Corrupted asthma drug trials spotlight FDA�s hasty approvals
By Martha Rosenberg
Online Journal Contributing Writer
Jun 4, 2009, 00:15
A major allergy and respiratory management company knowingly
produced flawed clinical trials of FDA approved drugs currently on the market,
a Texas physician has charged.
Trials of Singular, Serevent,
Foradil, Flovent, Xolair, Accolate and Xopenex conducted at the Tucson, Arizona, 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.
California-based Vivra Asthma & Allergy was the nation�s largest
respiratory disease physician practice until a merger with Lakewood, Colorado-based Gambro in 1997
and with El Segundo, California-based
DaVita in 2005.
In aggressive study
subject recruitment schemes in the late 1990s, 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, according to 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four times in 2007 and an antibiotic tested at Vivra, Raxar was withdrawn in 1999 after links to 13 deaths.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.
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 through 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
�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 report reads
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
�P.I. enrolled subject
into study despite subject having a clear study exclusion (maintenance inhaled
corticosteroid therapy),� the 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
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.
Nor was billing
apparently done by the book.
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, which
acquired Vivra in 1997, 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 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 inspections
were actually delayed to facilitate
the new drug applications the studies
were for -- a paradoxical but expected outgrowth of the 1992 Prescription Drug User Fee Act (PDUFA)
that allows drug companies to pay the FDA to accelerate approvals, says
�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.
physician Anne Kirkman Campbell began serving a sentence in a federal prison in
Lexington, Kentucky, 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, Alabama, 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 Vivra facility.
Martha Rosenberg is a Chicago
columnist/cartoonist who writes about public health. She may be reached at firstname.lastname@example.org.
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