Trials - Latest Comments

Educational opportunities available to Trial and Data Managers

Rachel Breen — 2010-09-01T00:00:00Z

I read with interest the article (provisional pdf) regarding Trial Management.
Managing clinical trials
Trials 2010, 11:78 doi:10.1186/1745-6215-11-78
Barbara Farrell, Sara Kenyon, Haleema Shakur.

However I felt that the article did not provide a balanced review of the educational opportunities available to Trials Managers and Data Managers. The article only mentioned the London School of Hygiene and Tropical Medicine's MSc in Clinical Trials. There are other MSc courses that have been developed to address trial management needs and could be argued to be more specific to the needs of Trial Managers than LSHTM. Examples include the Cranfield MSc and also MSc Clinical Research Administration run by the University of Liverpool, which is conducted completely in an online learning environment and was developed to meet the needs of Trials Managers in particular. This MSc encourages students to undertake research dissertations relevant to the practices of trial management. Typical examples of dissertation projects include: core outcome sets (an agreed standardised minimum set of outcomes that should be measured and reported in all clinical trials of effectiveness in a specific condition), consent issues, data capture, ethics committees in multicentre/multinational studies, non-response bias, study recruitment, trial monitoring, adherence to trial reporting standards and issues of relevance to the pharmaceutical industry or specific clinical areas.
This MSc is also linked to the activities of the MRC NWHTMR (www.methodologyhubs.mrc.ac.uk) in part due to the relevance of the dissertation projects. I would also recommend that interested readers contact the MRC Hub network to pursue trial management research.

Searching for new insights in subgroup analyses

Ewout Steyerberg — 2009-11-24T00:00:00Z

The SATIRE group is to be applauded for their effort to shed more light at the minefield of subgroup analysis, reporting, and interpretation. The question may however be what truly new insights will be obtained. One might predict that findings from a well-selected set of papers published in 2007 will be largely similar to what was found before in the studies shown in Table 1.

Of particular interest may be the answer to question 10 in Appendix 1: "Is the interaction consistent across closed related outcomes within the study?". In a previous individual patient data (IPD) meta-analysis of over 30,000 patients from 6 trials, we found statistically significant subgroup effects in 2 trials .. but in opposite directions [1]. Identifying such IPD meta-analyses may be difficult when the individual trial subgroup effects were reported in 2007; one might need to perform a specific search for these studies, and consider multiple years?

Another point of interest is how often interaction with prognostic risk, e.g. from a multivariable regression model, was studied, rather than an interaction with a single characteristic. Such an approach was emphasized by Pocock and Lubsen in 2008 [2], but earlier examples may well be available. For example, a similar relative effect of accelerated tissue plasminogen activator (TPA) versus streptokinase treatment was found across the full range of mortality risk from acute myocardial infarction in the GUSTO-I trial, where the authors based risk on a multivariable combination of 5 baseline characteristics in a logistic regression model [3].

I like to encourage the authors to consider these 2 specific points in their review, or perform specific studies if necessary.

References
1. Hernandez AV, Westerhout CM, Steyerberg EW, Ioannidis JP, Bueno H, White H, Theroux P, Moliterno DJ, Armstrong PW, Califf RM et al: Effects of platelet glycoprotein IIb/IIIa receptor blockers in non-ST segment elevation acute coronary syndromes: benefit and harm in different age subgroups. Heart 2007, 93(4):450-455.
2. Pocock SJ, Lubsen J: More on subgroup analyses in clinical trials. N Engl J Med 2008, 358(19):2076; author reply 2076-2077.
3. Califf RM, Woodlief LH, Harrell FE, Jr., Lee KL, White HD, Guerci A, Barbash GI, Simes RJ, Weaver WD, Simoons ML et al: Selection of thrombolytic therapy for individual patients: development of a clinical model. GUSTO-I Investigators. Am Heart J 1997, 133(6):630-639.

Protocol amendment to be implemented shortly

Peter Sandercock — 2009-10-16T00:00:00Z

This comment is for information only

Protocol amendments. A number of minor changes to the IST-3 protocol document have been submitted for ethical and regulatory approval. The amended main trial protocol (and a supplementary protocol to describe the planned analyses of the cerebral perfusion data) will be posted on the IST3 website (www.ist3.com) when all the appropriate approvals have been obtained, in the near future.

Trial progress: By 16th October 2009, 1862 patients had been recruited, and the trial is on track to meet the target of 3100 patients by mid 2011.

For up to date information on recruitment and the implementation of the amendments please see www.ist3.com.

The Pan African Clinical Trials Register (PACTR_: Compliance with the WHO minimum data-set in the first Pan African WHO-endorsed Primary Registry

Amber Abrams — 2009-10-01T00:00:00Z

In the article “Compliance of clinical trial registries with the World Health Organization minimum data set : a survey” Moja et. al. explains that in September 2004, the International Committee of Medical Journal Editors (ICMJE) proposed “comprehensive trials registration as a solution to the problem of selective awareness and announce[d] that all 11 ICMJE member journals will adopt a trials-registration policy to promote this goal” (http://www.icmje.org/clin_trial.pdf). Thus, clinical trials must be publicly registered before the first participants are enrolled if the intention of the investigators is to publish findings in a medical journal.

To this end and to increase transparency and provide local registration opportunities for researchers who conduct clinical trials in Africa, the South African Cochrane Centre (SACC), based at the South African Medical Research Council, established a clinical trials registry for trials on HIV/AIDS, tuberculosis and malaria in 2007 (ATM Clinical Trials Registry). Since June 2009, this registry has expanded to contain clinical trials on all diseases, transitioning from the ATMCTR to the Pan African Clinical Trials Registry (PACTR). The PACTR is funded by the European and Developing Countries Clinical Trials Programme (EDCTP) and is managed in partnership with the Cochrane Infectious Disease Review Group and the Cochrane HIV/AIDS Review Group.

According to Moja et.al., although the World Health Organization (WHO) has created a mandatory minimum data-set as a means of standardizing available information “individual registry entries are largely incomplete”. Thus, the WHO has developed criteria by which a working group reviews applications of trial registries, and only after a stringent review to ensure all minimum standards are met, do they endorse a registry. Gaining a WHO primary status endorsement is a lengthy process as their working group is often developing new minimum standards leaving applicants for primary registry status responsible to meet these changing standards – this ensures that those registries with WHO endorsement are rigorous in their review of applications to their registries, and do not accept trials with incomplete data-sets.

Thus, the PACTR’s application to the WHO for primary status has been an ongoing process which was successful in June 2009 with the announcement that the PACTR“has been accepted by the Assistant Director General of the Information, Evidence and Research cluster” as a primary trials registry. PACTR will feed data into the global WHO International Clinical Trials Registry Platform (ICTRP) Search Portal, facilitating African representation in the global picture of planned, ongoing and completed clinical trials. Researchers conducting clinical trials in Africa who use PACTR as their registry of choice will now meet international requirements for research transparency.

Since registries “provide an essential tool to assess completeness of the information about all initiated trials” and are the “necessary first step to enable identification of all trials and the subsequent tracking of their results” (Moja et.al., http://www.trialsjournal.com/content/10/1/56 ), having an African based registry will benefit both Africa and the world as PACTR will actively encourage trial registration. Registering a clinical trial greatly increases exposure of the trial and assists researchers in determining gaps in research, reducing the likelihood of duplicated research and wasted funding and man-power (http://www.icmje.org/clin_trial.pdf).

The intention is for PACTR to become the single reference point for clinical trials activities in Africa feeding directly into the global WHO International Clinical Trials Search Portal, ensuring African representation in this global search engine. Additionally, PACTR’s database will include regularly downloaded information from the South African National Clinical Trials Registry (SANCTR) and will continue to build information sharing networks with national or other localized registries (Grobler et al, 2008:1201 – 1202). To learn more about PACTR or to register a trial, please visit our website at www.pactr.org.

Citation:
Grobler L, Siegfried N, Askie L, Hooft L, Tharyan P, Antes G. 2008. “Are national and multinational prospective trial registers necessary?” The Lancet, Oct 4;372(9645): pp. 1201-2.

Re: Community-based trail of screening for Chlamydia trachomatis to prevent pelvic inflammatory disease: the POPI (prevention of pelvic infection) trial

T Aldeen — 2008-12-19T00:00:00Z

Dear Sir,

I read your study with great interest as we still lack information about the natural history of Chlamydia and PID.

However, your diagnosis of PID relies mainly on the clinical history and I would like to remind you that PID may be symptomatic or asymptomatic and wonder how could you identify asymptomatic PID in your participants. Even symptomatic PID, clinical symptoms and signs lack sensitivity and specificity (the positive predictive value of a clinical diagnosis is 65-90% compared to laparoscopic diagnosis). Also the absence of genital Chlamydia infection does not exclude PID (http://www.bashh.org/documents/118/118.pdf).

Further, although the study information sheet explains the risk, it is challenging to leave women in the control arm with possible asymptomatic genital infection untreated for one year. Similarly, treating women who become symptomatic and infected with Chlamydia in the control arm may eliminate the efforts of reaching the natural history of Chlamydia. Equally, participants may choose to use the barrier method after reading the study information sheet and this may reduce the prevalence of Chlamydia in the study sample, especially the study is targeting university students and excluding uneducated sexually active women who may have a high rate of PID.

Finally, I would like to share with you the difficulty in recruiting university students for Chlamydia screening. The poor response rate has been reported in similar previous studies (Rogstad K E et al 2002; Ivaz S et al 2006). The high refusal rate of the eligible students in your study may impair having a representative study sample that can accurately measure the incident of PID.

Yours sincerely,

Taha Aldeen

Atherosclerotic

John Tanner — 2003-02-23T00:00:00Z

Hello Dr. Ridker, I just came across your article re the anti-inflammatory effect of statin drugs in the cardiovasular system.

Recently, I have had time to do extensive recent basic science literature review along with considerable antecdotal evidence beginning in the late 1970's along with current clinical research such as yours.

It appears quite probable that overexpression of Cox 2 with its stimulation of the production of prostaglandin E2/kinins is the mediator of the inflammation known to exist in the coronary arteries of patients with atherosclerotic disease, for example. You and others have reasonably shown that the statin drugs benefit patients independently of their cholesterol lowering effects by acting in an anti-inflammatory manner.

I would hypothesize that the action of the statins is to inhibit Cox 2 as do Celebrex, Vioxx and Bextra.

Recent studies on the Atkins diet (Westman, et al Duke University) have shown cholesterol and triglyceride reductions far superior to those found in a matched cohort of subjects on the AHA low fat diet. In fact, the cholesterol and triglyceride reductions were shown to be independent of the weight loss observed, to occur long before the study was concluded, and to be do to food avoidance. No statins, Cox 2 "inhibitors" were administered.

A large number of antecdotal studies in the late 1970's by Philpott and others have strongly suggested that cholesterol, triglycerides and homocysteine are merely MARKERS of inflammation and are NOT RISK FACTORS in and of themselves.

I would further suggest that you would have seen the same clinical results that you observed in patients on statins, had you merely put them on very low carbohydrate diets. I would hypothesize that no matter what diet you prescribed, your patients would have shown reduction of cholesterol, triglycerides and homocysteine by treating them with Cox 2 inhibitors. (Incidentally, did any of your patients on statins comment on improved arthritis and general feelings of "well-being"--or were they asked?

the evidence suggests that those carbohydrates elimintated in Westman's very low carbohydrate diet were those acting as STRESSORS to each individual study participant; that is, one or more of the removed carbohydrate foods was a stressor and as such was the agent(s) that caused the Cox 2 overexprssion. Fat people by their nature are carbohydrate sensitive and fat storers.

William H. Philpott, MD, (Chocktaw, Oklahome) in the late 1970's demonstrated a significant drop in the pH of the duodenal content following the ingestion of a food known to be a STRESSOR (sensitizer). He demonstrated that a stressor food would act to inhibit pancreatic bicarbonate secretion and to stimulate prostaglandin E2/kinin production and clinical symptoms in any part of the body as determined by the patient's heredity.

At that time, neither he nor anyone else was aware of the exact mechanism or the cause of the prostaglandin E2/kinin production. Now, it is known to be the result of the Cox 2 overexpression.

If this chemistry be correct, and if all degenerative diseases (coronary disease as just one of many) are basically inflammatory (tissue acidosis, hypoxia and inflammation as we learned in medical school pathology and physiology class), then it is reasonable to hypothesize that ALL degenerative diseases have a common tissue basis and should be preventable by AVOIDING identified stressor foods in any given patient. When food avoidance is not possible or practical, treatment with ANY Cox 2 inhibitor whether it be Celebrex or Lipitor, etc., (or a statin drug--whichever is cheaper and with less side effects) should suffice.

Dr. Westman found that 5 GERD patients in his Atkins-AHA diet comparison lost all their symptoms with general carbohyrate avoidance. No study was done, however, to attempt to identify WHICH particular carbohyrate(s) were the stessors--the foods which caused the GERD. He also reported orally to me that several women noted loss of their PMS symptoms while on the very low carbohydrate diet (none on the AHA low fat diet).

My hypothesis to explain the cause of PMS is loss of estrogen-mediated, protective, anti-inflammatory activity during 3/4 of the menstrual cycle. When the premenstrual estrogen levels drop sufficiently, the inflammatory effects of one or more stressor food(s) manifest. I treated one woman with the most severe PMS I had ever seen by identifying the one food (unusual to be only one) that was the stressor. Her PMS consisted of large ecchymoses over most of her body, edema of her hands and feet and gross enlargement of her breasts. She had been worked up at a major university and told "nothing is wrong". All her hormone studies were normal as we expected. Avoidance of Coca-cola for the month before her next expected period completely eliminated her PMS for good.

I'm sure you are aware of the current cancer treatment studies underway with Celebrex in combination with chemotherapeutics based on its ability to block prostaglandinE2/kinin production. In addition, it has been reported to reset apoptosis and diminish angiogenesis.

The fact that almost all the studies are strongly positive in such diverse tissues as lung, prostate, colon, skin, and breast is a stong argument for the unified theory of ALL non-infectious diseases including cancer. In fact, more than one author have hypothesized that prostaglandin E2/kinins are the cause of cancer--if correct, then most cancer can be traced back to food stressors.

Anyway, thanks for reading to this point. I would very much appreciate your comments and thoughts my various hypotheses. It looks to me as if we are on the verge of a relatively simple clinical treatment regimen for almost all the chronic, degenerative diseases--and maybe cancer. John Tanner, MD