Vol. 8 No. 200
FDA Commissioner Margaret Hamburg’s call for aggressive enforcement action has resulted in a campaign that ranges from actions against KV Pharmaceutical and Caraco Pharmaceutical Laboratories to warning letters and an unapproved drugs initiative, an agency official says.
KV was cited for nonconformance with good manufacturing practices (GMPs) and the distribution of unapproved new drugs, Deborah Autor, director of CDER’s Office of Compliance, said at the Food and Drug Law Institute’s conference on enforcement and litigation. Within four weeks of the inspection’s completion, the company had entered a consent decree with the agency, she added (DID, March 3).
Detroit-based Caraco recently entered into a consent decree with the FDA that can help the company resume manufacturing at three plants in Michigan and win the return of products seized from those facilities. The drugs and active pharmaceutical ingredients were seized in June by U.S. marshals at Caraco’s facilities in Detroit, Farmington Hills and Wixom after the company was cited for not meeting current GMPs (DID, June 26).
The number of warning letters issued by CDER approached 120 during fiscal 2009, continuing an upward trend, Autor said.
Leslie Kux, deputy director at CBER’s Office of Compliance and Biologics
Quality, said warning letters are only one element of the strategy. The FDA also
is using criminal prosecution to enforce compliance. Kux cited the example of
one case CBER brought against Philip Guyett of Donor Referral Services. Guyett
was sentenced to eight years in prison for mail fraud related to his recovery
and sale of human tissues for transplantation.
Separately, a federal grand jury indicted two men from the Minneapolis-St. Paul area on one count of introduction into interstate commerce of misbranded drugs and one count of importation of non-narcotic Schedule IV controlled substances for selling counterfeit drugs, the U.S. Attorney’s Office for the District of Minnesota says in a statement posted on the FDA’s website.
The FDA’s Office of Criminal Investigation cooperated with U.S. Immigration and Customs Enforcement, the U.S. Postal Inspection Service and U.S. Customs and Border Protection in the investigation. The two men are accused of counterfeiting three erectile dysfunction drugs — Pfizer’s Viagra (sildenafil citrate), Eli Lilly’s Cialis (tadalafil) and Schering-Plough, Bayer and GlaxoSmithKline’s Levitra (vardenafil HCl) — as well as Merck’s male pattern baldness treatment Propecia (finasteride), according to the statement.
Autor also discussed the Unapproved Drugs Initiative, which was announced in June 2006. The FDA uses a risk-based enforcement program to root out drugs that could pose safety risks, lack effectiveness or have been reformulated to evade an FDA enforcement action.
Also Tuesday, the agency says in a statement that it has warned four companies to stop marketing unapproved codeine sulfate tablets, which are opioid analgesics that the FDA has no evidence are safe and effective.
The various centers within the FDA also are working to implement the Predictive Risk-based Evaluation for Dynamic Import Compliance Targeting (PREDICT) system agencywide that screens food, drugs and devices imported into the country to ensure their safety.
PREDICT has been used in the Center for Food Safety and Applied Nutrition and is being tested in a pilot program by the Center for Devices and Radiological Health (CDRH) in Los Angeles, according to Timothy Ulatowski, director of the Office of Compliance at CDRH.
Since the unapproved drugs initiative began, it has affected more than 200 companies, Autor said. Details of the initiative’s enforcement actions are available at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivities
byFDA/SelectedEnforcementActionsonUnapprovedDrugs/ucm118712.htm. — Elizabeth Jones
Senate Majority Leader Harry Reid (D-Nev.) will take charge of the effort to combine the healthcare overhaul bill passed by the Finance Committee with the Affordable Health Choices Act to create the legislation that will go to the Senate floor for debate.
The survival of several provisions unique to the America’s Healthy Future Act passed by Finance Tuesday also will be determined during the process, including the $2.3 billion in annual fees imposed on drugmakers as a means of financing the healthcare changes (DID, Sept. 10).
The Affordable Health Choices Act won approval from the Health, Education, Labor and Pensions Committee in July (DID, July 16). The measure includes a provision to create a regulatory pathway for follow-on biologics that would give innovator biologics 12 years of exclusivity (DID, July 15).
The Finance bill includes a pledge by drugmakers to provide a 50 percent discount on the negotiated price for brand drugs covered in plan formularies when Medicare beneficiaries fall into a gap in coverage called the doughnut hole. The legislation also would allow Medicare Advantage prescription drug plans to waive copayments for the first fills of a generic drug prescription as an incentive for beneficiaries to try less expensive formulations of drugs (DID, Oct. 8).
Funding for comparative-effectiveness research is likely to make its way into the Senate’s final healthcare overhaul legislation, as funding for the provisions is included in both bills.
Federal prosecutors are scrutinizing pharmaceutical companies’ reporting of clinical trial results and sales and marketing practices in an increased effort to detect fraud, experts said.
More than 180 pharmaceutical fraud cases involving more than 500 drugs are under investigation by the Justice Department, Jennifer Bragg, partner at Skadden, Arps, Slate, Meagher & Flom, said Tuesday, citing data from the public interest organization Taxpayers Against Fraud. Whistle-blower lawsuits also are included in that number.
In the case of clinical trial results, sponsors may omit relevant negative data in communications such as press releases, she said at the Food and Drug Law Institute conference in Washington, D.C.
The FDA’s Office of Criminal Investigations also is stepping up the number of probes of fraud. The number of convictions climbed 88 percent from 196 in fiscal 2004 to 369 in fiscal 2008, she said, citing FDA statistics.
Qui Tam Suits
Qui tam, or whistle-blower, lawsuits are becoming increasingly expensive for drugmakers. During the 12 months that ended Sept. 30, the FDA has settled six cases with drugmakers, including one with Pfizer for $2.3 billion over its promotion of Bextra (valdecoxib), Bragg said during the discussion (DID, Jan. 28).
Although many qui tam lawsuits have involved accusations about marketing claims or pricing practices — including charging government entities inflated prices — manufacturing problems will be a growing area of litigation, Eugene Thirolf, director of Justice’s Office of Consumer Litigation, said. The suits include one in which the drugs in question don’t meet FDA standards and the company suppressed adverse safety data about their products, he added.
Thirolf also named a number of enforcement trends that are emerging, including the increased number of instances in which the Foreign Corrupt Practices Act (FCPA) is being enforced against drug- and devicemakers. The FCPA is being used against devicemakers and increasingly drug manufacturers that pay doctors in foreign countries, many of whom also are government officials, to get and keep their business.
For example, the SEC announced in October 2006 it was conducting a formal investigation of certain of Bristol-Myers Squibb’s German subsidiaries and its employees. The SEC’s inquiry concerns potential violations of the FCPA and German law, according to a company SEC filing from February.
Justice is cooperating with the various offices in HHS to fight fraud, Thirolf said. The agencies have been in contact with their counterparts in other countries to fight counterfeit and misbranded drugs made in other countries. Offenders can expect jail time and higher fines, Thirolf said. — Elizabeth Jones
Experts say a new FDA draft guidance could lead to unethical conduct in clinical trials that test drugs to reduce the recurrence of duodenal ulcers in adults with Helicobacter pylori infections.
The draft recommends sponsors conduct at least two randomized, controlled trials in which the proportion of patients who are cured is the primary efficacy endpoint (DID, Oct. 5). The trials should establish the safety and efficacy of antimicrobial-containing regimens to treat H. pylori-associated duodenal ulcer disease, according to the draft.
The guidance does not acknowledge the generally low success rates of current approved multidrug regimens, a problem the agency has neglected, David Graham of the Michael E. DeBakey VA Medical Center in Houston told DID Tuesday.
He charged that the draft “potentially promotes unethical behavior by investigators,” including the widespread failure to provide true informed consent to clinical trial patients randomized to receive therapies that are known to have unacceptably low success rates.
Another expert had ethical concerns about the FDA permitting placebo controls in some circumstances. “The use of a placebo control would not be ethical since standard-of-care includes active therapy,” Lori Fischbach, assistant professor of epidemiology at the University of North Texas Health Science Center School of Public Health, told DID.
Factorial study designs, which also are discussed in the draft, would not be ethical either because they would require randomizing subjects to nonstandard single and combined therapies or placebos, she said.
The draft cites an article in the International Journal of Epidemiology for which Fischbach was the lead author to back up its recommendation that sponsors conduct at least one clinical trial in the U.S. or Canada due to the known differences in H. pylori response rates and susceptibility patterns in various parts of the world.
Fischbach told DID that while she agrees with this recommendation, the trials “also should be racially and socioeconomically diverse to better ensure a broad range of strains are studied. Additionally, trials should include immigrant populations since the burden of infection in the United States is greatest among immigrants.”
Fischbach and Graham said the final guidance should:
The document also “generally fails to take into account the vast amount of information that has accumulated since the last revision more than 10 years ago,” Graham said.
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 was published in the Federal Register Oct. 5.
The FDA cannot respond to individual comments at this point, but encourages input, spokeswoman Crystal Rice told DID.
“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
System design flaws at Sumitomo Chemical have raised serious concerns about microbial and endotoxin levels at the active pharmaceutical ingredient (API) facility, according to an FDA warning letter.
One of the API maker’s systems — redacted in the letter — is not designed to minimize the risk of microbial contamination, according to the Aug. 24 letter, posted recently to the FDA’s website. The letter mentions APIs including hydralazine HCl for use in parenteral drug products.
Sumitomo’s response to Form 483 observations states that it is replacing the distribution pipes, connections and flexible hoses. However, one of its tanks cannot be drained and has been in use since 1990, the letter notes. Also, the design of one of its distribution pipes is not conducive to controlling the system’s microbial and endotoxin levels. The 100-meter pipe contains numerous threaded connectors and at least two flexible hoses, the warning letter says.
“We continue to have serious concerns about the impact of your [redacted] system’s design on endotoxin and microbial load,” the letter says. The FDA requests a corrective action plan from the company.
The letter, sent after an April 6 to April 9 inspection, also cites Sumitomo for failing to use suitable processing for a certain step of its hydralazine HCl manufacturing.
“Your written response states that you do not intend to conduct endotoxin testing for [redacted] or sanitize your [redacted] system,” the letter notes. The firm also failed to test for total microbial count and endotoxins, it says.
The company’s new method validation for bicalutamide API also was cited for not including sensitivity, linearity, accuracy or an appropriate precision determination. The establishment inspection report indicates the new method has not been validated for those elements and the precision determination was conducted with only three injections.
The company’s response states it has revised its method validation protocol but does not indicate whether it includes the elements or if it has performed the method validation, the letter says. The FDA requests the company’s revised stability and method validation protocols and method validation report.
The extent of the analytical method validation studies will depend on the purpose of the analysis and the complexity of the manufacturing process, the FDA notes. For example, the validation of the assay method of a component may include performance elements such as accuracy, precision, specificity, linearity and range. For a method used to determine impurities, additional elements, such as quantitation limit and detection limit, will be required.
Sumitomo did not respond to requests for comment by press time. The warning letter is available at www.fdanews.com/ext/files/Sumitomo-Chemical-Co-Ltd.pdf. — April Hollis
Exclusive rights for schizophrenia drug Fanapt in the U.S. and Canada were sold to Novartis, which plans to introduce the drug in the U.S. early next year.
Novartis will give Vanda Pharmaceuticals an upfront payment of $200 million under the agreement, and as much as an additional $265 million when certain development and commercial milestones are met in the U.S. and Canada, Vanda says in a statement this week. Vanda will receive royalties on U.S. and Canadian sales of Fanapt (iloperidone) — a mixed dopamine D2/serotonin 5HT2A receptor antagonist.
Novartis also gains exclusive rights to develop and commercialize a long-acting injectable formulation of the drug for the two markets, Novartis says in a statement. Vanda will retain rights to the oral and injectable formulations outside the U.S. and Canada. The new agreement amended and restated a prior agreement between the companies, Vanda says.
The FDA approved Fanapt in May for the acute treatment of schizophrenia in adults (DID, May 8). The approval was supported by two placebo-controlled Phase III clinical studies comparing Fanapt with antipsychotic drugs in patients with schizophrenia.
Last year, the FDA issued a not-approvable letter for the drug, indicating that Vanda would need to conduct an additional clinical trial testing it against an active comparator such as Eli Lilly’s Zyprexa (olanzapine) or Johnson & Johnson’s Risperdal (risperidone) and generic formulations (DID, July 29, 2008).
Vanda acquired the worldwide rights to develop and commercialize Fanapt from Novartis in 2004. Vanda agreed to complete the iloperidone Phase III development program and seek product registration. — April Hollis
Antisoma’s drug candidate AS1411 has received orphan status in the U.S. and EU for acute myeloid leukemia (AML).
If the drug is approved, it would have seven years of exclusivity in the U.S. and 10 in the EU, Antisoma says in a statement Tuesday. A Phase IIb trial is expected to start in early 2010.
In earlier Phase II trials, addition of AS1411 to high-dose cytarabine increased response rates without significantly increasing side effects in patients with relapsed or refractory AML, the company says.
AS1411 already has orphan drug status in both the U.S. and the EU for renal cancer. A Phase II trial in renal cancer is ongoing, and the company expects to report initial data by the end of the year.
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