FDA Waved Through Asthma Drugs Despite Falsified Trials

by Martha Rosenberg

A major allergy and respiratory management company knowingly produced flawed clinical trials of FDA approved drugs currently on the market a Texas physician is charging.

Trials of Singular, Serevent, Foradil, Flovent, Xolair, Accolate and Xopenex conducted at the Tucson, AZ facility of Vivra Asthma & Allergy were corrupted by protocol violations and outright falsifications says Robert Davidson, MD, a former clinical research subinvestigator at the facility.

San Mateo, CA-based Vivra Asthma & Allergy was the nation's largest respiratory disease physician practice until a merger with Lakewood, CO-based Gambro in 1997 and with El Segundo, CA-based DaVita in 2005.

In aggressive study subject recruitment schemes in the late 1990's, patients with abnormal EKGs, multiple risk factors for coronary artery disease, arrhythmia, pulmonary embolism and rheumatic fever histories, acute illnesses and even pituitary tumors were enrolled with impunity in trials that earned investigators as much as $10,000 per patient charges Davidson. Patients were "prescreened" for asthma drug trials with medically unnecessary pulmonary function tests (PFTs) without their knowledge or consent and had medication dosages reduced in apparent efforts to qualify them for the lucrative trials.Staff could be seen to enter rooms where placebo and real drugs were mixed, unblinding and invalidating entire studies sent to the FDA as data for new drug applications.

The brazen "study buddy" and "cross over" arrangements, as staff referred to them, included churning or serial enrolling of patients into clinical trials despite risks to their health and early terminations, coercing unwilling patients to participate and direct falsification of patient study diaries say documents filed by Davidson in a federal complaint.

In 2006 the FDA mandated black box warnings on Serevent and Foradil, tested at Vivra and elsewhere, for increasing the risk of asthma-related death after adverse outcomes forced the early termination of a large clinical trial. Warning labels for Singulair, also tested at Vivra and under FDA investigation for suicidal side effects, were strengthened four times in 2007 and an antibiotic tested at Vivra, Raxar, was withdrawn altogether in 1999 after links to 13 deaths. Also tested at Vivra was norastemizole, a metabolite of Hismanal, an asthma drug withdrawn from the market in 1999 for cardiac-related deaths.

FDA inspections of the Vivra Tucson facility where Jay Grossman, MD served as principal investigator (P.I.) from 1993-2000 confirm the clinical subterfuge.

"Three study coordinators stated that they saw diary card blank prior to subject entering exam room with P.I. for visit 2," reads a report from a May 5 though June 28, 1999 inspection obtained under the Freedom of Information Act. "Five to ten minutes after, the diary had approximately two weeks of diary symptoms and peak flow entered."

"On multiple occasions over the last 8 months the P.I. strongly counseled the S.I. [subinvestigator] to NOT mention potential risks of study participation to potential study subjects, (such as arrhythmia, drug-drug interaction, etc.) so as to not 'scare them away'," the FDA report reads elsewhere.

"Coordinator stated that subject called to say she could not participate in a 12-hour a day study due to her schedule. P.I. called the subjects [sic] estranged husband to say that they had to get the disease under control."

Nor was patient safety apparently protected.

"P.I. enrolled subject into study despite subject having a clear study exclusion (maintenance inhaled corticosteroid therapy)," an FDA report states elsewhere. "Subject subsequently experienced a SAE [severe adverse event] (hospitalized) while in the study. Moreover, this subject had recently participated in a prior study which she required multiple prednisone bursts and multiple courses of antibiotic therapy for several bouts of acute sinusitis with asthma exacerbation."

FDA reports from a 1999 inspection at the Tucson Vivra facility also document missing informed consent forms, clinical records changed to minimize alcohol and cigarette consumption and records rewritten and ripped up by Dr. Grossman according to witnesses.

Reached by telephone, communications officials at Gambro and DaVita were unable to discuss the trials. Dr. Grossman did not respond to faxed and email messages.

Questions have also been raised about the billing procedures of Vivra, which was acquired by Gambro in 1997. Pulmonary function tests were performed on all patients regardless of medical necessity states former Vivra Tucson nurse Joanne Wray in court documents--amounting to a time and money saving gratuity for drug companies, shouldered by insurers, to prevent costly" screening failures" when studies began.

In 2000, Gambro agreed to a $40 million settlement for submitting false claims to Medicare, Medicaid and TRICARE and entered into a Corporate Integrity Agreement with the Department of Health and Human Services only to have to agree to another settlement for $350 million in 2004.

Yet despite the irregularities and red flags, clinical trials at the Vivra Tucson facility which still appear in the New England Journal of Medicine and the Annals of Internal Medicine, were not stopped by the FDA, institutional review boards, trial sponsors, contract research organizations or the Justice Department. Nor was the facility's clearance to conduct trials revoked.

In fact FDA inspections were actually delayed to facilitate the new drug applications the studies were for--like clearing a plane with mechanical problems for takeoff to not hold up travelers. This "safety last" policy is a expected outgrowth of the 1992 Prescription Drug User Fee Act (PDUFA) that allows drug companies to pay the FDA to accelerate approvals, says Davidson.

"It takes time to obtain a properly administered, formal informed consent with full disclosure of risks and benefits and that slows study-subject recruitment and ultimately, delays the time to obtain market approval from FDA," says Davidson. "It is virtually certain that there have been deaths of US citizens because of the fraudulent or seriously-flawed clinical research PDUFA encourages. Nor is FDA likely to revoke expedited market approvals because that would be tantamount to admitting that they 'goofed.'

When presented with 51 allegations of Vivra's medical wrongdoing in 2000, the Arizona Board of Medical Examiners also did not act, calling the evidence "insufficient to support a violation" of Arizona Revised Statutes.

This is not the first time bogus, pay-to-play research which risks study subjects and the public's health has surfaced. Recently Alabama physician Anne Kirkman Campbell began serving a sentence in a federal prison in Lexington, KY for clinical trials she conducted of the controversial, antibiotic Ketek, linked to liver failures and deaths.

Campbell "got greedy" and enrolled her own family, staff and more than one percent of the adult population of the town of Gadsden AL in clinical trials wrote the St. Petersburg Times in 2007.

Despite revelations of Campbell's fraud and problems found at other study sites by regulators while the drug was being tested, Ketek sailed through the FDA and was approved on April 1, 2004.

Ketek was also tested at the Tucson Vivra facility.