The fascinating history of clinical trials

From the June 3, 2020 article at The Conversation

“Clinical trials are under way around the world, including in Australia, testing COVID-19 vaccines and treatments.

These clinical trials largely fall into two groups. With observational studies, researchers follow a group of people to see what happens to them. With experimental studies, people are assigned to treatments, then followed. 

These study designs have come about from centuries of people trying out different ways of treating people.

Here are some of the key moments in the history of clinical trials that led to the type of trials we see today for COVID-19.”

Continue reading the article for examples as ginseng in China, rhubarb in 18th century England, Early 20th-century randomised trial, and tuberculosis and the randomised controlled trial

Additional resources and reading

—Randomised control trials: what makes them the gold standard in medical research?

–From the research lab to your doctor’s office – here’s what happens in phase 1, 2, 3 drug trials

— Health Check: can vitamins supplement a poor diet?

—ClinicalTrials.gov – a searchable database of privately and publicly funded clinical studies conducted around the world.

Precision Medicine at one year: A soaring White House summit and the potholes ahead (report)

From the 28 February 2016 post at HealthNewsReview

Excerpts

We’re pleased to publish the following guest post by Dr. Michael Joyner, a medical researcher at the Mayo Clinic who recently joined our team as a contributor. These views are his own. You can follow him on twitter @DrMJoyner.

---

Last week there was a big shindig at the White House reviewing progress from the first year of the million-person Precision Medicine Initiative (PMI).

As you might imagine, an event of this magnitude drew considerable (mostly glowing) coverage from major US health news media:

• Washington Post: White House to mark a year of effort on precision medicine initiative. Excerpt: In a briefing with reporters Thursday, NIH Director Francis S. Collins called the effort “the largest, most ambitious research project of this sort ever undertaken.”

…

This is an exciting scientific undertaking — one that merits the attention these outlets have devoted to it. But the coverage sounded mostly like cheerleading, and none of these stories included a skeptical word about the many challenges ahead and how they could thwart the initiative’s lofty objectives. I watched the webcast of the event with a critical eye and took notes as I was watching. Here are a six of the things that I thought journalists should have been thinking about and writing about as they covered the event:

1) A number of new partnerships and pilot programs related to enrollment of participants, data sharing, analytics, biobanks and privacy were announced. There are no real results yet, so it is simply too soon to tell what elements of what was announced will succeed, partially succeed, or stall.

2) Francis Collins, the director of the National Institutes of Health and a prime mover in Precision Medicine, clearly stated that it should take three to four years to meet the one million person enrollment goal of the program. This is an ambitious timeline. The last time that something like this was tried in the National Children’s Study, enrollment goals were never met and the program was ultimately cancelled. As STAT has previously reported, experts in population health have observed similarities between the PMI and the National Children’s Study and the comments by Dr. Collins are a clear marker for evaluating the success of PMI going forward.

3) There were a number of interesting presentations of patient and family vignettes at the meeting. While PMI is supposed to transform health and healthcare for all Americans, three of the four stories were about extremely rare diseases that have nothing to do with the big killers like diabetes, cancer, and heart disease. There is no argument by PMI skeptics about the role of gene sequencing in rare diseases, but dealing more effectively with those diseases has nothing to do with the prediction, prevention, and improved treatment of the major causes of death. The fourth presentation was about breast cancer and it was unclear to me exactly what elements of precision medicine were involved in the care of this patient (who happened to be a surgeon). In the absence of big transformative population findings for common diseases, some might argue that the rare disease community is being leveraged to generate support for a much larger and perhaps misdirected program.

4) There was no mention of some of the potholes that are out there or that have emerged in the last year. For example, the National Cancer Institute’s MATCH trial, designed to match the genetic signatures of tumors with targeted therapy, is having trouble “matching” (subscription required). And a study from Europe has cast at least some doubt on just how effective broad-based used of “targeted therapy” will be. There is also plenty of room to question the idea that data mining electronic health records is going to be transformative. The barriers to actually getting this done are significant and range from the quality of the data in electronic health records, issues related to who owns the data, protocols for data sharing, and a host of technical and statistical issues. Big data can certainly be helpful but it can also mislead.

 

[Reblog] Precision Medicine Initiative: Some quick resources

 

From the 30 January 2015 post BY PIA CHRISTENSEN  at Covering Health – Monitoring the Pulse of Healthcare Journalism 

 White House has announced its anticipated “Precision Medicine Initiative,” which it describes as an “emerging field of medicine that takes into account individual differences in people’s genes, microbiomes, environments, and lifestyles – making possible more effective, targeted treatments for diseases like cancer and diabetes. ”

….

The practice of medicine has always been personal regarding the treatment of individual patients, but science has fostered a new era of so-called personalized medicine that takes into account each person’s specific clinical, genetic, genomic and environmental information in designing tailored treatment plans

…

The White House released this fact sheet today.

This interview with the director of the program in personalized health at the University of Utah offers a good explanation of what personalized care is and examples of what it could do.

For Science magazine, Jocelyn Kaiser writes that the Obama precision medicine plan would create huge U.S. genetic biobank. She follows up with more details about the price tag and budget.

…

The White House released this fact sheet today.

This interview with the director of the program in personalized health at the University of Utah offers a good explanation of what personalized care is and examples of what it could do.

For Science magazine, Jocelyn Kaiser writes that the Obama precision medicine plan would create huge U.S. genetic biobank. She follows up with more details about the price tag and budget.

 

Related articles

• Five Accelerants to the Adoption of Connected Health (From the 28 January 2015 item at The cHealth blog)

“I have been thinking lately about the cultural and business phenomena that are currently shaping and accelerating the adoption of connected health and, in that context, came up with five accelerants.  The best part of the story is that four of the five are already going on and we can see their early-stage effects.

So, at the risk of ‘dumbing down’ adoption, here is my list of five accelerants.  If we could make these go faster, the adoption of connected health would accelerate too.”

1. Increase value-based reimbursement for providers.
2. Create more mechanisms for provider reimbursement for non face-to-face care (like the new CMS CPT code that just took effect).
3. Accelerate consumer choice in the marketplace as well as ‘consumer-driven health care’ (i.e., high deductible plans, health savings accounts (HSAs), etc.).
4. Make the consumer-facing technology truly frictionless.
5. Create a universal privacy/security technology and make it a public good.

• Integrated approach to customer relationship management and patient relationship management (From the 28 January 2015 post at Health Care Conversation)

  A comprehensive consumer and patient engagement model should help providers attract and engage individuals in the key areas they value:

  • Help in understanding and navigating the health care system
  • Personalize information and care based on an individual’s needs
  • Easy access and communication with provider and care team
  • Support in managing an acute episode or a chronic illness
  • Secure access to personal health records

 

Read the entire article here

Related articles

• Obama to detail personalized medicine initiative
• Obama Precision Medicine Plan Would Create Huge U.S. Genetic Biobank
• Got genes: Obama proposes genetic biobank of 1mn Americans’ DNA to fight disease

[Press release] MD Anderson and Bayer collaborate to create symptom assessment questionnaires in clinical trials

MD Anderson and Bayer collaborate to create symptom assessment questionnaires in clinical trials 

From the press release

MD Anderson News Release 1/23/2015

When cancer patients take part in a clinical trial to develop new therapies, they and their physicians want to know how they will feel and function during treatment. A new collaboration between Bayer and The University of Texas MD Anderson Cancer Center will go straight to the patients to learn how certain investigational new drugs affect them. The project will involve the use of questionnaires to assess how a drug may impact a patient’s disease-related symptoms.

“Fit-for-purpose patient-reported-outcome (PRO) measures are an invaluable resource for helping us to better understand how patients are actually being affected by new therapies,” said Charles Cleeland, Ph.D., chair of symptom research at MD Anderson. “This will be especially important in the developmental pathway of new drugs, given that these PRO measures will enhance information about treatment tolerability and potential symptom-reduction benefit earlier in the drug development process.”

Charles Cleeland, Ph.D.

The information will be beneficial in further evaluating the drug if it progresses to later stages of clinical development and is tested in larger numbers of patients. The importance of having data on the symptom burden or benefit conferred by therapy is often not recognized until late in that process.

“For patients and their physicians, knowing the probable effects of a treatment can help with decisions among treatment options when therapeutic outcomes are similar but symptomatic effects are not,” said Cleeland.

…

 Related Resources

• ClinicalTrials.gov
  • registry and results database of publicly and privately supported clinical studies of human participants conducted around the world

  • What Information Can I Find on ClinicalTrials.gov?

    Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following:

    • Disease or condition
    • Intervention (for example, the medical product, behavior, or procedure being studied)
    • Title, description, and design of the study
    • Requirements for participation (eligibility criteria)
    • Locations where the study is being conducted
    • Contact information for the study locations
    • Links to relevant information on other health Web sites, such as NLM’s MedlinePlus® for patient health information and PubMed® for citations and abstracts for scholarly articles in the field of medicine.

    Some records also include information on the results of the study, such as:

    • Description of study participants (the number of participants starting and completing the study and their demographic data)
    • Outcomes of the study
    • Summary of adverse events experienced by study participants
  • More information at ClinicalTrials.gov
    • Learn about clinical trials
    • MedlinePlus® Clinical Trials Information

      MedlinePlus is a Web-based health information service of the National Library of Medicine. It explains health topics using language that is easy to understand. Visit the Clinical Trials page (also available in Spanish) or the interactive tutorial on clinical trials (also available in Spanish) to learn more about clinical research and find answers to common questions.

Related articles

• MD Anderson and Bayer Announce Collaboration to Create Symptom Assessment Questionnaires in Clinical Trials
• Drug Development’s Long And Winding Road

HHS and NIH take steps to enhance transparency of clinical trial results

From the HHS Press Release,  Wednesday, November. 19, 2014

 The U.S. Department of Health and Human Services today issued a Notice of Proposed Rulemaking (NPRM), which proposes regulations to implement reporting requirements for clinical trials that are subject to Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA). The proposed rule clarifies requirements to clinical researchers for registering clinical trials and submitting summary trial results information to ClinicalTrials.gov, a publicly accessible database operated by the National Library of Medicine, part of the National Institutes of Health. A major proposed change from current requirements is the expansion of the scope of clinical trials required to submit summary results to include trials of unapproved, unlicensed, and uncleared products.

…

….

ClinicalTrials.gov currently contains registration information for more than 178,000 clinical trials and summary results for more than 15,000. These numbers include trials that are not subject to FDAAA. Among the primary benefits of registering and reporting results of clinical trials, including both positive and negative findings, is that it helps researchers prevent unnecessary duplication of trials, particularly when trial results indicate that a product under study may be unsafe or ineffective, and it establishes trust with clinical trial participants that the information from their participation is being put to maximum use to further knowledge about their condition.

Developed by NIH in close coordination with the FDA, the proposed rule details procedures for meeting the requirements established by FDAAA to improve public access to clinical trial information. FDAAA and the proposed rule apply to certain interventional studies of drugs, biological products, and devices that are regulated by the FDA, but, generally, not to phase 1 trials of drugs and biological products and small feasibility studies of devices. The proposed rule specifies how data collected and analyzed in a clinical trial would be required to be submitted to ClinicalTrials.gov. It would not affect requirements for the design or conduct of clinical trials or for the data that must be collected during clinical trials.

“This proposed rule would close an important gap, making additional information about clinical studies of investigational drugs, medical devices and biological products available to the public,” said FDA Commissioner Margaret A. Hamburg, M.D. “It would help eliminate unnecessary duplicative trials, advance biomedical innovation, and provide the public with a much richer understanding about the clinical trials for these products.”

Notable changes from current requirements and practice that are outlined in the proposed rule include:

A streamlined approach for determining which trials are subject to the proposed regulations and who is responsible for submitting required information.

Expansion of the set of trials subject to summary results reporting to include trials of unapproved products.

Additional data elements that must be provided at the time of registration (not later than 21 days after enrolling the first participant) and results submission (generally not later than 12 months after completion).

Clarified procedures for delaying results submission when studying an unapproved, unlicensed, or uncleared product or a new use of a previously approved, licensed, or cleared product and for requesting extensions to the results submission deadline for good cause.

More rapid updating of several data elements to help ensure that users of ClinicalTrials.gov have access to accurate, up-to-date information about important aspects of a clinical trial.

Procedures for timely corrections to any errors discovered by the responsible party or by the Agency as it processes submissions prior to posting.

 

 

Read a summary of the proposed changes: http://www.nih.gov/news/health/nov2014/od-19_summary.htm.

Read the entire text of the proposed regulations here. Options are available for comment submission electronically or in written form.

 

Biases in animal studies may differ from those in clinical trials — ScienceDaily

Biases in animal studies may differ from those in clinical trials — ScienceDaily.

From the 27 January 2014 article at ScienceDaily

Source:

University of California – San Francisco

Summary:

A new analysis of animal studies on cholesterol-lowering statins found that non-industry studies had results that favored the drugs even more than studies funded by industry.

new analysis of animal studies on cholesterol-lowering statins by UC San Francisco researchers found that non-industry studies had results that favored the drugs even more than studies funded by industry.

The analysis of 63 animal studies of statins, led by Lisa Bero, PhD, UCSF professor clinical pharmacy, was published online January 21, 2014, in the scientific journal PLoS Biology.

In previous studies, Bero determined that drug-company-sponsored clinical trials were associated with publication of outcomes that favor the sponsor. Bero’s work has been cited as part of policy reform efforts that have led many journal publishers, agencies and institutions to require researchers to disclose funding sources and possible conflicts of interest when presenting their research.

The impetus for the current study, Bero said, was to explore whether or not industry-funded animal studies also would be likely to yield more positive outcomes for the companies’ drug candidates.

But in their analysis the researchers found the opposite: Results of animal studies that had industry sponsorship were less likely to measure a benefit for statins in slowing or preventing arterial disease. Of the studies that disclosed funding, 9 of 19 industry-sponsored studies had results that favored statins, in comparison to 18 out of 28 studies that favored statins among studies not funded by industry.

The explanation may be, said Bero, that “the interests of the pharmaceutical industry might be best served by underestimating efficacy prior to clinical trials, and overestimating efficacy in clinical trials. By underestimating efficacy in preclinical studies, the pharmaceutical industry could reduce the money spent on clinical trials that did not lead to marketable products.”

“Because demonstrating drug efficacy in human studies is linked to drug company profits, drug companies may have more incentive to publish favorable efficacy findings of human drug studies than animal studies.”

However, the reason for the opposite findings obtained in analyzing animal and human studies merits additional investigation, Bero said. Selective reporting of study outcomes might play a role, she suggested.

Conclusions of all the studies tended to be favorable in Bero’s PLoS Biology analysis. While the industry-sponsored animal studies had somewhat less favorable results, they nonetheless were more likely to present conclusions that favored the statin even when data were less favorable. This result highlights the role of “spin” in communicating research findings, Bero said.

The UCSF researchers also found methodological problems to be common, both in non-industry and industry-sponsored studies. Furthermore, Bero found that harmful side effects were not investigated.

“Not a single animal study we looked at assessed adverse events following the statin intervention,” Bero said. “As toxicity data from animal studies must be submitted to drug regulatory authorities before a compound can proceed to testing in humans, it is surprising that so little data on harm appear in the published scientific literature.”

In about half the studies analyzed, it appeared that animals were not assigned to treatment or placebo arms of the study randomly, a requirement of high-quality clinical trials. Furthermore, in about half the animal studies analyzed animals were identifiable to the person assigning treatment, a violation of the practice of “blinding.”

Criteria for including or excluding animals from studies often were not included in published reports, the UCSF researchers found, and many studies also failed to account properly for changes in the assigned treatment arm that occurred during the course of treatment.

Most of the industry and non industry studies analyzed in Bero’s PLoS Biology report were done using rabbits and mice. To gauge atherosclerosis, targeted by statins, researchers quantified blood vessel qualities such as number of damaged blood vessels, blood-vessel diameter, plaque severity, blockage to coronary and other arteries, and plaque rupture.

[Reblog] Last week “clinical trial system broken”; this week “luxury journals distort/damage science”

From the 10 December 2013 HealthNewsReview.org post 

In the BMJ recently:

“The clinical trial system is broken and it’s getting worse, according to longstanding Food and Drug Administration investigator, Thomas Marciniak. …

“Drug companies have turned into marketing machines. They’ve kind of lost sight of the fact that they’re actually doing something which involves your health,” Marciniak says. “You’ve got to take away the key components of the trials from drug companies.”

Now, in The Guardian, Nobel Prize winner Randy Schekman writes, “How journals like Nature, Cell and Science are damaging science: The incentives offered by top journals distort science.” Excerpt:

“These luxury journals are supposed to be the epitome of quality, publishing only the best research. Because funding and appointment panels often use place of publication as a proxy for quality of science, appearing in these titles often leads to grants and professorships. But the big journals’ reputations are only partly warranted. While they publish many outstanding papers, they do not publish only outstanding papers. Neither are they the only publishers of outstanding research.

These journals aggressively curate their brands, in ways more conducive to selling subscriptions than to stimulating the most important research.”

And he goes on to state that he will avoid such journals in the future.

“Like many successful researchers, I have published in the big brands, including the papers that won me the Nobel prize for medicine, which I will be honoured to collect tomorrow.. But no longer. I have now committed my lab to avoiding luxury journals, and I encourage others to do likewise.”

Note:  in case you missed it, yesterday I linked to Dr. Richard Lehman’s BMJ journal review blog, in which he wrote:

“The Lancet is a very odd journal, in case you hadn’t noticed. Some weeks it contains pharma-funded phase 2 trials of astounding clinical irrelevance.”

One of my boilerplate slides in talks I give to journalists is the following, cautioning them not to treat journal publications as if they were Moses bringing the stone tablets from the mountaintop to the people.

Addendum on December 11:  The Retraction Watch blog states that Schekman’s “argument isn’t airtight” and that “the picture may be a bit more complicated than his Guardian piece let on.”  Excerpt:

“…just how many retractions have these journals had? And how does that compare to the number in the Proceedings of the National Academy of Sciences (PNAS) while one Randy Schekman was editor? Here’s the 2006-2011 data, analyzed according to Ferric Fang and Arturo Casadevall’s Retraction Index, which calculates the rate of retraction per 1,000 papers published:

Journal	Retractions	Articles	Retraction Index	Impact Factor
Science	10	5702	1.754	32.452
Nature	7	5403	1.296	36.235
Cell	11	2899	3.794	34.774
PNAS	23	21614	1.064	10.472

So yes, PNAS had a lower Retraction Index than the other journals, but not really that much lower than Nature. Put another way, however, PNAS retracted 23 papers from 2006 to 2011, while Cell, Nature, and Science retracted 28. And perhaps even more important, there were 1,300 retractions in journals other than those four.

“Wait,” you’re saying, “are more retractions really a bad thing? Didn’t you just publish a post about a study that said the opposite?” Well yes, yes we did. But Schekman is suggesting retractions are a mark against a journal, which we think makes PNAS’s record of retractions fair game.”

 

Related articles

• How Journals like Nature, Cell and Science Are Damaging Science (transcend.org)
• Randy Schekman Nobel winner boycotts top science journals (giftoftruth.wordpress.com)
• Nobel laureate Schekman boycotts top-tier science journals (dailycal.org)
• Nobel winner declares boycott of top science journals (3quarksdaily.com)
• “Distorting incentives” in academic research (peakmemory.me)
• Nobel Winner Schekman Boycotts Journals For ‘Branding Tyranny’ (science.slashdot.org)
• Nobel winning scientist to boycott top science journals (planet.infowars.com)
• ASCB: Nobel Winners for Discoveries on Cellular Vesicle Transport Voice Thoughts (medindia.net)
• To boycott or not to boycott: a privilege for the successful or a need for change? (upwithclimate.wordpress.com)

 

[Journal article] How Basic Scientists Help the Pharmaceutical Industry Market Drugs

Excerpt from the December 2013 PLoS article by Adriane Fugh-Berman 

In the 1970s, a Baltimore city senator who also owned a tavern backed legislation that helped his business. Accused of having a conflict of interest, Joseph J. Staszak, responded, “What conflict of interest? How does this conflict with my interest?” [1].

According to the Institute of Medicine, a conflict of interest is “a set of circumstances that creates a risk that professional judgment or actions regarding a primary interest will be unduly influenced by a secondary influence” [2]. More simply, conflicts of interest may be seen as circumstances in which “individuals’ professional responsibilities diverge from their personal interests (or when different professional responsibilities clash)” [3].

In biomedicine, discourse on conflicts of interest (also called competing interests) has focused on relationships between industry and physicians or clinical researchers. However, basic scientists are not immune to industry influence on research and publications, and may be important to industry in the production and dissemination of marketing messages.

Depending on Industry

In 2007, industry was the largest funder of biomedical research, paying for nearly twice as much research (58%) as the federal government (33%) [4]. Most of this funding goes to clinical research; the share of spending by pharmaceutical and device industry on preclinical research has decreased from about half (55%) in 1998 to a quarter (25%) in 2010 [5]. A 2007 survey of 3,080 academic life science researchers found that half (53%) have some form of relationship with industry [6]. Among the 1,663 research faculty at academic medical centers, 42% of basic scientists had a relationship with industry. This number was similar to health services researchers/clinical epidemiologists (40%), but less than clinical researchers (67%) translational researchers (61%), or “multimodal” researchers (71%) [7]. At the 50 universities that received the most NIH research funding, 43% of 2,167 life science researchers reported receiving a research-related gift in the late 1990s [8]. Gifts included biomaterials (24% of respondents), discretionary funds (15%), equipment (11%), travel funds to professional meetings (11%), student support (9%), and other (3%).

Researchers were aware that something was expected in return for the gift. Sponsor expectations that the gift be used for its intended purpose and not be re-gifted, and that the sponsor be acknowledged in publications, are certainly reasonable. Disturbingly, however, about a third (32%) of gift recipients reported that the funder wanted prepublication review of any articles or reports stemming from the use of the gift. This expectation was higher for gifts of biomaterials: 40% of respondents reported that the firm wanted to receive prepublication review of articles or reports. Also, 44% of firms wanted assurances that the biomaterial was not to be used for applications that competed with company products [8].

Industry Funding Affects Results

In clinical research, investigators who receive industry funding are more likely to publish results that favor a sponsor’s marketing goals than are investigators who do not receive industry funding. The Cochrane Collaboration, renowned for creating and publishing high-quality systematic reviews, analyzed 48 clinical studies, systematic reviews, and meta-analyses that compared results from studies of drugs or medical devices based on sponsorship. This systematic review found that industry-sponsored studies, compared to non-industry-sponsored studies, were more likely to report favorable efficacy results for drugs or medical devices; less likely to find harms; and more likely to conclude that a therapy was beneficial [9].

…

Selective Publication

Selective presentations and publications are important tactics for industry. Industry relies on abstracts and posters to convey marketing messages at scientific meetings, because abstracts and posters are usually not peer-reviewed and can be easily altered up to the time of presentation. Posters and abstracts are often used for preclinical studies, case reports, or preliminary results of clinical trials. Promising preliminary results might be presented as a poster, and the results may be publicized, but if the final results of the study do not support commercial goals, the full study may never be published – or may be buried in an obscure, low-impact journal. In either case, scientists may have a positive impression of a therapy from a poster, and never learn that the therapy failed to show efficacy in the final study.

…

Perhaps because negative outcomes from industry-funded studies are less likely to be submitted for publication, industry-funded clinical trials overall are less likely to be published. An analysis of 546 drug trials listed in ClinicalTrials.gov found that within two years of study completion, about a third of studies that received full (32%) or partial (39%) industry support were published. In contrast, more than half (54%) of trials funded by government, and 56% of trials funded entirely through nonprofit/nonfederal funds, were published [19].

The majority of meeting abstracts and posters are never published. Posters and abstracts with positive results are far more likely to be published than negative studies [14],[15].

..

Once a drug is on the market, it can be prescribed “off-label” – that is, for any condition other than that for which the drug was approved. Although it is legal for physicians and other prescribers to prescribe a drug off-label, it is illegal for pharmaceutical companies to promote drugs off-label. Off-label use is common, accounting for about one in five prescriptions [23]. It is unknown how much off-label use is due to promotion.

Pharmaceutical companies use paid speakers, consultants, and researchers to promote off-label use [24].

,,,

Companies have paid billions of dollars in fines for off-label promotion, often using company-generated research, company-paid speakers, and ghostwritten articles to imply clinical benefits in the absence of clinical trials (or the presence of negative trials); fines have also been imposed for suppressing risks or misleading clinicians about risks [34].

…

Read the entire article here

Related articles

• How basic scientists help the pharmaceutical industry market drugs (medicalnewstoday.com)
• ‘All Trials’: because no test should go unheralded (nsnbc.me)
• How Manipulated Clinical Evidence Could Distort Guidelines – the Case of Statins for Primary Prevention (hcrenewal.blogspot.com)
• UAlberta researchers uncover why combination drug treatment ineffective in cancer clinical trials (eurekalert.org)
• Drug Safety: Conditions bordering Corruption threaten Public Health (nsnbc.me)
• Why combination drug treatment ineffective in cancer clinical trials (medicalnewstoday.com)
• Transparency in cancer trials is vital (alltrials.net)
• Monitoring the healing resources by clinical research (socialdigitalbuzz.wordpress.com)

 

Unpublished trial data ‘violates an ethical obligation’ to study participants, say researchers

Flowchart of four phases (enrollment, intervention allocation, follow-up, and data analysis) of a parallel randomized trial of two groups, modified from the CONSORT 2010 Statement Schulz KF, Altman DG, Moher D; for the CONSORT Group (2010). “CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials”. BMJ 340 : c332. doi:10.1136/bmj.c332. PMC 2844940. PMID 20332509 . . (Photo credit: Wikipedia)

 

From the 29 October 2013 British Medical Journal press release

 

Study finds almost 1 in 3 large clinical trials still not published 5 years after completion

Almost one in three (29%) large clinical trials remain unpublished five years after completion. And of these, 78% have no results publicly available, finds a study published on bmj.com today.

This means that an estimated 250,000 people have been exposed to the risks of trial participation without the societal benefits that accompany the dissemination of their results, say the authors.

They argue that this “violates an ethical obligation that investigators have towards study participants” and call for additional safeguards “to ensure timely public dissemination of trial data.”

Randomized clinical trials are a critical means of advancing medical knowledge. They depend on the willingness of people to expose themselves to risks, but the ethical justification for these risks is that society will eventually benefit from the knowledge gained from the trial.

But when trial data remain unpublished, the societal benefit that may have motivated someone to enrol in a study remains unrealized.

US law requires that many trials involving human participants be registered – and their results posted – on the largest clinical trial website ClinicalTrials.gov. But evidence suggests that this legislation has been largely ignored.

So a team of US-based researchers set out to estimate the frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in theClinicalTrials.gov database.

They searched scientific literature databases and identified 585 trials with at least 500 participants that were registered with ClinicalTrials.gov and completed prior to January 2009. The average time between study completion and the final literature search (November 2012) was 60 months for unpublished trials.

Registry entries for unpublished trials were then reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.

Of 585 registered trials, 171 (29%) remained unpublished. Of these, 133 (78%) had no results available in ClinicalTrials.gov. Non-publication was more common among trials that received industry funding (32%) than those that did not (18%).

“Our results add to existing work by showing that non-publication is an important problem even among large randomized trials,” say the authors. Furthermore, the sponsors and investigators of these unpublished trials infrequently utilize the ClinicalTrials.gov results database.

The lack of availability of results from these trials “contributes to publication bias and also constitutes a failure to honor the ethical contract that is the basis for exposing study participants to the risks inherent in trial participation,” they add. “Additional safeguards are needed to ensure timely public dissemination of trial data,” they conclude.

 

 

 

 

 

Related articles

• Non-publication of large randomized clinical trials: cross sectional analysis (medicalnewstoday.com)
• ‘Ethical failure’ leaves one-quarter of all clinical trials unpublished (blogs.nature.com)
• A third of clinical trials haven’t published results (alltrials.net)
• Scientists voice fears over ethics of drug trials remaining unpublished (theguardian.com)
• The State of Infectious Diseases Clinical Trials: A Systematic Review of ClinicalTrials.gov (plosone.org)
• Scientists alarmed over ethics of drug trials remaining unpublished up to five years after they’re finished (rawstory.com)

 

[Reblog] Bad Pharma (the book) comes to the US

 

[Reblog] From the 2 February 2013 post at HealthNewsReview.org

British physician and writer Ben Goldacre is on a North American tour.  His book, “Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients,” is released in the US on February 5. The book has been discussed in The Economist, The Public Library of Science blogs, The Guardian, and elsewhere. (Addendum one day later:  Carl Elliott also reviewed the book in the BMJ.)

He also has an op-ed in the New York Times, “Health Care’s Trick Coin.”  Excerpt:

“…the entire evidence base for medicine has been undermined by a casual lack of transparency. Sometimes this is through a failure to report concerns raised by doctors and internal analyses…. More commonly, it involves the suppression of clinical trial results, especially when they show a drug is no good. These problems would be bad enough on their own, but they are compounded by a generation of “fake fixes” that have delivered false reassurance, and so prevent realistic public discussion.

The best evidence shows that half of all the clinical trials ever conducted and completed on the treatments in use today have never been published in academic journals. Trials with positive or flattering results, unsurprisingly, are about twice as likely to be published — and this is true for both academic research and industry studies.

If I toss a coin, but hide the result every time it comes up tails, it looks as if I always throw heads. You wouldn’t tolerate that if we were choosing who should go first in a game of pocket billiards, but in medicine, it’s accepted as the norm. In the worst case, we can be misled into believing that ineffective treatments are worth using; more commonly we are misled about the relative merits of competing treatments, exposing patients to inferior ones.”

 

 

[reblog]Journal editorials this week: the magic asterisk and transparency in clinical trials

From the 30 August 2012 blog posting at HealthNewsReview

Two journal editorials touching on different health care reform issues caught our eye.

Harold DeMonaco, MS, one of our story reviewers on HealthNewsReview.org, thought that an editorial in the New England Journal of Medicine by editor Jeffrey Drazen, MD, deserves some news attention.  DeMonaco wrote me:

“Over the past five years or so, there has been a gradual increase in the registration of clinical trials into a single database.  Although it would be nice to believe that the pharmaceutical industry has embraced the concept of transparency, it is more likely that the FDA Amendments Act of 2007 forced their hand.  Without registration of the clinical trial and reporting of the results, the FDA would not consider the data for submission for a New Drug Application.

As Dr. Drazen notes, there are some holes in the existing legislation.  Not all studies need be registered.  A newly introduced bill into the US House of Representatives would close the loopholes and provide ‘real transparency.’  There are always two sides to every story and the pharmaceutical industry has legitimate proprietary concerns that no doubt will be voiced loudly to members of the House and to the media.  It seems to me that this issue represents a wonderful opportunity for the media to inform and educate the public on this important piece of legislation for both sides on the issue.”

 

And in the JAMA Forum, David Cutler, PhD, of Harvard and the Institute of Medicine suggests that journalists and the public pay more attention to “the magic asterisk” in health policy discussions.

 

New Style and New Content for ClinicalTrials.gov

From the US National Library of Medicine August 2012 press release

ClinicalTrials.gov is the NLM-developed Web-based registry and results database of clinical research studies. The Web site provides patients, clinicians, researchers, and the public with access to information about interventional and observational studies. As of August 2012, ClinicalTrials.gov contained over 130,000 clinical research studies in all fifty states and in 179 countries.

On August 13, 2012, visitors to the ClinicalTrials.gov Web site and the accompanying Protocol Registration System (PRS) Information Web site (designed for data providers) saw a link to a beta site including a new integrated homepage and updated graphic design for the site (http://clinicaltrials.gov/beta/).

Visitors will also have access to new and reorganized written content about clinical research, background information about the site, searching for studies, and maintaining study records.

However, core functions of the site — including the basic and advanced search, search results options, and the study record data – will remain the same. The new site interface will run in parallel with the previous version for approximately four weeks after launch. After appropriate testing and additional minor changes it will permanently replace the previous interface.

The New Homepage

The homepage (see Figure 1) showcases the study search options and search help resources in one location, the “Search for Studies” area. Site visitors can begin a basic search here, go to the advanced search form, or begin browsing for studies by topic or on a world map. Site visitors can also get help with searching, finding studies with summary results posted on ClinicalTrials.gov, and reading study records.

A new menu bar provides direct access to each area of content on the site (See Navigating the Site). Custom views of this content have been created for different user groups. Patients and families, researchers, and study record managers are three significant groups that visit ClinicalTrials.gov. The homepage areas for these audiences provide an introduction to content for each user group, and the “Learn more” link in each area goes to an orientation page that highlights relevant resources on the site. For example, study record managers can find out which clinical trials should be registered with ClinicalTrials.gov and get help with setting up accounts, registering studies and updating records. Members of the press also have a new page with background information and statistics about the site (see the “Media/Press Resources” page under “About Us” in the menu bar).

Data about the site are highlighted in the right column of the homepage. Users can access “Trends, charts, and maps” content for more statistics. An enhanced Glossary provides descriptions of clinical research terms commonly used on ClinicalTrials.gov and “Using our RSS Feeds” explains how to get notification of new and updated study records.

Figure 1: New ClinicalTrials.gov homepage.

 

Please click here for more figures on how to

• How to search for clinical trials
• How to find information on study records (clinical trial sites and study organizers)
• How to find selected outreach and scholarly publications related to ClinicalTrials.gov and clinical research

Related articles

• New Look and Content for ClinicalTrials.gov (hslnews.wordpress.com)
• Clinical trials often fall short: US study (news.com.au)
• Global Clinical Trials: Preferred CRO Partnerships, 1-2 October 2012, Philadelphia, PA (medicalnewstoday.com)

“Too much ownership of data and secrecy involved”

From the 21 March 2012 article by Gary Schwitzer at HealthNewsReviews.org

That’s what one author writes in a series of papers published in Circulation: Cardiovascular Quality and Outcomes this month addressing issues involving the integrity of research data.

Yale’s Harlan Krumholz writes: “Patients facing a decision deserve information that is based on all of the evidence.”  Further excerpt:

Every day, patients and their caregivers are faced with difficult decisions about treatment. They turn to physicians and other healthcare professionals to interpret the medical evidence and assist them in making individualized decisions.

Unfortunately, we are learning that what is published in the medical literature represents only a portion of the evidence that is relevant to the risks and benefits of available treatments. In a profession that seeks to rely on evidence, it is ironic that we tolerate a system that enables evidence to be outside of public view. Those who own data, usually scientists or industry, have the choice of what, where, and when to publish. As a result, our medical literature portrays only a partial picture of the evidence about clinical strategies, including drugs and devices. Experts have recently drawn attention to this issue, including contributions in this issue of our journal, but there is resistance to change….

The article goes on outline how sharing of clinical trial and research data could be shared for the common good.

Read the entire article here

Related articles

• Bias and error are rampant in medical literature (kevinmd.com)
• Data sharing as a moral imperative (Marilyn Mann’s blog)
• Open Science and Data Sharing in Clinical Research
  Basing Informed Decisions on the Totality of the Evidence (Circulation)
• Strengthening and Opening Up Health Research by Sharing Our Raw Data (Circulation)
• The Importance of Clinical Trial Data Sharing (Circulation)
• Scientific evidence (sixpointnineme.wordpress.com)
• Many NIH-funded clinical trials go unpublished over 2 years after completion (eurekalert.org)

Kent Bottles Private Views: Health Hackers & Citizen Scientists Shake Up Medical Research

	Click on figure to enlarge Copy of Figure 1 describing the health care model of Health 2.0
	Emerging Patient-Driven Health Care Models: An Examination of Health Social Networks, Consumer Personalized Medicine and Quantified Self-Tracking, Int. J. Environ. Res. Public Health 2009, 6, 492-525; doi:10.3390/ijerph6020492Author – Swan M

Kent Bottles Private Views: Health Hackers & Citizen Scientists Shake Up Medical Research

From the 5 December 2011 blog item by Dr. Bottles

Whether you call it Health 2.0, Medicine 2.0, or e-Health 2.0, the Internet is changing medicine in ways that challenge the status quo. This article explores how a group of amateurs who call themselves “health hackers” and “citizen scientists” are trying to use the Internet to connect with other patients, run experiments, and conduct clinical trials on their own diseases.

Dr. Gunther Eysenbach states “Medicine 2.0 applications, services and tools are Web-based services for health care consumers, caregivers, patients, health professionals, and biomedical researchers, that use Web 2.0 technologies as well as semantic web and virtual reality tools, to enable and facilitate specifically social networking, participation, apomediation, collaboration, and openness within and between these user groups.” One review examined 46 different definitions of Health 2.0, and Eysenbach’s definition does not emphasize a key component of the concept:amateurs can use these new Internet tools to do work that in the past was only done by professionals. (1)

 …

The tension between the traditional approach to medical research and patient-initiated research can only be resolved by cooperation and two-way communication between the two groups. The Mayo Clinic and PXE examples clearly show that both groups can benefit by meaningful and respectful partnership. The AIDS and ALS examples demonstrate that patients with few options and new Internet tools will continue to push the traditional research community to be open to new ideas, new approaches, and new possibilities. Gilles Frydman, founder of the Association of Cancer Online Resources, has stated, “Better-informed people are more willing to participate in the advancement of science. Those patients taking Gleevec do not consider themselves guinea pigs. They are recipients of experimental medicine.” (8)

Read the entire blog item

Related articles

• The rise of citizen scientists and patient initiated research (jflahiff.wordpress.com)
• The rise of citizen scientists and patient initiated research (kevinmd.com)

Report On Human Subjects Protection Released By President’s Bioethics Commission

From the 19 December 2011 Medical News Today article

The Presidential Commission for the Study of Bioethical Issues has issued its report concerning federally-sponsored research involving human volunteers, concluding that current rules and regulations provide adequate safeguards to mitigate risk. In its report, “Moral Science: Protecting Participants in Human Subjects Research,” the Commission also recommended 14 changes to current practices to better protect research subjects, and called on the federal government to improve its tracking of research programs supported with taxpayer dollars. …

….

Key Findings:

In the report’s central finding, the Commission found that the “U.S. system provides substantial protections for the health, rights, and welfare of research subjects.”

In assessing the current regulations that protect human subjects, the Commission learned that there is no central source with information about the overall size, scope, and cost of the government’s research involving human subjects. [Flahiff’s emphasis]The Commission requested information from 18 individual agencies that conduct most federal human subjects research, but discovered that many federal offices could not provide basic data about the research they support.[Flahiff ‘s emphasis]…

…

Recommendations:

The Commission recommended several areas where improvements could be made to current rules and procedures. “Immediate changes can be made to increase accountability and thereby reduce the likelihood of harm or unethical treatment,” Gutmann said.

The Commission recommends that each federal department or agency supporting research with human subjects maintain a core set of data for their research programs that includes the title and lead investigator of each project, the location of each study, and the amount appropriated for the research. Each office should aid the public in learning more about the government’s research efforts by developing or improving publicly available electronic systems or releasing information through a government-wide system. To support these efforts, the Commission suggested that the Office for Human Research Protections or another office should administer a central web-based portal that links to each individual department or agency system. In addition, the government should consider developing a unified federal research database, which may ultimately be more cost-effective and efficient. ….

 

Related Resources

• The full text of the report may be found here
• Press release of the report may be found here

Related articles

• Report: Moral Science – Protecting Participants in Human Subjects Research (bespacific.com)
• President’s Bioethics Commission releases report on human subjects protection (medicalxpress.com)
• President’s Bioethics Commission releases report on human subjects protection (eurekalert.org)
• U.S. panel finds gaps in bioethics protections (thehindu.com)
• US panel urges protection of humans in research (vanguardngr.com)
• Panel Calls for Closer Tracking of U.S.-Funded Human Research, Proposes Compensation Fund (news.sciencemag.org)
• Obama goes troubleshooting on clinical trials (simondenegri.com)
• Bioethics Panel Urges Stronger Protections for Human Subjects (scientificamerican.com)

Corporate funding of research

Corporate funding of research.

From the  December 2, 2011 posting at Ethics Beyond Compliance

Many of us are suspicious of health and safety claims based on research funded by corporations that get rich off public confidence in the health and safety of their products. I don’t really trust manufacturers of drugs or genetically modified foods to tell me that they are safe. I also would feel better hearing that an oil spill is no threat to life or environment from someone other than the company that spilled the oil. (Many people seem to have made one inexplicable exception to this rule, which I will mention in the postscript.)

Further, when corporations fund research projects or labs, they gain control over what information is published. The scientists involved may have enough integrity to conduct rigorous research, but unwanted results are likely to be suppressed, especially if they will hurt the bottom line. This may be justified by claiming that only “useful” data need be published, but negative data can also be useful and can avoid wasted money and energy. If one researcher finds that something doesn’t work, publishing that data can help others avoid the same mistakes. Of course, researchers do share data, but some studies are also suppressed. Publication of misleading data and suppression of useful data are two possible hazards of corporations funding research that will affect their bottom line.

On the other hand, if corporations are the ones to benefit from research, it seems they should bear the cost of supporting labs, scientists, and related endeavors….