Dr. Ron Blankstein

“Surrogate Endpoints” in Clinical Testing – Are We Being Duped?



Posted: Monday, February 15, 2010

by Dr. Ron Blankstein
Chesapeake Nutraceuticals

Researchers in the field of immunotherapy have increasingly held out hope for therapeutic vaccines. However, a position paper published in the European Journal of Cancer, May 2009,(1) questioned the validity of vaccine trials and called for a critical appraisal of how the outcomes are determined and understood.

Therapeutic vaccines, unlike prophylactic vaccines, are designed to be administered after the onset of disease so as to trigger an immune system response. This emerging type of biological therapy is still mostly experimental, thus the vaccines are only available to patients enrolled in clinical studies.

Steven Rosenburg, M.D., Surgery Chief at the National Cancer Institute (NCI) in Bethesda, Maryland, argues that optimism about the clinical application of therapeutic vaccines is unjustified. His research team noted that cancer vaccine trials in 440 patients, conducted at NCI Surgery Branch, had an overall objective response rate of only 2.6%. Much lower than the 4.0% response rate reported in the 40 studies that involved 756 patients. The team concluded that the more favorable study results were based on surrogate end points rather than on proof of anti-tumor effects.(2)

A surrogate endpoint is a "marker" or measure of effect of a particular treatment that may or may not correlate with a definitive endpoint that will validate the study. Oftentimes, the primary endpoint of a study is an undesirable outcome a full manifestation of disease or even death. So the research team will zero in on "markers" that can serve as an alternative to test the benefit of a particular treatment.

The problem arises when the surrogate endpoint "correlates" with the actual endpoint but doesn't have a guaranteed relationship. For instance, tumor response is frequently used as a surrogate end point in therapeutic trials of cancer. The categories are: "complete response" (tumor not visible on examination), "partial response" (a reduction in tumor volume of 50% or more), and "no change of progression." Unfortunately, the measure of tumor response is NOT a determinate of overall survival. Which means that tumor response "correlates" to the subject at hand but has no real effect on mortality rates.(3)

The fact is, early-stage clinical trials usually involve only a small number of patients, for which the results are not always sustained in larger trials. Rarely is the validity of a surrogate endpoint rigorously established even though deviation from standard accepted criteria leads to considerable confusion.

Clinical trials in cancer patients are evaluated by criteria determined by either the World Health Organization or RECIST (Response Evaluation Criteria in Solid Tumors) which define objective response rates as 30% to 50% decrease in lesions with no appearance of new lesions. "Mixed responses" in which some tumors decrease while others increase do not qualify as objective responses in either set of standard criteria. An example of deviating from the standard criteria was seen in a study by Spanknebal et al, which reported "10 objective responses in 46 evaluable patients after one course of IL-2 therapy." However, five of those were mixed responders meaning the true objective response rate was not 22%, but rather, 11%.(4)

A classic case of misleading surrogate endpoints occurred when studying the effect of ventricular arrhythmia after myocardial infarction. Arrhythmias are a known risk factor for sudden cardiac death and the drugs, encainide and flecainide are quite effective in suppressing them. Consequently, almost half a million patients in the US started receiving those drugs for that purpose. Researchers convinced cardiologists that it would be unethical to withhold these drugs from patients in the clinical study.

Fortunately, a controlled study of encainide and flecainide took place. Amazingly, the results showed that while both drugs suppressed arrhythmias effectively, the actual death rate tripled! Yes, the drugs had a positive effect on arrhythmias, but they also had an unintended and previously unrecognized adverse effect on overall survival.(5) Surrogate endpoints do have a place in clinical study but it appears they should be used where they perform best in preliminary screening and phase 2 trials. Definitive phase 3 trials should provide reliable evidence based on true objective clinical response.

Sources:

  1. Eggermont, AMM, "Therapeutic vaccines in solid tumours: Can they be harmful?", Eur J Cancer. 2009 May 22
  2. Eggermont, AMM, "Therapeutic vaccines in solid tumours: Can they be harmful?", Eur J Cancer. 2009 May 22
  3. Moertel CG. "Improving the efficiency of clinical trials: a medical perspective", Stat Med. 1984; 3:455-68
  4. Rosenberg SA, Yang JC, Restifo NP. "Cancer immunotherapy: moving beyond current vaccines", Nat Med 2004; 10:90915
  5. Fleming, Thomas R, "Surrogate Endpoints And FDA's Accelerated Approval Process", Health Affairs, 24, no. 1 (2005): 67-78

Dr. Blankstein has been practicing for over 30 years as a leading Cardiologist.

Trained in traditional medicine and Board Certified in both Internal Medicine and Cardiovascular Disease, he knows the importance of good medical care. This consideration has allowed him to discover safe and natural ways of healing. His dedication to bringing the latest and best in health solutions to his patients and the public has given him the experience to research and develop proven natural remedies for many illnesses.

© 2009 Chesapeake Nutraceuticals

Reprint of this article, in whole or in part, digital or otherwise, is permitted provided that author by-lines are kept intact and unchanged and include an active link to http://www.chesapeakenutraceuticals.com.

 

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