Outcomes, survival, and HRQOL in trials of new drugs (and what they mean in practice)

A new paper in the journal Quality of Life Research has raised the question of whether it is possible to use available quality of life data from Phase III trials of new drugs in the treatment of advanced prostate cancer to make rational decisions about the use of those drugs in clinical practice.

Adamowicz examined data from 84 different studies involving 57,000+ patients published in 10 of the leading clinical journals and another 27 studies involving 7,270 patients in other journals.

He starts from the very reasonable premise that:

The chief therapeutic goal in metastatic prostate cancer is prolongation of survival with good quality of life.

And since the early 2000s, health-related quality of life (HRQOL) has often been used as a secondary endpoint in phase III trials for many new drugs in the management of metastatic and/or castration-resistant prostate cancer, but the value of using HRQOL in this context has not been assessed to date.

Adamowicz was able to identify reports of HRQOL data from 25 contemporary Phase III clinical trials in a total of 29 papers (either in the initial study reports or in follow-up reports on the primary study outcomes). Based on the data from these 25 Phase III trials, he reports that:

  • There was no evident trend in quality of life reported over two 8-year periods.
  • Explicit statistical comparisons of HRQOL data from the different arms of the trials were reported in 22/25 studies (88 percent).
  • There was a statistically significant difference in HRQOL between the trial arms in 10/25 studies (40 percent).
  • The difference in HRQOL favored the “new” investigational therapy in 8/25 studies (32 percent).
  • There was no significant association between improvements in HRQOL and improvements in overall survival (OS) or any other primary endpoint.
  • Just one study showed a difference in HRQOL with no difference in the primary endpoint.

Abramowicz concludes that:

HRQOL is an indicator of benefit during treatment of patients with metastatic prostate cancer, but it is unlikely that HRQOL results can help clinicians choose between treatments given that they are not correlated with changes in OS or at other primary endpoints.

This raises important questions about how we are actually designing and implementing clinical trials in the management of late stage prostate cancer.

There are three potentially “truly favorable” outcomes that can be imagined for a new form of drug therapy in the treatment of late-stage prostate cancer:

  • The new, experimental drug therapy or combination significantly extends patient survival and significantly improves HRQOL compared to current standard therapy (which is clearly the ideal outcome).
  • The new, experimental drug therapy or combination significantly extends patient survival but has no significant impact on HRQOL compared to standard therapy.
  • The new, experimental drug therapy has no significant impact on patient survival but significantly improves HRQOL compared to standard therapy.

There are also two “arguably favorable” outcomes that could lead to a new drug being approved by regulator authorities but which are rather less perfect:

  • The new, experimental drug therapy has a major impact on patient survival but significantly reduces HRQOL compared to standard therapy (because of a higher level of complications and adverse effects). For regulatory authorities, this would raise questions of whether the potential increase in survival was of equal or greater benefit to patients that the potential risk associated with adverse effects.
  • The new, experimental drug therapy significantly reduces patient survival but has a major impact on HRQOL compared to standard therapy (because, say, it eliminates risk for a common complication of treatment of advanced prostate cancer). For regulatory authorities, this would raise questions of whether the potential improvement in HRQOL was of equal or greater benefit to patients than the potential loss of survival time.

Ideally, it should be possible to generate data that would give clear indications for clinicians and their patients about the relative value of these very different outcomes from drug to drug (or probably more accurately from drug combination to drug combination) and to tie this to the overall “value” of the new drug based on the cost of a year of treatment.

Certainly, we aren’t there yet. And even if we were to get there, we also have to allow for the fact that differing patients are still going to place higher value on either the length of their life (increased survival time) or the quality of their life (fewer complications and side effects) based on very personal perceptions.

4 Responses

  1. Thank you for your commentary on the cited studies. Your post raises a very important philosophical and practical point. As you state, patient preference for length of life verses quality of life is a discussion that the treating physician must have with her patient whenever a treatment with potential serious side effects is considered. However, although the physician should respect the patient’s decision to choose quality of life over length of life, I believe there is inherent pressure on the physician to strongly recommend and pursue those treatments which extend life, even if the patient has expressed a contrary preference. The physician will probably be judged by peers, hospitals, academic institutions, and patients alike on whether he has followed the NCCN guidelines, whether she has utilized the recommendations of the most recent clinical trials, or how long her patients have survived, rather than by the intangible results of achieving a better quality of life for the patient. The fear of a malpractice suit is also probably in the back of some physician’s minds.

    I have expressed a desire for quality of life over length of life to my treating physicians, but the push back is constant (and understandable). The patient must be diligent and diplomatic in rejecting reasonably recommended treatments which may indeed extend life at the perceived expense of quality of life. The patient’s decision to follow the physician’s reasonably recommended treatment advice, even if the patient has a clear preference for quality of life, is not an easy one either. Further complicating the patient’s decision-making paradigm is the fact that there is rarely a situation when a recommended treatment for advanced prostate cancer has definitive individual predictable results (either for length or quality of life).

  2. Thank you Richard. You have, as usual, hit the nail right on the head!

    Your comments are highly relevant to the entire issue of what is meant by “value” for the patient in the management of prostate cancer (as opposed to “value” as perceived by physicians, insurers, and politicians).

  3. Could you please provide translations for the many acronyms you routinely insert. Either do it “on the fly” or send us a alphabetized list of most of the abbreviations you regularly use. Thanks

  4. Bruce:

    See this page for a long list of the many common acronyms. Any new ones used in specific pieces are always identified the first time that they occur in the relevant pieces.

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