Category: RCT

Three years post doctorate

27 April 2014
Transitions are life changes that allow us to pause, reflect and plan. Here’s a short history of my transition from the pre-doctoral to the post-doctoral stage. Read the full story here.
Hungary 2007. My Hungarian adventurewas a real turning point in my career. I had to commute to work and spent long hours in trams. Bored of watching cars and people, I started to read open-access articles about addiction. When I found something really relevant to my PhD, I felt like a gold miner who just dug his jewel out of piles of dirt. My passion grew stronger with every new paper.
Figure 1. Jano in transition
Ireland 2008. When we arrived to Ireland in late 2008, I had a small EU grant, with a budget of 3000 euros, and an unclear host organization. We survived for almost a year living from my wife’s EVSstipend and seasonal part-time jobs. My PhD and the EU grant took most of my time, leaving only a couple of hours for job-hunting. When I eventually ran out of money, it was late winter and the job market had dried up. Finally, I found an academic job, initially advertised as a PhD in Translational Medicine but my potential boss – Prof Walter Cullen – told me at the interview that I should apply for a p/t job on the same project. That’s how I came to research drinking among methadone patients in primary care at UCD.
Oregon 2013. In July 2011, only two months after receiving PhD, I have attended a summer school on addiction in Amsterdam, Netherlands. Dr McCarty, the school director, lectured about various policy models and evidence-based treatments for several days. Two years later, I did a NIDA fellowship with Dr McCarty at Oregon Health& Sciences University. Read this post about how I got there.

Lessons learned from junior post-doc

1) Write a lot. Like some teenagers, I used to write poems, songs and short stories. Then I stopped for many years. In Oregon, my wife surprised me with a Prompt-based creative writing course for my birthday. She thought it would be good for me and that I would enjoy it. Dr McCartyencouraged me to submit an essay to the Wellcome Trust Science Writing competition and to write a lot. Since then, writing became the core of my work.
2) Learn a lot. If you think of life as a huge learning experience, you welcome trouble as a gift.
3) Keep at it. Perseverance is critical in science. Progress takes years. New knowledge accumulates slowly. And the desired change is uncertain. While I was distributing clean needles to injecting drug users in inner-city Bratislava, Slovakia, I could see the effect of my work immediately. Now I have to wait ages and the change may not come in my life.
I’ve learned many more lessons than just these three, but I’ve learned how to separate the weed from the wheat from the chaff too. I don’t write about the minor lessons.

Future plans for senior post-doc

  • To stay true to myself
  • To reach a position of independence by:
    • conducting a randomized controlled trial
    • supervising work of junior investigators
  • To maintain a happy work-life balance
  • To pass the accumulated knowledge and skills on other:
    • Doctors and helping professions, by helping them become more competent and confident in addiction medicine research
    • Medical students, by helping them discover and master addiction medicine research

Clinical trials are about human dynamics: RCT course in Belfast, May 7-8

As a trialist, the pressure of working on a trial is much bigger than being in a small group educational session. Challenges of implementing a trial are multiple, mainly influenced by the values of outcomes for different people. Whose question is the trial answering? If you’ve ever found yourself puzzled by these issues, you may find some solace in reading my notes from a courseon clinical trials. 


7 instructors and 21 participants – all from Northern Ireland (except 2 Dubliners), 2 medics, three 1-st year PhD students and some professors – talked about clinical trials for two days last week at Queens University Belfast. The aim of the course wasn’t to learn everything, but to think laterally about trials. Professor Clarkecovered the basics of starting trials: formulating a clear research question, deciding on comparisons and placebos and dealing with confounding factors. The 7 main ways of dealing with confounding are:
  1. Matching
  2. Exclusion
  3. Stratified sampling
  4. Standardisation
  5. Multivariate modelling
  6. Randomisation

The pleasures and terrors of trial recruitment were described by Dr Maguire. Everybody struggling with meeting the recruitment targets should read the top 10 tipsfor recruiting into trials at the All-Ireland Hub for Trials Methodology Research website. Trialists should plan for what they’re going to do if things don’t go the way they planned. Recruiters can also become tired and it’s good to think ahead about what would possibly prevent them from recruiting. Even small rewards to recruiters, such as cream eggs, can increase their satisfaction. Satisfaction=Retention. Research networks for General Practitioners can facilitate recruitment.

Dr McAneney introduced us to the role of social networks in clinical trials. We are all connected.  All the users of Facebook can be linked by 3.74 steps. Networks make the trials work or crash. Networks allow diffusion of innovation. Decisions of participants and researchers are influenced by networks.

Prof McAuleyhelped the participants to write the protocol and funding application for their first trial. Publishing a trial protocol sets the bar pretty high for researchers – transparency and accountability are keyIf it’s not possible to publish the protocol in a peer-reviewed journal, then post it online. Every protocol is changed over time and they should be listed on the first page. The CONSORT diagram is an essential part of a protocol. It’s the only slide that’s projected during meetings of grant reviewers.

Dr Shorterand Prof Buntingcontinued with tips for analysing outcomes. The essence of any research is control. Although power calculations for trials seem difficult, they involve only a short sequence of basic steps. Categorical outcomes require more data and more participants than continuous outcomes. Analysis of clinical trials assumes that our participants are all from the same population. The classical assumption of trials analysis was that individual differences do not matter, they were ignored. Another assumption that things are measured perfectly never holds.

Finally, Dr Dunlopfinished the course presentations with ethics and data storage.

Conference of Cochrane Evidence: Useful, Usable & Used #CE3U

My journey with Cochrane started one summer afternoon in 2010, when I interviewed a Tallaghtdoctor (Tallaght is a rough suburb in Dublin, Ireland) about treatments for drinking problems of people who also use other drugs. I emphasized that brief psychosocial interventions were the treatment of choice for patients who don’t use other drugs and that there’s no reason why this should be different for drug users. He asked me whether I was Swedish, because of my accent, and replied by a single question which kept me awake at night and started my career as an addiction investigator: “Does it work?” I decided to celebrate the four years of trying to find an answer to his question at the Cochrane conference in Manchester, UK.
Wednesday 23rd April 2014
This year’s conference of UK and Irish Cochrane contributors’ swapped plenaries and workshops – Wednesday kicked off with two sessions of developmental workshops. The motto of the priority setting workshop was  “Don’t start a journey that you can’t finish”. Pragmatism is a very important part of priority setting. The value of setting priorities in healthcare is the expected gain from reducing the uncertainty. In another words, to reduce the probability that somebody somewhere is getting a wrong treatment.
Figure 1. Bees were the theme of Cochrane conference
The key question of the public health workshop was How to produce good reviews quickly? Growing number of people are interested in doing reviews under the public health group. Most public health studies are non-randomised. Evidence forms just one part of the complex process of public health policy – timeliness is the big factor. The idea of local context permeates all policies – is this relevant to your local area? All of us, as Cochrane reviewers, give shades of grey and they [policy makers] want black& white answers.
The first afternoon plenary started a faithful member of the Cochrane family, Nicky Cullum. She described how easy reviews were in the past. Her talk inspired 12 new tweets in the first 5 minutes of the plenary (#CE3Useful). The beginning of Cochrane nursing group was accompanied by skepticism “Are RCTs possible in nursing?  Is experimentation at odds with caring?” The explosion of nursing trials in the recent years posed new challenges “How on earth do we help non-academic clinicians to have both clinical and academic career?” Trisha Greenhalghconcluded the first with provocative lecture about boringness of Cochrane reviews. She used the example of young doctor Archie Cochrane in a German camp to demonstrate that the art of rhetoric consists of logos, ethos and pathos. Her other work on how innovations rise and how they spread further supported the rhetoric argument. While a logo is the only thing in scholarship rhetoric, factual knowledge can be rarely separated from ethical or social context. By trying to do so, the Cochrane researchers are stripping away the very thing they need to be exploring – how to change the world through science. The methodological fetishism developed in Cochrane collaboration (linked to control, rationalism and accountability) hinders production of more realist and interesting reviews.
Thursday morning plenaries helped the delegates to confer after the gala dinner last night. Rich Rosenfeld, a Professor and Chairman of Otolaryngology, explained how Cochrane reviewers can help policy makers by rapid reviews – Good is ok, perfect we don’t need [for guidelines]. A health economist, Karl Claxton, continued the discussion on when no more evidence is needed. Research takes long time and evidence that we already have can inform allocation of research funds for new projects. However, we should be cautious about judging the usefulness trials with hindsight, it’s wrong because we don’t know the context. Neal Maskery made the audience “lol” with very entertaining and interactive plenary which focused on what we know about how people make decisions. Our brain is so good at patterns recognition – it wants to do it all the time. This phenomenon is called Base rate neglect – a cognitive bias. Biases such as this one hinder innovation and affect our decisions in all areas from buying a car to prescribing medicines. Al Mulley, an expert on shared decision making, finished morning lectures with a story of how every patient brings their own context by using examples from his research on how bothersome is urinary dysfunction.

The special addition to the conference was presence of Students 4 Best Evidence, some of whom won prizes from UK Cochrane centre, including free travel and conference participation. Read more about their winning entries on prostatecancer, dentalhealth, smoking, and long-term illness.

From a personal perspective, starting a Cochrane review took me on a journey which led from a clinical question (from the Tallaght doctor), to policy development, medical education and further research in a very short time. I still don’t know whether counselling works for drink problems in people who also use other drugs, but I’ve learned how to find an answer using the Cochrane methodology.

Beg, steel or borrow: getting physicians to recruit patients in clinical trials

Leaflets, adverts and phone calls have all been used to recruit patients in clinical trials with some results. Still, the personal contact remains the most reliable method, if you can get the recruiter to do it. In this post, I explore some of the barriers of clinicians’ recruitment activity in randomised controlled trials.

Lack of time, specialist staff and patient motivation are the most frequently reported barriers that prevent clinicians to recruit their patients into clinical trials. Even though the physician signs up for the study and is informed about what is involved, they often do not complete the job. Some are distracted by competing clinical priorities, while others cannot get a positive answer from their patients. Regardless of the reason, the research suffers because of low participation numbers and prolonged study set-up.
iStockphotos.com


Researchers from the University Of Birmingham, UK, looked at all ways that improve the clinicians’ recruitment activity. Their systematic reviewof scientific literature compared the impact of different recruitment strategies and underlying clinician attitudes. To recruit successfully, the clinicians should be incentivised or supported in some way. Unfortunately, many researchers use supports that don’t work. What’s more worrying is that nobody knows how to boost clinicians’ recruitment rates. The study authors recommend that each clinical trial uses qualitative methods to ask clinicians what would work for them and use their suggestions. Another issue was what clinicians think of clinical trials. Misconceptions about trials methods still prevail and clinicians do not see the positives of trials; nor do their patients. Improved education and communication from researchers to physicians can overcome these issues.

Paying research participants for taking part can increase the number of people who agree to take part in the study, the so-called consent rate. It has become a norm in the Western world studies. Still, some studies and countries are unable to provide financial incentives to patients who volunteer for research. Direct payments may also be viewed as introducing unwanted bias into research results. Some may think that people who get paid for research would not participate if they did not get anything. Human motivation is a mysterious subject and money is part of it. It is the currency of modern society.

Is it ethical?

The healing relationship between the patient and doctor can be viewed as unsuitable for recruiting patients into clinical trials. Patients may feel obliged to agree, without making a fully informed decision. Ideally, the recruitment should be done by someone who isn’t involved in patients’ care; however, this is often not feasible in the real life. On one hand, the participants should make an informed decision about their participation and decide voluntarily. On the other hand, the researchers should not surprise patients who attend medical services for non-research purposes. The way to overcome this problem is through a two-stage recruitment process, as used in our study. The first step is to give information. The care provider gives a leaflet with information about the study to potential participants. The person goes home and reads the leaflet at their leisure. When they come to see their doctor next time, they can ask questions about the study, and decide to take, or not to take, part in the study.

Recruitment to randomised trials will probably always remain an issue for science. With an open mind, the investigators and clinicians can seek better solutions for creating trials that would attract human participants and help advance science for the benefit of all.

Cited articles:
Ben Fletcher, Adrian Gheorghe, David Moore, Sue Wilson, Sarah Damery: Improving the recruitment activity of clinicians in randomised controlled trials: a systematic review. BMJ Open 2012;2:1 e000496 doi:10.1136/bmjopen-2011-000496

Klimas J, Anderson R, Bourke M, Bury G, Field CA, Kaner E, Keane R, Keenan E, Meagher D, Murphy B, O’Gorman CSM, O’Toole TP, Saunders J, Smyth BP, Dunne C, Cullen W: Psychosocial Interventions for Alcohol Use Among Problem Drug Users: Protocol for a Feasibility Study in Primary Care. JMIR Res Protocols 2013;2(2):e26
doi: 10.2196/resprot.2678

Recruitment shock

3.6% response rate? Shocking! For our new feasibility study, we sent over 200 invitations to primary care doctors in Ireland and the invitees sent us back a very strong signal. “We are not interested”, or “we are too busy”, or “we don’t have enough eligible patients”? Whatever the reason, the message remained the same: No, thanks.

The primary objective of our study, as for most feasibility studies, is to estimate numbers needed for a definitive trial. We want to know how many people should be invited into the study; of those, how many should be randomized; of those, how many will stay until the end. Right from the beginning, we were faced with a question whether we can recruit enough people for a fully-powered experiment.

Statistical power

Power in research experiments is about finding the truth. Experimenters want to know whether their drugs or treatments work. If the drug or treatment works and they give it to a group of people, some of them will improve, some won’t. There’s a lot of chance and uncertainty in any drug or treatment administration. If we want to know the truth beyond the effects of chance, we need to give the drug or treatment to the right number of people. There’s a formula for it, known to most statisticians. It depends on many things, like the size of the improvement that you want to observe in the treated group, or other confounding factors. The higher power in a study, the more likely it says true (see, e.g., Dr Paul D Ellis’, PhD site here).
A rule of thumb says that the more people are in the study, the higher the chances of finding a meaningful impact of the intervention. Common sense also tells us that the more people in the trial, the more representative they are of the whole population – the more confidence you can be that your results apply to all; except for Martians – unless you really want to study Martian citizenship.

Solution

The easiest would be to call some friends, doctors, and ask for a favor. This should work, but it’s not really scientific. Or you can shut down the study and conclude that it’s not feasible. Or you can do the study with the small number of interested participants. Or you can send another mailshot, a reminder, to all – sometimes that can help.