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.

By Ricardo Carvajal & John R. Fleder –

On April 17, 2009, DOJ’s Office of Information Policy (“OIP”) issued guidance to federal agencies on President Obama’s FOIA Memorandum of January 21st and Attorney General (“AG”) Holder’s subsequent FOIA March 19th guidelines.  The President’s FOIA memorandum directed all agencies to administer the FOIA with a “clear presumption” in favor of disclosure.  In his subsequent guidelines, the AG encouraged agencies to make discretionary disclosures and avoid withholding information simply because it is legally possible.  In addition, the AG emphasized that agencies must consider whether partial disclosures can be made in the case of records that cannot be fully disclosed.  The AG’s guidelines also noted that DOJ will defend an agency’s denial of a FOIA request only if:

(1) the agency reasonably foresees that disclosure would harm an interest protected by one of the statutory exemptions, or
(2) disclosure is prohibited by law.

The AG’s guidelines explicitly rescinded AG Ashcroft’s FOIA memorandum of October 2001, which provided that DOJ would defend denials “unless they lack a sound legal basis or present an unwarranted risk of adverse impact on the ability of other agencies to protect other important records.”

OIP’s guidance describes the combined impact of the President’s Memorandum and the Attorney General’s guidelines as a “sea change in the way transparency is viewed across the government.”  The guidance sets out five points that are considered key to realizing the President’s directive to “usher in a new era of open government”:

(1) agency personnel “must alter their mind set” to “view all FOIA decisions through the prism of openness”;
(2) records should be reviewed “with a view toward determining what can be disclosed, rather than what can be withheld”;
(3) “information should not automatically be withheld just because an exemption technically or legally might apply”;
(4) where full disclosure is not possible, agencies should take reasonable steps to release both information that is nonexempt and information that, even though exempt, can be discretionarily released;
(5) records cannot be withheld to avoid embarrassing public officials, prevent the revelation of errors and failures, or “because of speculative or abstract fears.”

The OIP’s guidance makes clear that it will still be appropriate to withhold certain information to prevent harm to national security, personal privacy, and law enforcement interests, and that certain types of information are required to be withheld by other legal authorities (e.g., trade secrets and confidential commercial information under the Trade Secrets Act).

According to the OIP guidance, “[t]here is no doubt that records protected by Exemption 5  hold the greatest promise for increased discretionary release.”  Exemption 5 provides for the discretionary withholding of “inter-agency or intra-agency memorandums or letters which would not be available by law to a party other than an agency in litigation with the agency.”  It encompasses the deliberative process privilege, the attorney work-product privilege, and the attorney-client privilege.  Records covered by the deliberative process privilege (where government officials frequently discuss and debate what course of action they should take with regard to important government decisions) are the type of records that could be most affected by the guidance in terms of a new policy of openness and disclosure.

It is too soon to know what effect the OIP guidance will have on FDA’s information disclosure policies and practices.  However, the timing of the issuance of the President’s FOIA Memorandum, together with the prompt publication of the AG’s guidelines and OIP’s guidance, suggest that the issue of increased transparency is one of considerable importance to the new Administration.

By William T. Koustas –

On April 20th, the Federal Trade Commission ("FTC") announced that it has brought, and at the same time tentatively settled, charges of false advertising brought under the FTC Act against Kellogg, the world’s largest cereal maker.  The FTC accused Kellogg of falsely asserting that Frosted Mini-Wheats are “clinically shown to improve kids’ attentiveness by nearly 20%.”  Kellogg also asserted that children who eat Mini-Wheats experienced a 20% increase in attentiveness compared to children who ate no breakfast.  According to the FTC, the study Kellogg cited for substantiation of its claim shows that only about one in nine children who ate Mini-Wheats improved their attentiveness by 20% or more.  In comparison with children who ate no breakfast, children who ate Mini-Wheats were slightly less than 11% more attentive on average, with very few children actually being 20% more attentive.  

The proposed settlement Kellogg has agreed to consists of two major components: (1) prohibiting Kellogg from making similar claims regarding Frosted Mini-Wheats, or any of its cereals and snacks unless the claims are substantiated; and (2) barring Kellogg from misrepresenting the results of future studies regarding its products.  The FTC has unanimously approved the tentative settlement, but will publish it in the Federal Register seeking public comment.

In the late 1970s, the FTC embarked on a crusade against national advertisers of food products for children.  That effort was criticized by some as FTC’s attempt to act as “our Nation's Nanny.”  Will today’s action, under the FTC's new Chairman, Jon Leibowitz, signal a more broad-based effort in this area?

By Kurt R. Karst –      

We previously reported (here and here) on concerns as to whether a company submitting an ANDA (or a 505(b)(2) application) containing the results of an in vivo bioequivalence study must certify on Form FDA 3674 that new Public Health Service Act (“PHS Act”) § 402(j), as added by Title VIII of the FDA Amendments Act (“FDAAA”), applies and that in vivo bioequivalence studies  have to been registered at ClinicalTrials.gov.  PHS Act § 402(j)(1)(A) defines an “applicable drug clinical trial,” which is subject to the databank registration requirements,  to mean, in relevant part, “a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug subject to [FDC Act § 505] . . . .” (emphasis added).  In a recent comment submitted to the National Institutes of Health (“NIH”), the Generic Pharmaceutical Association (“GPhA”) requests that NIH clarify that a clinical endpoint bioequivalence study should not be considered an “applicable drug clinical trial.”

In December 2008, NIH issued a draft document, titled “Elaboration of Definitions of Responsible Party and Applicable Clinical Trial” discussing, among other things, the applicability of the FDAAA Title VIII requirements to bioequivalence studies.  The draft “elaborations” document was updated in March 2009 to clarify that it “represent[s] the [NIH’s] current thinking on this topic.” According to the draft document:

In the agency’s view, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) is considered to be a controlled clinical investigation. In this case, the control generally would be the previously approved drug product.

Although a bioequivalence study is a controlled clinical investigation, the draft guidance goes on to note that:

Under certain circumstances, a clinical investigation designed to demonstrate that an investigational drug product is bioequivalent to a previously approved drug product, or to demonstrate comparative bioavailability of two products (such as for purposes of submitting an abbreviated new drug application under 21 USC § 355(j) or a new drug application as described in 21 USC § 355(b)(2)) will be considered to be a Phase 1 clinical investigation under 21 CFR § 312.21 for purposes of determining whether a particular clinical trial is an “applicable drug clinical trial” under Title VIII of PL 110‐85 (section 402(j)(1)(A)(iii) of the PHS Act).  Although Phase 1 clinical investigations are generally designed to fit sequentially within the development plan for a particular drug, and to develop the data that will support beginning Phase 2 studies, 21 CFR § 312.21(a) does not limit Phase 1 trials to that situation.  Bioequivalence or comparative bioavailability studies that fall within the scope of the studies described in 21 CFR § 320.24(b)(1), (2), and (3) share many of the characteristics of Phase 1 clinical investigations as described in 21 CFR § 312.21(a), and therefore will be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85. However, bioequivalence or comparative bioavailability trials that fall within the scope of 21 CFR § 320.24(b)(4) do not share the characteristics of Phase 1 trials as described in 21 CFR § 312.21(a), and thus would not be considered to be Phase 1 trials for purposes of Title VIII of PL 110-85.

Elaborations Document at 10 (emphasis added).

Bioequivalence studies that fall within the scope of 21 CFR § 320.24(b)(4) and that are not exempt from reporting on ClinicalTrials.gov are generally clinical endpoint studies.  According to an FDA Manual of Policies and Procedures, such studies are typically “applied to dosage forms intended to deliver the active moiety locally, forms that are not intended to be absorbed, or drug products for which traditional pharmacokinetic studies are not feasible,” such as drug products in topical dosage forms. 

In advance of an April 20, 2009 public meeting to solicit input on issues that NIH will consider as it develops regulations to expand the clinical trial registry and results data bank in accordance with FDAAA Title VIII, GPhA submitted a letter to NIH requesting that the agency reconsider its position that a clinical endpoint bioequivalence study is an  “applicable drug clinical trial” that must be registered on ClinicalTrials.gov.  According to GPhA:

We agree with NIH’s determination that most bioequivalence studies are “Phase I” studies and therefore excluded from the “applicable drug clinical trial” definition.  However, we disagree with NIH’s decision to include bioequivalence studies that use clinical endpoints to establish bioequivalence within such definition.  NIH’s position is inconsistent and without scientific merit.  There is no basis to distinguish between bioequivalence studies based solely on the endpoints used to establish bioequivalence.  These studies are not intended to prove the safety or efficacy of a drug product.  In contrast, Section 505(j) states that these studies are only permitted to include information and data sufficient to compare the bioavailability of the reference (i.e., innovator) and test (i.e., generic drug).  ANDA applicants are permitted to establish bioequivalence in a variety of ways, but the end result is always the same—a comparison of the rate and extent to which the active ingredient becomes available at the site of action.  All bioequivalence studies are performed for the same underlying reason and therefore should receive similar treatment under the ClinicalTrials.gov database.  Specifically, they are all “Phase I” studies that are excluded from the definition of “applicable drug clinical trial.”

The GPhA letter also takes issue with a statement in the draft “elaborations” document, which states: 

When a clinical investigation includes sites both within the U.S. (including any territory of the U.S.) and outside of the U.S., if any of those sites is using (for purposes of the clinical investigation) a drug that is subject to section 505 of the FDC Act, then the agency will consider the entire clinical investigation to be an “applicable drug clinical trial,” assuming that it meets the rest of the statutory definition.  A clinical investigation that is being conducted entirely outside of the U.S. (i.e., does not have any sites in the U.S. or in any territory of the U.S.) may be an “applicable drug clinical trial,” depending on where the drug being used in the clinical investigation is manufactured. If the drug is manufactured in the U.S. or any territory of the U.S., and is exported for study in another country under an IND, pursuant to 21 CFR § 312.110, or pursuant to section 802 of the FDC Act, then the drug is considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act (as applicable), and the clinical investigation may be an “applicable drug clinical trial,” if it meets the other statutory criteria.  If the drug is manufactured outside of the U.S. or its territories, the trial sites are all outside of the U.S., and the trial is not being conducted under an IND, then it would not be considered to be subject to section 505 of the FDC Act or section 351 of the PHS Act, and the clinical investigation would not be an “applicable drug clinical trial.”

Elaborations Document at 8 (emphasis added).

According to GPhA, the exemption highlighted above “will disadvantage U.S. companies and provide an incentive to move operations outside of the U.S.”

A videocast of the April 20, 2009 public meeting at which GPhA and several other organizations and firms that have submitted public comment to NIH will present, including PhRMA and BIO, can be viewed here.

By Ricardo Carvajal –      

According to a CVM Animal Feed Safety System update, the CVM Division of Animal Feeds has formed an Ingredient Safety Team that will begin accepting GRAS notification submissions for animal feed ingredients as part of a pilot program starting this summer.  According to the update

The Team will work with other components of CVM to review the notices.  Under the GRAS notification program, a notifier submits a summary of publicly available information in support of its claim that a substance (as described in the notification) should be considered GRAS under specific conditions of its intended use and not be considered a food additive, which requires pre-market approval by FDA. The information supplied by the notifier would address both the safety and utility of the substance. CVM will evaluate the submitted notification to determine whether it provides a sufficient basis for a GRAS determination or whether information in the notification or otherwise available to FDA raises issues that cause the Agency to question whether use of substance in feed, which includes pet food, is GRAS.

It appears that CVM’s program would be similar to the program that CFSAN has been operating for human food ingredients for several years, but CVM would consider “utility” in addition to safety.  At this time it is unclear what CVM means by "utility" and therefore whether consideration of "utility" would be consistent with the statuory definition of general recognition of safety in 21 U.S.C. § 321(s).  We look forward to learning more about the basis for CVM’s consideration of “utility” in the context of GRAS notifications, as well as what CVM ’s criteria for “utility” are.

By Kurt R. Karst –      

FDA’s April 15th decision to approve ANDAs for generic versions of Topiramate Sprinkle Capsules signals a new FDA interpretation of the 180-day generic drug exclusivity provisions of the FDC Act, which were amended in December 2003 under Title XI of the Medicare Modernization Act (“MMA”).  Although Topiramate Sprinkle Capsules is the first drug product approved that is subject to this new interpretation, according to FDA, there are other products that are affected.

Under the pre-MMA version of the statute, 180-day exclusivity was patent-based, such that an ANDA applicant (or different applicants) could be eligible for 180-day exclusivity with respect to different Orange Book-listed patents covering the Reference Listed Drug (“RLD”) if they submitted the first ANDA to FDA containing a Paragraph IV certification to a particular patent.  Pre-MMA 180-day exclusivity is triggered either by first commercial marketing (for all patents), or by a court decision favorable to an ANDA applicant (with respect to a particular patent).  The MMA amended the FDC Act such that the first company to submit an ANDA to FDA containing a Paragraph IV certification to any Orange Book-listed patent covering the RLD – i.e., a “first applicant” – is eligible for 180-day exclusivity.  Post-MMA, 180-day exclusivity is triggered by first commercial marketing of the drug product by any first applicant.  A first applicant can forfeit 180-day exclusivity eligibility under one or more forfeiture provisions created by the MMA. 

The MMA includes – at § 1102(b)(1) – an effective date provision for purposes of deciphering when the pre- or post-MMA 180-day exclusivity regime will apply.  That provision states:

. . . the amendment made by subsection (a) shall be effective only with respect to an [ANDA] filed . . . after [December 8, 2003] for a listed drug for which no [paragraph IV certification] was made before [December 8, 2003].

In explaining this provision, FDA’s October 2004 draft guidance document, titled “Guidance for Industry: Listed Drugs, 30-Month Stays, and Approval of ANDAs and 505(b)(2) Applications Under Hatch-Waxman, as Amended by the Medicare Prescription Drug, Improvement, and Modernization Act of 2003 – Questions and Answers,” stated only that “[w]ith two exceptions, the [MMA] provisions relating to 180-day exclusivity govern only ANDAs filed after the date of the MMA’s enactment (December 8, 2003) that reference a listed drug for which no paragraph IV certification was made in any ANDA before that date.”  This had led some people to believe that the pre-MMA 180-day exclusivity regime would apply only when there was an ANDA pending pre-MMA containing a Paragraph IV certification.  In a “Dear ANDA Applicant” letter FDA issued on April 15th, however, FDA explains that this is not the case, and that while the MMA’s effective date provision at § 1102(b)(1) is ambiguous, the Agency interprets the law such that pre-MMA patent-by-patent 180-day exclusivity applies.  FDA’s letter states, in relevant part, that:

when one or more applications were submitted before December 8, 2003, but the first paragraph IV certification was submitted after December 8, 2003, the statutory effective date provision is ambiguous. . . .  After consideration of the statutory language and the nature of each approach to exclusivity, we have concluded that it is appropriate to apply the pre-MMA statutory 180-day provisions to these applications.

Applying this interpretation to Topiramate Sprinkle Capsules ANDAs, FDA determined that two applicants – Cobalt and Barr – are eligible for 180-day exclusivity as a result of their Paragraph IV certifications to a single Orange Book-listed patent covering the RLD.  Barr submitted the first ANDA to FDA pre-MMA.  That ANDA contained a Paragraph III certification to a patent that has since expired.  After the MMA’s enactment, Cobalt submitted the first ANDA to FDA containing a Paragraph IV certification to that now-expired patent.  Both Cobalt and Barr later amended their ANDAs to include a Paragraph IV certification to a later-listed Orange Book patent covering the RLD, and both companies, as a result of FDA’s interpretation of MMA § 1102(b)(1), are eligible for 180-day exclusivity.

We understand that FDA’s new interpretation could affect a handful (or two) of products for which an ANDA was first submitted to FDA before the MMA’s enactment – even if such ANDA did not include any patent certification (because, for example, there was no patent listed in the Orange Book pre-MMA).  Because FDA’s Paragraph IV Certification List only identifies the date on which an ANDA (that has been received by FDA) containing a Paragraph IV certification was submitted to FDA, it is unclear what products are affected by FDA’s new interpretation.  Hopefully, FDA will devise a method for identifying what drug products are subject to the Agency’s new interpretation.  Absent such identification, an applicant could be under the false impression that the MMA’s 180-day exclusivity regime applies and that it is a first applicant and that another applicant cannot qualify for 180-day exclusivity based on a later-listed Orange Book patent.

By William T. Koustas –      

On April 15th, the Department of Justice announced that the U.S. has entered into a global criminal and civil settlement with Quest Diagnostics Inc. (“Quest”) and its subsidiary Nichols Institute Diagnostics (“NID”).  NID pleaded guilty to a felony charge of misbranding its Advantage Intact Parathyroid Hormone (“PTH”) Assay (“Intact Assay”) in violation of the FDC Act.  The government alleged that NID distributed marketing materials describing the Intact Assay as having “excellent correlation” with the IRMA Assay.  However, the company allegedly was aware the Intact Assay did not produce such correlated results, but instead provided elevated PTH readings.  Under the guilty plea, NID admitted that it “knowingly, intentionally and with intent to mislead, introduce[d] into interstate commerce, and caused the introduction into interstate commerce of the [Intact Assay], that was misbranded.”  NID will pay a $40 million criminal fine.

The civil settlement arose from a whistleblower suit brought under the qui tam provisions of the Federal False Claims Act.  The relator and the government alleged that NID sold PTH assays knowing that they produced erroneous and unreliable results, thus causing clinical laboratories that purchased and used those tests to submit false claims for reimbursement to federal health care programs.  Interestingly, the government also alleged a second “tier” of false claims: the inaccurate results of the tests allegedly caused practitioners to prescribe vitamin D and parathyroidectomies that were not necessary, thereby resulting in the submission of false claims for those products and procedures.  Quest denied the allegations, other than those to which the company pleaded guilty under the FDC Act.  The civil settlement requires Quest and NID to pay $262 million plus interest.  Quest has also agreed to pay $6.2 million to settle state Medicaid claims and to enter into a Corporate Integrity Agreement with the Office of the Inspector General of the Department of Health and Human Services.  The whistleblower will receive approximately $45 million.