DID - Jan. 13, 2009 Issue

Vol. 8 No. 7

FDA Final Guidance Permits Reprints of Articles on Off-Label Use

Drugmakers will be able to distribute journal articles discussing off-label uses of approved products if the articles are separate from promotional information and companies include publications with contrary or differing conclusions, the FDA says in a final guidance.

The guidance issued today incorporates changes from a draft version that drew criticism from members of the House Committee on Oversight and Government Reform who charged that it would lower advertising standards and hinder prosecution of illegal promotion against drugmakers (DID, Sept. 9, 2008).

The final version was revised to encourage manufacturers to seek approvals and clearance for new indications and intended uses, according to the FDA’s notice accompanying it. The agency also says it will not require pre-submission of articles and other mandatory review practices because the sunset of provision 401 of the FDA Modernization Act (FDAMA) puts such requirements outside the agency’s authority.

The guidance allows a company to disseminate such articles if, among other conditions, they are from peer-reviewed journals, not false or misleading and are accompanied by approved labeling and a number of disclaimers and disclosures. Articles should not be in the form of a special supplement funded by a manufacturer of the product.

Off-label uses “may be important and may even constitute a medically recognized standard of care,” the guidance says. There are “important public policy reasons” for allowing manufacturers to distribute such information, the guidance continues, but it also warns that such information must be truthful and not misleading.

PhRMA says it supports the FDA’s efforts for responsible communication of accurate medical information about prescription medicines.

“Such prescribing can save lives, especially in practice areas where there are few effective treatments,” PhRMA’s Senior Vice President Ken Johnson says in a statement. “The FDA guidance supports the public health by helping to assure that medical professionals receive timely and accurate medical information prior to the lengthy process for inclusion in the FDA-approved labeling.”

Requirements for Dissemination

If manufacturers follow its recommendations and products are lawfully promoted, the FDA will not view distribution of medical and scientific information as evidence of manufacturer intent to promote an unapproved use, the guidance says.

It states that journal reprints or reference publications should be accompanied by prominently displayed statements disclosing the following:

  • That the uses have not been approved or cleared by the FDA;
  • The manufacturer’s interest in the drug or device discussed in the article;
  • Any author with financial ties to the product or manufacturer;
  • Any person who has provided funding for the study;
  • Any significant risks or safety concerns known to the manufacturer concerning the unapproved use that are not discussed in the text;
  • The approved labeling for the drug or device; and
  • A comprehensive bibliography of publications that discuss previously published, well-controlled clinical studies about the use of the drug or device.

The guidance also recommends that scientific or medical journal articles should be published by an organization that has an editorial board with expertise in the subject matter and is independent of reviewing, selecting, rejecting or providing comment on the proposed articles. The organization also must adhere to conflict-of-interest policies.

Publications should not be primarily distributed or written, edited, excerpted or published for, or at the request of, a drug or device manufacturer. Accordingly, articles should not be edited or influenced by anyone with financial ties to the drug or device manufacturer, the guidance says.

Abstracts, letters to the editor, reports of Phase I trials in healthy subjects and reference publications that contain little discussion of the relevant investigation or data are not considered consistent with the good practices outlined in the guidance.

Comments on the guidance are due before March 13. The guidance can be viewed at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0053-gdl.pdf. — Renee Frojo


Good Importer Practices Detailed in Draft Guidance

Importers regulated by the FDA should know the foreign producers, consolidators, trading companies and distributors of their products and monitor them to help prevent potential contamination and counterfeiting, the agency says in a new draft guidance.

The draft lists four guiding principles of good importer practices. The first is the establishment of a product-safety management program. This should feature a clear management structure; organized compliance records; a communication and information system; and a formal quality assurance program; documented policies, specifications and procedures, and a process to analyze, evaluate and control risks in the product life cycle. In addition, the importer should designate specific individuals who are responsible for product control and compliance.

The second principle is knowing the product and applicable requirements. For example, the importer should know the product’s use, packaging, size, quantity, quality, composition, specifications and safety concerns. It also should know which regulatory requirements apply and the risks and compliance history of the product and the firms that manufacture, distribute or transport it.

The third principle relates to controlling, monitoring and verifying product and company compliance with requirements throughout the supply chain and product life cycle — before the arrival of the product in the U.S., during entry and during U.S. distribution.
The fourth principle involves taking corrective and preventive action in cases of noncompliance. Importers should:

  • Develop corrective action plans, including how noncompliant or unsafe products are to be disposed of, destroyed or exported;
  • Identify and investigate the root cause of noncompliance;
  • Take steps to remediate and prevent harm from present and future shipments, and ensure that noncompliance and safety problems do not recur; and
  • Work with the noncompliant company to meet U.S. requirements or stop doing business with it.

This advice for developing good importer practices applies “at various points in a product’s life cycle — growing, harvesting, designing, manufacturing, processing, packing, receiving, storing, transporting, importing and distributing,” the draft says.

Importers that already use best practices to ensure that their products comply with U.S. requirements may not have to change what they are doing, the draft says.

The draft can be viewed at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2009-D-0675-gdl.pdf. Comments are due April 13. — Martin Gidron


OIG: FDA May Not Be Aware of Conflicts of Interest

The FDA lacks a complete list of clinical investigators and doesn’t tell its onsite Bioresearch Monitoring (BiMo) program inspectors to check for complete financial information from sponsors, the HHS Office of the Inspector General (OIG) says.

As a result, the agency may not be aware of conflicts of interest that could influence clinical trial results, according to an OIG report. Sponsors are required to collect financial information from clinical investigators before they start trials and to submit this information to the FDA with their marketing applications after the trials end. 

The FDA could provide a complete list of clinical investigators for only 7 percent of the marketing applications it approved in fiscal 2007, the OIG says. The FDA responded that while it does receive this information in marketing applications, the OIG did not request it for the report.

OIG countered that it did request the information and, while there is often no list of clinical investigators in marketing applications, the lists of clinical investigators the FDA did provide could not be checked for validity or completeness. Moreover, “BiMo inspectors review financial information only when an FDA reviewer specifically requests it or when an inspector takes personal initiative,” the report says.

Incomplete Records

Forty-nine of the 118 drug, device and biologic marketing applications the FDA approved in fiscal 2007 included at least one clinical investigator with a disclosed financial interest, the OIG says. Six applications included 10 or more clinical investigators with a disclosed financial interest; in one case, 38 clinical investigators disclosed financial interests.

More than three-quarters of disclosed financial interests involved payments from sponsors to investigators, mostly for consulting services or general honoraria, OIG says. The median reported payment was $47,252. In another 19 percent of the cases, the disclosed financial interests were for equity interests, primarily stock options, with a median reported value of $65,000.

Only 1 percent of the clinical investigators listed in the financial forms, or 206 of 29,691 researchers, disclosed a financial interest. Of those, a half-dozen disclosed more than one financial interest and three investigators disclosed financial ties that, in their judgment, might have influenced a study’s outcome, the OIG found.

Even when the information was provided, in one out of five cases neither the FDA nor sponsors took action to minimize the possibility of bias. The agency approved 7 percent of applications without any financial disclosure forms, the OIG says.

The OIG found that 42 percent of FDA-approved marketing applications were missing financial information; 23 percent were missing a certification, disclosure form or required attachments; and 28 percent of sponsors used the due diligence exemption to indicate that they were unable to provide complete financial information.

The FDA responded that the “use of the due diligence exemption is justified in a number of situations … [so] marketing applications in which the exemption was claimed should not have been considered to be missing financial information.”

OIG says that even so, “sponsors’ failure to submit financial information for all clinical investigators, whether they indicated due diligence or not, constitutes missing financial information.”

The FDA did not review any financial information for 31 percent of the applications. However, when its reviewers used a review template, they were more likely to go over financial information.

A String of Recommendations

The OIG recommends that the FDA:

  • Use a complete list of clinical investigators to check on whether sponsors have submitted financial information for them;
  • Ensure sponsors submit all required attachments to financial forms;
  • Update its guidance to sponsors regarding the due diligence exemption;
  • Add a review of financial information to the BIMO onsite inspection protocol. The FDA says it has done so;
  • Ensure that reviewers consistently check financial information and take action in response to disclosed financial interests;
  • Require that all centers consistently use a template that includes a prompt for its reviewers to check on financial information;
  • Provide additional guidance and training to reviewers;
  • Ensure that sponsors submit complete financial information for all clinical investigators. The FDA says it is considering revising its guidance to instruct sponsors to provide a table listing all clinical investigators and indicating whether a certification form, a disclosure form or the due diligence exemption is being provided; and
  • Require sponsors to submit financial information for clinical investigators as part of the pretrial application process.

The FDA agrees with all of the OIG recommendations except the last. “Implementation of this recommendation would require repeated FDA review of clinical investigators’ financial disclosure information and the protocol over the duration of a clinical study; however, data from the study may never be submitted in support of a marketing application,” FDA spokeswoman Crystal Rice told DID.

Approximately 8 percent of new medicinal compounds entering Phase I testing reach the market and less than 1 percent of clinical investigators had disclosable financial information, Rice added.

“Clinical investigator financial interests are only one potential source of bias,” she added.  “This recommendation could have the unintended effect of adding to the complexity and cost of the clinical trial enterprise with no commensurate gain in the protection of human subjects or the quality of the data.”

The OIG report can be viewed at www.oig.hhs.gov/oei/reports/oei-05-07-00730.pdf. — Martin Gidron


Frank Torti Tapped to Be Acting FDA Commissioner

Acting FDA Commissioner Frank Torti faces a number of problems, including safety concerns about drugs and devices and physicians’ financial ties to drugmakers, until someone is nominated and confirmed during the next administration as FDA commissioner.

“I think it sends a couple of interesting messages, one of which has not been recognized yet,” Peter Pitts, director of Center for Medicines in the Public Interest, told DID Monday. “It sends the message that career staff at the agency are to be trusted. There has been a hue and cry lately that current top-level staff are not to be trusted.”

Torti had been serving as the director of the Comprehensive Cancer Center of Wake Forest University when he joined the FDA last year as the first chief scientist and principal deputy commissioner (DID, April 10, 2008). One of his main tasks was to help launch a two-year fellowship program designed to train scientists and engineers on the scientific foundations the FDA’s regulatory actions (DID, July 21, 2008).

Pitts said he thinks it is “highly unlikely” that Torti will be named permanent commissioner.

HHS Chief of Staff Rich McKeown confirmed that Torti was named acting FDA commissioner in a Friday email to senior agency staff.  In the email, McKeown also said Assistant HHS Secretary Charlie Johnson will serve as acting secretary from Jan. 20 until Secretary-designate Tom Daschle is sworn in after confirmation hearings in the Senate.

President-elect Barack Obama’s transition team declined to comment on the Torti appointment. — Elizabeth Jones


Warner Chilcott, Watson Settle Lawsuits, Sign Agreements

Watson Pharmaceuticals and Warner Chilcott have agreed to resolve patent litigation over the oral contraceptives Loestrin 24 Fe and Femcon Fe.

New Jersey-based Warner Chilcott has granted Watson a nonexclusive license to the U.S. patents covering Loestrin 24 Fe (ethinyl estradiol/norethindrone acetate) and Femcon Fe (ethinyl estradiol/norethindrone) under the settlement terms. 

The Loestrin 24 Fe agreement will allow Watson, based in California, to start selling its product about Jan. 22, 2014, or the date on which another generic version of the contraceptive enters the U.S. market.

Watson will be allowed to begin selling its version of Femcon Fe around Jan. 1, 2013, about 180 days after Barr Laboratories starts marketing its generic version, according to a joint statement issued by both companies.

Warner, based in California, and Watson will file dismissals without prejudice that will conclude both patent lawsuits. Additional details concerning the settlements have not been disclosed.

Background of Litigation

Warner brought its Loestrin 24 Fe suit, Warner Chilcott Company, Inc., v. Watson Pharmaceuticals, Inc., et al., in July 2006 in the U.S. District Court for the District of New Jersey after Watson submitted an ANDA to market a generic version of the product.

In its complaint, Warner alleged Watson’s product would infringe on Warner’s ’394 patent, which expires July 22, 2014, according to court documents.

In October 2007, Warner brought a separate suit after Watson filed an ANDA to manufacture generic Femcon Fe before the ’050 patent expires April 6, 2019. Warner also sued Barr Laboratories for infringing on the same patent, and the two cases were consolidated last February.

The case against Barr was dismissed late last month, and the consolidation of the two cases was reversed. Barr now has a license to sell Femcon Fe as early as July 1, 2012, according to a Warner statement. 

Loestrin 24 Fe generated revenue of $50.8 million in the quarter that ended last September, an increase of 32.9 percent over the quarter in the previous year, according to Warner’s earnings statement.

Femcon Fe generated revenue of $11.4 million during the quarter that ended last September compared with $9.4 million during the same quarter in 2007, Warner adds in the statement.

Other Agreements

Separately, Watson agreed to co-promote Warner’s hormone therapy product, Femring (estradiol acetate). Watson’s specialty products sales force will promote the product to obstetricians and gynecologists and will receive fee-based compensation.

Warner also will pay Watson a portion of the net sales on the product, which is indicated to treat the moderate-to-severe vasomotor symptoms and vulvar and vaginal atrophy associated with menopause.

Net sales of Femring were roughly $15.7 million for the 12 months that ended last Sept. 30, according to a joint statement.

In addition, Warner has granted Watson an exclusive license to market and sell WC3026, an oral contraceptive product in late-stage development.

Warner will have the responsibility to complete the development and obtain approval of this product and expects to submit an NDA during the second half of the year. Warner will supply Watson exclusively with the product. In return, Watson will pay Warner royalties based on product net sales, according to a joint statement. — Elizabeth Jones


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