Making smart investment decisions in clinical research

A recent randomized controlled trial in rheumatoid arthritis (RA) patients determined that a strategy of first adding two Disease-modifying Antirheumatic Drugs (DMARDs) to methotrexate (a combination known as Triple Therapy) is neither inferior nor less safe than first adding the biologic anti-TNF drug etanercept to methotrexate in patients with active disease despite the methotrexate [1]. The Rheumatoid Arthritis Comparison of Active Therapies (RACAT) trial, for which ethical approval was obtained from the institutional review boards for each of the sites in the United States and Canada, strengthens findings of earlier strategy trials that have found triple therapy to be noninferior to biologic agents, [2, 3] and a metaanalysis suggesting no difference in their ability to prevent disease progression [4, 5].

The implication of the study, for which all 353 participants provided written informed consent, is that inexpensive triple therapy - a combination promoted for over a decade but infrequently used - should be initiated prior to commencing expensive biologic therapy in patients whose disease is not completely controlled by methotrexate alone. Furthermore, when patients fail a regimen containing a biologic, they should switch to Triple Therapy if it has not previously been tried instead of presuming that a different biologic regimen is needed. The results are particularly significant from a healthcare cost and sustainability perspective since spending on biologic therapies (which all appear to have near equal efficacy [6]) for patients with RA ranks among the top expenditure category in the formulary budgets of most Western healthcare systems [7]. If implemented in practice, Triple Therapy would delay the use of biologic treatment by at least 6 months without impairing a patient’s disease progression, thereby saving $100’s of millions each year.

It will, however, be a major challenge to change rheumatologists prescribing patterns given their familiarity with biologics and guidelines advocating biologic use [8]. Arguably, the multimillion-dollar question raised by the RACAT trial is why was it not conducted earlier? Both biologics and Triple Therapy were independently shown to be effective in comparison to methotrexate more than 15 years ago, [9, 10] but only recently have been compared (Table 1).

Clinical trials are expensive to conduct, and more trials are proposed than can be funded. Despite this, it seems that priority is rarely given to trials where the ultimate objective is to reduce future costs. While “present and future resource implications” [11] are often considerations in funding research, it is rarely recognized that there exists an opportunity cost associated with each funding decision and that reducing costs has a potential to significantly improve health, by releasing money to be spent on alternative healthcare services that provide greater health benefits. It seems the potential opportunity for a blockbuster that industry recognizes can make enormous profits is not reciprocated by payers and research funders with the opportunity to save an enormous amount of money.

With the benefit of hindsight, the $13 million spent on the RACAT trial would have been recouped many times over if conducted in the early 2000s. By looking back, we consider the evidence and the uncertainties relating to this trial in the early 2000s and reflect if we had the foresight then to fund this trial. Most importantly, we consider the lessons to determine which smart investments should be made in research today to save potential future costs.

Whether the RACAT trial will lead to reductions in the use of biologics in patients with RA, and therefore paying for the investment remains to be seen. It is clear that over 10 years ago, the RACAT trial would have been a smart investment – we demonstrate that the anticipated rewards would have indicated the risk was worth taking many times over (Table 2). The result of the trial would have had an influence on jurisdictions beyond the funding agency; however, the case for multinational studies such as RACAT, where the costs are shared and the external validity is strengthened, are even more compelling. With many new expensive treatments are emerging for diseases such as asthma, hepatitis and cancer, among others, a change in thinking about research investments has the potential to save billions of dollars in the next 10 years.

An important issue to consider is who should pay for these clinical trials? Regulatory bodies typically require efficacy studies instead of the comparative effectiveness studies like RACAT, and there is little incentive for pharmaceutical manufacturers to bear the cost. There is a strong argument for regulatory studies to require comparative effectiveness studies, but they tend to be funded through national health research budgets [15]. However, it would have been the payers that would have ultimately saved their budget through this trial. We believe payers need to have a stronger voice in terms of both what regulators require in terms of comparators from phase III studies, and in terms of the way research funders invest in evidence. If the healthcare system is serious about providing quality, cost-effective care, tremendous opportunities remain through smart investments in clinical research.