FDA refrain from issuing guidance on class-specific biological products, FDA points to the text of the BPCIA, which permits the Agency to issue “specific” guidance “with respect to the licensure of a biological product under [PHS Act § 351(k)].”  Perhaps signaling future guidance, FDA comments that while the Agency “thus far has not published draft guidance on the subject of product class biological products, the [BPCIA] clearly contemplates that the Secretary may issue this type of guidance.”

Genentech specifically requested in its citizen petition that FDA provide advance notice and a pre-deprivation hearing if the Agency decides to issue guidance on biotechnology-derived product/therapeutic protein similarity/sameness issues using trade secret or confidential information.  In FDA’s February 2012 petition response, the Agency declined to address Genentech’s Constitutional and trade secret law arguments, and instead reasserted that that Agency “acts within its authority when it issues guidance documents in its areas of scientific expertise for purposes of executing its mandate as an agency.”  Moreover, says FDA, the draft biosimilars guidances “do not implicate, disclose, or rely upon Genentech’s (or any other company’s) confidential commercial or trade secret information.”

By Kurt R. Karst & David B. Clissold –   

Three House lawmakers (Reps. Henry Waxman(D-CA), Ed Markey (D-MA), and Diana DeGette (D-CO)) sent letters (here and here) to FDA Commissioner Dr. Margaret Hamburg and NIH Director Francis Collins earlier this week expressing their concern over a recent report published in the British Medical Journal (“BMJ”) documenting the underreporting of results of clinical studies on ClinicalTrials.gov.  According to the article published in the January 2012 issue of the BMJ, titled “Compliance with mandatory reporting of clinical trial results on ClinicalTrials.gov: cross sectional study,” a database search of trials registered on ClinicalTrials.gov which completed in 2009 and that are covered by the 2007 FDA Amendments Act (“FDAAA”) showed that “[o]f the 738 trials that were classified as subject to mandatory reporting, 163 (22%) had reported results.  In comparison, 76/727 (10%) trials covered by the FDAAA but not subject to mandatory reporting had reported results . . . . ”

Section 801 of FDAAA amended PHS Act § 402 to expand the clinical trial registry data bank created by Section 113 of the Food and Drug Administration Modernization Act of 1997.  FDAAA § 801 expanded the clinical trial data bank (i.e., ClinicalTrials.gov) in two ways.  First, a broader range of “applicable” clinical trials must now be registered at ClinicalTrials.gov.  Second, certain results information from applicable clinical trials must now be submitted to the clinical trial registry data bank.

An “applicable drug clinical trial” is defined in PHS Act § 402(j)(1)(A)(iii) to mean “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .”  An “applicable device clinical trial” is defined in PHS Act § 402(j)(1)(A)(ii) to mean “a prospective clinical study of health outcomes comparing an intervention with a device subject to section 510(k), 515, or 520(m) of the [FDC Act] against a control in human subjects (other than a small clinical trial to determine the feasibility of a device, or a clinical trial to test prototype devices where the primary outcome measure relates to feasibility and not to health outcomes); and a pediatric postmarket surveillance as required under [FDC Act § 522].”  In March 2009, NIH posted a revised draft document on its website concerning FDAAA and clinical trial registration.  The document provides more detailed information on applicable clinical trials, including defining such trials to include certain in vivo bioequivalence studies used to support the approval of a generic drug under an ANDA (see our previous post here).

Under PHS Act § 402(j)(2)(C), the responsible party of an applicable clinical trial that is initiated after September 27, 2007, or that is ongoing on December 26, 2007, must submit to NIH certain required information for inclusion in the clinical trial data bank by December 26, 2007, or 21 days after the first patient is enrolled in the clinical trial, whichever is later.  The only exception to this rule is that if the clinical trial was ongoing on September 27, 2007 and was not for a serious or life-threatening disease or condition, the information must have been submitted by September 27, 2008. 

PHS Act § 402 also requires the submission of certain results information of applicable clinical trials to the clinical trial registry bank.  FDA, NIH, and the responsible parties for applicable clinical trials all have responsibilities under the law.  Among other things, NIH is responsible for maintaining the public database of trial results on ClinicalTrials.gov, and FDA is responsible for enforcing the statutory requirements.  (FDA and NIH were supposed to have, by September 27, 2010, expanded the results database by rulemaking to possibly include a summary of the clinical trial and its results, the full protocol, and other information.  That rulemaking has not yet been issued, but it might happen soon, according to the Fall 2011 DHHS Unified Agenda.)  Responsible parties for applicable clinical trials are responsible for, among other things, submitting certain results information to the basic results section of ClinicalTrials.gov. 

Subject to specified exceptions, the general rule is that as of September 27, 2008, the responsible party for an applicable clinical trial must submit the basic results information no later than 1 year “after the earlier of the estimated complete date of the trial . . . or the actual date of completion” (PHS Act § 402(j)(3)(E)).  One important exception is that if the trial is completed before the drug is approved or the device is cleared, the responsible party can delay submitting the results information until no later than 30 days after the drug or device is approved (PHS Act § 402(j)(3)(E)(iv)).  If the manufacturer of a drug or device or sponsor of an applicable clinical trial is seeking approval for a new use of the drug or device, the same information must be submitted on the earliest of 30 days after approval, 30 days after FDA issues a not approval letter or a not substantially equivalent letter, or 30 days after the application is withdrawn without resubmission for no less than 210 days (PHS Act § 402(j)(3)(E)(v)). 

The failure of a responsible party to submit the required clinical trial information under PHS Act § 402(j) is a prohibited act (FDC Act § 301(jj)) that could result in significant penalties of up to $10,000 per day (FDC Act § 303(f)(3)).  FDA has not, to our knowledge, taken any enforcement action with respect to PHS Act § 402(j). 

The February 14th letters from the trio of lawmakers to FDA and NIH raise both common concerns (e.g., “publication delays may allow ineffective or dangerous drugs to remain on the market, resulting in significant harm to patients and waste in the health care system”) and agency-specific concerns, such as “whether FDA is adequately enforcing the law requiring such reporting” and “whether NIH is adequately implementing the law requiring such reporting” (emphasis added).  The letters also contain requests specific to FDA and NIH to help the lawmakers better understand the issue.  FDA is asked to provide answers to the following questions:

1) Do the findings of the [study reported in the BMJ] correspond with FDA‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA?  Please summarize FDA‘s internal compliance data.

2) Has FDA issued any warning letters, imposed any fines, or otherwise initiated any enforcement actions related to these reporting requirements?

3) Does FDA have adequate resources and authority to enforce these reporting requirements?

4) Does FDA believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?

NIH is asked to provide answers to the following questions:

1) Do the findings of the [study reported in the BMJ] correspond with NIH‘s internal data on compliance with the reporting requirements of Section 801 of the FDAAA?  Please summarize NIH‘s internal compliance data.

2) Does NIH have adequate resources and authority to implement these reporting requirements?

3) Does NIH believe additional statutory changes are necessary to address the issues of underreporting of clinical trial data and non-compliance with the reporting requirements in Section 801 of the FDAAA?

Depending on how FDA and NIH respond to the inquiries – particularly the queries regarding whether additional statutory changes are necessary – it is possible that we could see even more proposed legislation that might be taken up this year alongside the various user fee bills. 

An interesting finding of the BMJ paper was that the source of funding for the clinical trials greatly influenced the reporting of results.  Industry-funded studies were far more likely to report results (40%) than were studies “not solely industry funded“ (9%).  Of note, the latter category included studies funded solely by NIH and other government agencies.  This suggests that even NIH and FDA are not in compliance with their own reporting requirements, which would surely complicate enforcement and any attempted legislative correction.  Further, the “source of funding“ used by the BMJ authors does not necessarily reflect the “responsible party.”  As permitted under the statute (PHS Act § 402(j)(1)(A)(ix)), even industry-funded studies can designate “the principal investigator” as the party responsible for the submission of clinical trial information.  Before rushing to portray these findings as another example of “industry“ not in compliance with the law, it would seem prudent to know how many NIH employees designated as either the “sponsor“ or the “responsible party“ have failed to meet these reporting obligations.

By Jeffrey K. Shapiro –

This post is the second in an occasional series that will examine significant or interesting warning letters involving medical device companies. 

As a reminder, FDA issues warning letters to allege violations of the Federal Food, Drug, and Cosmetic Act and/or implementing regulations.  A warning letter is a statement of FDA’s enforcement position and a threat to pursue legal remedies if the target does not comply.  On occasion, FDA issues a warning letter that reveals a new or little known enforcement position.  This type of warning letter will be our critical focus.

On December 27, 2011, the Philadelphia district issued a warning letter focused on Medical Device Reporting ("MDR") issues. 

This warning letter has a fascinating comment about the presumption that a malfunction is likely to contribute to a serious injury or death if it were to recur.  Essentially, FDA criticizes the target company for following the agency’s own written guidance on this issue.

As background, under the MDR regulation, a malfunction is reportable if a recurrence would likely cause serious injury or death.  21 C.F.R. § 803.50(a).  The question is, if a malfunction actually causes a serious injury or death, must the manufacturer presume that subsequent occurrences of the malfunction are “likely” to do so as well?  In 1997 guidance, FDA said:

“FDA believes that once a malfunction has caused or contributed to a death or serious injury, a presumption that the malfunction is likely to cause or contribute to a death or serious injury has been established. This presumption will continue until the malfunction has caused or contributed to no further deaths or serious injuries for two years, or the manufacturer can show, through valid data, that the likelihood of another death or serious injury as a result of the malfunction is remote.”  (Emphasis added.)

The target of the warning letter apparently had incorporated the foregoing “two year presumption” in its warning letter procedure.  FDA did not approve.  The warning letter admonishes:

Also, your firm states in [redacted] that malfunctions causing or contributing to a death or serious injury will be reported to FDA until the malfunction has not caused or contributed to further deaths or serious injuries for two years. The guidance document “Medical Device Reporting for Manufacturers,” dated March, 1997, contains a discussion of malfunctions and reportability. The guidance advises that malfunctions should be reported until valid data shows that the likelihood of another death or serious injury occurring as a result of the malfunction is remote and references a two year period. The guidance is intended to assist industry with interpreting the requirements of the MDR regulation, 21 CFR Part 803. However we currently recommend that manufacturers who wish to stop reporting a malfunction contact the MDR Policy Branch for further discussion at 301-796-6670 or by email at MDRPolicy@fda.hhs.gov.

Stepping past the District's misleading characterization of the guidance document, the warning letter is troubling on two levels.  First, it appears that FDA is disavowing the “two year presumption.”   Apparently, FDA now wishes to adjudicate the expiration of the presumption on a case by case basis.  This policy change is unfortunate.  The two year presumption has been a rare “bright line” rule among a welter of MDR reporting elements that are mostly subjective and difficult to apply in the real world.  It has been in place for 16 years with no apparent ill effect.  The decision to now require case by case adjudication of the presumption will increase the cost and uncertainty of MDR reporting.  There does not seem to be an obvious benefit to doing so.

Second, many firms have relied upon FDA’s published guidance to incorporate the two year presumption in their MDR procedures.  To our knowledge, FDA has not publicly modified the guidance.  Therefore, it seems reasonable for firms to rely upon the guidance in formulating their MDR procedures.  Yet, the warning letter suggests that firms are no longer safe in doing so. 

It is arbitrary and capricious for an administrative agency to modify published guidance via individual warning letters.  This is the opposite of transparency.  If FDA wishes to alter the two year presumption, it should follow its own Good Guidance Practices.

The terminology of the warning letter creates even more confusion.  It couches the directive to consult the MDR Policy Branch as a “recommendation.”  So, is it now violative to have a two year presumption in an MDR procedure, or not?  Must firms proactively revise their procedures?  Or should they simply wait until an inspector criticizes the procedure or issues a Form 483 observation?  Perhaps this enforcement position is unique to the Philadelphia district?  It is hard to know.

What we do know is that this warning letter has taken the helpful certainty of the two year presumption and thrown it to the wind.

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.

By Kurt R. Karst –      

Last week, Representative Bobby Rush (D-IL) announced the introduction of H.R. 3995, the Protecting Consumer Access to Generic Drugs Act of 2012.  The bill is the latest piece of legislation that attempts to stymie so-called pay-for-delay patent settlement agreements.  In January 2011, Senator Herb Kohl (D-WI) introduced S. 27, the Preserve Access to Affordable Generics Act (see our previous post here), and in November 2011, a group of bi-partisan Senators introduced S.1882, the Fair And Immediate Release of Generic Drugs Act, or the “FAIR GENERxICS Act” (see our previous post here), which also seeks to pull 180-day exclusivity into the mix by making some significant changes to the FDC Act’s exclusivity provisions.

The latest bill – H.R. 3995 – is different than the currently pending legislation, but harkens back to an older version of the Preserve Access to Affordable Generics Act introduced as S. 369 in February 2009, both in terms of substance and length.  Gone from new legislation is the controversial presumption that an agreement, if challenged by the Federal Trade Commission, is anticompetitive and unlawful unless it can be demonstrated by clear and convincing evidence that the procompetitive benefits of the agreement outweigh the anticompetitive effects of the agreement.  Instead, the Protecting Consumer Access to Generic Drugs Act of 2012 simply says that:

It shall be unlawful for any person to directly or indirectly be a party to any agreement resolving or settling a patent infringement claim in which – (1) an ANDA filer receives anything of value; and (2) the ANDA filer agrees not to research, develop, manufacture, market, or sell, for any period of time, the drug that is to be manufactured under the ANDA involved and is the subject of the patent infringement claim.

There are, of course, some exceptions.  For example, the bill would not prohibit agreements in which the value received by the ANDA sponsor includes no more than the right to market the drug product before the expiration of certain patents and non-patent marketing exclusivities.  The FTC may also promulgate regulations to further implement the exceptions included in H.R. 3995.

As in previous versions of legislation addressing patent settlement agreements, H.R. 3995 would amend the 180-day exclusivity forfeiture provision at FDC Act § 505(j)(5)(D)(i)(V) (the so-called “Collusive Agreement Forfeiture Provision”) to make a violation of the Protecting Consumer Access to Generic Drugs Act of 2012 a forfeiture-triggering event. 

H.R. 3995 has been referred to the House Judiciary and Energy and Commerce Committees.  There, it will join a growing number of FDA-related bills that have recently been introduced in the current wave of FDA legislation as folks gear up for user fee creation and reauthorization – see our Legislation Tracker.  

By Nisha P. Shah –

On February 9, 2012, FDA released a new guidance document called, “Guidance For Sponsors, Investigators, and Institutional Review Boards – Questions and Answers on Informed Consent Elements, 21 CFR § 50.25(c).”  The guidance is intended to help small businesses understand the new informed consent requirements described in 21 C.F.R. § 50.25(c), which requires that informed consent documents and processes for “applicable clinical trials,” initiated on or after March 7, 2012, include a specific statement that clinical trial information will be entered into the clinical trial registry databank maintained by the National Institutes of Health/National Library of Medicine.  That statement is, “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

In the guidance, FDA clarifies that if an IRB has approved any informed consent documents for the applicable clinical trial before March 7, 2012, then the trial will be considered “initiated” prior to the compliance date, and the new statement will not be required in the informed consent documents.  Guidance, p. 4.  FDA also explains that any applicable clinical trial, including those conducted outside of the United States, must include the new statement in informed consent documents.  Regarding waiver of documentation of informed consents, the agency affirms that, “the trial participant still provides consent and the statement is required during the oral presentation of the research and/or in the written statement regarding the research, if required by the IRB under 21 CFR § 56.109(d).”  Guidance, p. 5.  Finally, according to the guidance, if an informed consent document fails to properly include the statement, then the IRB should be notified and a revised consent form containing the statement should be provided to the IRB for review and approval. 

By Ricardo Carvajal –

In a decision sure to bring joy to the U.S. Department of Agriculture (“USDA”), the D.C. District Court granted the government’s motion for summary judgment in a lawsuit challenging a USDA regulation that requires domestically produced almonds to be treated for Salmonella.  The regulation was issued in the wake of Salmonella outbreaks associated with raw almonds, and it is credited with eliminating the domestic market for raw almonds.  The regulation was issued in part under the authority of the Agricultural Marketing Agreement Act of 1937 (“AMAA”).  The AMAA authorizes the issuance of marketing orders that dictate the “grade, size, or quality” of a commodity sold in a particular region of the U.S. 

Plaintiffs alleged that USDA had exceeded its authority because the regulation was a food safety measure, and not a quality measure.   The court noted that “quality” is not defined in the AMAA, and concluded that the term is ambiguous based in part on its dictionary definition (“[a]n attribute, property; a special feature or characteristic,” or “[a] particular class, kind, or grade of something, as determined by its character, esp[ecially] its excellence”).  The court further concluded that USDA’s interpretation of the AMAA as authorizing a food safety measure was reasonable, in that the AMAA “specifically contemplates interventions relating to ‘quality’” that are needed to “respond to both general market conditions and external threats, such as the Salmonella outbreaks…, which have the potential to cause significant market disruption.”

Curiously, in concluding that “quality” encompasses “safety,” the court did not delve into the definition of “safety” – and we won’t either.  However, we note that robust discussions of the distinction between safety and quality has taken place in other food-related contexts (see, e.g., the preamble to the dietary supplement GMP final rule). 

It’s not yet clear whether plaintiffs will appeal the court’s decision.  If so, they may also have to overcome the government’s argument that plaintiffs waived their claims by not raising them during the comment period preceding issuance of USDA’s final rule.  This potential hurdle highlights the importance of submitting timely comments during agency rulemaking.

By Jennifer D. Newberger –

On Wednesday, February 8, Representatives Mike Rogers (R-MI) and Ed Markey (D-MA) introduced H.R. 3975, The Pediatric Medical Device Safety and Improvement Reauthorization Act of 2012.  The bill would put into effect a rule previously withdrawn by FDA regarding the inclusion of pediatric information in certain medical device submissions to FDA, notwithstanding the requirements of the Administrative Procedure Act ("APA") to obtain and consider public input prior to implementing a final rule. 

A little background to the withdrawn rule is helpful in understanding the intent of this bill.  On April 1, 2010, FDA issued a proposed rule along with a direct final rule “that was intended to make noncontroversial amendments to existing regulations which would require the submission of readily available pediatric medical device information as a part of premarket approval applications, requests for humanitarian use device exemptions, and any product development protocols.”  Although the rule was intended to be noncontroversial, the agency received “significant adverse comment” and therefore withdrew the direct final rule on July 19, 2010. 

The withdrawal of the direct final rule due to receipt of significant adverse comment indicates that the APA worked precisely as intended—to allow for public participation in the rulemaking process.  This seems to be of no matter to the sponsors of this bill, which would have the withdrawn direct final rule take effect on January 1, 2013, notwithstanding the APA “and any other provision of law.” 

Certainly, just as Congress created the APA, it can create exceptions to the APA.  Before doing so, however, it should consider whether it truly wants to force upon the public a rule much of the public explicitly decried. 

REMINDER: HP&M is hosting FDA Appeals – Improving Your Odds of Success: Trends, Expectations, Strategies, a webinar on March 21, 2012, 12:30 – 2:00 p.m. ET.  Click here to register.