DID - Sept. 9, 2008 Issue

Vol. 7 No. 176

Congressional Displeasure Continues With FDA’s Reprint Guidance

Congressional committee staff have voiced continuing concern that the FDA’s draft guidance permitting drugmakers to use reprints of medical journal articles about off-label uses would lower advertising standards and hinder prosecution of illegal promotion.

The draft has “troubling implications for FDA’s enforcement authority in the future. … Our concern is that this will undercut activity of state attorneys general and the Department of Justice by muddying the waters about what they can cite as evidence of illegal promotion,” Ann Witt, health counsel for the House Committee on Oversight and Government Reform, said at Monday’s Food and Drug Law Institute conference on advertising and promotion in Washington, D.C.

The draft, intended to replace an expired provision in the FDA Modernization Act (FDAMA) that allowed temporary use of journal articles under certain conditions, would allow a company to disseminate scientific articles on unapproved uses if, among other conditions, they were from peer-reviewed journals, not false or misleading and were accompanied by approved labeling and a number of disclaimers and disclosures (DID, Feb. 18).

It has drawn heat from observers like Witt who charge that the FDA reversed its views due to political pressure from the Bush administration. She said the agency had previously “eloquently opposed” the FDAMA provisions that led to the issuing of February’s draft guidance.

The oversight committee, which is chaired by Rep. Henry Waxman (D-Calif.), continues to have concerns. “If we permit companies to promote on the basis of preliminary evidence, that’s all we’ll have — preliminary evidence,” Witt said, referring to information for drugs not yet approved by the FDA for the use in question. “Some companies would continue to conduct rigorous studies but others would not, and [those that still did] would be under tremendous competitive pressure not to. That would result in a lowering of standards.”

She said the draft “cherry-picked some conditions from FDAMA” that would have restricted how drugmakers could use reprints. However, she added, the agency left out key restrictions; for example, the draft “doesn’t require companies to ever seek approval for the off-label use … and doesn’t require companies to distribute contrary articles if they are out there.”

While the draft says drug companies must provide a bibliography with promotional reprints, it’s “not realistic” to expect physicians to actually look up all the articles listed, given their workloads, Witt said.

Drugmakers also are not satisfied with the draft, according to Paul Kim, an attorney with Foley Hoag. For example, it does not specify whether the “comprehensive bibliography” must be “balanced or representative,” he said.

Some drugmakers have submitted comments to the FDA claiming the draft’s requirement for adequate, well-controlled trials is too stringent and pointing out that epidemiological, pharmacokinetic or pharmacodynamic studies also can be useful, Jeffrey Senger, deputy chief counsel in the FDA’s Office of the Chief Counsel, said.

The Washington Legal Foundation, which sued the FDA over the implementation of FDAMA before the draft guidance was issued, says the draft requirements restrict free speech and is threatening to sue again.

Other pharma industry supporters note that off-label use is common for such therapeutic areas as oncology, psychiatry, dermatology and certain orphan diseases and argue that blocking drugmakers from discussing off-label uses with physicians denies patients important benefits, harming public health.

Senger cited the example of former FDA Deputy Commissioner Scott Gottlieb, now a resident fellow at the American Enterprise Institute, who has written that the ban on off-label promotion of the breast cancer drug Herceptin (trastuzumab) probably prevented Genentech from telling physicians before early 2005 about an off-label indication of the drug that has since become common.

“If they’re threatening to sue us from both sides, maybe we’ve got it about right,” Senger joked. The guidance is “only a draft and will be revised based on the comments we have received,” he added.

The draft, “Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publications on Unapproved New Uses of Approved Drugs and Approved or Cleared Devices,” can be seen at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0053-gdl.pdf. — Martin Gidron


QbD Manufacturing Guidance Under Development

The FDA is working on a new manufacturing guidance covering quality-by-design (QbD) concepts for both investigational drugs and marketed products, CDER Director Janet Woodcock says.

“We are now [writing] guidance that would allow [QbD] submissions at any time — either premarket or postmarket — and getting to what we call regulatory agreements,” Woodcock said Monday at the Parenteral Drug Association-FDA Joint Regulatory Conference in Washington, D.C.

The guidance would cover design space-type approaches to manufacturing changes, Woodcock said. Under the principles of QbD, manufacturers would be able to institute manufacturing changes within a wider range of parameters without getting the FDA’s prior approval. The changes would be covered by agreements — also known as Chemistry, Manufacturing and Control Post Approval Plans — between the agency and manufacturers.
“We’re internally working on how to word that guidance and make that document work,” Woodcock said. She added that the agency is working on another guidance on filing various types of manufacturing supplements.

After a successful QbD pilot program for small-molecule drugs, the FDA said earlier this year it would start a new pilot for biologics (DID, July 2).

Pharmaceutical Inspectorate

Woodcock also said the FDA wants to bring new life to its pharmaceutical inspectorate, which was created under the agency’s Pharmaceutical GMPs for the 21st Century Initiative. The inspectorate is a group of specialized FDA inspectors.

John Thorsky, director of the FDA’s Kansas City District Office, said there are only 11 certified members of the inspectorate — the FDA was targeting 50 members. Seven additional candidates are completing the certification process, he said.

As part of its effort to revitalize the Office of Regulatory Affairs, the agency has hired 200 new employees to become consumer safety officers — many with expertise in biotech drugs, chemistry, biomedical engineering as well as individuals with quality assurance and regulatory affairs backgrounds from industry, Thorsky said.

These new hires could be used to expand the pharmaceutical inspectorate, he said. The FDA also is looking to shorten the time it takes a new employee to become a certified member of the pharmaceutical inspectorate from six to seven years to one year. — Christopher Hollis


New FDA Vaccine Guidance Targets Applications to Treat Non-U.S. Diseases

The FDA is advising sponsors to submit INDs for vaccines and meet with CBER even if the primary market for their drugs is outside the U.S.

The guidance, “General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases,” recommends regulatory pathways to use in developing vaccines for global infections.

The agency says it wants to ensure that potential sponsors and vaccine manufacturers realize that it can license vaccines to protect against diseases or conditions not endemic in the U.S.; that regulatory pathways for licensure of these vaccines are the same as those for diseases not endemic to the U.S. and that they may submit data from clinical trials conducted outside the U.S. to support licensure.

FDA approval may be useful to sponsors seeking approvals outside the U.S. in that it signifies the agency has found a vaccine to be safe and effective, which may assist other national regulatory authorities in their evaluation of the drug.

Applicable Regulations

Section 351 of the Public Health Service Act (PHSA) grants the FDA authority to approve marketing authorizations for diseases primarily endemic to other countries. In addition, Congress inserted section 524 of the Federal Food, Drug & Cosmetic Act last year, allowing the agency to grant priority review to applications for products to treat and prevent specified tropical diseases, including tuberculosis, malaria and cholera.

The PHSA also permits a BLA to be approved if data show the product is “safe, pure and potent” and that the manufacturing facility meets standards designed to assure that the biological product “continues to be safe, pure and potent.”

Accelerated approval may be granted for certain products based on clinical trials showing the product has an effect on a surrogate endpoint that is “reasonably likely … to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity,” the guidance states.

In addition, approval will be subject to the requirement that the sponsor study the product further to verify its clinical benefit when the relation of the surrogate endpoint to the clinical benefit is uncertain. Postmarketing studies also will be required.

Clinical Studies

Sponsors interested in developing vaccines for conditions not endemic to the U.S. should begin their interactions with the FDA early in product development, such as through pre-IND meetings.

Foreign efficacy trials are likely to be necessary if the disease has a low incidence in the U.S. The FDA has licensed vaccines based on efficacy data derived from studies solely conducted in disease-endemic countries.

The FDA will accept a well-designed, well-conducted foreign study not performed under an IND to support an application if certain conditions are met. The studies must be performed in accordance with good clinical practice and be reviewed and approved by an independent ethics committee. The sponsor will be required to pay a BLA user fee even if it does not intend to market the product in the U.S.

In some situations, it may be possible to conduct challenge studies in human subjects early in development in lieu of clinical trials in the endemic area to demonstrate proof-of-concept. Human challenge studies also may be conducted to demonstrate efficacy.

Finally, the guidance notes that vaccines often are tested first in adults and then in children. However, for many global infections, the pediatric population may face greater morbidity than adults, and it may be necessary to test infants or children first.

If the course of the disease and the drug’s effects are sufficiently similar in adult and pediatric patients, the FDA may conclude that pediatric effectiveness may be extrapolated from well-controlled studies in adults. Sponsors also must submit adequate safety information to support the drug’s use in the pediatric population.

The guidance is available at www.fda.gov/cber/gdlns/gidvacc.htm. — Elizabeth Jones


Perrigo Gets Rights for Generic Allergy Drug

Perrigo has acquired exclusive U.S. rights to sell and distribute levocetirizine tablets, the generic version of Xyzal, from Dutch drugmaker Synthon Pharmaceuticals.

Xyzal (levocetirizine dihydrochloride), which is marketed by UCB and Sanofi-Aventis in the U.S., is approved to treat seasonal and perennial allergic rhinitis and uncomplicated skin manifestations of chronic idiopathic urticaria in adults and children 6 years and older. Synthon says it is the first to file an ANDA for a generic version of the drug, entitling it to 180 days of exclusivity upon approval.

UCB and Sanofi are suing Synthon in the U.S. District Court for the Eastern District of North Carolina for infringing on Xyzal’s ’558 patent. The plaintiffs have asked the court to enjoin Synthon from selling generic versions of the drug before the patent expires in September 2012.

The firms also are suing Sun Pharmaceutical, Sandoz and Barr in the North Carolina court for filing applications for generic Xyzal.

The brand drug was launched in the U.S. last October. It is estimated to have annual sales of roughly $200 million, according to data provided by Wolters Kluwer. — Elizabeth Jones


FDA-University Collaboration Could Send New Hires to the Agency

The FDA and the University of Pennsylvania have signed a memorandum of understanding (MOU) to collaborate on research that will advance medical product development and the regulatory approval process.

The main goal of the collaboration is to bridge the divide between issues that arise during basic research and clinical trials on new drugs and medical devices, Garret FitzGerald, director for the university’s Institute for Translational Medicine and Therapeutics (ITMAT), told DID.

Through the MOU, the FDA will sponsor research activities at Penn’s ITMAT for translational therapeutics, diagnostics, bioinformatics, new clinical trial models, drug and device co-development and original drug therapy-monitoring programs.

Both organizations hope to increase the number of experts with cross-training in the translational therapeutics field  — a small group relative to the global demand, FitzGerald said.

He says the MOU will benefit the FDA by contributing a number of experts the agency is seeking as part of its hiring initiative. “It really serves the interest of both parties because one thing that has become apparent on the academic side is that we need to understand constraints and opportunities on the regulatory side,” he said.

Other goals include advancing new technologies to stimulate the development of safer medical products; using pharmacoepidemiology to monitor efficacy; understanding co-development processes for companion drug diagnostics; advancing market entry of cheaper, safer medical products; and improving the quality and number of trained professionals in the field.

In the branch of translational therapeutics, the FDA and ITMAT will strive to create a more solid base of information for specific medical products before performing clinical trials, making it easier to ensure rational dose selection and safe delivery of medical products to humans. 

The organizations anticipate the studies will contribute a more comprehensive understanding of drug actions before the products are tested in clinical trials. A better understanding of how these drugs work will accelerate the approval process, minimize withdrawals and be more cost-effective, FitzGerald said.

The studies also will look at unanticipated uses or effects of certain drugs to identify other areas of use. Joint research programs will examine the environmental and genetic factors that contribute to the variation in human responses to different medical products and the need to develop new approaches to clinical trial design and analysis.

“When it comes to performing clinical trials, clearly the issue here is to be more informed … and understand factors that contribute to the variability of drug responses,” FitzGerald said. “Drug approval is only a step in the process of understanding how drugs act. The more information we can have at the time of drug approval, the better it is for everyone.”

The FDA said it hopes to develop similar satellite activities at other academic medical centers throughout the U.S. — Renee Frojo

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