Observational studies: The Final Common Pathway of Medical Investigations

By Peter Laird, MD

Dr. Chertow and others wish to tie payment for high dose dialysis (such as, short daily and nocturnal dialysis strategies) to the outcomes of a Randomized Controlled Trial (RCT) as the justification for payment. However, Dr. Chertow acknowledges that these trials will likely never be completed thus rendering the payment for high dose dialysis in a permanent state of limbo.

Yet, outside of the narrow context of dialysis outcomes, modern medicine is replete with examples of observational studies changing and enhancing medical care without the benefit of any secondarily confirming randomized control trials. Cigarette smoking is universally believed to be the causative agent in most lung cancers as well as cardiovascular disease without any RCT ever done. In such, consideration of a RCT on the issue of cardiovascular disease and lung cancer is deemed unethical due to the overwhelming observational evidence available for decades.

In a similar fashion, The Framingham Heart Study and the Nurses' Health Study have added greatly to our knowledge of cardiovascular risk factors.

It is my opinion that much of the debate over RCTs in high dose dialysis is undermined by a complete disregard for any data accumulated in observational studies by those that oppose payment for high dose dialysis. When and why observational studies are used and are also at times the optimal form of studying differing issues is readily seen when we review the basic concepts involved:

In statistics, an observational study draws inferences about the effect of a treatment on subjects, where the assignment of subjects into a treated group versus a control group is outside the control of the investigator.[1] This is in contrast with controlled experiments, such as randomized controlled trials, where each subject is randomly assigned to a treated group or a control group before the start of the treatment.

Medical investigators are at times limited to uncontrolled experimentation for several reasons:

1. A randomized experiment would violate ethical standards.
2. The investigator may simply lack the requisite influence.
3. A randomized experiment may be impractical.

I contend that randomized control trials for high dose dialysis will not be able to be completed for all three of the listed reasons above. First, we do have several well done RCT regression studies on LVH and other intermediate data points that have conclusively shown the benefits of high dose dialysis strategies. Secondly, with the number of the control and experimental dialysis populations needed to show a true difference in mortality rates is set at over 5000 in each group; thus finding enough patients willing to be randomized is likely to be beyond the control of any investigator. Lastly, given the fiduciary responsibility of informed consent where all potential benefits and risks of not receiving the proposed treatment necessary for any human medical experimentation, it is once again not only unethical but also impractical to conceive of a RCT that would meet the qualifications needed in bringing these studies to pass.

That leaves us with the likelihood that the well done observation studies on high dose dialysis will be our best data to judge the efficacy of these modalities for a long time to come.

This all belies an undeclared contention in the debates on randomized control trials that has not been clearly defined to date. It is common knowledge that RCTs do offer the best possibility of defining causality among independent factors being studied in any given disease process. What is not often cited is that after the RCT is completed, its results are subjected to one further test, that of the external validity of a clinical trial. Beyond the Randomized Clinical Trial:

Yet even when an RCT demonstrates substantial net benefit for a specific therapy, its optimal role in routine clinical practice can remain unclear. Concerns frequently relate to how well the therapy may perform in different clinical settings and in broader patient populations than those studied in traditional RCTs. In addition, it is often unclear how therapies are best applied within the larger environment of the healthcare delivery system where costs and availability become issues for patients and clinicians. These concepts, which refer to the external validity of a real clinical trial, become important as new therapies are applied in real world setting and are a key focus area for many studies in health services and outcomes research.

Anyone that is willing to diligently study the high dose dialysis observational studies avalilable over the last four decades must readily concede that the practical application of high dose dialysis has already passed the real world test of this much unfairly maligned alternative dialysis modality. It is time to apply real time, real world acknowledgement of a proven therapy to save the lives of thousands of American CKD-5 patients and at the same time save billions of precious health care dollars by diminishing dialysis related complications. This needs to be implemented immediately without giving any more attention to of the pretence to those wishing to subvert real world observational data to a nonexistent state and thus subjucate dialysis patients in America to substandard care that already has been superceded by high dose dialysis strategies accepted by all other western nations.

Comments

[Anupama]

Hi Bill,

Great to see your blog !!
I am Anu from India, Bangalore....
I am under dialysis for the last 8yrs. I am 28yrs old. I have undergone transplant twice but it didnt work for me :-( ....

I will not take much of your time...I have my brother in Canada. I have not visited any foreign country till date. But I want to go to Canada atleast once... I have travelled in India. The problem is I dont have any insurance. I got to know that Dialysis abroad costs 320-350 $.

What do you say about this? Is there any solution to get dialysed at a cheaper cost? will they give me any discount?

Pls reply.....

[Dori]

I agree, Peter. There are dozens of large, well-controlled RCTs in, say, cardiology--because tens of millions of Americans are affected by heart disease. Kidney failure, on the other hand, is experienced by fewer than half a million. Large, well-controlled RCTS are COSTLY. WIth such a small potential market (though quite an expensive one to care for), the political and economic will are just not there.

Common sense does not require RCTs. You pointed out that no-one has ever done a randomized controlled trial to see if tobacco smoking really causes cancer. Carl Kjellstrand, MD, PhD, will also tell you that no-one has ever done an RCT to determine whether survival is better with or without a parachute when you jump out of an airplane at 20,000 feet.

In ESRD, researchers found that the HEMO study "proved" that more dialysis did not improve survival. Reanalysis determined that this RCT was flawed, in that the "more" dialysis condition was limited by the amount of treatment that could be delivered within the 3x/week in-center paradigm. Rajiv Saran et al, in the international, observational DOPPS (Dialysis Outcomes & Practice Patterns) study of 22,000 people on in-center hemodialysis found that giving a minimum of 4.5 hours of dialysis 3x/week increased the chance of survival by 30%, and EVERY additional 30 minutes FURTHER increased it by 7%. Longer and/or more frequent dialysis that does a better job of maintaining homeostasis helps people feel better and live longer--and stay out of the hospital. Common sense. Who needs an RCT? No RCTs were done to fix the standard of 3x/week treatments in the first place.