Challenges in clinical trial design in inflammatory arthritis

The prognosis for patients with rheumatoid arthritis has improved dramatically, thanks in large part to many new therapies and therapeutic approaches. Paradoxically, this has created problems for rheumatologists since clinically useful information from appropriate clinical trials has not kept pace with all the new therapeutic options. Essentially, rheumatologists now have many more therapeutic options than they know what to do with. This article discusses why we are in this situation and suggests opportunities to move forward.

Patients with new-onset rheumatoid arthritis (RA) in 2010, if diagnosed early and treated by a rheumatologist, can look forward to excellent control of their disease and a normal to near-normal life in most cases. This is dramatically different from the prognosis patients would have had just 20 years ago. Patients and the physicians caring for them have never had more or better treatment options. Currently, at least 19 different individual medications that qualify as disease-modifying anti-rheumatic drugs (DMARDs) are available to prescribe and at least another several dozen are in development. If we use these 19 treatments individually or in combinations of two to four medications as we often do, we have a spectacular but dizzying array of options (13 249 if you are counting, excluding the possibility of multiple biologic combinations). Therefore, with all these options, many of which are terrific, where is the crisis? This tremendous array of options is part of the current problem because at the level of the individual patient, we have a paucity of data to direct our use of this vast arsenal. Certainly, soon we will have studies to help us use the plethora of treatments in an appropriate and evidenced-based way for effective and economical care of our patients. Unfortunately, if we continue to perform clinical trials using the current models, we will never get where we need to be:quoting Irwin Corey, “If we don’t change direction soon, we will end up where we are going.”

What then are the critical issues that current clinical trial design in RA is not addressing? Why are we not getting the answers our patients and our health-care systems need and deserve? And what can we do about it?

Meaningful investigator-initiated clinical trials are the exception in the past decade or so while pharmaceutical-supported trials are the rule. There are examples of important investigator-initiated trials , but the vast majority of clinical trials in rheumatology, especially in the United States and especially with biologicals, are pharmaceutical trials (references too numerous to list). Paradoxically, this has brought highly effective and badly needed treatments , albeit very expensive ones, to our patients and taught us much about RA, while at the same time creating a huge and widening gap in our knowledge about how to optimise these options to provide the best cost-effective care. Pharmaceutical trials are designed as they should be, with companies’ interests in mind; anything less would clearly be unfair to the stockholders. Pharmaceutical companies do not want to compare their expensive new treatment to older cheaper drugs; they want to make head-to-head comparisons if possible with placebos and they do not want to test strategies where their product is only part of the solution, and they infrequently are interested in studying parameters that might suggest that their products are best for only a subset of patients.

Current problems in trial design include:

1.

Most trials are funded and conducted by pharmaceutical companies.
2.

The majority of trials compare active therapy to placebo not to active comparators.
3.

Trials most frequently randomize patients to therapy A vs. B in a rigid manner and ask which group is better after one year? Or worse, two years? This does not parallel clinical treatment.
4.

There is a paucity of organized attempts to look at parameters (clinical combined with biological) that predict differential response
5.

Little if any meaningful data on cost effectiveness has emerged (see #1 and #2 above).
6.

Fundamental ethical issues are being ignored. Including: the use of placebos (where many proven options exist), lengthy proscribed continuations of failed therapies and the timing of knowledge about treatment assignment to patient and treating physician.
7.

Finally, many trials are being conducted in patient populations that may be very different than those where the studied treatment will be used.

The most common design of a clinical trial in the past decade has compared a given therapy with placebo in RA patients with active disease despite methotrexate . Again, a paradox, this has served us well and gotten many therapies to market with indications in RA, but because of the many proven effective therapies (16 if you count only those commercially available ) for this group of patients, clinicians need comparison trials to optimally use these therapies. How helpful is it to have a 17th or an 18th option for this group of patients when there is only one blinded, randomised trial published that has compared active therapies to each other in this group of patients? How then can a clinician make an appropriate therapeutic choice among these 16 options for this common patient?

Clinical trials, in general, compare two therapies in a rigid manner often with fixed doses of the medications for a fixed period sometimes as long as a year or two. Current best clinical practice demands that we change and/or adjust therapies in all of our patients to achieve at least a low level of disease activity, if not remission . Further, we should make these adjustments as soon as we have given therapies an opportunity to be maximally effective; with most of our current therapies, this is certainly no longer than 6 months and most clinicians wait no longer than t3 months to change therapy. Why then are studies that compare therapy A with B (or worse A to a placebo) for a year or two relevant to clinicians when therapies that have obviously failed in many of the studied patients have been continued for months after we knew they have failed and would have been changed long ago if the same patient was being followed in the clinic?

A decade from now we hopefully will no longer be interested in what happens in clinical trials to large unselected groups of RA patients. Questions such as ‘What is the best therapy for earlier RA or for RA patients with active disease despite methotrexate?’ will be largely irrelevant. We will have progressed to the point where we will be able to profile individual patients. We will be able to select among therapies that we know will have a very high success rate because of the patient’s genetics, their cytokine profile, their autoantibody profile, the initial trigger of their disease or a combination of these factors (and probably many others). Armed with this information and the literally thousands of options clinicians already have, we will be poised to take the next quantum leap forward in therapy for our RA patients. Unfortunately, many clinical trials have not attempted to address these questions because of the lack of biological specimens (serum, DNA, RNA, synovial tissue, etc.) that are married to the clinical data, because sponsors are not interested in these answers, the substantial expense involved or a myriad of other reasons. Until this happens, we will continue to spin the therapeutic-option roulette wheel.

Ultimately, we as clinicians will be asked to prescribe the most cost-effective therapy for all of our patients. This is already happening in many countries and in many health-care delivery systems. A well-run, cost-effective, health-care delivery system will be essential for any country that wants to compete in the global marketplace. We are particularly ill-equipped to address this concern; essentially, no meaningful data on the cost-effectiveness of our current therapies are available from clinical trials that in any way mirror clinical practice. Most clinical trials have compared active products to placebos and any cost-effective analysis that compares a therapy to a placebo (if other effective treatments are available) is, at best, highly suspect. Unfortunately, if good cost-effectiveness data are not available, many systems may force us to use the least expensive therapy which could have severe consequences for our patients, and ultimately, society, as we bear the burden of the increased indirect costs that will certainly result from such an approach.

We should have grave ethical concerns about the current ‘accepted’ clinical trial design. Major concerns with the current ‘standard’ include the use of placebos, the duration of continuation of failed therapies and the timing of providing treatment information to patients and clinicians subsequent to study completion or withdrawal. Placebo controls are currently widely used in clinical trials in situations where many proven therapies exist, and guidelines and trial data clearly show that patients would benefit if these therapies were introduced earlier. Many experts strongly advocate that aggressive therapy be used very early in the treatment of RA, while at the same time taking part in trials where placebos are continued for months to years. With our current state of knowledge, how do we justify continuing a failed therapy for 6 months or more past the point that it should have been maximally effective? Finally, patients and their treating clinician are often blind to the therapy they received in a clinical trial for months or even years after they have reached the primary endpoint of the trial. How do we justify withholding this vital information from patients and their treating physician?

How can we change the direction we are going and truly allow our patients to reap the benefits of the remarkable therapeutic options we currently have? Pharmaceutical trials have given us effective treatment options but can only be expected to take us so far. Clinical trials funded by agencies (National Institutes of Health (NIH), Canadian Institute of Health Research (CIHR), VA, insurers, governments, etc.) that do not have a stake in the outcome are critically needed to supplement pharmaceutical trials. Trial design of the next decade needs to catch up with best clinical practice and be designed to more closely mirror clinical practice. Examples of this would be designing switches of therapies within a trial (in a blinded fashion) for patients who have not achieved an optimal response by a reasonable time or requiring patients who do not achieve improvement at a reasonable time to be removed from the trial and counted as a failure. If active therapies are compared in randomised, blinded, clinical trials and appropriate data are collected, we will for the first time have the opportunity to collect meaningful cost-effective data. When active therapies are compared, we will need to consider equivalence trials and come to grips with what clinical equivalence means, especially in the context of the cost differential of many of our therapies. Trials must be married to biological repositories so that genetic and serological parameters can be closely examined to ultimately allow us to profile patients so that future patients will get optimal effective treatments in a timely fashion.

We badly need a revolution in trial design. If we are successful in getting trials funded that come to grips with some of the issues raised above, we will be able to change course. If we cannot and continue in the direction we are headed, we may indeed ‘end up where we are going’ with more options for treatment then we have any idea what to do with, with patients who are reluctant to enroll in trials because of ethical concerns and payors telling us we must always use the cheapest therapy until we can provide evidence to the contrary.

Research agenda

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