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Old 09-28-2010, 10:23 PM
gdpawel gdpawel is offline
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Default FDA issues final rule on safety information during clinical trials

The U.S. Food and Drug Administration today issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics.

“This final rule will expedite FDA’s review of critical safety information and help the agency monitor the safety of investigational drugs and biologics,” said Rachel Behrman, M.D, associate director for medical policy in the FDA’s Center for Drug Evaluation and Research. “These changes will better protect people who are enrolled in clinical trials.”

The new rule requires that certain safety information that previously had not been required to be reported to FDA be reported within 15 days of becoming aware of an occurrence. These reports include:

* findings from clinical or epidemiological studies that suggest a significant risk to study participants

* serious suspected adverse reactions that occur at a rate higher than expected

* serious adverse events from bioavailability studies which determine what percentage and at what rate drug is absorbed by the bloodstream and bioequivalence studies which determine whether a generic drug has the same bioavailability as the brand name drug

The rule also provides examples of evidence that would suggest that an investigational product may be the cause of a safety problem. Under current regulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event. Such reporting complicates and delays the FDA’s ability to detect a safety signal. The examples address when a single event should be reported or when there is need to wait for more than one occurrence.

In addition, the rule revises definitions and reporting standards so that they are more consistent with two international organizations, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use and the World Health Organization’s Council for International Organizations of Medical Sciences. The changes are designed to help ensure harmonized reporting of globally conducted clinical trials.

Along with this final rule, the FDA also issued a draft guidance for industry and investigators that provides information and advice about the new requirements and other information.

For more information

[url]http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDApplication/ucm226358.htm
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Old 09-28-2010, 10:26 PM
gdpawel gdpawel is offline
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Default Looking For Published Cancer Trials?

Less than 20 percent of registered clinical trials of cancer drugs are eventually published in medical journals, according to a review published online by the The Oncologist medical journal.

A search of the National Institutes of Health's ClinicalTrials.gov web site identified 2,028 registered research studies of cancer treatments. Major medical journals require all studies considered for publication be registered at ClinicalTrials.gov or another publicly accessible database.

And a subsequent search of the National Library of Medicine's PubMed database showed that just 17.6 percent of the trials were eventually published in peer-reviewed medical journals.

The publication rate was particularly low for industry-sponsored studies, such as those funded by drugmakers (just 5.9% compared to 59% for studies sponsored by collaborative research networks. Of published studies, nearly two-thirds had positive results in that the treatment worked as hoped. The remaining one-third had negative results like the outcome was disappointing or did not merit further consideration of the tested treatment, they report.

The finding raises concern about publication bias in cancer treatment trials, according to the researchers, Scott Ramsey and John Scoggins of University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

The researchers suspect the rate of negative results is much higher in the studies that have gone unpublished. "It is likely that many unpublished studies contain important information that could influence future research and present practice policy," they wrote.

Of course, we know why a registered trial may not be published, some fail and a researcher may decide the result doesn't enhance knowledge or one's reputation. And some sponsors don't want negative results out there. Same goes for some journal editors.

But "unpublished trials may have special importance in oncology, due to the toxicity and/or expense of many therapies," they wrote. In other words, the knowledge base is incomplete. And who does that help?

Source: Pharmalot
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Old 09-28-2010, 10:28 PM
gdpawel gdpawel is offline
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Default

There is a tendency for major drug manufacturers hide data about the safety and efficacy of its drugs, and produce data of scant clinical value. Conflicts of interest have thoroughly corrupted American medical research. There are dangerous potential for conflicts of interest when pharmaceutical and other for-profit businesses control the dissemination of findings generated by medical research.

The ability of drug companies to pick and choose the research they provide in support of their products is an outrageous conflict of interest and puts all patients in harm's way. It can undermine public trust in and support for scientific research, endanger research subjects and patients, and boost medical costs by encouraging doctors and patients to use new treatments that are no better than cheaper alternatives.

Studies with positive findings are more likely to be published than studies with negative results. Even negative results can provide useful information about the effectiveness of treatments. Any tendency to put negative results into a file drawer and forget them can bias reviews of treatments reported in medical literature, making them look more effective than they really are.

With most clinical trials, investigators never give out information as to how people are doing. Most trials are failures with respect to actually improving things. The world doesn't find out what happen until after a hundred or 500 or 2,000 patients are treated and then only 24 hours before the New England Journal of Medicine publication date.

Having all the information you can gather for the participants and investigators is essential to maintain good doctor-patient communication that is beneficial for cancer patients.

Dangerous drugs have been allowed to reach the market because conflicts of interest have become so endemic in the system of drug evaluation, a trend that has been exacerbated by the rise of for-profit clinical trials, fast-tracking drug approvals, government-industry partnerships, direct consumer advertising and industry-funded salaries for FDA regulators.

The collaborations between academia and industry has clearly brought discernible influence on clinicians, bringing with it erroneous results, suppressed data, or harmful side effects from these drugs.

There is an inherent conflict of interest when organizations provide guidelines for treating disease who receive funding from corporations that benefit financially from those recommended treatments. There is no proof beyond reasonable doubt for any approach to treating cancer today. There is only the bias of clinical investigators as a group and as individuals.

The use of clinical trials to establish prescribing guidelines for evidence-based medicine is highly criticized because such trials have little relevance for the individual patient in the real world, the individuality and uniqueness of each patient. The choice of physicians to intergrate promising insights and methods remains an essential component of quality cancer care.
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Old 03-22-2011, 12:45 PM
gdpawel gdpawel is offline
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Default What happens when a clinical trial goes awry?

From the publishers of Pharmalive.com, Pharmalot editor Ed Silverman, has reminded us about doctors who sign up as clinical trial investigators have certain responsbilities. These include, but are not limited to, protecting the rights, safety and welfare of participants; ensuring the control of drugs used in the trial, personally conducting the trial and supervising other activities. However, while certain tasks can be delegated, general responsibilities may not.

But one doctor failed to follow through. To wit, he relied on a research nurse to carry out all sorts of things back in 2007. Such as? The nurse signed his name on protocol documents, including a financial disclosure form and two serious adverse event reports. Meanwhile, two of four subjects did not meet eligibility criteria. Yet, the doctor was apparently unaware until another research nurse told him.

As the FDA notes in a March 14 letter to John Griffin of Cardiovascular Associates in Virginia Beach, Virginia: "Had you provided adequate oversight, you would have observed from a review of the study documents that the signatures on the study-related documents were not yours and that the two randomized subjects were not eligible according to the protocol."

[url]http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm247469.htm

This sort of problem is known as noncompliance with Good Clinical Practice. And so in 2008, Griffin subsequently scrambled by notifying the Institutional Review Board overseeing the trial and conducting his own internal investigation. The research nurse, meanwhile, admitted to improperly signing his name and so what did he do? He fired her and reported her actions to the State Board of Nursing. The IRB, meanwhile, had to investigate “the extent of involvement of the research nurse and verify the level of misconduct” and the sponsor booted him from the trial.

Griffin may have been correct in firing his nurse. After all, she should have known not to sign his signature on such forms. But as the FDA points out, where was he all that time? Did he think a rubber stamp would suffice? And what about checking on patient status? What’s more, he apparently still hasn’t convinced the FDA that such an episode won’t be repeated. The warning letter acknowledges that Griffin identified the problem and took corrective actions, but the FDA writes, “we find that you have not adequately addressed how you will improve your supervision of study staff in the future.”

In other words, next time a trial goes awry, firing the nurse may not be good enough.
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  #5  
Old 09-09-2011, 03:13 PM
gdpawel gdpawel is offline
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Default Retractions in the scientific literature: the incidence of research fraud increasing?

Retractions in the scientific literature: is the incidence of research fraud increasing?

R Grant Steen, Medical Communications Consultants, LLC 103 Van Doren Place, Chapel Hill, NC 27517, USA; g_steen_medicc{at}yahoo.com

24 December 2010

Background:

Scientific papers are retracted for many reasons including fraud (data fabrication or falsification) or error (plagiarism, scientific mistake, ethical problems). Growing attention to fraud in the lay press suggests that the incidence of fraud is increasing.

Methods:

The reasons for retracting 742 English language research papers retracted from the PubMed database between 2000 and 2010 were evaluated. Reasons for retraction were initially dichotomised as fraud or error and then analysed to determine specific reasons for retraction.

Results:

Error was more common than fraud (73.5% of papers were retracted for error (or an undisclosed reason) vs 26.6% retracted for fraud). Eight reasons for retraction were identified; the most common reason was scientific mistake in 234 papers (31.5%), but 134 papers (18.1%) were retracted for ambiguous reasons. Fabrication (including data plagiarism) was more common than text plagiarism. Total papers retracted per year have increased sharply over the decade (r=0.96; p<0.001), as have retractions specifically for fraud (r=0.89; p<0.001). Journals now reach farther back in time to retract, both for fraud (r=0.87; p<0.001) and for scientific mistakes (r=0.95; p<0.001). Journals often fail to alert the naïve reader; 31.8% of retracted papers were not noted as retracted in any way.

Conclusions:

Levels of misconduct appear to be higher than in the past. This may reflect either a real increase in the incidence of fraud or a greater effort on the part of journals to police the literature. However, research bias is rarely cited as a reason for retraction.

J Med Ethics 2011;37:249-253 doi:10.1136/jme.2010.040923
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  #6  
Old 09-09-2011, 03:17 PM
gdpawel gdpawel is offline
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Default Re: Retractions in the scientific literature

Over the past decade, the number of medical journals that have issued retractions has climbed precipitously. Since 2001, the overall number of papers that were published in research journals increased 44 percent, but at the same time, the number of papers that were retracted climbed more than 15-fold, according to The Wall Street Journal, citing data from Thomson Reuters.

Put another way, there were just 22 retraction notices that appeared in journals 10 years ago, but 139 were published in 2006 and by last year, the number reached 339. Through July of this year, there were a total 210 retractions, according to Thomson Reuters Web of Science, which maintains an index of 11,600 peer-reviewed journals.

Meanwhile, retractions related to fraud rose more than sevenfold between 2004 and 2009, exceeding a twofold rise traced to mistakes, according to an analysis published in the Journal of Medical Ethics. After studying 742 papers that were withdrawn from 2000 to 2010, the analysis found that 73.5 percent were retracted simply for error, but 26.6 percent were retracted for fraud. Ominously, 31.8 percent of retracted papers were not noted as retracted.

The conclusion? Either there is more fraud or more policing? Ivan Oransky, the executive editor of Reuters Health and a co-founder of the Retraction Watch blog that began recently in response to the spate of retractions, writes us that the simple use of eyeballs and software that can detect plagiarism has made it possible to root out bad papers.

He also notes, however, that there are more journals, which explains why there are more papers, in general, being published. “So the question is whether there have been more retractions per paper published,” Oransky writes, and then points to a chart to note that were, indeed, many more.

“That’s really no surprise, given the increasing numbers of eyeballs on studies, and the introduction of plagiarism detection software. It’s unclear whether the actual amount of misconduct and legitimate error has grown; it may just be that we’re picking up on more of it,” he continues. “What makes it difficult to tell is a problem we often see at Retraction Watch: Opaque and unhelpful retraction notices saying only ‘this study was withdrawn by the authors.’ How does that make for transparent science? We think journals can do a lot better, by demanding that authors and institutions come clean about what went wrong.”

And why is there more fraud? As the Wall Street Journal notes, there is a lot to be gained - by both researchers and journal editors - to publish influential papers. “The stakes are so high,” The Lancet editor Richard Horton tells the Journal. “A single paper in Lancet and you get your chair and you get your money. It’s your passport to success.”

A few notable retractions include an episode at the Mayo Clinic, where a decade of cancer research - which was partly taxpayer-funded - was undermined after the clinic realized that data about harnessing the immune system to fight cancer had been fabricated. A total of 17 papers published in nine research journals were retracted and one researcher, who maintained innocence, was fired.

Recently, 18 journals indicated plans to retract a total of 89 published studies by a German anesthesiologist, many concerning a drug used for maintaining blood pressure during surgery. Meanwhile, authorities in the UK are reviewing usage guidelines and a prosecutor in Germany is conducting a criminal probe, because data may have been fabricated.

And the Journal goes into detail in one instance. A 2003 paper in The Lancet that compared two high blood pressure meds and found to be much better in combination than either alone. Patients given the combination experienced a 76 percent drop in protein loss, compared with 42 percent with one drug by itself and 44 percent with the other one alone.

The dramatic findings prompted suspicion, which led to a lengthy investigation, but one that took very long. After noting “serious concerns,” The Lancet did not issue a retraction for more than six years. By then, however, more than 100,000 patients had been prescribed the combo and thousands of people are probably still taking the drugs.

An investigation by a Japanese hospital where the lead author had worked found the researchers never obtained proper patient consent or approval for the study from the ethics committee of the hospital where they said the research was done. And the involvement of a statistician in the clinical trial could not be verified.

One of the doctors who suspected article was dubious criticized The Lancet and its peer reviewers for not being more skeptical about the dramatic results. “Journals all want to have spectacular results,” Regina Kunz tells the paper. “Increasingly, they’re willing to publish more risky papers.”

The Lancet’s Horton pooh-poohs her criticism, and insists journals are becoming more conservative about publishing “provocative” research. But he concedes journals lack adequate systems to investigate misconduct. The apparent rise in scientific fraud, he tells the Journal, “is a scar on the moral body of science.”

Source: Pharmalot
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Old 11-17-2011, 05:32 PM
gdpawel gdpawel is offline
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Default Some Phase III trials presented at ASCO never published in peer-reviewed publications

Compendium of unpublished phase III trials in oncology: characteristics and impact on clinical practice.

Tam VC, Tannock IF, Massey C, Rauw J, Krzyzanowska MK.

Princess Margaret Hospital, 610 University Ave, Ste 5-206, Toronto, Ontario, Canada M5G 2M9.

Abstract

PURPOSE:

Many phase III trials presented at annual meetings of the American Society of Clinical Oncology (ASCO) remain unpublished. The results of these unpublished trials, if more generally known, might have an impact on clinical practice.

METHODS:

Abstracts of large phase III trials evaluating systemic cancer treatment were identified from conference proceedings of the 1989 to 2003 ASCO annual meetings. PubMed, Medline, and Embase were searched for corresponding publications. A compendium of unpublished phase III trials was assembled. Clinical significance of nonpublication was determined by disease site-specific oncology experts from two academic cancer centers in Canada.

RESULTS:

A total of 709 phase III trials were identified of which 66 (9.3%) remain without a subsequent publication at a minimum of 6.5 years of follow-up and 94 (13%) were published after a delay of ≥ 5 years from their initial presentation. Of the unpublished trials, 48% were presented as oral sessions at an ASCO meeting, and 71% of the abstracts reported negative results. The experts judged that 70% of the unpublished trials addressed an important question and 59% might have had clinical impact if their results had been published promptly.

CONCLUSION:

A substantial number of cancer clinical trials with potential influence on clinical practice remain unpublished and many other trials are published after a substantial delay. Nonpublication of clinical trials breaks an implicit contract with participants, institutional review boards, and sponsors.

J Clin Oncol. 2011 Aug 10;29(23):3133-9. Epub 2011 Jul 11. PMID: 21747079
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Old 03-29-2012, 12:53 PM
gdpawel gdpawel is offline
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Default Many Cancer Studies Are Actually Unreliable

Ed Silverman
Pharmalot

Ever wonder why some oncology research never becomes a clinical success? Two cancer researchers were curious and so they reviewed 53 so-called landmark papers, which were published in leading journals and emanated from reputable laboratories. What did they find? An overall poor quality of published preclinical data, and 47 papers - or 89 percent - could not be replicated.

“The scientific community assumes that the claims in a preclinical study can be taken at face value,” wrote C. Glenn Begley, former vp and global head of hematology and oncology research at Amgen and now a senior vp at TetraLogic, and Lee Ellis, a professor of surgical oncology and cancer biology at the University of Texas MD Anderson Cancer Center, in Nature. There is an assumption that “the main message of the paper can be relied on… Unfortunately, this is not always the case.”

“It was shocking,” Begley tells CNBC. “These are the studies the pharmaceutical industry relies on to identify new targets for drug development. But if you’re going to place a $1 million or $2 million or $5 million bet on an observation, you need to be sure it’s true. As we tried to reproduce these papers, we became convinced you can’t take anything at face value.” A team of about 100 Amgen scientists were involved in the effort.

[url]http://www.cnbc.com/id/46882434

The piece prompted some handwringing from the editors at Nature, who confessed to a growing unease with carelessness. In general, they cited such possibilities as “unrelated data panels; missing references; incorrect controls; undeclared cosmetic adjustments to figures; duplications; reserve figures and dummy text included; inaccurate and incomplete methods; and improper use of statistics — the failure to understand the difference between technical replicates and independent experiments."

[url]http://www.nature.com/nature/journal/v483/n7391/full/483509a.html

Such gaffes were mentioned in the context of making mistakes, although fraud remains a big concern, especially amid the growing number of retractions that take place. Over the past decade, the number of retractions in scientific journals rose more than 10 times while the number of journal articles published has increased by just 44 percent. Why? Good science is not always the highest priority.

“Incentives have evolved over the decades to encourage some behaviors that are detrimental to good science,” Ferric Fang, a University of Washington professor of laboratory medicine, microbiology and medicine told a National Academy of Sciences committee earlier this week about retraction issues, according to UPI.

The reason, according to Fang is simply that too many researchers are competing for too few dollars, creating a Darwinian contest for funding and prestige. To what extent this accounts for sloppiness is unclear. But the Nature editors confess the comment published by Begley and Lee “throws up many questions. Here are three of them. Who is responsible? Why is it happening? How can it be stopped?”

For their part, Begley and Lee tried to sort things out by attempting to contact original authors; discuss discrepancies; exchange reagents; and repeat experiments under author direction, sometimes even in the lab of the original investigator. Some authors, though, required them to sign a confidentiality agreement barring them from disclosing data that contradicted initial results.

“The world will never know” which of the 47 studies may actually convey incorrect information, Begley tells CNBC. So how to explain the discrepancies? Often, the authors of the papers would tell Begley and his colleagues that they simply “didn’t do it right.” He recounted one instance in which he met with a leading researcher for breakfast at a conference to review the issue.

What he was told upset him. “We went through the paper line by line, figure by figure,” Begley also tells CNBC. “I explained that we re-did their experiment 50 times and never got their result. He said they’d done it six times and got this result once, but put it in the paper because it made the best story. It’s very disillusioning.”

There are, however, few incentives for verifying research. A decade ago, most potential cancer-drug targets were backed by 100 to 200 publications, CNBC writes, but each one may have just a handful. “If you can write it up and get it published you’re not even thinking of reproducibility,” Ken Kaitin, director of the Tufts Center for the Study of Drug Development, tells CNBC. “You make an observation and move on. There is no incentive to find out it was wrong.”

[url]http://www.nature.com/nature/journal/v483/n7391/full/483531a.html#/affil-auth
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