Source: http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2008/11/index.html
Timestamp: 2017-03-26 01:37:07
Document Index: 633643401

Matched Legal Cases: ['§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 505', '§ 2461', '§ 17', 'art 110', 'art 110', 'art 110']

FDA Law Blog: November 2008
By Kurt R. Karst - On November 25, 2008, FDA granted in full a citizen petition (petition supplements are available here and here) submitted by Osmotica Pharmaceutical Corp. earlier this year requesting that FDA determine that any company with a pending Abbreviated New Drug Application ("ANDA") for a proposed Venlafaxine HCl Extended-Release Tablets drug product, and in particular Sun Pharmaceutical Industries Ltd. ("Sun"), be required to submit to FDA a new ANDA citing Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product as the Reference Listed Drug ("RLD"), and that FDA require any such ANDA applicant to conduct new bioequivalence studies comparing its proposed drug product to Osmotica's approved drug product. FDA's 26-page decision: (1) affirms FDA's longstanding "RLD Change Policy," which requires a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approves an application for the drug product covered by the suitability petition; (2) affirms FDA's "RLD Choice Policy," under which a generic applicant must choose the most pharmaceutically equivalent listed drug as the RLD; and (3) and implements FDC Act § 505(j)(2)(D)(i), which was added to the statute in 2003 by the Medicare Prescription Drug, Improvement, and Modernization Act ("MMA") and precludes an applicant with a pending ANDA from amending that application to change RLD. It is the first citizen petition covered under FDC Act § 505(q) that FDA has granted in full - see the FDA Law Blog FDC Act § 505(q) Citizen Petition Tracker.
Under FDA's longstanding RLD Change Policy, the Agency has required a generic applicant with a pending ANDA subject to an approved suitability petition to change RLD and provide appropriate bioequivalence information once the Agency approved an application for the drug product covered by the suitability petition. For example, after FDA approved NDAs for Carboplatin Injection drug products that were also the subject of pending ANDAs submitted pursuant to an approved suitability petition, the Agency required generic applicants to change RLD. FDA has also required generic applicants to take the same action in an Rx-to-OTC switch scenario, where the Agency approved a new NDA for an OTC drug product - thus creating a new RLD listed in the Orange Book to which generic applicant must cite. FDA's RLD Change Policy became particularly important with the enactment of the MMA in 2003. The MMA amended the FDC Act to add § 505(j)(2)(D)(i), which states: "[a]n applicant may not amend or supplement an [ANDA] to seek approval of a drug referring to a different listed drug from the listed drug identified in the application as submitted to [FDA]." A similar provision was added to FDC Act § 505(b)(4)(A) with respect to 505(b)(2) applications. That provision states: "[a]n applicant may not amend or supplement [a 505(b)(2) application] to seek approval of a drug that is a different drug than the drug identified in the application as submitted to [FDA]." Thus, given FDA's RLD Change and Choice Policies, a generic applicant must cite the most appropriate RLD, and must change RLD (for a pending application) when a pharmaceutically equivalent listed drug is approved. However, the MMA precludes an ANDA applicant with a pending application from changing RLD. Instead, Osmotica argued in its citizen petition that a new application must be submitted citing the appropriate RLD, and such application must contain the required bioequivalence data comparing the proposed generic drug to the new RLD (in this case, Osmotica's approved Venlafaxine HCl Extended-Release Tablets drug product). In October 2004, FDA issued a draft guidance document discussing, among other things, FDC Act § 505(j)(2)(D)(i). FDA's draft guidance document states, in relevant part:
All changes that would have the effect of seeking approval for a drug product different from the listed drug cited in the initial submission (e.g., different active ingredient, dosage form, route of administration) should be made in a new application. When the Orange Book identifies as a separate listed drug a product with the characteristics (e.g., active ingredient, dosage form, route of administration) for which the applicant is seeking approval, the applicant should submit a separate ANDA referencing the corresponding listed drug. The applicant should not submit a supplement or amendment to its pending or approved application to seek approval for such a change. In the Federal Register notice announcing the availability of the draft guidance, FDA stated:
Despite the apparent uncertainty in 2004, however, FDA has completed its analysis and has determined that a generic applicant with a pending ANDA subject to an approved suitability petition must submit a new ANDA citing the appropriate RLD when the drug product described in the approved suitability petition is approved under an NDA. FDA's petition response states: our requirement that an applicant with a pending ANDA subject to an approved suitability petition change the RLD upon FDA approval of an NDA for the same drug product described in the approved suitability petition reflects the Agency's judgment that considerations regarding an ANDA's limited reliance on an approved suitability petition are outweighed by the need for a clear determination of therapeutic equivalence for a generic drug product and protection of intellectual property rights accorded an NDA holder. . . . [T]his approach reduces the potentially confusing proliferation of pharmaceutically equivalent drug products that have not demonstrated therapeutic equivalence, and ensures that ANDAs for venlafaxine HCl extended-release tablets will be therapeutically equivalent and thus substitutable for the RLD, Osmotica's venlafaxine HCl extended-release tablets. . . .
Posted at 07:30 AM in Hatch-Waxman | Permalink
FDLI to Hold Conference on Regulation of Controlled Substances
On December 4 and 5, FDLI will hold a conference on Regulation of Controlled Substances: Balancing Medical Need and Diversion Control. The conference will focus on issues related to drug scheduling and regulation of controlled substances and List I chemicals and provide information on new initiatives to ensure medical availability of these drugs while reducing diversion. John Gilbert of HPM will be speaking at the conference along with other government and industry representatives. More information on the conference can be found at: http://www.fdli.org/conf/446/index.html. Posted at 02:21 PM in Drug Enforcement Administration | Permalink
By James P. Ellison In a November 10, 2008 response posted on November 24, 2008, FDA denied an April 27, 2005 Citizen Petition challenging a March 29, 2005 Interim Final Rule increasing Color Additive Certification Fees as violating the FDC Act and the Administrative Procedure Act (APA), because notice and comment rulemaking was required under the law. FDA's response rejected the argument by the International Association of Color Manufacturers that notice and comment rulemaking was required, citing the APA's "contrary to public interest" exception to the general rule requiring notice and comment rulemaking.
While the question of whether FDA should proceed with an interim final rule, a direct final rule, a direct final rule in tandem with a proposed rule, or simply a proposed rule--in this case specifically or in connection with rulemakings generally--raises potentially interesting APA questions, one cannot help but feel that the writing was on the wall in connection with this issue as the increased fees have been in effect for over 3 and 1/2 years. Those who are intrigued by agency decisions concerning publication of rules may want to stay tuned to see how FDA proceeds in connection with its next Color Additive Certification Fee increase, which given the delay in responding to this Citizen Petition, may be just around the corner.
Posted at 02:00 PM in FDA News | Permalink
FTC Reveals Agenda for Follow-On Biologics Roundtable
By William T. Koustas & Kurt R. Karst – We previously reported that the Federal Trade Commission (“FTC”) is planning a Roundtable on Follow-on Biologics (“FOBs”) to be held on November 21, 2008 in Room 432 at FTC Headquarters in Washington, D.C. The Roundtable was first announced earlier this year in the Federal Register. In that notice, the FTC requested comment on two sets of questions concerning regulatory exclusivities and FOB competition, and patent dispute resolution issues. Comments responding to the FTC’s notice are available here. Discussion at the Roundtable will likely aid the FTC as it drafts a report analyzing the potential impacts on the marketplace of FOBs, which the FTC reportedly plans to issue in spring 2009.
On November 18, 2008, the FTC issued a press release detailing the scope and providing an agenda for the November 21, 2008 Roundtable. The Roundtable is scheduled to begin with remarks from FTC Commissioner Pamela Jones Harbour, who recently gave a speech on the FTC’s perspectives on FOBs, followed by a presentation on FOBs by FDA’s Rachel Behrman. The FTC’s press release notes that the session will the be broken out into panel discussions on the following five issues: “the price and market share effect of entry of both biosimilar and biogeneric drugs, the likely competitive effects of reference product regulatory exclusivity, biotechnology patent issues, the likely competitive effects of follow-on biologic regulatory incentives, and the patent resolution process.”
The panel session regarding the effects of entry by biosimilar and biogeneric products will specifically address how the competition between FOBs and innovator products will affect reimbursement by private and public payers. The second panel, related to competitive effects of reference products and regulatory exclusivity, will focus on the benefits and drawbacks of FOB non-patent market exclusivity for innovator companies and follow-on applicants. The third panel on biotechnology patent issues will discuss the differences between patents on biologics and small molecule drugs with specific emphasis on claim drafting, Patent and Trademark Office approval, judicial review, and how patent and non-patent market exclusivity affect business planning. The fourth panel on the competitive effects of FOBs and regulatory incentives is scheduled to center on whether Hatch-Waxman-like statutory exclusivity incentives are needed to promote the growth of FOBs. Finally, the patent dispute resolution panel will consider the different ways to structure a system to resolve patent disputes between innovator companies and follow-on competitors using case study. The Roundtable is free and open to the public without the need for pre-registration. Only a photo ID is necessary to enter the FTC Headquarters. A live webcast will be available on the day of the Roundtable. The issue of non-patent FOB market exclusivity has been hotly debated in Congress and by scholars. Recent papers by the American Enterprise Institute’s Alex Brill and Duke University Fuqua School of Business Professor Henry Grabowski (both of whom are scheduled to present at the Roundtable) have taken different views about the appropriate period of such exclusivity, assuming FOBs can overcome the scientific, statutory, and regulatory hurdles currently in place.
Posted at 10:52 AM in Hatch-Waxman | Permalink
A Sign of the Times – FDA’s Medical Device Top Brass Under Fire From Within and From Capitol Hill
By James R. Phelps & Kurt R. Karst – On November 17, 2008, Representatives John Dingell (D-MI), Chairman of the Committee on Energy and Commerce, and Bart Stupak (D-MI), Chairman of the Subcommittee on Oversight and Investigations of the U.S. House of Representatives, announced their most recent investigation of FDA – “whether managers within the [FDA] Center for Devices and Radiological Health (CDRH) knowingly corrupted the scientific review process and approved or cleared medical device applications in gross violation of laws and regulations designed to assure the safety and effectiveness of medical devices.” The investigation was prompted by an October 14, 2008 letter written on behalf of a group of CDRH scientists and physicians who allege that CDRH managers have “corrupted the scientific review of medical devices.” The October 14, 2008 letter to Chairman Dingell is quite remarkable and includes several serious allegations. According to the letter:
This misconduct reaches the highest levels of CDRH management including the Center Director and the Director of the Office of Device Evaluation (ODE) . . . . To avoid accountability, these managers at CDRH have ordered, intimidated and coerced FDA experts to modify their scientific reviews, conclusions and recommendations in violation of the law. Furthermore, these managers have also ordered, intimidated and coerced FDA experts to make safety and effectiveness determinations that are not in accordance with scientific regulatory requirements, to use unsound evaluation methods, and accept clinical and technical data that is not scientifically valid nor obtained in accordance with legal requirements, such as obtaining proper informed consent from human subjects. These same managers have knowingly avoided and failed to properly document the basis of their decisions in official Agency records.
Under the banner of regulatory “precedent,” managers at CDRH have demanded that physicians and scientists review regulatory submissions employing methods, and accepting evidence and conclusions, that are not scientifically proven and clinically validated. These demands appear to be based on the misguided notion that because flawed methods, evidence and conclusions were used or accepted in the recent or even the remote past, we must continue to blindly and knowingly accept these flawed methods, evidence and conclusions and continue to use them as the basis for regulatory recommendations. Such invalid regulatory “precedent” goes against current scientific and clinical evidence. Rather than remedy past regulatory or scientific errors after they come to light, and rather than applying the best and latest scientific knowledge and methodology, these managers at CDRH knowingly continue to make the same regulatory and scientific mistakes over and over again. Rather than recall, re-evaluate or otherwise deal with potentially unsafe or ineffective devices that are already on the market, these managers at CDRH continue to approve more devices of the same kind in a non-transparent and non-scientific manner. This is especially true of the 510(k) program but also applies to the PMA program as well as the advice and guidance given to manufacturers before they make regulatory submissions. The practices described above represent an unwarranted risk to public health and a silent danger that may only be recognized after many years.
The October 14, 2008 letter reportedly follows up on a similar letter sent by some CDRH scientists to FDA’s Assistant Commissioner for Integrity and Accountability on May 31, 2008. In a November 17, 2008 letter from Reps. Dingell and Stupak to FDA Commissioner von Eschenbach, the Representatives: (1) express concern that “no action has been taken to address the serious concerns raised by CDRH scientists or the retaliatory behavior of CDRH managers toward those concerned FDA employees;” (2) remind FDA officials that it is a violation of Federal law to retaliate against whistleblowers and to interfere with a congressional inquiry; and (3) request a briefing by FDA no later than December 1, 2008 of what actions have been or will be taken to respond to the allegations raised in the October 14, 2008 letter. Managing FDA is an excruciatingly difficult task. One of the principal reasons this is so is laid bare in the letters discussed above. At this stage, it is impossible to know what will happen to the CDRH personnel involved. Do the complainants have a better grasp of good scientific methodologies than the senior people at CDRH? Will they be viewed as heroic whistleblowers or back-stabbing knaves? We may never learn.
We can, however, foresee yet another season of congressional activity - grillings by Hill staff and maybe hearings. The one easily predictable consequence of all this is that FDA, and especially CDRH, will for some time to come be in a defensive mode. When this happens, history teaches that FDA reviews will reach a new level of difficulty. The affected personnel will be distracted to attend to the allegations. The managers will have a heightened interest in making judgments that no one – not even the worst informed employee – can criticize. Will the enhanced rigidity of the approval system that occurs as Congress sorts out FDA’s personnel issues give the public access to new technologies in an appropriate time frame? Time will tell.
Posted at 01:57 PM in Medical Devices | Permalink
Are the Stars Lining Up for FDA Civil Penalties? By James P. Ellison - FDA’s November 12, 2008 Federal Register Notice of its Direct Final Rule to comply with the Federal Civil Penalties Inflation Adjustment Act, 28 U.S.C. § 2461 note, is not in itself a blogworthy event, but it could be part of something bigger. While FDA has used its civil penalty authority sporadically (for example settling in July of this year with Advanced Bionics LLC for $1.1M based on an administrative complaint seeking $2.2M), generally speaking, based on historical enforcement, one would not list FDA civil penalty actions among the top ten things likely to keep CEOs in FDA regulated industries up at night. But see The Pursuit of Civil Money Penalties— An Important Weapon in FDA’sEnforcement Arsenal (discussing the TMJ Implants case).
A new administration, the FDA Amendments Act ("FDAAA"), and an inflation increase for older civil penalties may just be the triple threat that civil penalties need to move up that top ten list of things keeping CEOs awake, however. The law requires FDA to adjust its civil monetary penalties at least one time every 4 years to account for inflation, and FDA last adjusted these penalties in 2004. While the increases do not affect the new civil penalty authority granted FDA under FDAAA in 2007, the Notice does list the nine (9) new civil penalties created by FDAAA, which we previously described.
The resulting new 21 C.F.R. § 17.2 may now have sufficient heft to warrant more FDA enforcement resources, especially because of coincidental timing that nevertheless almost compels one to speculate about the enforcement priorities of an Obama administration FDA. The FDA’s Rule was published as a direct final rule, which means that FDA did not believe notice and comment rulemaking was necessary under the Administrative Procedure Act. To prevent the Rule from becoming final, significant adverse comments on it are due by January 26, 2009 (i.e., 6 days after Inauguration Day). If no such comments are received, the increased civil penalties become effective on March 27, 2009, by which time a new President may have selected a new FDA Commissioner who is just getting down to work on enforcement priorities. Posted at 04:15 PM in Enforcement | Permalink
Public Service Announcement: Don't Trust FDA Impersonators . . . By Jeffrey N. Wasserstein –
First, it was the son of the former Nigerian dictator who wanted my bank account information (I’m still waiting for the bank transfer, by the way!). Now, apparently FDA “special agents” are in on the act. In a scam originating out of the Dominican Republic, scammers impersonating FDA personnel are extorting money from unwitting consumers. Don’t be fooled: FDA personnel do not call you on the phone demanding money – they leave that to the Department of Justice. Posted at 04:02 PM in Miscellaneous | Permalink
Food GMP Modernization: Whole Hog or Piecemeal?
By Ricardo Carvajal & Diane B. McColl – FDA has announced a pretest of a survey instrument designed to gather information about five issues relevant to modernization of the food CGMP regulations at 21 C.F.R. Part 110. The food CGMP regulations are essentially unchanged since 1986, and the information to be solicited by the survey will assist FDA in its effort to revise the regulations. The survey will focus on five issues: employee training, sanitation and personal hygiene, allergen controls, process controls, and recordkeeping. Selection of these issues was based on a report issued in 2005 by CFSAN’s Food CGMP Modernization Working Group. After considering public comments, that group concluded that there is “generally strong support for limited revision of the CGMP regulation.”
Several factors are likely to influence the outcome of FDA’s food CGMP modernization effort. First and foremost is whether FDA will have sufficient resources to devote to the task given its other existing food safety and defense responsibilities, and the new ones that are almost certain to be heaped upon the agency in the coming year. Second is whether FDA chooses to maintain the relative vagueness of the existing regulations, which has been lauded by some as permitting needed flexibility for a highly heterogeneous industry, but criticized by others as being so flexible as to mean little. If the dietary supplement CGMP final rule is any indication, a revised food CGMP regulation could be considerably more detailed than current Part 110. Third is whether someone chooses to raise a challenge on some of the more contentious issues at play (records maintenance and access requirements other than those mandated under the Bioterrorism Act stand out in this regard). For the moment, an overhaul of Part 110 appears to be what FDA has in mind. But as events unfold, if that climb proves to be as steep and lengthy as it did with FDA’s issuance of the dietary supplement CGMP final rule (10 years!), FDA could choose to tackle the highest risk food CGMP issues piecemeal by issuing more guidance documents such as those that address fresh-cut fruit and vegetable safety and Listeria in ready-to-eat foods. That approach would not satisfy those who want specific, enforceable requirements, but it’s an approach that could yield a decent return on investment – not a small thing in these lean times.
Posted at 11:03 AM in Foods | Permalink
By Dara Katcher Levy & Ricardo Carvajal – On November 12, 2008, FDA issued an Import Alert on all food containing milk products from China. The Import Alert was issued because of concerns over melamine contamination of China’s milk products, including Chinese infant formula, which has been linked to 53,000 illnesses and at least four infant deaths. To request removal from the new Import Alert, firms will need to provide (1) evidence of five consecutive non-violative shipments (demonstrated through independent laboratory analyses and subsequent FDA release); (2) documentation from a third-party, in whom FDA has sufficient confidence, demonstrating that controls are in place such that products will not be contaminated with melamine and melamine analogues; and (3) documentation that the firm is in compliance with all Chinese government requirements for exporting the product to the United States. Notably, the new Import Alert references appropriate standards for third party laboratories to test for melamine and cyanuric acid in foods. In 2007, FDA issued an Import Alert on bulk vegetable proteins from China before it had established acceptable testing standards for melamine. For several weeks thereafter, compliant products were subjected to unnecessary import delays. Without appropriate testing standards in place, importers were left with no means of providing adequate information to FDA to secure the product’s release from Customs. It appears that this scenario will not repeat itself. However, a different, equally unpleasant scenario appears to be unfolding. Although the Import Alert is for food containing milk products, foods that do not contain milk products but are imported using a product code listed in the Import Alert also are likely to be detained (e.g., cereal preparations, snack foods, and candy specialties).
Posted at 04:05 AM in Foods | Permalink