DID - Jan. 15, 2009 Issue

Vol. 8 No. 9

New Drug Import Program Is Under Consideration

The FDA will test a secure supply-chain pilot program for imported drugs and active pharmaceutical ingredients (APIs) to determine whether such a plan is practical.

Companies participating in the pilot program would have a greater chance of gaining expedited entry for their imported finished drugs or APIs, according to a Jan. 15 Federal Register notice.

“FDA plans to substantially increase the rate at which entries of the finished drug products and APIs selected for the … pilot program are given a ‘May Proceed’ without human entry review or examination at the time of entry,” the agency says.

The pilot program, which will be run by CDER and the Office of Regulatory Affairs, still needs Office of Management and Budget approval. Once the FDA is cleared to proceed with the pilot program, it will select participants and launch the pilot within 180 days.

The FDA plans to accept applications to participate in the program from 100 companies, with no more than five drug products per applicant. The pilot project is expected to run for two years, according to the FDA.

The effort will help determine whether the agency should establish a secure supply-chain program and what its parameters should be. In addition, the FDA may decide to expand or modify the program, the agency says.

Applicants must hold an NDA or ANDA or be the foreign manufacturer of an imported finished drug product or API. The applicant must have applied to become or be certified as U.S. Customs and Border Patrol Customs-Trade Partnership Against Terrorism Tier II, the FDA says.

Applicants must have established a plan for promptly correcting any concerns the FDA has regarding their supply chain, or specific imports, and for recalling or correcting finished drug products or API that are violative.

The application for the program is available at www.fda.gov/cder/fedreg/fda-3676.pdf. The notice is at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-N-0656-N.pdf. — Christopher Hollis


IRB Registration Becomes Mandatory in July

All institutional review boards (IRBs) for clinical trials in the U.S. will be required to register electronically with HHS by July 14 under final rules issued simultaneously by the FDA and the Office for Human Research Protections (OHRP).

The FDA has authority over IRBs that oversee industry-sponsored clinical trials and OHRP has authority over those that supervise research conducted or supported by HHS or otherwise covered by an applicable “federalwide assurance” approved by the office. The assurance means the agency guarantees that the institution will comply with all HHS regulations, also known as the Common Rule, to protect the research subjects.

Both institutional and commercial IRBs are covered by the rules, which require each IRB to register by submitting physical and email addresses, telephone and fax numbers and other contact information for the board, its chairperson, the institution that oversees its activities, the responsible official there (who should not be an IRB member or staffer) and the person supplying the information. IRBs must renew their registration every three years, according to the rules.

IRBs also are required to disclose the approximate number of study protocols to which they granted initial, continuing or expedited approval during the preceding 12 months and a description of the types of products involved. The purpose of the new rules is to make it easier to inspect IRBs and provide them with information, according to the FDA and OHRP.

Additionally, OHRP will require each IRB to disclose the approximate number of full-time equivalent positions devoted to its administrative activities, a stipulation not found in the FDA rule.

The FDA requires an IRB to report within 90 days any change in its contact information or that of its chairperson, and within 30 days if it decides to review new types of FDA-regulated products, stops reviewing clinical trials or disbands. Any other changes may be included with its regular renewals, the FDA says. OHRP’s rule contains similar wording.

The FDA and OHRP estimate that initial registration will take about an hour and renewals will take less time.

Registration’s Beginnings

While OHRP has been operating an IRB registration system since December 2000, the FDA says it “never compiled a comprehensive list of IRBs” under its authority until now. The agency has required some clinical trial investigators and sponsors to provide the names and addresses of the IRBs reviewing their studies, its requirements differed by product, and it did not consistently demand complete, up-to-date information.

The FDA hadn’t required the IRBs themselves to register directly although the HHS Office of the Inspector General recommended such a requirement in 1998. The FDA and OHRP published draft rules on IRB registration simultaneously in July 2004.

Several commenters on the FDA draft disagreed about whether foreign IRBs should have to register, the agency says. The solution is to allow foreign and any domestic IRBs that are not otherwise required to register to do so voluntarily.

The FDA rejected proposals to impose fines or place trials on clinical hold if the sponsor or investigator uses an unregistered IRB. “We believe that it would be premature
for us to consider the use of such sanctions before we and the regulated community have gained sufficient experience with the IRB registration program,” the agency says.

The FDA rule can be seen at federalregister.gov/OFRUpload/OFRData/2009-00682_PI.pdf, and the OHRP rule can be seen at federalregister.gov/OFRUpload/OFRData/2009-00588_PI.pdf. IRBs can register electronically at ohrp.cit.nih.gov/efile. — Martin Gidron


PhRMA’s Tauzin Supports Fixed Terms for FDA Commissioners

Fixed terms for future FDA commissioners would help shield them from politics, PhRMA CEO Billy Tauzin said Wednesday.

The former chairman of the House Energy and Commerce Committee, Tauzin also said he hopes President-elect Barack Obama will select a commissioner who has good management skills and supports science-based decisionmaking. 

“We need an FDA that’s really on top of its game,” Tauzin said at a meeting. “And to do that, I think we need a commissioner that is a little politically insulated, scientifically chosen, [with] great management skills. And then with a fixed term so that he or she is not as affected by the winds of political change.”

The European Medicines Agency (EMEA) is gaining a reputation that it is more scientific and less political than the FDA, according to Tauzin. “Our FDA ought to be the gold standard for the world,” he added.

Congress should appropriate more funds for the FDA, and the agency’s budget should become less dependent on user fees, he said.

Alan Goldhammer, deputy vice president for regulatory affairs at PhRMA, said industry finances approximately 75 percent of the FDA’s budget. Tauzin said that figure should be less than 50 percent.

The agency needs resources for projects such as a modernization effort to move toward digital filings and reviews, which Tauzin said is critical. There also is a morale problem among FDA staff, creating what he characterized as a “brain drain.”

FDA Commissioner Andrew von Eschenbach told Tauzin that the biggest problem the agency has in attracting new talent is a lack of resources. “They really need to rebuild the attractiveness of the FDA for young scientists to enter and have careers in,” Tauzin advocated.

Medicare Part D

Tauzin, who declared Wednesday that he was healthy despite rumors that he was ill, said that PhRMA hopes user fees for direct-to-consumer advertisements will be authorized this year. He also weighed in on the possibility of HHS gaining direct price-negotiating authority for Medicare Part D.

The prescription drug program has a satisfaction rate of 90 percent, and tinkering with it might prove detrimental, Tauzin suggested. “The bottom line is that seniors not only like and appreciate this program, they’re not going to be pleased if people mess with it,” he said.

“It’s working well for them. The premiums are lower than anyone ever predicted. The costs to the government are nearly … half a trillion dollars below those predicted by the government when the bill was passed,” Tauzin continued.

“There are huge savings to the government and the citizens because of the competitive nature of the program. When you put the government in the process, you almost certainly freeze out private competitors. They drop out of the program,” he added. — Christopher Hollis


FDA Guidance Clarifies Unanticipated Adverse Event Reporting

A final FDA guidance designed to curb unnecessary reporting of adverse events recommends that sponsors of multicenter clinical trials determine when an incident is serious, unanticipated and should be reported to an investigational review board (IRB).

The guidance clarifies when an adverse event might require modification of the study protocol. For example, an adverse event might cause a change in the inclusion/exclusion criteria or the addition of a new monitoring requirement, informed consent or investigator’s brochure, according to the guidance.

Many adverse events should be evaluated using an aggregate analysis of similar events to determine whether a problem is anticipated. The guidance recommends investigators rely on study sponsors to decide whether an incident is unanticipated, according to the guidance.

Individual site investigators who report individual, unanalyzed events to IRBs may lead to the submission of reports to the boards that are uninformative and could hinder their ability to ensure the protection of human subjects.

The guidance says the following adverse events should be considered unanticipated problems that should be reported to the IRB:

  • A single occurrence of a serious event that is uncommon and strongly associated with drug exposure;
  • A single or small number of serious, unexpected events that are not commonly associated with drug exposure but considered uncommon in the study population;
  • Multiple occurrences of an adverse event that, based on an aggregate analysis, is determined to be an unanticipated problem;
  • An adverse event that is described in an investigator’s brochure, protocol or informed consent documents but occurs at a severity level that is inconsistent with prior observations;
  • A serious adverse event that is addressed in the brochure, protocol or informed consent documents but happens at a rate representing a clinically significant increase in the expected rate of occurrence; and
  • Any other event that would cause the sponsor to modify the brochure, study protocol or informed consent documents or would prompt other IRB action to ensure the safety of human subjects.

The “Guidance for Clinical Investigators, Sponsors and IRBs: Adverse Event Reporting to IRBs  — Improving Human Subject Protection” is available at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2007-D-0202-gdl.pdf. — Elizabeth Jones


University Denies Researcher Misled Ethics Committee on ADHD Drug

Australia’s Curtin University of Technology denies that one of its clinical investigators gave false information to the ethics committee reviewing a study of attention deficit hyperactivity disorder (ADHD) drugs.

The university was aware before approving the trial that the FDA had ordered a black box warning on the label of one of the study drugs, Eli Lilly’s non-stimulant Strattera (atomoxetine HCl), according to the institution’s statement to DID. The label warns of an “increased risk of suicidal ideation in children or adolescents.”

An Australian newspaper reported that the clinical investigator Heather Jenkins falsely told the ethics committee that the FDA had lifted the warning. Acting Vice Chancellor Linda Kristjanson, the head of research at the university, told DID this week that the institution was fully informed by Jenkins and she behaved ethically.

The study was an investigator-initiated trial examining the educational and social impact of Strattera on children in the classroom setting. The study also looked at dexamphetamine, a stimulant used to treat the condition, in the same situation, Lilly spokesman David Shaffer told DID Tuesday. The dexamphetamine later was replaced with Novartis’ Ritalin and Ortho-McNeil-Janssen’s Concerta, he said. Both contain the active ingredient methylphenidate HCl.

The results are being analyzed and will be published in a peer-reviewed journal. No drugmaker will be allowed to influence the results, Kristjanson said.

Children’s Prescriptions

The study enrolled children who were being treated with a range of ADHD medications prescribed by their personal pediatricians, who did not serve as investigators in the study, the university says. 
“All medication was prescribed and monitored by the diagnosing pediatricians independently of the study,” the university adds. “Decisions regarding the use of specific medications rested with the children’s doctors and parents.”

Moreover, Jenkins had nothing to do with diagnosing the children or prescribing their medication, according to the statement.

“Curtin’s Human Research Ethics Committee conducted a rigorous review of the research proposal prior to it being approved. The review complied with the National Statement on Ethical Conduct in Research Involving Humans, as prescribed by the [Australian] National Health and Medical Research Council,” Kristjanson said.

Lilly spokesman Shaffer told DID, “Lilly agreed, as manufacturer of Strattera, to be involved to further extend knowledge of patient outcomes on ADHD medications. …  We provided $45,000 in direct financial support over the three years and provided the Strattera used in the study.” He emphasized that there have not been any suicides in clinical trials of the drug. — Martin Gidron


Schering-Plough Gets Complete Response Letter for Saphris

The FDA has delayed the approval of Schering-Plough’s Saphris, a potential treatment for schizophrenia and bipolar I disorder, and requested supplemental trial data.

The agency has not asked for additional clinical trials, Schering-Plough says in a statement. The NDA for Saphris (asenapine) includes data from trials of more than 3,000 patients with schizophrenia and bipolar mania. In addition to its supplemental data request, the agency has proposed labeling for both indications.

Schering-Plough anticipates providing the requested information this quarter, the company says.

A Schering-Plough spokesman told DID the company has not projected potential sales for the product but notes that the size of the U.S. antipsychotics market is roughly $13.5 billion and the worldwide market is about $20 billion.

In addition, the company still anticipates filing a marketing authorization application in the EU this year, the spokesman said.

Schering-Plough obtained the rights to Saphris in November 2007 through its acquisition of Organon BioSciences, which developed the drug. — Elizabeth Jones


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