After close to 5 years, we have finally had our Asia-Pacific epidemiological survey on invasive fungal diseases  (IFDs) among patients with haematological disorders accepted for publication in the European journal Clinical Microbiology & Infection (it is unfortunately behind the infamous Elsevier pay wall!). This study was funded by the pharmaceutical giant Merck, Sharpe & Dohme, (MSD) and in many ways, it would not have been possible to complete this study without their support, especially that of their previous regional director of medical affairs, the late and great Dr. Charles Farthing. It is one of a pair of regional fungal studies funded by MSD – the other (also completed) being an Asia-Pacific survey of Candida spp. isolated from bloodstream infections.

Had we known of the difficulties beforehand, perhaps we would not have initiated these studies. But ignorance is sometimes bliss in research, and oftentimes we dare attempt things only because we are ignorant! I will describe the process in getting the study started and completed here, and the results in a subsequent post, since I feel there are somewhat relevant lessons in both.

In May 2010, taking advantage of the fact that MSD had invested heavily in antifungal agents (the first echinocandin caspofungin as well as a unique triazole posaconazole), a colleague and I attended an MSD-sponsored fungal infection symposium in Tagatay, Philippines and pitched our study ideas to the MSD representatives. There was not much available (and reliable) data on fungal infections in the Asia-Pacific region except from Australia and Japan, so we – the chaps from Singapore – would design the studies to collect such data whereas MSD – with branches and representatives in most countries in the region – would help us find local partners in neighbouring countries. And MSD would fund the whole thing.

Much to our amazement, we got moved up the hierarchy rapidly to talk to Dr. Farthing, and he was surprisingly receptive. So we submitted our Letters of Intent after the meeting, and were invited to submit full proposals shortly thereafter. Incidentally, the whole process has remained unchanged from 2010 and is part of the Merck Investigator Studies Program. By December 2010, the studies had been approved.

Then we got to the business of engaging research partners from different regional hospitals, and MSD organised the meeting in 2011 to introduce all potential participants and to discuss the study methodologies. Wisely, Dr. Farthing and MSD had also engaged a contract research organisation – IHMA – to help ensure their money was not going to be squandered by inexperienced researchers. By the end of 2011, eleven hospitals from eight Asia-Pacific regions had signed up for the IFD study, and rather more for the candidaemia study. The IFD study sites are shown in the map below.

Regional hospitals participating in the MSD-sponsored invasive fungal disease study.

The premise of the IFD study is simple: the investigators would try to recruit as many haematological patients with IFDs as possible over the 2-year study period, and record their demographic and clinical parameters in order to determine what were the risk factors and types of fungal infections that afflicted their patients. The subjects would then be followed up to see if they survived or died from the IFDs. Separately, the investigators would provide the number of patients with “high risk” (high risk for IFD) conditions (such as acute myeloid leukaemia, myelodysplastic syndrome, acute lymphoblastic leukaemia, etc.) or treatment (allogeneic haematopoietic stem cell transplantation, etc.) at their hospitals over the study period as a denominator. The total number of patients with IFD they failed to recruit, which occurs in all clinical studies for a variety of reasons (refusal to participate, died or discharged before being approached, etc.), will be captured as a separate statistic.

Naturally, with just eleven hospitals, the data we obtained were not going to be representative for most of the countries/regions except perhaps for Singapore (SGH and NUH together account for all the haematopoietic stem cell transplantations and intensive chemotherapy for leukaemia done in the public sector at the time of the study) and Vietnam (the National institute of Hematology and Blood Transfusion is the largest institute providing treatment for haematological diseases in Vietnam). But we were just happy to get participants from these countries and to get the study off the ground!

The actual recruitment period was between June 2012 and June 2014 – it took over half a year for all the different hospitals to obtain ethics approval, which perhaps is quite fast compared to the rather slow ethics review process for clinical studies today, even in efficient Singapore. It was quite unsettling during the earlier part of the recruitment period, wondering why no cases were being logged. Fortunately, recruitment picked up for all sites subsequently. Dr. Farthing also helped  to ensure that the study ran smoothly, organising monthly teleconferences between site investigators and MSD representatives at each site. The only other way we kept in touch with the investigators from other countries was via email, and I am glad that our co-investigators usually responded quickly and positively. The rest of it was about monitoring – checking the data entries to make sure the data were valid (even with the best intentions, there were many errors), backing up the database monthly, etc. We were glad we did the latter when an overzealous research assistant overwrote the entries from a few other sites – something that technically should not have happened given that each site’s investigators were not supposed to be able to access the records put up by other sites, but that’s technology and database security for you.

Analysing the final dataset felt like a breeze compared to what had gone before. We were happy that the results were interesting and appeared to make sense, but more about this in the next post. Writing up the paper – and deciding on the journal to send the paper to – was the final step, and fortunately there wasn’t much jockeying for authorship positions that had been reported from other research groups. Nonetheless, finding a journal “home” for the paper is more of a game than anything else. Many researchers try to publish papers in journals with the highest impact factors because of the rather skewed academic incentive scheme (“high impact publications” – that is, papers published in journals with high impact factors – facilitate academic promotion and raise one’s “stature”, among other benefits). Personally, I try to get papers accepted as fast as possible, which often means trying for journals with lower impact factors. But for this study, given the amount of time and effort expanded, and the scale of the study, we felt obliged to try for one of the more established international infectious diseases journals. It was quite fortunate that the reviewers for Clinical Microbiology & Infection were kind, and we had the paper accepted after just one round of reviews and revision.

On hindsight, the multi-centre and multi-country IFD study was far more daunting and difficult than we had anticipated. We were very fortunate to have had the support that we had, and to complete the study. A great part of the success can be attributed to Dr. Charles Farthing’s unstinting support, who unfortunately died just before the study was completed. It was worthwhile doing the study, not just because the data and results were valuable (although I think they are), but also for the firsthand experience of running such a multi-centre study in Asia.