Tuesday, January 20, 2009

Inspector General of HHS confirms clinical trial bias problems

My son, Paul, has four times been denied access to clinical trials not because the clinical trial is full, and not because he does not have the condition that the clinical trial investigational drug is being tested on. No, he has been denied over and over because he is too sick with the condition that the investigational drug is supposed to help. He was most recently excluded just this week.

You might think that he is being excluded for good scientific reasons. But you would be wrong. The sickest patients should be the first ones signed up in the clinical trials. Once medications are FDA approved for sale to the public, the sickest patients are first in line to try the new meds as nothing else has worked for them. The doctors of these very sick patients will prescribe these meds as soon as they are allowed. However, FDA and more importantly the prescribing doctor will have NO INFORMATION about the effects of the new medication on these very sick patients because these patients were systematically excluded from the clinical trials.

Why are the clinical trial investigators so compelled to rid the trials of the very ill? Could it be money? Some people think so. Here is what one scientist said in the article below, "...bias, whether intended or not, can slip into the process when money is involved."

Here are the views of another prominent American physician and researcher quoted in the article below: "If a study is funded by a drug company to investigate its product and if the investigator also has relationships with that company, you can be darn sure that if the study makes it to publication, it's going to favor that product."

Clinical Trials in the United States have inclusionary and exclusionary criteria to carefully select only very particular patients with the intent of getting the FDA approval. No other purpose comes close--not scientific accuracy--not getting answers to the tough questions--not finding out new information, not for helping the suffering volunteers, and never for any kind of compassionate use. I have read that less than 3% of DYING cancer patients are given access to clinical trials by Big Pharma.

Why do three prominent American physicians and researchers (see below) declare that "lax or absent (FDA) regulatory oversight implies a lack of concern and a tacit acknowledgment of a lack of (FDA) enforcement of existing rules" ?

We are often told that Big Pharma really needs volunteers for clinical trials. If more people would just volunteer,clinical trials could move faster and drugs would be approved sooner. The impression given by Big Pharma is that it is really difficult to get people to volunteer. The opposite is true. There are huge number of volunteers but most are rejected. Big Pharma encourages volunteers because it needs huge numbers so it can carefully cherry pick just the right ones so the "right" results can be obtained. This process of course is the opposite of good science. It is in fact a rigged game.

It is not just me criticizing the FDA, here is another quote from the article below :"...nobody cares and clearly that is the message the FDA is sending out"

There is no question that clinical trials in the US volunteers are picked to get fixed results. It is one thing for me to notice but now I am not the only one saying it. Now the BUSH appointed secretary General of Health and Human Services confirm that the game is rigged. This fact soon becomes apparent to every patient who tries to get into a clinical trial or harbors the false hope that ther eis the possibility of qualifying for compassionate use of an investigational drug. Here is the URL of the article: http://www.medscape.com/viewarticle/586980_print

and here is the article:

FDA Not Effectively Monitoring Investigator Conflicts of Interest, HHS Watchdog Says
Neil Osterweil
Medscape Medical News 2009. © 2009 Medscape

January 16, 2009 — More than one third of new drug marketing applications approved by the US Food and Drug Administration (FDA) were missing information about potential conflicts of interest for clinical trial investigators, which could allow bias to creep into the approvals process, a government report released this week has found. The FDA has said that it agrees with most of the report's findings.

Federal regulations require clinical trial sponsors to collect financial information from investigators at the outset of trials, and to report on their efforts to minimize the possibility that financial self-interest could color trial results, notes the report from the office of Daniel R. Levinson, Inspector General of the Department of Health and Human Services (HHS).
Trial sponsors — usually the company developing or licensing the drug or device in question — only have to disclose this information when they apply for marketing approval, and even then there's a loophole: they can claim that they "acted with due diligence" to collect financial information from each investigator to satisfy regulations.

Report Found Few Financial Disclosures

Yet 42% of new drug marketing applications filed in fiscal year 2007 were short on investigator financial disclosures, and in fully one fifth of cases where such information was disclosed, FDA reviewers took no action, the watchdogs reported.

"In FY 2007, only 1% of clinical investigators disclosed a financial interest," the report's authors write. "By way of comparison, the Journal of the American Medical Association reported that between 23% and 28% of academic researchers had financial interests in medical companies. Further, we found a number of limitations in FDA's oversight, leaving FDA unable to determine whether sponsors submit financial information for all clinical investigators."

In addition, the HHS inspector general's staff found that FDA can't verify whether relevant information has been collected on all investigators because of incomplete data and the lack of on-site verification procedures.

Collection and review of such information should be routine, as should appropriate action when required, and all of it should occur before a trial ever gets off the ground, contends a former FDA reviewer interviewed by Medscape Medical News.

"You want to intervene at a time when there's an ability to do something about it," said John H. Powers III, MD, now an assistant clinical professor of medicine at the George Washington University (GWU) and University of Maryland Schools of Medicine.

"To have a situation where the sponsor has already done the trial, submits the information, and then the FDA says 'you have conflicts of interest with your investigators,' puts the sponsor in a bad spot, the investigator in a bad spot, and it puts the FDA in a bad spot. It seems to me that if you're going to regulate here that you should do it a proactive manner," he said.

"Management Failure"

Federal regulations concerning drug marketing approvals require that "adequate measures are taken to minimize bias on the parts of the subject, observers, and analysts of the data," Dr. Powers noted, yet one of the most common sources of potential bias — investigator relationships with industry — are overlooked or ignored.

"This is a management failure," said David B. Ross, MD, PhD, a former FDA reviewer who is now a clinical assistant professor at GWU. "The managers who have set this policy have done nothing to enforce it and there are no consequences, and the reason is that nobody thinks it matters; they're kind of doing this for show."

When Dr. Ross was at the FDA, he and other reviewers warned agency management that a study used to support approval of the antibiotic telithromycin (Ketek, sanofi aventis) was marred by per-patient payments to investigators of up to $400, and, in at least one case, by fraud on the part of the investigator who enrolled the most patients (she was later sentenced to 57 months in federal prison), and by "serious violations in trial conduct" in 9 other trial sites, leading to 4 referrals for criminal investigation.

Despite the warning, and despite ongoing concerns about reported hepatotoxicity from the drug, FDA management failed to take substantive action in response to reviewer concerns, a failure that Dr. Ross said is emblematic of the agency's apparent indifference to the possible influence of investigator financial relationships with industry.

"...CDER [the Center for Drug Evaluation and Research] is not doing that good of a job, and with what they do track, what are they doing with it? It's like having laws against speeding and not writing any tickets," Dr. Ross said.

Relationships Can Have Profound Effect

Eric G. Campbell, PhD, an associate professor at the Institute for Health Policy and the Department of Medicine at Massachusetts General Hospital and Harvard Medical School in Boston, said that financial considerations — whether honoraria, consulting fees, stock options, or direct payments — can have a profound effect on which trials get published or promoted.
"The important thing to remember is that relationships with industry — they may not always be conflicts — are ubiquitous in all aspects of medicine, medical research, and medical regulatory affairs," Dr. Campbell said. "If a study is funded by a drug company to investigate its product and if the investigator also has relationships with that company, you can be darn sure that if the study makes it to publication, it's going to favor that product," he said.

Like Dr. Ross and Dr. Powers, Dr. Campbell pointed out that lax or absent regulatory oversight implies a lack of concern and a tacit acknowledgment of a lack of enforcement of existing rules.

"The bottom line is that if you don't report stuff and nobody pays attention to whether it's reported or not, you're just signaling that it's not important and that nobody cares, and clearly that's the message that FDA is sending out," he told Medscape Medical News.

Key Findings

The report, prepared by staff from the Chicago regional Office of Evaluations and Inspections in the HHS Inspector General's Office, was based on reviews of financial forms, attachments, and accompanying FDA review notes for all 118 marketing applications approved by the agency in fiscal year 2007. The watchdogs also reviewed FDA regulations and guidance, conducted structured interviews with FDA officials, and surveyed FDA reviewers.

The key findings were:

1% of clinical investigators (206 of 29,691) disclosed a financial interest.

FDA does not have a complete list of clinical investigators and does not use on-site inspections to confirm that submitted financial information is complete, meaning that reviewers cannot determine whether sponsors have submitted financial information for all clinical investigators

42% of FDA-approved marketing applications were missing financial information,

23% of approved marketing applications were missing a certification or disclosure form or required attachments, and

in 28% of applications, sponsors used the due-diligence exemption to indicate that they were unable to provide complete financial information.

FDA did not document a review of any financial information for 31% of marketing applications.

Reviewers who followed a review template were more likely to include financial information than those who did not.

In 20% of applications with disclosed financial conflicts, neither the FDA nor sponsors took action.

The Inspector General's recommendations for the FDA were as follows:
Ensure that sponsors submit complete financial information for all clinical investigators.
Use a complete list of clinical investigators to check that sponsors have submitted financial information for all.
Require that sponsors submit financial information for clinical investigators as part of the pretrial application process.
Check that sponsors have submitted all required attachments to financial forms.
Update guidance to sponsors regarding the due-diligence exemption.
Add a review of financial information to the on-site inspection protocol.
Ensure that reviewers consistently review financial information and take action in response to disclosed financial interests.
Require that all centers consistently use a template that includes a prompt to document a review of financial information.
Provide additional guidance and training to reviewers.

FDA Replies

In response to a request from Medscape Medical News for comment, FDA spokesperson Karen Riley sent a statement noting that the agency agreed with all of the HHS recommendations except the one stating that the FDA should request information from clinical investigators prior to trial initiation.

"The intent of clinical investigator financial disclosure is not to discourage investigators from being included in the study," the FDA response says. "Rather, it allows sponsors to identify and manage potential conflicts throughout the development of a regulated product, from design through the conduct of the clinical trials."

The statement goes on to say that this recommendation for financial disclosures before trial initiation could needlessly add to "the complexity and cost of the clinical trial enterprise with no commensurate gain in the protection of human subjects or the quality of the data."

This pretrial disclosure recommendation is not meant to be punitive or burdensome, Dr. Powers said, but it recognizes the fact that bias, whether intended or not, can slip into the process whenever money is involved.

"When people bristle at regulations, I always think of James Madison's quote," he remarked. "Madison said that 'If all men were angels, no government would be necessary.' The reasons why we do these things is not because everybody is inconsistent or immoral: it's because some people are. It seems onerous to people who have no intention of doing the wrong thing, but unfortunately these rules are written for people who aren't going to do the right thing."

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