Non-publication of large randomized clinical trials: cross sectional analysis

Source: British Medical Journal

Full Text

 

Objective To estimate the frequency with which results of large randomized clinical trials registered with ClinicalTrials.gov are not available to the public.

Design Cross sectional analysis

Setting Trials with at least 500 participants that were prospectively registered with ClinicalTrials.gov and completed prior to January 2009.

Data sources PubMed, Google Scholar, and Embase were searched to identify published manuscripts containing trial results. The final literature search occurred in November 2012. Registry entries for unpublished trials were reviewed to determine whether results for these studies were available in the ClinicalTrials.gov results database.

Main outcome measures The frequency of non-publication of trial results and, among unpublished studies, the frequency with which results are unavailable in the ClinicalTrials.gov database.

Results Of 585 registered trials, 171 (29%) remained unpublished. These 171 unpublished trials had an estimated total enrollment of 299 763 study participants. The median time between study completion and the final literature search was 60 months for unpublished trials. Non-publication was more common among trials that received industry funding (150/468, 32%) than those that did not (21/117, 18%), P=0.003. Of the 171 unpublished trials, 133 (78%) had no results available in ClinicalTrials.gov.

Conclusions Among this group of large clinical trials, non-publication of results was common and the availability of results in the ClinicalTrials.gov database was limited. A substantial number of study participants were exposed to the risks of trial participation without the societal benefits that accompany the dissemination of trial results.

Ten Practice Changes I Will Make After Attending ASCO ??

Endobronchial radiation therapy for non-small cell lung cancer. AP view (Photo credit: Wikipedia)

After ASCO someone wrote this last week. Will you change your mind just for a meeting which major sponsor is Big Pharma ? 

 I have looked back and seen which of the changes have become standards of practice. I have adopted most of these changes many months prior to them becoming standards of care.
In the past these have included:

• Avoiding CYP2DP inhibitors in patients taking tamoxifen
• Trying pregabalin for hot flashes in patients with breast cancer
• Adopting the use of pemetrexed maintenance in patients with stable disease after chemotherapy for non-squamous non–small cell lung cancer (NSCLC)
• Adding cisplatin to gemcitabine for patients with advanced biliary cancer
• Recommending no full axillary dissection in breast cancer patients with positive sentinel nodes provided they met the criteria of the ACOSOG Z11 study
• Recommending no radiation therapy for patients ≥ 70 years with estrogen receptor (ER)–positive clinical stage I breast cancer
• Using denosumab instead of zolendronic acid in certain patients with bone metastases
• Offering naproxen as prophylaxis for pegfilgrastim-induced bone pain
• Recommending yoga to cancer patients experiencing insomnia and fatigue
• Using FOLFIRINOX as first-line therapy for patients with advanced pancreatic cancer with good performance status
• Substituting capecitabine for infusional fluorouracil (5-FU), along with radiation for neoadjuvant rectal cancer treatment
• Extending the duration of imatinib as adjuvant treatment for high-risk patients with gastrointestinal stromal tumors (GIST)
• Treating patients with castrate-resistant advanced prostate cancer with abiraterone
• Using ipilimumab for treatment of patients with melanoma
• Using crizotinib for patients with ALK-positive NSCLC
• Using bendamustine/rituximab as first-line therapy for low-grade lymphoma
• Monitoring vitamin D levels in breast cancer patients on aromatase inhibitors
• Using more steroids for patients on palliative care
• Trying duloxetine for chemotherapy-induced peripheral neuropathy

Here is this year’s list from ASCO 2013:

1. Consider continuing adjuvant tamoxifen for 10 rather than 5 years, based on the aTTom study, which was presented at the plenary session (Abstract 5). Results support the data reported from the ATLAS study, and, putting all the data together, there seems to be a several percentage point–improvement in progression-free survival (PFS), with slightly less improvement in overall survival (OS), to date. Additional toxicity was minimal.
2. Decrease the frequency of screening CT in patients in remission from diffuse large B-cell lymphoma and Hodgkin’s disease (Abstracts 8504 and 8505). There seemed to be no improvement in survival in patients who had routine scans ordered as opposed to those patients who were only scanned when they had symptoms or abnormal physical findings.
3. Consider using entecavir rather than lamivudine as prophylaxis for hepatitis B reactivation in lymphoma patients (Abstract 8503). It seems to be more effective, but the higher cost could be an issue.
4. Use more single-fraction XRT for palliation of painful bone metastases in patients with end-stage cancer (Abstract 9502). This study supports the findings of a number of previous studies, which reported equivalent palliation with the easier and shorter course of radiation therapy.
5. Use second-line therapy with docetaxel in appropriate patients with advanced gastroesophageal junction adenocarcinoma (Abstract 4023). As opposed to supportive care without chemotherapy, there was an improvement in survival and quality of life.
6. Stop using “preventive” calcium and magnesium infusions in patients getting oxaliplatin for colorectal cancer. Neither therapy prior to and/or after oxaliplatin infusion prevented neuropathy in a double-blind randomized Alliance trial (Abstract 3501) reported by Loprinzi et al.
7. Reconsider the role of maintenance therapy for metastatic colorectal cancer, based on results of the CAIRO3 (Abstract 3502) and SAKK 41/06 (Abstract 3503) trials. In the CAIRO trial, there was a slight improvement in OS, but, in the SAKK trial, bevacizumab as a single agent did not improve PFS or OS. This is in contrast to retrospective data, previously reported. Putting all the studies together, the case for any type of maintenance during “chemotherapy holidays” is not very compelling.
8. Give patients who are being treated with adjuvant paclitaxel after adjuvant chemotherapy the option of 12 weekly doses, which was equivalent to 6 doses of higher-dose paclitaxel every 2 weeks with pegfilgrastim in the S0221 study (Abstract CRA1008). It was less toxic and, overall, less expensive, although somewhat more inconvenient. One could probably extrapolate and use 8 weekly doses instead of 4 doses every 2 weeks, as well.
9. Consider retreatment with ipilimumab in patients with advanced melanoma who previously responded to that drug and then relapsed, as there are increasing reports of safety and probable efficacy (Abstracts 9041 and 9059). Of note, there are a number of long-term survivors (12%–49%!) after first-line treatment (Abstract 9053), and the drug appears to be safe and effective in elderly patients (Abstract 9063).
10. Reassure patients with stage I seminoma and nonseminoma germ cell tumors that active surveillance is a reasonable and safe option (Abstract 4502 and 4503). Survival was close to 100% in both retrospective reviews.

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What does "evidence" mean in chronic pain

Source: Bandolier

 

Clinical bottom line

As well as well understood biases, new forms of bias or potential bias in chronic pain studies are emerging. Unless we take care, we can make the wrong decisions when comparing therapy efficacy unless like is compared with like, and at the highest level of evidence.

---

Moore et al. "Evidence" in chronic pain--establishing best practice in the reporting of systematic reviews. Pain 2010 150: 386-389.

Starting point

We know that there are limitations in evidence, and that higher quality studies produce, almost overwhelmingly, more conservative results than those with less rigorous methods. Understanding exactly what quality, or validity, means, is a dynamic, and we have to keep relearning lessons and ratcheting up the minimum standards we accept for "evidence". This review casts a cold and fishy eye over evidence in chronic pain trials.

Suggestions

The review makes the following points about what constitutes good evidence:

• Randomisation, preferably properly done and concealed.
• Blinding, preferably properly done so that all concerned are unaware of treatment.
• Imputation method. This is a new one, and recognises that withdrawal rates in chronic pain trials can be high - up to 50-60% in chronic low back pain. Right now, the last observation carried forward method is commonly used, so that patients not taking the medicine can contribute to efficacy estimates. The recommendation is that this not be done, and that only those patients taking the medicine contribute, as no analgesia can come if you don't take the medicine. Right now there is little evidence on this, but more is emerging, and this could have a major effect on efficacy estimates.
• Study duration should be reasonably long - ideally 12 weeks. There is increasing evidence from longitudinal individual patient analyses that short studies can overestimate treatment effects, particularly for less effective therapies.
• Average pain score data will mislead. Responder analyses should be used instead. Again, individual patient data analysis indicates that distributions in pain trials are U-shaped, not Gaussian, making average values rather silly.
• There may be exaggerated treatment effects in crossover trials. and a predominance of crossover trials may be considered a possible source of additional bias.
• Size is crucially important, and when there are fewer than 200 events (an event would be a patient achieving a given level of response, for example), then results cannot be trusted, simply because of the magnitude of random chance effects.

Core outcomes

It seems likely that future systematic reviews, and trial analysis, will be based on some core outcomes of benefit and harm. A likely set of outcomes for chronic pain is likely to include some or most of the following:

• Pain
• - At least 50% pain reduction
• - At least 30% pain reduction
• - Proportion below 30/100 mm (no worse than mild pain)
• - Patient global impression (very much improved)
• Function
• General
• - Quality of life measure
• - Patient global impression
• Adverse events
• - Withdrawal due to adverse event
• - Serious adverse events
• - Death

Making comparisons

Indirect comparisons between treatments can be made where there is an adequate amount of good quality data. Comparability is imperilled when like is not compared with like - when, for example, results from small, short studies with easily-attained but inadequate outcomes are compared with large, long duration studies with clinically relevant outcomes that are hard to attain. It is also imperilled when different doses or treatments are erroneously combined under a general label and then discussed as identical. Meaningful comparison of efficacy with other interventions is not possible where quality, validity, and size standards are not met by any one of the comparators.
Yet making comparisons between treatments is what we try to do all the time, in making decisions about individual patients, when making policy, and making guidelines. The bottom line is that we will have to be much more careful in future.

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Call to action on selling sickness: final statement

 Source: Call to action on selling sickness
 
The Selling Sickness conference of February, 2013 was designed to be part of a global progressive and activist health movement. A CALL TO ACTION statement can help unify professionals, researchers, activists, scholars, caregivers, advocates and all citizens alarmed by disease-mongering.
The statement below was shaped by many contributors and discussed at “Selling Sickness, 2013: People before Profits” in Washington, DC, In February, 2013.

CALL TO ACTION ON SELLING SICKNESS

Washington, DC

We come together as researchers, health care professionals, activists, advocates, patients, caregivers and citizens deeply troubled about the growing corruption of medical science and health care.
We demand an end to industry-promoted disease-mongering that manipulates health concerns and causes harm through practices that medicalise normal life and deceive professionals and the public.
Commercial imperatives are being allowed to corrupt clinical, research and marketing practices which now include hiding data, inflating diagnostic categories, unnecessary screening and treatment, deceptive marketing, faulty and biased research and publishing, inadequate oversight, a neglect of social factors and injustices, and uncritical, unbalanced reporting.
We are alarmed at how undergraduate and post-graduate professional education are based on untrustworthy “science” designed to expand markets rather than impart valid knowledge or improve individual or public health.
Hazardous practices and distorted science harm patients, waste public resources, create illness and health anxiety, hoodwink the public, corrupt knowledge, corrode professionalism, and expose everyone to unnecessary, costly and dangerous tests and treatments.
Recognizing that we all will enact this commitment differently, we pledge our support to a new movement of alliances and actions to ensure that:

• a clear firewall is created between industry/commercial influence, on the one hand, and, on the other, the regulators of drugs and devices as well as the developers and authors of clinical practice guidelines;
• direct-to-consumer advertising of prescription drugs and medical devices is much more tightly regulated or, if possible, is prohibited and effective surveillance programs created;
• drugs, diagnostic tests, and devices are tested, approved, reported and marketed solely with the goal of ensuring patient safety, scientific integrity and individual and public health;
• drugs and devices are tested against appropriate controls, usually the current best treatment, in appropriate populations;
• unsafe or ineffective marketed products are quickly identified, their harms and inadequacies are widely publicized, and they are removed from use;
• all clinical trials are registered and access to all raw clinical trial data is made available for independent analyses at least at the time of approval, but preferably before approval;
• the patent system for medicines is reformed so commercial benefit does not overshadow real clinical benefits for patients;
• patients and health care consumers are fully informed about and involved in individual health decisions, as well as in research priorities, research design, and regulatory policy;
• human subjects participating in clinical trials are adequately protected by ethical review boards that are functioning properly, accurate and complete informed consent, and the provision of full compensation for any harms;
• journalists, whose job it must be to independently vet claims made by third parties, realize the harm that is done when news stories disseminate disease-mongering sales and promotion messages in an unchallenged, unverified manner;
• health care regulations, health professional training, and clinical practice guidelines acknowledge and make allowance for marginalized and vulnerable groups who may be more susceptible to harms and exploitation;
• the usually less profitable non-pharmaceutical treatments and therapies, as well as disease prevention and community-centered interventions, are raised in research and publishing priority to levels comparable to drug and device therapies.

These reforms will substantially improve public health and safety in a complex world of escalating technologies and communications media, and will save money, thereby lessening pressure on individual and public budgets and private health insurance programs.
We believe the urgent threat to human health from disease-mongering requires the united and creative action of citizens and professionals.
We pledge ourselves to act, individually and collectively, to distribute and to implement the measures outlined in this statement and encourage continuing outreach to interested others.

PLEASE SIGN THE STATEMENT TO INDICATE YOUR ENDORSEMENT. 

JOIN OUR GLOBAL MOVEMENT!

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Controlled Clinical Trials in Tripdatabase

Today we released a new refine option in Trip, one for Controlled Trials (mainly RCTs).

After help with filters from Julie Glanville we have grabbed trials from PubMed and Mendeley and this has resulted in approximately 500,000 trials being added to Trip (too see the filter used, click here).  Give the nature of filters used to highlight controlled trials there is a compromise between sensitivity and specificity. Over the next few months we'll work to improve the quality and also the quantity of trials. 

In testing, I've used the feature extensively and it's worked really well.  It really is a powerful addition to Trip.  To use it yourself, simply go to Trip and search as you would normally and simply press the 'Controlled Trials' link/button in the refine area on the right hand side of the search results.

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News from Trip database

Latest evidence.

These can be edited via the ‘Edit my profile’ link below.

Lots has been going on in the last month and we released a new content area – controlled trials (mainly randomised controlled trials). We have added approximately 500,000 trials to Trip. Just search the site normally and select the ‘Controlled trials’ link on the right hand side of the results page. For further information read this link and this link.

I had the pleasure of presenting at Evidence Live 2013 and have written up the main points of my presentation, which is a critique of the Cochrane Collaboration, this can be read here. My basic point is that the current methods are unsustainable, which is a real worry. I think Cochrane should concentrate their efforts of reducing the cost (finance, time, opportunity) for each systematic review. Systematic reviews are vital and therefore we need as many as we can get!

One little feature of interest is our ‘Share feature’ (click here for further information). This allows users to easily share results on Trip via email and social media. It really is easy to use!

FULL TEXT ALERT! Finally, we’re working hard to push out a new batch of updates to Trip, possibly by the middle of May. One key area that we need some input in is the full-text link outs - to allow the seamless linking between Trip and an institutions full-text holdings. We know this is important as many people have been asking for this for years. So, we need librarians and clinicians to work with us to achieve this. If you’re interested in linking Trip up to your organisations full-text documents then please let me know.

Best wishes

Jon

Jon Brassey
Trip Database

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