Phase 4 Studies in Heart Failure - What is Done and What is Needed?

Abstract

Congestive heart failure (CHF) therapeutics is generated through a well-described evidence generating process. Phases 1 – 3 of this process are required prior to approval and widespread clinical use. Phase 3 in almost all cases is a methodologically sound randomized controlled trial (RCT). After this phase it is generally accepted that the treatment has a significant, independent and prognostically beneficial effect on the pathophysiological process. A major criticism of RCTs is the population to whom the result is applicable. When this population is significantly different from the trial cohort the external validity comes into question. Should the continuation of the evidence generating process continue these problems might be identified. Post marketing surveillance through phase 4 and comparative effectiveness studies through phase 5 trials are often underperformed in comparison to the RCT. These processes can help identify remote adverse events and define new hypotheses for community level benefits. This review is aimed at exploring the post-marketing scene for CHF therapeutics from an Australian health system perspective. We explore the phases of clinical trials, the level of evidence currently available and options for ensuring greater accountability for community level CHF clinical outcomes.

Risk stratification for coronary artery disease in multi-ethnic populations: Are there broader considerations for cost efficiency?

“…But in all developed health systems it is premature to invest public resources to understand variations in established observations that do not meet robust requirements of need, especially cost-efficiency. We accept differentials exist in phase 1-3 trials that assume largely private capital, so this argument is largely for phase 4 trials or post translational observations[99-102]. The observations presently is “the cost efficiency of using unimodal risk stratification of CAD within health clusters that serve a multiethnic patient population with varying stages of epidemiological transition based on findings and guidelines from homogenous populations”.…”

“…The primary focus are delivery models and cost-efficiency across established health service Taxonomy domains. Nesting this question within larger studies could also broaden the funding appeal[102-105].…”

Health care in a globalised world: is there more than one type of patient?

“…Phase 4 studies have indicated that acting on clinical trial‐derived evidence does not achieve the expected outcomes unless the findings have been validated at the community level . In organised programs with this aim, the art of medical practice becomes evident when assessing non‐phenotypic factors such as rapport, compliance, trust, satisfaction, behavioural change, and personal psychology.…”

“…Western health practice is built on scientific evidence about the known, rationalising or debating the uncertain, and clarifying by investigation the unknown. Increasingly heterogeneous patient encounters challenge relying only on scientific evidence about the knowns, as conventional evidence gathering rarely focuses on translational elements (phase 4 clinical research) . New approaches are therefore emerging, such as standardising, coding and classifying heterogeneity (eg, taxonomies), broadening the evidence base, and developing local solutions based on post‐trial evidence …”

Cardiac Imaging in Heart Failure with Comorbidities

“…CMR can similarly detail CR in CRI. As there are other determinants of LVH beyond hypertension including calcium-phosphate balance, this method can inform the adequacy for RRT [ 205 - 213 ]. Impairment in strain rates from all fibers, which go onto correlates with outcomes, is noted in early CRI and hemodialysis [ 210 , 211 ].…”