On January 16, 2008, FDA issued a proposed rule that would “reaffirm [the Agency’s] longstanding position that” labeling changes for approved drugs, biologics, and medical devices may only be made to show newly acquired information or to “add or strengthen a contraindication, warning, precaution, or adverse reaction” when there is sufficient evidence to support the change. 

FDA’s current regulations at 21 C.F.R. §§ 314.70(c), 601.12(f), and 814.39(d) allow changes to be made to drug, biologic, and device labeling in certain situations upon FDA’s receipt of a supplemental application, commonly referred to as a “changes being effect supplement,” or a “CBE supplement,” for drugs and biologics, and a Premarket Approval Application (“PMA”) supplement or Special PMA Supplement for devices.  (For convenience, we use the term CBE supplement to refer to drug, biologic, and device labeling supplements.) FDA’s proposal, if finalized, would make explicit that CBEs may only be used to update newly acquired safety information, which FDA proposed to define as “data, analyses, or other information not previously submitted to the agency, or submitted within a reasonable time period prior to the CBE supplement, that provides novel information about the product.”  For example, if a postmarket study suggests a more severe and significant adverse reaction than previously known, then a CBE supplement “may be appropriate;” but if a study only provides additional data on a known adverse reaction, a CBE supplement would not be appropriate.  Further, according to FDA, a CBE supplement may only be used for labeling changes relating to “contraindications, warnings, precautions, or adverse reactions in circumstances when there is sufficient evidence of a causal association with the drug, biologic, or medical device.” 

Because FDA’s proposal would merely codify existing FDA policy, it would not significantly alter Agency practice or establish new regulatory requirements.  However, the proposed rule, if finalized, could give significant support to firms that invoke an FDA preemption defense in product liability cases where plaintiffs argue that firms should revise their own labeling in accordance with state law.  Specifically, by revising its CBE supplement regulations to state that such applications require “newly acquired information,” FDA could limit the number of cases in which the results from certain studies could be used to support a stronger labeling warning and a product liability lawsuit.  FDA states in the proposal that:

To the extent that state law would require a sponsor to add information to the labeling for an approved drug or biologic without advance FDA approval based on information or data as to risks that are similar in type or severity to those previously submitted to the FDA, or based on information or data that does not provide sufficient evidence of a causal association with the product, such a state requirement would conflict with federal law. In such a situation, it would be impossible to market a product in compliance with both federal and state law, and the state law would “stand[] as an obstacle to the accomplishment and execution of the full purposes and objectives of Congress,” Hines, 312 U.S. at 67.  Moreover, such a state law requirement relating to a medical device would constitute a requirement that is different from, or in addition to, a federal requirement applicable to the device, and which relates to the safety or effectiveness of the device. 21 U.S.C. 360k(a).

Indeed, this is precisely the issue the Supreme Court will consider later this year in Wyeth v. Levine – whether prescription drug labeling preempts state law product liability claims. Documents on the case are available from SCOTUSBlog.  Last week, the Court agreed to hear the case. 

In 2006, the Vermont Supreme Court ruled against Wyeth concerning the company’s labeling of PHENERGAN (promethazine HCl) and held that the FDC Act “provides a floor, not a ceiling, for state regulation.”  FDA has previously stated (pages 3934-35) that “FDA approval of labeling under the [FDC Act] . . . preempts conflicting or contrary State law,” and that “FDA interprets the [FDC Act] to establish both a ‘floor’ and a ‘ceiling,’ such that additional disclosures of risk information can expose a manufacturer to liability under the act if the additional statement is unsubstantiated or otherwise false or misleading.”

FDA has invited comments on the Agency’s proposal regarding when safety information relating to a drug, biologic, or medical device should be considered “newly acquired.”  All comments to the proposed rule are due March 17.

We previously reported on FDA’s request for public comment to help resolve 180-day exclusivity issues concerning a generic version of the antinauseant and antiemetic drug KYTRIL (granisetron HCl) Injection.  Specifically, in October 2007, FDA established a public docket in response to a letter from Teva Parenteral Medicines (“Teva”), in which the company argued that “the plain language and structure of the [FDC Act] compel the conclusion that Teva is entitled to 180-day exclusivity because Teva is the first applicant that submitted a substantially complete paragraph IV ANDA.”  Earlier today, FDA posted its January 17, 2008 response concluding that Teva did not forfeit 180-day exclusivity.  This conclusion had been anticipated, because earlier this month Teva announced the approval of the company’s granisetron HCl ANDA with 180-day exclusivity. 

At issue in this case are the “failure to market” 180-day exclusivity forfeiture provisions at FDC Act § 505(j)(5)(D)(i)(I) added by the Medicare Modernization Act (“MMA”) in 2003.  Under these provisions, a generic applicant whose ANDA contains a paragraph IV patent certification and who is a “first applicant” eligible for 180-day exclusivity forfeits eligibility for such exclusivity if the firm fails to market the drug by the later of:

(aa) the earlier of the date that is –

(AA) 75 days after the date on which the approval of the application of the first applicant is made effective under subparagraph (B)(iii); or

(BB) 30 months after the date of submission of the application of the first applicant; or

(bb) . . . the date that is 75 days after the date as of which, as to each of the patents with respect to which the first applicant submitted and lawfully maintained a certification qualifying the first applicant for the 180-day exclusivity period under subparagraph (B)(iv), at least 1 of the following has occurred:

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

(BB) In an infringement action or a declaratory judgment action described in subitem (AA), a court signs a settlement order or consent decree that enters a final judgment that includes a finding that the patent is invalid or not infringed.

(CC) The patent information submitted under [FDC Act § 505(b) or (c)] is withdrawn by the holder of the application approved under [FDC Act § 505(b)].

In May 2004, Teva submitted the first ANDA to FDA containing a paragraph IV certification for a generic version of KYTRIL.  The application also contained a paragraph III certification (date of patent expiration) and a “section viii statement” to a method-of-use patent.  Roche, the NDA holder/patent owner, did not sue Teva (or any subsequent ANDA applicant) for patent infringement, and FDA tentatively approved Teva’s ANDA in August 2005.  The patent subject to the paragraph III certification expired in December 2007; however, the 30-month period described in FDC Act § 505(j)(5)(D)(i)(I)(aa)(BB) above expired in November 2006. 

Teva argued that despite the expiration of the 30-month period, the firm remained eligible for 180-day exclusivity, which would be triggered by Teva’s commercial marketing of the drug.  Specifically, Teva’s letter states:

[T]he plain language and structure of the [FDC Act] compel the conclusion that Teva is entitled to 180-day exclusivity because Teva is the first applicant that submitted a substantially complete paragraph IV ANDA . . . .  Teva’s exclusivity has not been forfeited . . . because there is a continuing possibility of ANDA-based patent litigation that could result in a “later” forfeiture event under [FDC Act § 505(j)(5)(D)(i)(I)]. . . .

[The FDC Act] requires FDA to determine which is “the later of” (1) a determinate forfeiture trigger . . . “or” (2) a contingent forfeiture trigger . . . .  But there is no conceivable way for FDA to determine which of those 2 potential triggers occurs “later” until (a) one of the contingencies that could give rise to a forfeiture trigger [under FDC Act § FDC Act § 505(j)(5)(D)(i)(I)(bb)] has occurred, or (b) none of the contingencies can occur.  After all, it is impossible to know whether a contingent event has occurred before it does occur — and twice as hard to determine that such an event will not occur until it no longer can occur.

Teva echoed this argument in the company’s comments submitted to the docket FDA established to solicit public comment on acarbose (PRECOSE) 180-day exclusivity issues.

FDA’s granisetron docket response agrees with Teva’s argument.  FDA states:

We find that under the plain language of the statute, 180-day exclusivity is not forfeited for failure to market when an event under subpart (aa) has occurred, but – as in this case – none of the events in subpart (bb) has occurred.  The “failure to market” provision results in forfeiture when there are two dates on the basis of which FDA may identify the “later” event as described in section 505(j)(5)(D)(i)(I).  The provision does not effect a forfeiture when an event under subpart (aa) has occurred, but no event under subpart (bb) has yet occurred.

This is not a situation in which it would be impossible for a later event to occur. Although at the time FDA made its exclusivity decision, there was no litigation regarding the ‘548 patent pending that could result in a forfeiture event under subitem (AA) or (BB) of subpart (bb), there was nevertheless the possibility that either an additional ANDA applicant would be sued as a result of a paragraph IV certification to the patent or one of the applicants would bring a declaratory judgment action against the NDA holder or patent owner. Either of these actions could result in a forfeiture event.  In addition, the patent could be withdrawn by the NDA holder, resulting in a forfeiture event under subitem (CC).  Because at least one of the events described in subpart (bb) could still have occurred and, if it did, would necessarily occur “later” than December 1, 2006, Teva did not forfeit its exclusivity.

FDA also states in a footnote that:

Inherent in the structure of the “failure to market” forfeiture provisions is the possibility that a first applicant would be able to enter into a settlement agreement with the NDA holder or patent owner in which a court does not enter a final judgment of invalidity or non-infringement (i.e., without a forfeiture event under subpart (bb) occurring), and that subsequent applicants would be unable to initiate a forfeiture with a declaratory judgment action.  This inability to force a forfeiture of 180-day exclusivity could result in delays in the approval of otherwise approvable ANDAs owned by applicants that would market their generic drugs if they could but obtain approval.  This potential scenario is not one for which the statute currently provides a remedy.

FDA has not yet issued responses to other public dockets involving 180-day exclusivity issues – namely ramipril and acarbose.  We understand, however, that a decision on ramipril is imminent; particularly because FDA’s latest Orange Book Cumulative Supplement shows a period of 180-day exclusivity for the drug products covered under Cobalt’s ANDA (identified as “PC” or “Patent Challenge” exclusivity). 

By Kurt R. Karst

On January 14, 2008, Nu-Pharm Inc., a Canadian drug company formerly owned by Apotex, Inc., filed a complaint in the U.S. District Court for the District of Columbia against FDA seeking declaratory and injunctive relief with respect to the company’s Abbreviated New Drug Application (“ANDA”) for divalproex sodium delayed-release 500 mg tablets.  The drug is marketed by Abbott Laboratories under the trade name DEPAKOTE for the treatment of mania, migraine, and epilepsy, and was first approved in 1983 under NDA #18-723.

According to the complaint, Nu-Pharm submitted ANDA #77-615 to FDA in March 2005 with paragraph IV certifications to two Orange Book-listed patents covering DEPAKOTE: U.S. Patent #4,988,731 (“the ‘731 patent”) and #5,212,326 (“the ‘326 patent”).  These patents are scheduled to expire on January 29, 2008; however, in December 2007, FDA granted Abbott pediatric exclusivity for the drug, thereby delaying generic approval under certain circumstances until July 29, 2008. 

Earlier, Abbott sued Nu-Pharm in the U.S. District Court for the Northern District of Illinois (Eastern Division) for infringement of both patents, thereby triggering a 30-month stay of approval of Nu-Pharm’s ANDA.  According to Nu-Pharm, the 30-month stay expired on November 13, 2007, without any substantive merits ruling on patent infringement.  Nu-Pharm then contacted FDA requesting that the Agency grant final ANDA approval. 

According to the complaint, in December 2007, FDA informed Nu-Pharm that the Agency would not grant final approval based on an order entered in a contempt proceeding in the U.S. District Court for the Northern District of Illinois (Eastern Division) in Abbott Labs v. Apotex.   In that proceeding, the charged conduct was the submission of repetitive ANDAs by Apotex and Nu-Pharm to FDA for generic DEPAKOTE.  In October 2007, the U.S. Court of Appeals for the Federal Circuit reversed the district court’s judgment of contempt “because the district court erred in finding Apotex in contempt when the conduct at issue was not within the express terms of the injunction.”  By way of background, in previous paragraph IV patent litigation in that case concerning Apotex’s ANDA #75-112 for generic DEPAKOTE, Judge Richard Posner, sitting by designation in the U.S. District Court for the Northern District of Illinois, ruled that Apotex’s product infringed the ‘731 and ‘326 patents, enjoined the company from manufacturing, using, selling, or offering to sell generic divalproex sodium, and stated that the effective date of approval of ANDA #75-112 would be no earlier than January 29, 2008 when the patents expire – without pediatric exclusivity.  The decision was affirmed in 2005.  Apotex subsequently entered into an agreement with Nu-Pharm under which Apotex would pay for the costs associated with preparing and submitting a new ANDA (i.e., ANDA #77-615) for generic DEPAKOTE and Nu-Pharm would take on the “litigation risks” arising from the submission of the ANDA. 

According to the Nu-Pharm complaint, FDA orally refused to grant final approval for ANDA #77-615 on January 9, 2008.  Considering FDA’s decision to be final agency action, the company filed a complaint.  Nu-Pharm alleges that FDA’s refusal to approve the company’s ANDA violates the FDC Act and the Administrative Procedure Act because “FDA’s decision violates the plain and unambiguous language of the [FDC Act], which provides that FDA shall immediately approve an ANDA where, as in this case, the applicable 30-month stay has expired” and there has been no finding of infringement or validity, and that FDA “has no lawful basis or authority to withhold final approval . . . based on a court order in a wholly separate contempt proceeding to which Nu-Pharm was not a party.”

By Kurt R. Karst

UPDATE:

• A copy of Nu-Pharm’s memorandum supporting the company’s motion for a temporary restraining order and/or preliminary injunction is available here.  FDA is expected to file its brief soon.

On January 31, 2008, the New York State Bar Association will hold its annual meeting of the Food, Drug, and Cosmetic Law Section.  Some of the topics slated for discussion are the current political and regulatory landscape in the wake of the enactment of the FDA Amendments Act, the current status of follow-on biologics legislation, and the status of pending drug and device preemption cases before the Supreme Court.  Hyman, Phelps & McNamara, P.C.’s Robert A. Dormer will be speaking at the event, as well as FDA’s recently-named Chief Counsel, Gerald F. Masoudi.  A copy of the brochure for the event is available here – register today!

We previously reported on the new voluntary Direct-To-Consumer (“DTC”) television ad user fee program established by the FDA Amendments Act (“FDAAA”) and FDA’s establishment of Fiscal Year 2008 DTC television ad user fee rates.  Due to inadequate funding by Congress, however, the new program will not launch.

FDAAA provides that the new DTC user fee program established under FDC Act § 736A will not commence if FDA fails to receive at least $11.25 million within 120 days after enactment of FDAAA (i.e., January 25, 2008).  Such funding consists of a combined total of the advisory review and operating reserve fees established by FDA.  Based on industry’s interest in participating in the program, it seemed that the program would commence.  FDAAA also provides, however, that the DTC fees “shall be collected and available for obligation only to the extent and in the amount provided in advance in appropriations Acts.”

On December 26, 2007, President Bush signed into law the Consolidated Appropriations Act, 2008.  (A copy of the new law, Pub. L. No. 110-161, is available by searching here.)  Among other things, the law makes appropriations to FDA for necessary Agency expenses, such as salaries.  The new law, however, does not appropriate user fee funds for the new DTC user fee program.  As such, FDA does not have the authority to collect and spend DTC television ad user fees, and invoices to those companies expressing their intent to participate in the program will not be sent.  Tomorrow, FDA will issue a notice in the Federal Register discussing the end of the program.

Instead of funding the new DTC television ad program, the Consolidated Appropriations Act reportedly increases the funds available from the U.S. Treasury for FDA ad review by $4 million, to $6.25 million.  These funds are only available for Fiscal Year 2008, however, so Congress will have to address the issue again next year when it considers Fiscal Year 2009 appropriations. 

By Kurt R. Karst

The United States Sentencing Commission (“Commission”), which sets the guidelines that are usually followed by federal judges sentencing defendants convicted of federal crimes, has issued proposed Sentencing Guidelines (“Guidelines”) that would likely greatly enhance the criminal penalties applied to some criminal violations of the Federal Food, Drug and Cosmetic Act (“FDC Act”), and has requested public comment whether to increase penalties for all other violations of the FDC Act.  We previously reported that the Commission was considering amending the Guidelines.

In our previous post, we noted that a Commission vote on proposed amendments to the FDC Act was likely in January 2008.  At its public meeting held on January 9, 2008, the Commission voted to publish proposed amendments to the Guidelines and to seek comments on certain issues relating to human growth hormone (“HGH”) offenses, Prescription Drug Marketing Act (“PDMA”) offenses, and other FDC Act offenses.  (The PDMA, which was enacted in April 1988, amended the FDC Act to, among other things, require State licensing of wholesale distributors of prescription drugs under certain Federal guidelines; ban the sale, trade, or purchase of drug samples; and require wholesale distributors to audit drug sample distribution and accounting.)

Once published in the Federal Register, the public will have 60 days to submit comments on the proposed amendments and issues raised in the notice.

The action by the Commission with respect to FDC Act violations committed by individuals (but not corporations) is a rare one.  More than 20 years ago, in connection with the initial promulgation of the Guidelines, the Commission issued § 2N2.1, which then, like now, applied to FDC Act regulatory offenses.  Section 2N2.1 has always contained a cross-reference to the fraud guideline (formerly § 2F1.1, presently § 2B1.1).  Approximately 11 years ago, in response to efforts by the federal government, the Commission proposed making all FDC Act violations subject to the tougher fraud guidelines.  After substantial industry opposition to that proposal, it was withdrawn, and the status quo was maintained.

Now, after more than a decade since it last showed any inclination to address the issue, the Commission appears prepared to consider fundamentally altering how the Guidelines are applied in cases involving FDC Act offenses, and not likely with an eye towards making them less harsh.  To date, § 2N2.1 Guidelines application issues have been simple as compared to other sentencing considerations. 

According to the Commission’s proposed amendments and issues for comment, “[t]he Commission has received some public comment stating that the penalties under §2N2.1 are inadequate to deter second or subsequent violations of the [FDC Act, and] [s]ome commentators also state that §2N2.1 does not adequately punish violations of the PDMA, which carry a 10 year statutory maximum term of imprisonment.”  Based on these comments and other considerations, the Commission has now asked “[s]hould the Commission provide alternative base offense levels, specific offense characteristics identifying aggravating factors warranting an enhanced sentence, or some combination of these to more adequately address these offenses?” Moreover, the Commission invites suggestions regarding “what should be the offense levels associated with alternative base offense levels and/or specific offense characteristics.”  These statements strongly suggest that any Commission action will result in harsher Guidelines.

Significantly, the Commission may, based upon public comment, vote to recommend a revised § 2N2.1 to Congress without ever first publishing for public comment the details of proposed amendments to § 2N2.1.  It seems clear that those advocating for stiffer Guidelines sentences for FDC Act offenses have made their voices heard and will continue to do so.  It would also seem clear that the regulated industry should present its views on this matter to try to affect any final Commission action, unless the regulated industry wants to concede the need for stiffer Guidelines and the resulting longer terms of imprisonment and increases in other associated criminal penalties.

In addition to its more open-ended invitation for comment, the Commission’s notice contains certain more concrete proposals, particularly with respect to setting forth a Guideline for HGH.  The proposed amendments to the Guidelines do the following with respect to HGH:

1.  Adds 21 U.S.C. § 333(e) – distribution of HGH – to the list of offenses to which § 2D1.1, the general controlled substance Guideline, applies.

2.  Makes a defendant convicted of an HGH offense subject to a two level enhancement under § 2D1.1(b)(6) for “mass marketing [HGH] by means of an interactive computer service.”  This existing specific offense characteristic currently applies to only controlled substances, which HGH is not..  Application Note 23 provides guidance regarding how this provision is applied as well as the definition of “interactive computer service.”

3.  Adds 21 U.S.C. § 333(e)(2) – distribution of HGH to a person under 18 years of age – to the § 2D1.2 Guideline, which presently applies to controlled substance offenses involving protected locations (e.g., schools) or pregnant or underage persons.

The notice also identifies various issues for comment regarding HGH offenses.

With respect to other FDC Act offenses, the proposed amendments:

4.  Add the first and only specific offense characteristic to § 2N2.1.  The purpose of this amendment appears to be to increase the Guidelines level for second or subsequent FDC Act convictions where the defendant is not convicted of committing the offenses with the “intent to defraud and mislead.”  At present, despite the second offense being a felony – regardless of intent to defraud or mislead – the Guidelines did not take that statutory difference into account.

5.  Add an application note to § 2N2.1 to include substantial risk of bodily harm as a basis for upward departure.  While actual death and physical injury are currently identified grounds for an upward departure under 5K2.1 and 5K2.2 respectively, for FDC Act and other offenses, those sections do not apply to the risk of death or injury.

As we previously reported, the Commission must submit Guideline amendments to Congress no later than May 1, 2008.  As we have noted, because a Guidelines amendment requires a public Commission meeting, such a meeting would have to take place in April at the latest, and could come up for a vote in March.  Prior to such a meeting, there is likely to be a public hearing.   

In sum, these proposed amendments and the issues raised in the notice could result in significantly increased penalties for persons regulated under the FDC Act, and therefore, those persons should carefully consider the potential impact of the proposed amendments and issues raised for comment in the notice and determine how to best to inform the Commission and staff of any improper or unduly harsh consequences that could flow from the Commission action on these Guidelines. 

By John R. Fleder, Douglas B. Farquhar, and J.P. Ellison

UPDATE:

• On January 28, 2008, the United States Sentencing Commission issued a notice in the Federal Register on the Commission’s proposed amendments to the Sentencing Guidelines.  The notice also states that “[t]he Commission will be scheduling a public hearing on its proposed amendments.”

UPDATE (February 7, 2008):

• Today, the Commission announced that the Public Briefing on the proposed amendments- which was the subject of our earlier update- will be held on February 13, 2008 from 9:30 AM to 11:30 AM.

• HPM Attorneys John Fleder and John Gilbert have been selected to participate in a panel testifying before the Commission regarding the proposed FDC Act and PDMA amendments.

On January 8, 2008, the District of Columbia Council passed the SafeRx Act of 2007 (“Act”), which requires pharmaceutical detailers to be licensed by the Board of Pharmacy.  The Act will be presented to Mayor Adrian Fenty for his signature and then to Congress if signed by the mayor.  Earlier versions of the legislation are available here.  Note that the final version as passed is not yet available.  A copy of the press release announcing the Act’s passage is available here. 

The Act defines the practice of pharmaceutical detailing as “the practice by a representative of a pharmaceutical manufacturer or labeler of communicating in person with a licensed health professional or an employee or representative of a licensed professional, located in the District of Columbia, for the purposes of selling, providing information about, or in any way promoting a pharmaceutical product.”  The qualifications for licensure include a college degree, a notarized statement that the applicant understands and agrees to the requirements of pharmaceutical detailing practice in the District of Columbia, and payment of a licensure fee to be set by the Board of Pharmacy.  The educational requirement can be waived for any applicant who has worked full time as a pharmaceutical detailer for at least 12 months preceding the effective date of the Act.  The Mayor is required to establish continuing education requirements as a condition of license renewal.  Under the Act, the penalty for detailing without a license would be a fine of up to $10,000.

A pharmaceutical detailer is prohibited from engaging in any deception or misleading marketing of a pharmaceutical product.  (Previous versions of the legislation deemed off-label information to be deceptive or misleading marketing.  We were informed by the D.C. Council’s Office of General Counsel that this language has been deleted from the bill as passed.)  Detailers are also prohibited from using a title or designation that might lead a licensed health practitioner or his/her employees to think that the detailer is a licensed health practitioner, unless the detailer is a licensed health practitioner.  In addition, detailers would not be able attend patient examinations without patient consent.

The Act also permits the Board of Pharmacy to establish a code of ethics for the practice of pharmaceutical detailing and to collect information from a pharmaceutical detailer regarding the detailer’s communications with licensed health professionals and their employees. 

By Bryon F. Powell

UPDATE:

A copy of the enrolled version of the Act is available here.

Earlier today, The Plain Dealer, a Cleveland newspaper, reported that Senator Sherrod Brown (D-OH) submitted a request to the Congressional Research Service (“CRS”) requesting information on FDA’s “Fast Track” designation program.  CRS provides policy and legal analysis to committees and to Members of both the U.S. House of Representatives and the U.S. Senate. 

Fast Track was created by the FDA Modernization Act in 1997 to help facilitate the development and expedite the review of drugs and biologics for serious or life-threatening conditions that demonstrate a potential to address unmet medical needs.  Under FDC Act § 506, companies may request Fast Track designation for their product at the time they submit an Investigational New Drug Application to FDA or at any time thereafter.  FDA must determine whether to grant such designation within 60 calendar days after receipt of a designation request.  The benefits of Fast Track designation include scheduled meetings to seek FDA input into development plans, the option of submitting an NDA for “rolling review” (i.e., submission in sections rather than all components simultaneously), and the option of requesting evaluation of studies using surrogate endpoints or clinically meaningful endpoints.  In addition, most drugs that are eligible for Fast Track designation are likely to be considered appropriate to receive a 6-month priority review instead of a 10-month standard review.  Information on FDA’s Fast Track designations is available here, here, and here.  FDA’s Fast Track guidance document is available here.  Statutory Fast Track under FDC Act § 506 is very similar to FDA’s “Accelerated Approval” regulations, and, according to FDA, “essentially codifies in [the] statute FDA’s accelerated approval regulations.”

According to the report in The Plain Dealer, Sen. Brown requested the information on FDA’s Fast Track designation program “to help determine whether a case exists for changing or eliminating the 10-year-old initiative that was intended to speed the availability of drugs for serious diseases.”  Sen. Brown’s request follows a series of articles that appeared in The Plain Dealer in December 2007 that concluded that Fast Track designation provides little actual benefit to consumers.  According to the Plain Dealer’s research, “[Fast Track] designation has amounted to a government blessing, which has served as a marketing tool for drug companies and a boon for investors looking to make quick money on the stock market. . . . Since 1998 . . .  Fast Track announcements for almost 200 drug treatments triggered one-day stock price increases that averaged 10 percent.”  Copies of The Plain Dealer articles are available here, here, here, here, and here.

On February 8, 2008, Hyman, Phelps & McNamara, P.C. (“HPM”) is sponsoring a Medical Device Seminar in Newport Beach, California.  The topic of this seminar will be “Striving for Regulatory Success in a Changing Environment.”  Scheduled speakers for the seminar are Jeff Gibbs, Brian Donato, Doug Farquhar, Jeff Shapiro, and Anne Marie Murphy.  The seminar will cover a wide range of medical device-related subjects and provide an update on developments at FDA’s Center for Devices and Radiological Health.  A copy of the brochure and registration form are available here.  Additional information on the seminar is available here.  HPM’s clients are entitled to a reduced registration fee for this event.

We previously reported on FDA’s plans to take enforcement action with respect to firms manufacturing and distributing unapproved drugs containing hydrocodone.  According to the October 1, 2007 FDA Federal Register notice:

Anyone marketing unapproved hydrocodone products that are currently labeled for use in children younger than 6 years of age must end further manufacturing and distribution of the products on or before October 31, 2007. Those marketing any other unapproved hydrocodone drug products must stop manufacturing such products on or before December 31, 2007 and must cease further shipment in interstate commerce on or before March 31, 2008.

FDA intended the notice to wrap up the Agency’s previous conclusions made under the Drug Efficacy Study Implementation (“DESI”) program for certain pre-1962 FDA-approved hydrocodone drug products, which were last addressed in 1982 Federal Register notices. 

In late December 2007, a group known as the “GRAS/E Coalition” submitted a petition for reconsideration and stay of action to FDA requesting that the Agency “reconsider its plan to take enforcement action against those persons who manufacture or ship liquid cough/cold hydrocodone products that are not labeled for use in children under six years of age” (emphasis in original).  The GRAS/E Coalition contends that FDA did not fully consider the possibility that such drug products are Generally Recognized As Safe and Effective (“GRAS/E”) and do not require an approved marketing application.  As an alternative action, the GRAS/E Coalition requests that FDA “stay its enforcement action against manufacturers and shippers of liquid cough/cold hydrocodone products in a manner consistent with its previous actions . . . by extending the grace period for two years until December 31, 2009.” 

The GRAS/E Coalition takes particular issue with a statement in FDA’s June 2006 Compliance Policy Guide on marketed unapproved drugs in which the Agency states that if a final DESI determination classified a drug as effective for its labeled indication, then “FDA still requires approved applications for continued marketing of the drug and all drugs [Identical, Related, or Similar (‘IRS’)] to it – NDA supplements for those drugs with NDAs approved for safety, or new ANDAs or NDAs, as appropriate, for IRS drugs. DESI-effective drugs that do not obtain approval of the required supplement, ANDA, or NDA are subject to enforcement action.”  According to the GRAS/E Coalition petition, this position is contrary to law: 

We believe that the correct interpretation of the law would be that those products that had safety-only NDAs or were IRS to safety-only NDA drug products, that had [Active Pharmaceutical Ingredients (“APIs”)] that were found to be effective under the DESI review, that have been marketed subsequently for a material time and extent for over thirty years without any significant safety issues, and that have been allowed to remain on the market for over forty years due with FDA’s implicit approval can be considered GRAS/E.

GRAS/E status should apply to marketed unapproved liquid cough/cold hydrocodone drug products, according to the petition, because:

(1) there is a long history showing that these products are safe and effective as antussives; (2) [they] are marketed in the same basic dosage form as versions found to be safe and effective; (3) [their] labeling . . . is similar to versions found to be safe and effective; and (4) [they] comport with the applicable compendial criteria, are manufactured in compliance with [current Good Manufacturing Practices], and are required to have all adverse events regarding their use reported to the Agency.

In addition, the GRAS/E Coalition contends that its position is further bolstered by the fact that the Drug Enforcement Administration has regulated the distribution of hydrocodone API for over thirty years as either a Schedule II or Schedule III controlled substance.

Last week, the United States Court of Appeals for the Seventh Circuit concluded that the Federal Trade Commission Act (“FTC Act”) does not require placebo-controlled, double-blind testing for consumer products. 

The ruling, issued in Federal Trade Commission v. QT Inc., upheld a decision by the United States District Court for the Northern District of Illinois (Eastern Division) that the Q-Ray Ionized Bracelet, a metal bracelet promoted as a “test-proven” cure for chronic pain, was a fraud.  Advertisements claimed that the bracelets were either gold or silver and wearing them enhanced “the flow of bio-energy.”  In fact, both courts found that the claims were not test-proven to help reduce pain, and the bracelets were made of brass and did nothing to enhance the flow of bio-energy, a phrase the lower court called “techno-babble.” 

The appeals court stated that “a person who promotes a product that contemporary technology does not understand must establish that this ‘magic’ actually works.”  The court noted that a placebo-controlled, double-blind test “is the best” way to support product claims, but acknowledged that such tests are expensive and may not be financially feasible for all products.  As such, the court held that “something less” than a placebo-controlled, double-blind test “may do.” 

The court did not provide any specific criteria that evidence must meet in order to be deemed reliable, other than to note that “a statement that is plausible but has not been tested in the most reliable way cannot be condemned out of hand.  The burden is on the [FTC] to prove that the statements are false.”  The defendant in the case did have one test that essentially discovered a placebo effect for people wearing the bracelet.  Outside of this test, which the court called “bunk,” however, the only support for the bracelet’s effectiveness came from testimonials, which the court held “are not a form of proof.” 

The ruling in this case is limited; it only applies to the FTC Act.  However, companies that market consumer products may rest easier knowing that one court has ruled that the FTC cannot require them to conduct placebo-controlled, double-blind studies.

Title VIII of the recently-enacted FDA Amendments Act (“FDAAA”) requires the responsible party of an applicable clinical trial (for both drugs and devices) to certify that the new requirements of Public Health Service Act (“PHS Act”) § 402(j) have been met.  Under PHS Act § 402(j)(2)(C), as amended by FDAAA § 801(a)(2), 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 the National Institutes of Health certain required information for inclusion in the clinical trial data bank (i.e., ClinicalTrials.gov) by December 26, 2007, or 21 days after the first patient is enrolled in the clinical trial, whichever is later, unless the clinical trial is ongoing on September 27, 2007 and is not for a serious or life-threatening disease or condition, in which case the information must be submitted by September 27, 2008. 

An “applicable drug clinical trial” is defined in new 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 new 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].”

Pursuant to PHS Act § 402(j)(5)(B), as amended by FDAAA § 801(a)(2), drug and device sponsors must include a certification with their regulatory submissions that they have complied with new PHS Act § 402(j).  Specifically, PHS Act § 402(j)(5)(B) states:

At the time of submission of an application under [FDC Act §§ 505, 515, 520(m), or PHS Act § 351], or submission of a report under [FDC Act § 510(k)], such application or submission shall be accompanied by a certification that all applicable requirements of [PHS Act § 402(j)] have been met.  Where available, such certification shall include the appropriate National Clinical Trial control numbers.

Therefore, as a result of the dates listed in PHS Act § 402(j)(2)(C), those drug and device sponsors that make a submission on or after December 26, 2007 must certify to FDA that the requirements of PHS Act § 402(j) have been met. 

On December 26, 2007, FDA announced the availability of a new form for the certification (Form FDA 3674).  According to the new form, drug and device sponsors must make one of the following certifications:

A.  I certify that the requirements of 42 U.S.C. § 282(j), Section 402(j) of the Public Health Service Act, enacted by [FDAAA], do not apply because the application/submission which this certification accompanies does not reference any clinical trial.

B.  I certify that the requirements of 42 U.S.C. § 282(j), Section 402(j) of the Public Health Service Act, enacted by [FDAAA], do not apply to any clinical trial referenced in the application/submission which this certification accompanies.

C.  I certify that the requirements of 42 U.S.C. § 282(j), Section 402(j) of the Public Health Service Act, enacted by [FDAAA], apply to one or more of the clinical trials referenced in the application/submission which this certification accompanies and that those requirements have been met.

FDAAA requires FDA to issue guidance on new PHS Act § 402(j), which should further discuss the types of clinical trials covered by the new certification requirement.  Information on registering clinical trials in the ClinicalTrials.gov data bank is available on the National Library of Medicine’s Protocol Registration System website.

On December 21, 2007, the United States Attorney’s Office for the District of Massachusetts announced that pursuant to a plea agreement reached on October 30, 2007, under Federal Rule of Criminal Procedure 11(c)(1)(C), under which the parties can agree to the particular sentence imposed (subject to court approval), Bryan Corporation pled guilty to misdemeanor violations of the federal Food, Drug, and Cosmetic Act (“FDC Act”) under 21 U.S.C. § 333(a)(1), and to obstruction of an administrative proceeding under 18 U.S.C. § 1505. 

Bryan Corporation agreed to pay a criminal fine of $4,514,700.  In addition, pursuant to a civil settlement agreement, the company agreed to pay $485,300 to resolve potential liability under the civil federal False Claims Act.  A copy of the plea agreement is available here.  In light of the small size of the company and its small sales figures, the penalty imposed was relatively large compared to settlements with larger companies. 

The criminal FDC Act conduct admitted by Bryan Corporation related to an interstate shipment of misbranded drug product and adulterated devices.  The criminal obstruction conduct related to the creation of false records regarding those drugs and devices during an FDA inspection, as well as hiding other documents and moving drugs and devices to avoid inspection.  The civil allegations focused on the lack of drug approval or device clearance and nonconformance with current good manufacturing practices.

Bryan Corporation’s owner and former president was indicted on July 19, 2007 on felony FDC Act charges, obstruction, mail fraud, and criminal conspiracy.  That case remains pending.

By J.P. Ellison

On November 27, 2007, the Drug Enforcement Administration (“DEA”) issued a proposed rule to implement a new format for DEA Official Order Forms (so-called “DEA-222s”).  DEA requires registrants to acquire Schedule I or II controlled substances using triplicate, carbon-paper DEA-222s.  DEA observes that processing transactions with carbon copies, which was developed more than 30 years ago, has become outdated.

DEA proposes the use of a single sheet DEA-222 order form that will require execution by registrants in the same manner as the three-part forms.  DEA will issue the order forms on a single sheet of sturdier paper with an embedded watermark, which DEA says will hinder counterfeiting.  Rather than send specific copies to their supplier, purchasers will send the original form to the supplier and make a copy of the form for their records.  Suppliers will annotate the number of commercial or bulk containers furnished and the date shipped to the purchaser on the original form, maintain the original form and send a copy to DEA.  The purchaser must record on its copy of the DEA-222 the number of commercial or bulk containers furnished and the dates they are received.

DEA will amend its regulations governing use of the single sheet DEA-222s.  Registrants will be able to use the triplicate DEA-222s until they are phased out within about 2 years following implementation of the single sheet DEA-222s.

DEA requests comments on the proposed rule by January 28, 2008.

It is worth noting that DEA has been working on an electronic DEA-222 for the last few years.  Registrant errors in completing DEA-222s have been a source of significant civil penalties.  This action may alleviate some of these issues.

By John A Gilbert & Larry K. Houck

The Drug Enforcement Administration’s (“DEA”) final rule allowing individual practitioners to issue multiple Schedule II prescriptions to individual patients to be filled sequentially went into effect on December 19, 2007.  The rule will allow practitioners to prescribe up to a 90-day supply of a Schedule II controlled substance. 

The federal Controlled Substances Act (“CSA”) and the regulations implementing the CSA prohibit the refilling of Schedule II prescriptions.  DEA’s final rule amends the regulations to allow individual practitioners to issue multiple prescriptions authorizing patients to receive “a total of up to a 90-day supply of a Schedule II substance,” provided:

1.         Each separate prescription is issued for a legitimate medical purpose by an individual practitioner acting in the usual course of professional practice;

2.         The practitioner provides written instructions on each prescription indicating the earliest date on which a pharmacy can fill the prescription;

3.         The practitioner concludes that providing multiple prescriptions to the patient “does not create an undue risk of diversion or abuse;”

4.         Issuing multiple prescriptions is permissible under applicable state law; and

5.         The practitioner fully complies with all other requirements under the CSA and regulations as well as state requirements. 

DEA asserts that nothing in the amended regulation should “be construed as mandating or encouraging” practitioners to issue multiple prescriptions or to see their patients only once every 90 days.  Practitioners “must determine on their own, based on sound medical judgment, and in accordance with established medical standards, whether it is appropriate to issue multiple prescriptions and how often to see their patients.”  In addition, practitioners must include instructions on each multiple prescription indicating that it shall not be filled until a certain date, and pharmacists cannot fill it before that date. 

The final rule asserts that the amended regulations do not alter the longstanding principle that neither the CSA nor the regulations contain a “specific limit on the number of days worth of a schedule II controlled substance that a physician may authorize per prescription.” 

By John A. Gilbert & Larry K. Houck