DID - Oct. 5, 2009 - Issue

Vol. 8 No. 193

FDA Draft Guidance Recommends Two Trials for Antimicrobial Ulcer Drugs

Sponsors of clinical trials of antibacterial drugs to reduce the recurrence of duodenal ulcers in adults with a Helicobacter pylori infection should conduct at least two randomized, controlled trials in which the proportion of patients who are cured of their infection is the primary efficacy endpoint, the FDA says in a draft guidance.

When finalized, the draft guidance will supersede advice on H. pylori in a 1997 draft guidance on antimicrobial drugs, “Guidance for Industry: Evaluating Clinical Studies of Antimicrobials in the Division of Anti-Infective Drug Products,” the FDA says. The new draft is slated to be published in the Federal Register Oct. 5.

Sponsors should conduct at least one of the trials for this pathogen in the U.S. or Canada because of known differences in response rates and susceptibility patterns outside North America. Investigators from geographically diverse areas should enroll a broad range of patients so that many H. pylori strains are studied. H. pylori infections are found in as much as 95 percent of patients with peptic ulcers, the draft says.

All currently approved treatment regimens involve both antimicrobial and anti-ulcer drugs because neither drug can eradicate H. pylori alone, the draft says. Sponsors should consider one of three designs: adding their new drug to an approved regimen, substituting the new drug for one component of an approved regimen or developing a completely new regimen. In the first case, the component of the approved regimen that the new drug is replacing is considered the active control; in the second case, the trial should be placebo-controlled; and in the third case, the sponsor should demonstrate how each component contributes to the overall effect, which can be done with a factorial design.

Either superiority or noninferiority study designs may be acceptable, but the latter type of study should not be conducted unless the sponsor has adequate historical information regarding the effect of the active control in the current regimen, the draft says.

For any study design, sponsors should seek to enroll adult patients with H. pylori infection — diagnosed from biopsy specimens collected during an upper endoscopy. Patients may also undergo a urea breath test to confirm infection, before or after the endoscopy. To be eligible, patients should also have an active duodenal ulcer with a diameter of 3 mm to 25 mm or a documented history of duodenal ulcer disease within the past five years. The 1997 draft guidance says patients with ulcers more than 2 cm in diameter should be excluded or analyzed separately.

Patient exclusion criteria have been expanded and include:

  • Gastric outlet obstruction;
  • Hypersecretory states, such as Zollinger-Ellison syndrome;
  • A history of esophageal or gastric surgery, except for simple closure of a perforated ulcer;
  • A history of gastric cancer or a gastric biopsy test result that is positive for cancer on the baseline endoscopy;
  • Presence of an ulcer smaller than 3 mm or larger than 25 mm, active gastric and duodenal ulcers, or three or more active ulcers;
  • Treatment with proton-pump inhibitors or full therapeutic doses of histamine H2-receptor antagonists within 14 days of screening diagnostic testing; and
  • Treatment with systemic antibiotics known to have in vivo efficacy against H. pylori or bismuth-containing compounds within 28 days of screening diagnostic testing.

The 1997 draft guidance mentioned only five exclusionary criteria: Zollinger-Ellison syndrome, allergy to study medications, presence of more than one ulcer, pregnancy (depending on the specific agents studied), and use of nonsteroidal anti-inflammatory drugs.

The new draft guidance also supersedes more general guidance: “Clinical Evaluation of Anti-Infective Drugs (Systemic),” “Clinical Development and Labeling of Anti-Infective Drug Products” and “Guidelines for the Evaluation of Anti-Infective Drug Products,” which was produced by the FDA with the Infectious Disease Society of America.

The primary efficacy endpoint should be eradication of H. pylori as measured through a urea breath test or an endsocopy in a test-of-cure visit 28 to 56 days after treatment ends. A patient should be considered to have failed therapy pylori if infection persists (as documented by a urea breath test or endoscopy) any time after treatment ends, or if there was no determination if the infection was eradicated.

The draft guidance “Helicobacter pylori-Associated Duodenal Ulcer Disease in Adults: Developing Drugs for Treatment” is available at www.fdanews.com/ext/files/UCM184500.pdf. — Martin Berman-Gorvine


Senate Panel Set to Vote This Week on Healthcare Reform Bill

The Senate Finance Committee plans a vote this week on the healthcare overhaul bill introduced by Sen. Max Baucus (D-Mont.), after it receives a complete score of the cost of the legislation from the Congressional Budget Office.

The committee vote on America’s Healthy Future Act could happen as early as Tuesday, Andrea Saul, a spokeswoman for Sen. Orrin Hatch (R-Utah), told DID. Sen. Chuck Grassley (R-Iowa) and several other Republican committee members failed in several efforts to append amendments that might have removed the proposed $2.3 billion in fees on makers of brand drugs (DID, Sept. 24).

The fees, which remain in the final version and would be allocated by company market share, are designed to help finance the legislation that was introduced last month (DID, Sept. 10).

The Baucus legislation probably would go next to a conference of senators led by Senate Majority Leader Harry Reid (D-Nev.) to be merged with the Affordable Health Choices Act passed by the Health, Education, Labor and Pensions Committee in July.

“We have a long way to go,” President Barack Obama says in a statement Friday. But he adds that he is confident that Congress will pass healthcare reform legislation this year.

Other healthcare legislation on the Hill includes the Affordable Health Choices Act, which passed the Senate Health, Education, Labor and Pensions Committee in July (DID, July 16). The House Energy and Commerce Committee passed the America’s Affordable Health Choices Act of 2009, H.R. 3200, in August, after approval by the House Education and Labor and Ways and Means committees (DID, Aug. 4). — Elizabeth Jones


Allergan Sues for Right to Inform Doctors on Safe Off-Label Drug Use

Allergan has filed a federal lawsuit against the FDA, citing the First Amendment and seeking the right to tell physicians how to safely administer Botox for off-label uses such as relieving spasticity.

The FDA is requiring Allergan to warn about safety risks potentially associated with the use of Botox (botulinum toxin Type A) for spasticity in a risk evaluation and mitigation strategy (REMS), Allergan says in a statement last week. Botox is routinely used off-label for certain types of adult and juvenile spasticity.

The suit, if successful, would allow Allergan to disseminate information to physicians on dosing guidelines, patient selection criteria and proper injection technique for Botox as a treatment for off-label conditions, the company says. Allergan spokesman Caroline Van Hove told DID no other pharmaceutical company has undertaken this type of action.

In 2008, the FDA said Botox, Botox Cosmetic and Solstice Neurosciences’ Myobloc (botulinum toxin type B) have been linked to severe adverse events that may be related to overdosing, including respiratory failure and death, after being used for a variety of conditions, including off-label uses (DID, Feb. 11).

In the lawsuit, Allergan contends the prohibition on proactively communicating truthful information to physicians about off-label uses violates the First Amendment and is inconsistent with the Federal Food, Drug and Cosmetic Act.

The lawsuit relates to Botox, Allergan’s Van Hove said, adding, “We are not crusaders for the broader industry and potentially other off-label issues.”

Allergan says it hopes this suit will lead to clear regulatory guidance on how it can lawfully provide information on the issues physicians should consider in determining the best therapies for patients. 

The FDA has required safety updates to the prescribing labels and a REMS program for all botulinum toxin products approved in the U.S., including Botox (DID, May 1). Companies are required to strengthen warnings in product labeling and add a boxed warning regarding the risk of adverse events when the effects of the toxin spread beyond the injection site. The agency told DID it could not comment on the lawsuit.  

The lawsuit, Allergan, Inc. v. United States of America; United States Food & Drug Administration; Dr. Margaret Hamburg, Commissioner of the United States Food & Drug Administration; and Kathleen Sebelius, Secretary of the United States Department of Health & Human Services, was filed Oct. 1 in the U.S. District Court for the District of Columbia and does not involve Botox Cosmetic, the company says.

Last year, Allergan disclosed a subpoena from the Justice Department requesting documents that detail its promotional practices for Botox as part of an inquiry into alleged off-label promotion of the product as a headache treatment (DID, March 5, 2008).

Last week, the FDA issued the first of its long-awaited draft guidances on REMS for drugs and biologics, sparking concerns from industry that it may add too much time to the approval process (DID, Oct. 1). — April Hollis


Caraco Completes Purchase of Forest Drugs in Settlement

Detroit-based Caraco Pharmaceutical Laboratories has completed its acquisition of several drugs from Forest Laboratories’ Inwood business.

The acquisition is part of a settlement agreement between Forest, Caraco and H. Lundbeck. Forest and Lundbeck accused Caraco in 2006 of infringing the ’712 patent on Lexapro (escitalopram oxalate), which has pediatric exclusivity through March 2012 (DID, July 12, 2006). The dispute centers on the antidepressant, and the litigation was filed in the U.S. District Court for the Eastern District of Michigan, according to Caraco.

Lundbeck — a Danish drugmaker that licenses Lexapro to New York-based Forest — and Forest have agreed to give Caraco licenses to market a generic version of Lexapro when other companies start doing so. Forest will reimburse some of Caraco’s attorneys’ fees related to the litigation, according to a July 16 filing with the SEC.

Lexapro had sales of $565.5 million in the quarter that ended June 30, according to a Forest earnings statement.

The purchase agreement is part of the lawsuit Forest Laboratories Inc., et al. v. Caraco Pharmaceutical Laboratories, Ltd. — Elizabeth Jones


BMS, AstraZeneca Diabetes Drug Meets Phase III Goals

Bristol-Myers Squibb (BMS) and AstraZeneca’s diabetes drug candidate dapagliflozin, combined with metformin, improved glycemic control and weight reduction in patients compared with the effect of metformin and a placebo in a Phase III trial.

Results from the 24-week study show significant mean reductions in glycosylated hemoglobin level and in fasting plasma glucose in patients taking both drugs, BMS and AstraZeneca say in statements Friday. The study also showed that patients taking dapagliflozin had statistically greater mean reductions in weight compared with individuals taking placebo.

Dapagliflozin is a potential first-in-class sodium glucose co-transporter 2 (SGLT2) inhibitor being developed by BMS and AstraZeneca as a once-daily oral treatment for Type 2 diabetes (DID, Jan. 12, 2007). 

SGLT2 inhibitors facilitate the elimination of glucose by the kidney, which helps return serum glucose to a normal level. — April Hollis


Oncolytics Cancer Drug to Begin Phase III Trial

Canadian drugmaker Oncolytics Biotech will begin a Phase III study of its cancer treatment Reolysin after reaching an agreement with the FDA under the special protocol assessment (SPA) process.

The SPA should ensure the randomized, two-armed, double-blind, multicenter, two-stage adaptive study is adequately designed to provide data that could lead to a BLA submission, Oncolytics says in a statement Friday. The protocol is the first approved by the FDA for a Phase III trial of an intravenously administered oncolytic virus.

Reolysin will be studied in combination with chemotherapy, comprised of paclitaxel and carboplatin, in patients with platinum-refractory head and neck cancers, the company says, and results from those patients will be compared with data from those receiving chemotherapy alone.

The primary endpoint for the trial will be overall survival, and the secondary endpoints will be progression-free survival, objective response rate, duration of response and safety and tolerability.

The decision to pursue the Phase III trial was based on positive results from previous trials of the Reolysin combination, Oncolytics says. A Phase I trial of the combination showed an overall response rate of 42 percent, which the company says was a several-fold increase over historical outcomes. Results from a Phase II trial are expected to be presented in the fourth quarter of this year. — David Belian

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