Vol. 10 No. 26
The FDA’s Oncology Drug Advisory Committee will meet Tuesday to discuss ways to improve the planning and conduct of postmarketing studies designed to confirm the clinical benefit of new drugs and biologics endorsed under accelerated approval.
The overall aim of the meeting is to optimize the accelerated approval process by reducing the time required to confirm or disprove clinical benefit while maintaining early access to promising new cancer products.
Specifically, the committee wants to know when a randomized trial should be required for accelerated approval and when single-arm studies are appropriate to confirm clinical benefit.
According to background material provided for the meeting, 29 of the 49 accelerated approvals of cancer drugs thus far have been based on single-arm studies, which provide limited data on clinical benefit and safety and usually involve refractory populations with no alternative treatment options.
Randomized trials could yield a broader array of endpoints and lead to better characterization of the product’s safety, the panel says.
Possible scenarios suggested by the committee include a randomized trial in a less refractory population that compares the test agent with an active control using a surrogate endpoint analyzed at an earlier point in time and a randomized study in a refractory population comparing the investigational product to best supportive care or selected treatments.
The panel will discuss the appropriateness of requiring sponsors to conduct at least two adequate and well-controlled confirmatory trials as criteria for accelerated approval of new anti-cancer agents. Currently, most new oncology drugs are approved on the basis of a single study.
Other questions the panel hopes to address are whether accelerated approvals should be postponed until confirmatory trials are underway, and whether sponsors that utilize cooperative groups to perform such trials should conduct an additional trial under their direct supervision to ensure that postmarketing requirements are met by a specified date.
The panel will also hear updates on the status of Phase IV trials of five products that received accelerated approvals before Jan. 1, 2009. They are:
The Senate Judiciary Committee has once again passed Sen. Patrick Leahy’s (D-Vt.) Patent Reform Act and the bill is causing a split between the brand- and generic-drug industries.
The legislation, which was sent to the full Senate Thursday for the third time since 2008, would overhaul the U.S. patent system by easing venue changes, tightening the standard for claims of willful infringement and giving courts more sway in determining patent dispute damages.
But the section of the bill that has caught drugmakers’ attention is language that would ease the current standards for inequitable conduct.
Currently, inequitable conduct standards allow a court to render a patent unenforceable if the patent applicant made material misrepresentations or withheld information during the application process with intent to deceive the PTO.
Weakening those standards “will simply result in providing innovators with a greater incentive to be less than honest when seeking patents, thereby making it harder for companies to challenge dubious patents,” the Generic Pharmaceutical Association (GPhA) says.
“The U.S. patent system can be reformed without jeopardizing current protections that have enabled Americans to enjoy considerable savings from generic drugs,” GPhA adds.
PhRMA, however, has taken a different view of the bill, saying it will “strengthen the patent system while protecting patent owners and maintaining incentives for innovation.”
That stance was echoed by the Biotechnology Industry Organization, which said the legislation “would benefit all sectors of the U.S. economy by enhancing patent quality and the efficiency, objectivity, predictability, and transparency of the patent system.”
How the bill, which is cosponsored by Sens. Orrin Hatch (R-Utah) and Chuck Grassley (R-Iowa), will be received in the Senate remains to be seen. The legislation last made it out of the Judiciary Committee in 2009 but failed to be approved by the full Senate (DID, April 3, 2009). — David Belian
As the FDA’s backlog in reviewing ANDAs continues to grow, generic-drug makers are now facing a situation where they could potentially lose initial marketing exclusivity on their products as a result.
By the end of last year, the number of ANDAs waiting to be reviewed by the agency had reached 2,361, Kurt Karst, an attorney with Hyman, Phelps & McNamara said Friday.
In addition, the average approval time for an application at the end of the year was about 31 months, Karst said. The FDA has not released those figures publicly.
The delay in approval times is a major concern for drugmakers who were the first to file an ANDA for a generic version of a brand drug and would stand to gain 180 days of marketing exclusivity once the application is approved.
Under current law and with few exceptions, if a drugmaker fails to win tentative approval for its ANDA within 30 months of it being filed, regardless of who is at fault, the exclusivity — and the huge financial windfall that comes with it — is forfeited.
Such a situation could become reality for companies this year, Karst told DID Friday, adding that challenging the FDA in court to regain exclusivity would be difficult because the agency would likely claim that complications with an application caused the delay.
“If you’re going to challenge [the FDA], you better have a clean file,” Karst said.
For its part, the FDA has said the accumulation of ANDAs has not prevented new generic drugs from entering the market because a majority of applications awaiting review are for products that could not immediately enter the market anyway, due to their brand counterparts’ exclusivity (DID, Sept. 20, 2010).
The agency has gone as far as to hire an outside consulting firm to try to help clear up the backlog, but it has also been advocating for the creation of a user-fee system on generic drugs as a potential solution to the problem (DID, Oct. 21, 2010).
“An effective [user-fee] program negotiated between FDA and industry would reduce review times and make funding more flexible,” FDA Commissioner Margaret Hamburg said last year at the agency’s public meeting on the subject.
Whether drugmakers will oblige remains to be seen, but the Generic Pharmaceutical Association has been generally supportive of adopting the fees. The group has insisted, however, that the FDA develop a program that provides generic-drug makers with specific agency performance goals. — David Belian
Six death-row inmates in three states have brought a lawsuit against the FDA for allegedly assisting states in importing unapproved shipments of the anesthetic sodium thiopental (ST) for use in lethal injections.
The suit, filed in federal court in Washington, seeks to enjoin the agency from allowing further shipments of the drug and require the agency to destroy the unapproved product previously admitted by the states.
Bradford Berenson, a partner with Sidley Austin who is representing the inmates from California, Arizona and Tennessee, says the FDA has “abdicated its responsibilities and violated federal law.”
The imported ST, manufactured by Sandoz and purchased through the London-based distributor Dream Pharma, has a lower concentration of active ingredient than required by U.S. Pharmacopeia standards and appears to be less effective as an anesthetic, Berenson told DID.
“Without FDA approval, there is no assurance that the products will work properly,” he said.
The FDA did not return a request for comment on the lawsuit, but in a Jan. 6 Notice of Action acknowledging the receipt of imported drugs, an agency official disavows responsibility for reviewing the products.
“In keeping with established practice, FDA does not review or approve products for the purpose of lethal injection. FDA has not reviewed the products in this shipment to determine their identity, safety, effectiveness, purity or any other characteristics,” Patricia Schafer, acting director of the New Orleans District Office, writes.
States began importing ST last year after facing shortages of Pentothal, Hospira’s ST product. Emails between state officials indicate that the drug was imported with cooperation from FDA officials, including Susan Halpenny and Ruth Dixon, supervisory investigators for import operations in the agency’s New Orleans office.
An un-named FDA official “notified his chain of command in Washington, D.C.,” of the imports and gave “recommendation that the shipment be processed expeditiously as it was for use in executions and not for use by the general public,” according to an email between the Arizona and California Departments of Correction.
Berenson notes that FDA-approved alternatives to ST do exist, and one such product, Lundbeck’s Nembutal, is currently used by Ohio in lethal injection. AstraZeneca’s Propofol is also approved as an injectable anesthetic.
Hospira, the company that once produced most of the ST used in U.S. lethal injections, no longer manufactures the drug. The company attempted to relocate manufacture of ST to its Italian plant, but national authorities there forbid the manufacture of the drug for use in executions.
Rather than risk being held liable by Italian authorities, Hospira ceased manufacture of ST in 2009 and recently stated it is permanently halting production. Hospira has never condoned use of its product in executions, the company says.
The FDA’s role in regulating execution drugs previously went to the court in 1985 with Heckler v. Chaney, a case in which death-row inmates alleged that use of ST for lethal injection violated the Federal Food, Drug, and Cosmetic Act and requested the FDA take enforcement actions.
The FDA refused the request, and while an appeals court ruled that the FDA’s refusal “was an abuse of discretion,” the U.S. Supreme Court held that the agency’s decision was not subject to judicial review. — Wilson Peden
The FDA has granted accelerated approval to KV Pharmaceutical’s Makena, the first treatment for women to reduce the risk of preterm birth, the company said Friday.
Makena (hydroxyprogesterone caproate injection), previously known as Gestiva, is a hormone medicine approved to reduce the risk of preterm birth in women who are pregnant and who have delivered a baby too early in the past.
Makena will be available in early March, Jennifer Forst, a spokeswoman for KV, told DID.
While there are no controlled trials demonstrating a direct clinical benefit, the treatment’s effectiveness is based on a study of 463 women who had experienced a previous preterm birth. It showed that in comparison to a control group, treatment with Makena reduced the proportion of women who delivered preterm at less then 37 weeks, a surrogate endpoint.
Of Makena-treated subjects, 37 percent delivered early (before 37 weeks), compared to 55 percent of the women in the control group.
Makena is administered through a weekly intramuscular injection at the hip starting between 16 and 20 weeks of pregnancy and continuing until week 37 or delivery.
An additional study looking at the development of children born to mothers in the trial showed children between 2.5 and 5 years old reached comparable developmental targets, regardless of whether the mother was in the control or Makena group. The study is ongoing and will be followed by a similar infant study slated for completion around 2018.
Although certain pregnancy-related fetal and maternal complications, including miscarriage, stillbirth, admission for preterm labor, gestational hypertension, gestational diabetes and oligohydamnios, were increased in Makena-treated subjects, the most common adverse reactions were injection site reactions, swelling, pruritus, nodule, urticaria, nausea and diarrhea.
Makena’s worldwide rights will be transferred to KV from Hologic, the drug’s developer, under the terms of an existing asset purchase agreement. Terms include a $12.5 million cash payment from KV to Hologic that must be completed by Feb. 11, $79.5 million in cash payments Hologic has already received and additional payments totaling $107.5 million in the future.
Makena’s approval comes at a critical time for KV, which has recently suffered a slew of problems. In September, the company was able to return its first product to market following a consent decree signed with the agency in 2009 over manufacturing issues (DID, Sept. 13, 2010).
Former KV CEO and chairman of the board Marc Hermelin was excluded from participation in federal healthcare programs in November after the company marketed unapproved drugs under his watch (DID, Nov. 18, 2010). — Molly Cohen
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