By Carrie S. Martin –

On April 29, 2009, FDA issued a final rule requiring new labeling for over-the-counter (“OTC”) pain relievers and fever reducers, also known as internal analgesic, antipyretic, and anti-rheumatic drug products (“IAAAs”).  The rule revises 21 C.F.R. Part 201 to require manufacturers to add specific warnings to their labeling about the safety risks associated with acetaminophen and non-steroidal anti-inflammatory drugs (“NSAIDs”), like aspirin, ibuprofen, naproxen, and ketoprofen.  In addition, the final rule requires that certain information, such as ingredient names, be prominently displayed on principal display panels (“PDPs”) of these products. 

FDA did not, however, issue final rules for several labeling issues discussed in its 2006 proposed rule.  As a result, OTC IAAA manufacturers can likely expect FDA to issue additional labeling changes at some point in the future. 

What products are covered under the new rule?

The final rule applies to all OTC pain relievers and fever reducers that contain acetaminophen or an NSAID, including combination products that contain one of these ingredients and other non-analgesic ingredients.

What new labeling is required?

There are four new major labeling requirements in FDA’s final rule:

Warnings 

• Manufacturers of products containing acetaminophen must add a warning about severe liver injury on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(1)(iii)-(v).

• Likewise, manufacturers of products containing an NSAID must add a warning about severe stomach bleeding on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(2)(iii)-(v).

• The new rules contain the specific language that must be included based on whether the product is indicated for adults, children under the age of 12, or both.  New 21 C.F.R. §§ 201.326(a)(1)(iii)-(v), (a)(2)(iii)-(v).

Statement of Identifies 

• The ingredient names (e.g., acetaminophen, aspirin, ibuprofen) of the IAAA products must be:  (a) highlighted (e.g., fluorescent, color contrast) or be in bold type; and (b) be in a prominent print size on the PDP.  This requirement applies to combination products as well.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

• For NSAID products or combination products containing an NSAID, the term “(NSAID)” must be:  (a) highlighted or be in bold type; and (b) be in a prominent print size on the PDP as part of the established name of the drug or after the general pharmacological (principal intended) action of the NSAID ingredient.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

Temporary Directional Statement 

• The PDP for IAAA products must include a directional statement—“See new warnings information”—for the next 12 months (i.e., until April 29, 2010).  The statement must also be highlighted or in bold type and be in a prominent print size.  New 21 C.F.R. § 201.326(b).

Alcohol Warnings 

• The new warnings about liver injury and stomach bleeding must also incorporate the warning on alcohol use while using the IAAA products instead of being a separate warning, as was previously required.   New 21 C.F.R. §§ 201.326(a)(1)(iii), (a)(2)(iii). 

What labeling requirements are precatory?

FDA’s new rule allows for voluntary highlighting of information under the “Active Ingredient” and “Purpose” headings in the Drug Facts section for all OTC IAAA drug products.  New 21 C.F.R. §§ 201.326(a)(1)(ii), (a)(2)(ii).

Who is required to implement the provisions of this rule?

Manufacturers of OTC pain relievers and fever reducers are required to comply with the new rule.  If an OTC drug product was approved via a new drug application (NDA), the NDA holder must submit the labeling changes as a supplement under 21 C.F.R. § 314.70(c).  The labeling, however, can be used without advance FDA approval.  New 21 C.F.R. § 201.326(c).

When does the rule go into effect?

All manufacturers must re-label their products to comply with the new rule within one year, i.e., April 29, 2010.

Why are these new labeling requirements being required?

FDA first proposed these labeling changes in a 2006 proposed rule based on the Agency’s review of data concerning the risk of liver damage and stomach bleeding with IAAA products.  FDA’s analysis found that unintentional overuse of acetaminophen was associated with a large number of emergency visits and hospital admissions and is responsible for approximately 100 deaths a year.  Post-marketing reports concerning NSAIDs showed that serious stomach bleeding can occur even when the products are used according to the directions and the warnings on the label.  Moreover, the proposed labeling changes corresponded to recommendations made by a 2002 FDA Advisory Committee meeting that addressed OTC IAAA products.

What is not covered by this final rule?

In the interest of time and the public safety, FDA decided not to address certain issues raised in the proposed rule in this final rule.  Some of these include the following:  (1) the safe daily dose for acetaminophen in healthy users; (2) the safe daily dose for acetaminophen users with chronic liver disease; (3) the safe daily dose for acetaminophen with alcohol use; (4) certain pediatric dosing; (5) various warnings that were proposed in 21 C.F.R. Part 343 but are not part of 21 CFR part 201; (6) acetaminophen-narcotic combinations; and (7) prescription labeling for OTC IAAA drug products.  FDA will, however, continue to evaluate the issues and address them in separate Federal Register notices.  The Agency did not, however, give a timeline as to when such notices might be issued.  In addition, on June 29 and 30, 2009, two FDA Advisory Committees will convene to discuss additional steps needed to warn about risks of acetaminophen overdoses.  As a result, industry should be on the look-out for additional labeling requirements involving OTC IAAA products to be coming down the pike.  This new rule, is likely only the beginning.

By Kurt R. Karst –      

“Is the Obama Administration Poised to Undo FDA’s Preemption Stance?” We posed this question in a post earlier this year after a pre-publication version of a 96-page final rule concerning new organ-specific warnings and related labeling for Over-The-Counter (“OTC”) Internal Analgesic, Antipyretic, and Antirheumatic (“IAAA”) drug products was posted and then quickly removed from the advance display Federal Register feature of FDA’s website late on January 23, 2009.  The pre-publication version of the final rule included a section titled “Federalism” stating, in relevant part, that:

We have determined that the rule will have a preemptive effect on State law.  Section 4(a) of [Executive Order 13132] requires agencies to “construe . . . a Federal statute to preempt State law only where the statute contains an express preemption provision or there is some other clear evidence that the Congress intended preemption of State law, or where the exercise of State authority conflicts with the exercise of Federal authority under the Federal statute.”  Section 751 of the Federal Food, Drug and Cosmetic Act (the act) (21 U.S.C. 379r(a)) is an express preemption provision.  Section 751r(a)) provides that “no State or political subdivision of a State may establish or continue in effect any requirement– . . . (1) that relates to the regulation of a drug that is not subject to the requirements of section 503(b)(1) or 503(f)(1)(A); and (2) that is different from or in addition to, or that is otherwise not identical with, a requirement under this Act, the Poison Prevention Packaging Act of 1970 (15 U.S.C. 1471 et seq.), or the Fair Packaging and Labeling Act (15 U.S.C. 1451 et seq.).”  Currently, this provision operates to preempt States from imposing requirement related to the regulation of nonprescription drug products.  Section 751(b) through (e) of the act outlines the scope of the express preemption provision, the exemption procedures, and the exceptions to the provision. . . .

Although this final rule would have a preemptive effect, in that it would preclude States from promulgating requirements related to these drug products that are different from or in addition to, or not otherwise identical with a requirement in the final rule, this preemptive effect is consistent with what Congress set forth in section 751 of the act.  Section 751(a) of the act displaces both state legislative requirements and state common law duties. We also note that even where the express preemption provision is not applicable, implied preemption may arise (see Geier v. American Honda Co., 529 US 861 (2000)).

Although we do not yet have a definitive answer to our question, it appears as though the Obama Administration is backing off from the Bush Administration’s preemption position. 

In an interesting turn of events this 100th day of the Obama Administration, FDA has officially published the OTC IAAA final rule.  The “Federalism” section of the rule has been significantly revised to remove much of the pro-preemption language included in the earlier version.  Now that section states: 

FDA has analyzed this final rule in accordance with the principles set forth in Executive Order 13132.  We provided the States with an opportunity for appropriate participation in this rulemaking when we sought input from all stakeholders through publication of the proposed rule in the Federal Register of December 26, 2006 (71 FR 77314).

On December 27, 2006, FDA’s Division of Federal and State Relations provided notice via email transmission of a letter to elected officials of State governments and their representatives.  The letter advised the States of the publication of the proposed rule and stated that when published as a final rule, this regulation would preempt State law in accordance with section 751 of the Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 379r(a)). The letter encouraged State and local governments to review the proposed rule and to provide any comments to the docket (Docket No. 1977N–0094L) by May 25, 2007, or to contact certain named individuals.  FDA did not receive any comments in response to this notice, or any comments from the States in response to the publication of the proposed rule. 

In conclusion, we believe that we have complied with all of the applicable requirements under the Executive order and have determined that the preemptive effects of this rule are consistent with Executive Order 13132.

In another turn of events reported by Drug and Device Law Blog yesterday, the Solicitor General submitted a letter to the U.S. Court of Appeals for the Third Circuit in Colacicco v. Apotex.  That case concerns whether actions taken by FDA pursuant to the FDC Act and the Agency’s implementing regulations preempt plaintiffs’ state law failure-to-warn claims against certain drug manufacturers with respect to certain  selective serotonin reuptake inhibitors.  Several parties, including FDA, entered and argued the case as amici for the appellee.  According to the Solicitor General’s April 28, 2009 letter:

[T]he United States does not take a position on whether plaintiffs-appellants’ claims in this case are preempted.  The Food and Drug Administration has not yet conducted the sort of reexamination of various preemption issues following the Supreme Court’s decision in Wyeth that would be necessary to inform a position of the United States in this case.  Accordingly, the United States hereby withdraws the amicus brief previously filed in this Court. 

Stay tuned, as other incremental changes in the government’s preemption position seem likely to occur.

By Ricardo Carvajal –      

FDA has announced that it expects compliance with its final rule prohibiting the use of certain cattle origin materials (e.g., brains and spinal cords from cattle 30 months of age and older) in the food or feed of all animals on October 26, 2009.  When the final rule was published, the effective date was listed as April 27, 2009.  In response to rumblings that a number of affected parties would be unlikely to achieve compliance by that date, FDA solicited comment for 7 days on whether it should delay the effective date of the rule by 60 days.  The comments revealed that a 60 day delay would not be nearly enough.  However, FDA evidently had no appetite for a significant postponement of the effective date of the rule.  Instead, FDA has announced that the effective date remains April 27 – but the “compliance date” is now October 26, 2009.

Of late, more attention has been paid to the essential role that the states play in maintaining food safety, and to the problematic lack of uniformity in standards, practices, and funding from state to state.  It appears that the lack of uniformity extends to carcass disposal.  As noted by FDA, “State law may dictate whether dead animals can be buried or composted, or whether an incinerator needs to be approved before one is built.”  Thus, a number of states may be lacking the infrastructure needed to absorb the quantities of cattle material that will be diverted from animal feed under the final rule.  FDA has promised to help by finalizing its Draft Small Entities Compliance Guide for Renderers and by engaging in more outreach to State agencies and the rendering industry.

By Susan J. Matthees –

At the request of the Centers for Disease Control and Prevention ("CDC"), FDA announced last night that it would issue Emergency Use Authorization ("EUA") of flu medicines and diagnostic tests in response to the recent swine flu outbreak.  Two antiflu drugs, Tamiflu and Reneza, and the rRT-PCR Swine Flu Panel diagnostic test were given EUAs.  Both Tamiflu and Reneza have been approved to treat influenza, but the EUAs allow for Tamiflu to be used in children under age 1 and broadens the dosing recommendations for children older than 1 year.  The EUA gives CDC the ability to distribute the rRt-PCR Swine Flue Panel diagnostic test to qualified personnel who can perform the test and interpret the results. 

FDA was given authority to grant EUAs as part of the Project BioShield Act of 2004, which amended section 564 of the Federal Food, Drug, and Cosmetic Act ("FDC Act") to allow FDA to authorize use of an unapproved or uncleared medical product or unapproved or uncleared uses of a medical product during a declared emergency.  The Secretary of Health and Human Services can declare an emergency based on a determination of an emergency by the Secretary of Homeland Security, the Secretary of Defense, or on his or her own determination of a public health emergency.  (See FDA guidance document here.)  In this case, the Department of Health and Human Services made a determination that swine flu created a national public health emergency on Sunday. 

This is not the first time that FDA has authorized EUAs.  FDA authorized EUAs for anthrax vaccines for individuals deemed to be at high risk of exposure to an anthrax attack.  In fall 2008, FDA authorized use for doxycycline hyclate tablet emergency kits.

FDA will soon issue a Federal Register notice announcing the specific content of the EUA.  In the meantime, CDC published its treatment recommendations for the emergency use of these products on their website this morning.

By John R. Fleder –

On April 28, 2009, the United States Supreme Court issued an important ruling on an administrative law issue.  In FCC v. Fox Television Stations, the Court by a 5-4 vote ruled that the FCC had properly explained its decision that Fox had allowed "indecent" language to appear on two live broadcast incidents where performers (Cher, Nicole Richie, and Paris Hilton) uttered alleged obscenities.  The Second Circuit Court of Appeals had earlier reversed the FCC's decision when that court concluded that when an agency changes its policy on a matter, the agency must give a "more substantial explanation" for its new policy.  The Supreme Court reversed and concluded: "[w]e find no basis in the Administrative Procedure Act or in our opinions for a requirement that all agency change be subjected to more searching review."  Instead, the Court stated that an agency should ordinarily acknowledge that it is changing its position and that there are good reasons for the new policy.  However, according to the Supreme Court, the agency need not demonstrate to a court's satisfaction that the reasons for the new policy are better than the reasons for the old one. 

One can safely assume that the new Obama Administration will cite this ruling whenever it chooses to alter a policy developed in the prior Administrations.

By William T. Koustas –      

Earlier this month, FDA announced that Institutional Review Board (“IRB”) Coast IRB, LLC of Colorado Springs, Colorado (“Coast”) voluntarily agreed to stop reviewing new FDA-regulated studies and halt enrollment of new subjects in ongoing trials after FDA determined it committed several violations of laws and regulations in approving a fake research study during a U.S. Government Accountability Office ("GAO") undercover investigation. 

In its investigation, GAO selected three independent IRBs to submit fake research protocols to that contained significant problems.  The GAO created a fake medical device company, a fake medical device with no history and fake specifications and vague information about some aspects of the proposed study.  Coast was the only one of the three IRBs to approve the fake study.  FDA identified the following violations in its Warning Letter to Coast following the investigation:

1. “The IRB failed to determine that risks to subjects are minimized.”  21 C.F.R. § 56.111(a)(1).
2. “The IRB failed to determine that risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.”  21 C.F.R. § 56.111(a)(2).
3. “The IRB failed to determine the applicability of 21 CFR Part 812 and failed to make a risk determination for the investigational device study.”  21 C.F.R. §§ 812.2(c)(2), 812.66, 812.20(a).
4. “The IRB failed to ensure that basic elements of informed consent are included in the IRB-approved consent form.”  21 C.F.R. §§ 50.25(a)(2) and 56.109(b).
5. “The IRB failed to demonstrate its ability to ascertain the acceptability of the proposed research in terms of regulations, applicable law, and standards of professional conduct and practice.”  21 C.F.R. § 56.107(a).

In light of these findings, several significant customers severed their relationship with Coast, leading the IRB to “cease future company operations.”  FDA and Coast officials reportedly met in Colorado Springs on April 22nd to discuss ways to minimize the disruption for patients and sponsors involved in clinical trials reviewed by Coast.  Approximately 300 ongoing studies and 3,000 investigators across the U.S. could be affected. 

By Susan J. Matthees –

Last week FDA published a memorandum titled “FDA Comments on Symbols Public Hearing and Current Plans for Addressing Issues.”  The memorandum responds to questions and issues raised during a September 10-11, 2007 hearing titled "Use of Symbols to Communicate Nutrition Information, Consideration of Consumer Studies and Nutritional Criteria," and discusses FDA’s current plans for front-end nutrition labeling.  The memorandum explains that FDA still “has gaps” in its understanding of the issues related to the use of symbols and “will continue to actively evaluate the issues regarding the use of nutrition symbols in food labeling.” 

FDA has concentrated discussions on front-end nutrition labeling on three main issues: nutrition issues, which are related to the types of symbols and the requirements for those symbols; consumer issues, which are related to how consumers understand and use symbols; and economic issues, which are related to “the economic impacts of nutrition symbols on food labels.”  FDA’s memorandum explains that the meeting and comments that followed did not provide sufficient data to fully answer all the questions surrounding these issues. 

With respect to the nutrition information, the memorandum states that FDA got little information on how consumers understand the symbols.  FDA further states that “the public hearing produced little usable research or other information on the majority of consumer issues listed in the public hearing notice.”  As a result, FDA plans to conduct studies “using qualitative and quantitative research techniques” in order to learn more about how consumers use and understand nutrition symbols.  Finally, FDA found that the cost of implementing a nutrition symbol program varies by manufacturer and that it is unclear whether the symbols actually encourage consumers to buy specific products. 

FDA outlines a plan for developing more information on the use of symbols in nutrition labeling, which is primarily focused on continued research of the topic.  However, the Agency makes no statements about when it will address the issue again, and it is likely that it could be several years before the agency addresses the issue again. 

By Ricardo Carvajal & John R. Fleder –

In Federal Trade Commission v. Medlab, Inc., the United States District Court for the Northern District of California granted summary judgment on April 21, 2009, to the FTC in an action against a marketer of weight loss products, which the FTC alleged had engaged in false advertising and deceptive business practices.  Defendants claimed in their advertising that their products quickly caused substantial weight loss with no dieting or exercising (and that this effect had been demonstrated in clinical studies), and that their products caused permanent weight loss.  In support of its decision, the court cited expert testimony that defendants’ claims were “clearly outside the realm of plausible science.”  Both individual and corporate defendants are liable for restitution in the amount of $2.7 million, which the court calculated by reference not just to profits, but to “the full amount lost by consumers.”

By Carmelina G. Allis –

In June 2008, we reported that the Accreditation Council for Continuing Medical Education (“ACCME”) had issued for comment a proposed restrictive paradigm under which commercial support for continuing medical education (“CME”) would be permissible if certain conditions were met.  In an interest to continue those earlier efforts to find alternatives to a complete ban on commercial funding, ACCME is now requesting comments on two proposals that create two new designations and review processes for providers of CME programs – the “Commercial Support-Free™ Accredited CME” and the “Promotional Teacher and Author-Free™ Accredited CME” – and one proposal that creates an independent CME funding entity.

The Commercial Support-Free™ Accredited CME would be a new designation and review process for providers that wish to identify their CME programs as those that do “not utilize funds from commercial interests that have been donated to support continuing medical education.”  ACCME proposes that in order to meet the Commercial Support-Free™ Accredited CME designation, no CME activity or part of the program can receive commercial support.  The CME program also cannot underwrite the costs with funds obtained from advertising or promotion paid by an ACCME-defined commercial interest.

The Promotional Teacher and Author-Free™ Accredited CME would be a new designation and review process for those providers that wish to identify their CME program as “one that does not utilize teachers/authors that have acted for a commercial interest in promotional and marketing activities.”  In order to meet this designation, Standard 2, Resolution of Personal Conflicts of Interest of the ACCME Standards for Commercial SupportSM would be fulfilled by recusal.  That is, no person who has ACCME-defined relevant financial relationships derived from promotional and marketing activities may teach in or write for any CME program or part of a CME program that qualifies for this designation.

The independent CME funding entity is being proposed with the intent to create an organization that will accept unrestricted donations to be designated for the special purpose of funding accredited CME.  This funding proposal would ensure the independence of commercially supported CME if the program receives funds from a pooled source.  The pooled funds would be distributed to ACCME Recognized and Accredited organizations to be used for the development and presentation of CME.  In its proposal, ACCME suggests that the funding entity be independent of ACCME; would not provide funds to ACCME; have its own independent management and governance structure; would establish its own granting criteria that meet ACCME’s content validation policies; and would fund CME for U.S. learners.

ACCME is accepting comments on each of these proposals until May 21, 2009, which can be submitted electronically here.

By Kurt R. Karst –      

FDA’s April 2009 response to a September 2007 suitability petition requesting permission to submit an ANDA  for a lyophilized generic version of  ZOMETA (zoledronic acid) Injection and an FDA determination that such drug product, if approved, would be therapeutically equivalent to a ready-to-use solution version of ZOMETA Injection reaffims a recent change in the therapeutic equivalence definition of “AP” rated drug products described in the Orange Book Preface.  That change clarified that lyophilized powders for reconstitution and ready-to-use solutions are pharmaceutical alternatives and are not “AP” rated to one another. 

Pharmaceutically equivalent prescription drug products (i.e., generally drug products in the same strength, route of administration, dosage form, and containing the same active ingredient) are identified in the Orange Book with either an “A” or “B” therapeutic equivalence code designation.  “A-rated” drug products are considered to be to therapeutically equivalent to other pharmaceutically equivalent products, because there are no known or suspected bioequivalence problems, or such problems have been resolved with adequate evidence supporting bioequivalence.  “B-rated” drug products are not considered to be therapeutically equivalent to other pharmaceutically equivalent drug products, because actual or potential bioequivalence problems identified by FDA have not been resolved by adequate bioequivalence evidence. 

Drug products assigned an “A” rating fall under one of two categories: (1) those active ingredients or dosage forms for which no in vivo bioequivalence issue is known or suspected, and for which bioequivalence to the Reference Listed Drug (“RLD”) is presumed and considered self-evident based on other data in an application or by a showing that an acceptable in vitro dissolution standard is met; or (2) those active ingredients or dosage forms presenting a potential bioequivalence problem, but the applicant’s approved application contains adequate scientific evidence establishing (through in vivo and/or in vitro studies) the bioequivalence of the product to a selected RLD.  Drug products that fall under the first category are assigned a therapeutic equivalence code depending on the dosage form.  These codes include “AA,” “AN,” “AO,” “AP,” or “AT.”  Drug products that fall under the second category are coded “AB” (the most common code assignment).  AP-rated drug products are injectable aqueous solutions and, in certain instances, intravenous non-aqueous solutions.

The 2007 Orange Book Preface stated with respect to AP-rated drug products that:

Injectable products available as dry powders for reconstitution, concentrated sterile solutions for dilution, or sterile solutions ready for injection are all considered to be pharmaceutically and therapeutically equivalent provided they are designed to produce the same concentration prior to injection and are similarly labeled.

That description was changed in the 2008 Orange Book Preface to state:

Injectable products available as dry powders for reconstitution, concentrated sterile solutions for dilution, or sterile solutions ready for injection are pharmaceutical alternative drug products.  They are not rated as therapeutically equivalent (AP) to each other even if these pharmaceutical alternative drug products are designed to produce the same concentration prior to injection and are similarly labeled.

This clarification was made after FDA responded to a July 2006 suitability petition in which the petitioner requested that FDA determine whether a lyophilized formulation of ELOXATIN (oxaliplatin) Injection was withdrawn for safety or effectiveness reasons, permit the submission of an ANDA for a lyophilized generic version of ELOXATIN, and determine that the proposed generic product “would be therapeutically equivalent to the currently marketed [ready-to-use solution] product.”  In its response, FDA stated:

The Eloxatin powder formulation would be considered to be a different dosage form than the Eloxatin aqueous solution because injectable dry powders and injectable solutions are different dosage forms.  Two drug products are rated as therapeutic equivalents in the Orange Book, only if, among other things, they are pharmaceutical equivalents, which is defined, in part, as being of the same dosage form . . . .  An injectable dry powder would be considered a pharmaceutical alternative to an injectable solution . . . .

FDA’s response concerning generic ELOXATIN tracks FDA’s response on the same topic for generic ZOMETA. 

Apparently the AP rating description in the 2007 Orange Book Preface had led some to believe that injectable dry powders and solutions would be AP-rated.  This is understandable, because, until recently, FDA lumped most injectable drug products into a single “Injectable” dosage form descriptor, even though the Agency has historically considered injectable dry powders and solutions to be different dosage forms. 

By JP Ellison & John R. Fleder –

The Supreme Court’s April 22, 2009 decision in NKEN v. HOLDER relates to expediting the removal of aliens from this country.  The decision merits mention here because it preserves the ability of appellate courts to stay government action pending an appeal.  Regulated companies should remember that the government’s view, and even the view of a trial court, may not be the final word.  Appellate review of trial courts and administrative actions plays an important role in our system, and the Court’s decision reinforces that point.  This decision also has an interesting discussion of what the Court described as the differences between a “stay” and an “injunction”

By Christine P. Bump – 

On April 22, 2009, FDA announced that it sent a letter to the manufacturer of Plan B stating that the Agency would, “upon submission and approval of an appropriate application,” permit the sale of Plan B without a prescription to women 17 years of age and older.  Plan B is manufactured by Duramed Research, Inc., a subsidiary of Barr Pharmaceuticals. 

FDA’s announcement was in response to the scathing 52-page opinion issued by the United States District Court for the Eastern District of New York.  As we previously reported, the decision vacated FDA’s denial of a Citizen Petition which requested that the Agency make Plan B (and all emergency contraceptives like it) available without a prescription to women of all ages, and ordered FDA to permit Barr Pharmaceuticals to make Plan B available without a prescription to 17-year old women.   FDA’s statement yesterday specified that its letter to Duramed Research, Inc. was in accordance with the court’s order, and that it was “consistent with the scientific findings since 2005 by the Center for Drug Evaluation and Research.”  The government is not going to appeal the decision of the United States District Court for the Eastern District of New York.

Plan B, often referred to as the morning after pill, is an emergency contraceptive that can be used to reduce the risk of unwanted pregnancy if taken within 72 hours of unprotected sex or the failure of contraception.  It contains one of the same active ingredients used in prescription birth control pills (levonorgestrel), but at a much higher dose, and is not for routine use. 

Plan B has been available by prescription since 1999.  On August 24, 2006, FDA approved non-prescription use of Plan B for women 18 years and older.  Women 17 years and younger, however, still needed a prescription to obtain the drug.  FDA described its August 2006 decision as a conclusion reached through an “extensive process” of obtaining expert advice and public comment.  The Agency stated that the non-prescription use of Plan B presented novel issues, and that FDA was committed to “a careful and rigorous scientific process,”  although an advisory panel convened by FDA had recommended by a vote of 23-4 that Plan B be available over-the-counter without any age restrictions.   Note that the effect of both the District Court's decision and FDA's notice would still require a prescription for girls under the age of 17, although the District Court remanded the matter back to FDA for the Agency to “reconsider its decisions regarding the Plan B switch to OTC use.”

By Carrie S. Martin –      

As we reported previously, FDA decided to institute a class-wide Risk Evaluation and Mitigation Strategy (“REMS”) for 24 different opioid products. 

FDA held a private meeting on March 3, 2009, with the 16 manufacturers of the opioid products to discuss the design and development of the REMS.  Dr. Sharon Hertz, Deputy Division Director for the Division of Anesthesia, Analgesia and Rheumatology Products, explained that FDA’s proposed REMS includes a Medication Guide and elements to assure safe use.  Among the elements to assure safe use are certification requirements for health care providers and those who dispense drug and an implementation system that includes a database of all enrolled health care providers and a system to monitor and evaluate the REMS.

FDA has now announced that it will hold a public meeting on May 27 and 28, 2009, to obtain additional input regarding the development of the opioid REMS.  (We have updated our REMS Tracker to include this information.)  Affected sponsors and other interested parties are invited to present their views on FDA’s proposed REMS, how FDA can structure the REMS to minimize the burden patients and health care practitioners while protecting patients, and how FDA should evaluate the effectiveness of the REMS.  Specifically, FDA is seeking public comment on the following questions, among others:

• What education should be required of prescribers and those who dispense medication so that they are properly educated about the risks of the products and can counsel patients on the appropriate use of their medication?

• What education should be provided to patients and should it include a prescriber-patient agreement?

• What additional elements are necessary to support the safe use of approved opioids?

• How extensive should the REMS restrictions be?

• Should the REMS include controls on those who distribute the products to pharmacies and other health care providers and, if so, what kinds of controls?

• What existing systems already exist that could be used to implement the REMS?

• What obstacles need to be addressed before FDA can develop a single, shared system for innovator and generic drug manufacturers?

• What metrics should FDA use to assess the success of the REMS?

To attend the meeting, FDA requires registration via e-mail to OpioidREMS@fda.hhs.gov by May 15, 2009.  Seating is limited, however, and registration will be based on a first-come, first-served basis.  Interested persons may also submit comments to FDA by June 30, 2009, regardless of attendance.  Electronic comments can be submitted to http://www.regulations.gov.  Written comments should be submitted to the Division of Dockets Management (HFA-305), FDA, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

By Jamie K. Wolszon & Anne Marie Murphy –

On April 20th, the Pharmaceutical Research and Manufacturers of America (“PhRMA”) issued a revised “Principles on Conduct of Clinical Trials and Communication of Clinical Trials Results.”  The revision outlines, among other things, the trade group’s Principles on the appropriate conduct of clinical research, registration of clinical trials ¬on a public website, and disclosure of study result summaries. 

PhRMA released the revised measures on the same day it testified at a public meeting on issues that the National Institutes of Health will consider as it develops regulations to expand the clinical trial registry and results data bank in accordance with the FDA Amendments Act of 2007 (“FDAAA”) Title VIII.  We previously reported on the meeting.

PhRMA first issued its Principles in 2002, and issued revisions in 2004.  The Principles address issues including: protecting research participants; conduct of clinical trials; ensuring objectivity in research; and providing information about clinical trials.  The revised voluntary code takes effect on October 1, 2009.

Some of the more significant provisions of the Principles are as follows:
 
Registration of Clinical Trials.  PhRMA advises member companies to register on a public database timely summary information about all clinical trials that study products in patients.  PhRMA defines timely as 21 days of enrollment of the first patient in the clinical trial.

PhRMA defines clinical trials subject to registration as those, including Phase I studies, conducted in patients.  Use of the word “patients” is significant as PhRMA’s definition excludes most Phase I studies, i.e., those performed in healthy volunteers.  In this respect, PhRMA’s Principles may be viewed as more comprehensive than the text of the FDAAA provision, which defines an “applicable drug clinical trial,” subject to the databank registration requirements, to mean, “a controlled clinical investigation, other than a phase 1 clinical investigation.”

PhRMA recommends that sponsors, when registering trials, provide all of the information mandated in FDAAA, even for studies not subject to the new law, “except if providing such information could jeopardize the [product’s] intellectual property protection.”

Submission of Summary Results.  As it did in its prior version, PhRMA promises to disclose summary results of all clinical trials for approved drugs, regardless of the study’s outcome.  In a major change from its prior version, however, PhRMA also promises to post timely summary results of all clinical trials if the sponsor discontinues development of the drug.  PhRMA defines timely as 12 months after the trial ends, 30 days within drug approval or a year after a company discontinues the drug development program. 

Conflict of Interest Disclosures for Articles.  The revision urges sponsors to encourage physicians and researchers to disclose conflict of interest information when authoring manuscripts to medical journals.  Authors that submit a manuscript to a medical journal, according to PhRMA, should disclose “all financial and personal relationships that might bias their work,” and explicitly state whether potential conflicts exist.  The trade group also recommends that authors identify “individuals who provide writing or other assistance and disclose the funding source for this assistance.”  Furthermore, authors should describe several aspects of the sponsor’s involvement with the study.

Increased Qualifications Needed for Authorship.  The revised Principles would make it more difficult to be listed as an author of an article in a medical journal.  These more stringent guidelines adhere to the standards of the International Committee of Medical Journal Editors.

Provision of Study Results to Investigators and Participating Patients.  PhRMA directs sponsors to provide all investigators with a full summary of the study results even if an investigator does not contribute to the publication of the study.  The trade association offers investigators in a multi-site clinical trial an opportunity to review data for the entire study.  The document also supports efforts of investigators to communicate a summary of the trial results to research participants after the study ends.

Sponsor Right to Review.   PhRMA also confirms that sponsors have the right to review manuscripts, presentations, or abstracts that result from the sponsor’s studies or use the sponsor’s data prior to publication or presentation.

Conforming with PhRMA Code on Interactions with Healthcare Professionals.  PhRMA Principles also conform to the revised PhRMA Code on Interactions with Healthcare Professionals, effective January 2009.  We previously reported on the revised PhRMA Code, a voluntary code that focuses on appropriate industry interactions with healthcare professionals as they relate to the marketing of products. For instance, the Principles discourage: the use of resorts as venues for meetings with clinical investigators and staff; sponsor provision of entertainment or recreational events for clinical investigators and staff; and sponsor payment of honoraria or travel or lodging expenses for those who are not involved in the clinical trial.  

By Ricardo Carvajal & John R. Fleder –

On April 20, 2009, the U.S. Supreme Court let stand the Third Circuit’s decision in Fellner v. Tri-Union Seafoods.  As we discussed in a prior posting, Fellner’s lawsuit contends that Tri-Union is guilty of negligence under New Jersey law for failing to warn consumers of the risks posed by methylmercury in its canned tuna products.  The U.S. District Court for the District of New Jersey granted Tri-Union’s motion to dismiss the lawsuit on federal preemption grounds, but the Third Circuit reversed that decision.  We will have to see if the Supreme Court’s action not to hear the case now suggests that it will rule in the future that there is no federal preemption of claims such as Fellner’s.