Blog entry by Meguid El Nahas
Targets, trends, excesses, and deficiencies: refocusing clinical investigation to improve patient outcomes.
Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada.
Clinical trials in nephrology have focused on achieving targets, supplementing deficiencies, and correcting excesses in order to improve patient outcomes. The majority of interventions have failed to demonstrate benefit and some have caused harm. It may be that therapies aiming to 'normalize' parameters may actually disturb evolutionary adaptation, thus causing harm. By refocusing on the physiology of disease, and complexity of adaptation, we may design better trials. We review successful and unsuccessful trials in nephrology and other disciplines and suggest a set of principles by which to design future clinical trials:(1) acknowledge heterogeneity of chronic kidney disease populations and appropriately characterize populations for studies; (2) develop better validated biomarkers (through proteomics, genomics, and metabolomics) to identify responders and nonresponders to interventions; (3) design interventions that mimic physiological processes without collateral detrimental effects; (4) reconsider the status of the randomized-controlled trial as the only 'gold standard' and perform large-scale pragmatic trials comparing current care with the intervention(s) of interest, and (5) broaden nephrology research culture so that the majority of patients are enrolled into observational cohorts and intervention studies, which foster greater knowledge acquisition and dissemination. Improved understanding of pathophysiological mechanisms, in conjunction with more innovative but stringent clinical trial design, will ultimately lead to improved patient outcomes.
This is a very important review of the state of clinical investigation and trials in Nephrology.
It highlights discrepancies betwen between observational and cohort studies and randomised control trials (RCTs); whereby the former often points to interesting associations suggesting interventional studies that ultimately prove consistently negative!
The authors explore potential reasons and explanations for such an intervention "gap".
They highlight the heterogenity of CKD patients, the lack of adequate surrogate markers that predict reliably hard endpoints.
They suggest that a better understanding of the pathophysiology that underpins clinical investigation may mitigate the consistent disappointment generated from interventions based on delusionary endpoints and modifiable parameters.
Finally, they question the place of the RCT as the "only gold standard" and put forward well condcuted pragmatic studies.
In my mind, the problem with Nephrology trials is that they deal with a heterogeneous and also very complex and MULTIFACTORIAL conditions.
Consequently, it is naive to expect that the modification of a single parameter:
Anemia, PO4, PTH, FGF23, BP, LIpids, etc...would suffice to reverse the relentless trend towards increased mortality.
It is high time to consider MULTIFACTORIAL therapies for a MULTIFACTORIAL disease.
It is high time to use combined therapies pitched against standard practice. This has been implemented in diabetes and diabetic nephropathy with some promise (http://www.ncbi.nlm.nih.gov/pubmed/18256393).
The issue and opposition for such an approach will come from the Pharmaceutical industry that dictates the terms and conditions of most clinical investigation in Nephrology and medicine in general.
The Pharmaceutical industry is there to promote ONE compound and not a multifactorial approach that would blur the impact of a given agent and subsequently blur their marketing strategy....
Also, Pharma rush to success leads clinical investigations in Nephrology to rely on soft and often inappropriate surrogate markers instead of taking the time (and cost) of aiming at altering hard endpoint ssuch as morbidity and mortality.
Alternate sources of funding of clincial investigation in Nephrology is key to the success of therapies and intervention in nephrology.
Government agents and NGOs need to take the lead and support clinical investigations that rely on:
1. Hard enpoints to improve patients outcomes.
2. Systematic Observational cohort studies involving more than one centre and more than one country.
3. Clinical investigations that pay attention to socio-demographic and geographic variability; involving emerging countries and their CKD/ESRD patients.
4. Moving away from statistical manipulation of data to serve commercial purposes
5. Moving away from soft and delusional surrogate endpoints
6. Moving away from the obsession with albuminuria reduction; another inappropriate and misunderstood surrogate marker
Ultimately, Nephrologists need to improve their understanding of piublished clinical investigations:
1. Improve their critical appraisal skills
2. Understanding that Proof of Concept (pahse2) trials are NOT conclusive
3. Understanding that subgroup and posthoc analyses are NOT conclusive; instead hypothesis generating
4. Improve their own data collection
5. Improve their own observational skills
It will take time, but a critical evaluation of the state of Clinical Investigation in Nephrology, as undertook by Levin and her colleagues, is timely and should encourage us all to re-think investigations and treatment strategies. This will ultimately translate into tangible and real improvement in patients outcomes. It will also lead to avoidance of harm!