Sounding the Alarm (Again) in Oncology

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Sounding the Alarm (Again) in Oncology

Five years ago Fojo and Grady sounded the alarm about value in many of the new oncology drugs [1]. They raised the following issues and challenged oncologists and others to get involved in addressing these issues:

  • There is a great deal of uncertainty and confusion about what constitutes a benefit in cancer therapy; and,
  • How much should cost factor into these deliberations?

The authors review a number of oncology drug studies reporting increased overall survival (OS) ranging from a median of a few days to a few months with total new drug costs ranging from $15,000 to $90,000 plus. In some cases, there is no increase in OS, but only progression free survival (PFS) which is a weaker outcome measure due to its being prone to tumor assessment biases and is frequently assessed in studies of short duration. Adverse events associated with the new drugs are many and include higher rates of febrile neutropenia, infusion-related reactions, diarrhea, skin toxicity, infections, hypertension and other adverse events.

Fojo and Grady point out that—

“Many Americans would likely not regard a 1.2-month survival advantage as ‘significant’ progress, the much revered P value notwithstanding. But would an individual patient agree? Although we lack the answer to this question, we would suggest that the death of a mother of four at age 37 years would be no less painful were it to occur at age 37 years and 1 month, nor would the passing of a 67-year-old who planned to travel after retiring be any less difficult for the spouse were it to have occurred 1 month later.”

In a recent article [2] (thanks to Dr. Richard Lehman for drawing our attention to this article in his wonderful BMJ blog) Fojo and colleagues again point out that—

  • Cancer is the number one cause of mortality worldwide, and cancer cases are projected to rise by 75% over the next 2 decades.
  • Of the 71 therapies for solid tumors receiving FDA approval from 2002 to 2014, only 30 of the 71 approvals (42%) met the American Society of Clinical Oncology Cancer Research Committee’s “low hurdle” criteria for clinically meaningful improvement. Further, the authors tallied results from all the studies and reported very modest collective median gains of 2.5 months for PFS and 2.1 months for OS. Numerous surveys have indicated that patients expect much more.
  • Expensive therapies are stifling progress by (1) encouraging enormous expenditures of time, money, and resources on marginal therapeutic indications; and, (2) promoting a me-too mentality that is stifling innovation and creativity.

The last bullet needs a little explaining. The authors provide a number of examples of “safe bets” and argue that revenue from such safe and profitable therapies rather than true need has been a driving force for new oncology drugs. The problem is compounded by regulations—e.g., rules which require Medicare to reimburse patients for any drug used in an “anti-cancer chemotherapeutic regimen”—regardless of its incremental benefit over other drugs—as long as the use is “for a medically accepted indication” (commonly interpreted as “approved by the FDA”). This provides guaranteed revenues for me-too drugs irrespective of their marginal benefits. The authors also point out that when prices for drugs of proven efficacy fall below a certain threshold, suppliers often stop producing the drug, causing severe shortages.

What can be done? The authors acknowledge several times in their commentary that the spiraling cost of cancer therapies has no single villain; academia, professional societies, scientific journals, practicing oncologists, regulators, patient advocacy groups and the biopharmaceutical industry—all bear some responsibility. [We would add to this list physicians, P&T committees and any others who are engaged in treatment decisions for patients. Patients are not on this list (yet) because they are unlikely to really know the evidence.] This is like many other situations when many are responsible—often the end result is that “no one” takes responsibility. Fojo et al. close by making several suggestions, among which are—

  1. Academicians must avoid participating in the development of marginal therapies;
  2. Professional societies and scientific journals must raise their standards and not spotlight marginal outcomes;
  3. All of us must also insist on transparency and the sharing of all published data in a timely and enforceable manner;
  4. Actual gains of benefit must be emphasized—not hazard ratios or other measures that force readers to work hard to determine actual outcomes and benefits and risks;
  5. We need cooperative groups with adequate resources to provide leadership to ensure that trials are designed to deliver meaningful outcomes;
  6. We must find a way to avoid paying premium prices for marginal benefits; and,
  7. We must find a way [federal support?] to secure altruistic investment capital.

Delfini Comment
While the authors do not make a suggestion for specific responsibilities or actions on the part of the FDA, they do make a recommendation that an independent entity might create uniform measures of benefits for each FDA-approved drug—e.g., quality-adjusted life-years. We think the FDA could go a long way in improving this situation.

And so, as pointed out by Fojo et al., only small gains have been made in OS over the past 12 years, and costs of oncology drugs have skyrocketed. However, to make matters even worse than portrayed by Fojo et al., many of the oncology drug studies we see have major threats to validity (e.g., selection bias, lack of blinding and other performance biases, attrition and assessment bias, etc.) raising the question, “Does the approximate 2 month gain in median OS represent an overestimate?” Since bias tends to favor the new intervention in clinical trials, the PFS and OS reported in many of the recent oncology trials may be exaggerated or even absent or harms may outweigh benefits. On the other hand, if a study is valid, since a median is a midpoint in a range of results and a patient may achieve better results than indicated by the median, some patients may choose to accept a new therapy. The important thing is that patients are given information on benefits and harms in a way that allows them to have a reasonable understanding of all the issues and make the choices that are right for them.

Resources & References

Resource

  1. The URL for Dr. Lehman’s Blog is—
    http://blogs.bmj.com/bmj/category/richard-lehmans-weekly-review-of-medical-journals/
  2. The URL for his original blog entry about this article is—
    http://blogs.bmj.com/bmj/2014/11/24/richard-lehmans-journal-review-24-november-2014/

References

  1. Fojo T, Grady C. How much is life worth: cetuximab, non-small cell lung cancer, and the $440 billion question. J Natl Cancer Inst. 2009 Aug 5;101(15):1044-8. Epub 2009 Jun 29. PMID: 19564563
  2. Fojo T, Mailankody S, Lo A. Unintended Consequences of Expensive Cancer Therapeutics-The Pursuit of Marginal Indications and a Me-Too Mentality That Stifles Innovation and Creativity: The John Conley Lecture. JAMA Otolaryngol Head Neck Surg. 2014 Jul 28. doi: 10.1001/jamaoto.2014.1570. [Epub ahead of print] PubMed PMID: 25068501.
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Proton Beam Therapy For Prostate Cancer

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Proton Beam Therapy For Prostate Cancer

As of this writing, there is insufficient evidence to conclude that proton beam is more effective in treating prostate cancer than conventional radiation therapy; and there is no evidence of significant differences between proton therapy and radiation therapy in total serious adverse events.  Readers may be interested in a recent article where the investigators point out that patients diagnosed with prostate cancer and  living in areas where proton beam therapy is readily available are more likely to be treated with this new technology than with conventional radiation therapy. The cost of treating prostate cancer with proton beam therapy can exceed $50,000 per patient which is twice the cost of radiation therapy. Increasingly, we are seeing new technologies with staggering costs. In prostate cancer, for example, as we write this, proton centers are being built all over the country at a cost of up to $200 million.

Reference

Aaronson DS, Odisho AY, Hills N, Cress R, Carroll PR, Dudley RA, Cooperberg MR. Proton beam therapy and treatment for localized prostate cancer: if you build it, they will come. Arch Intern Med. 2012 Feb 13;172(3):280-3. PubMed PMID:22332166.

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Best Care at Lower Cost: The Path to Continuously Learning Health Care in America

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Best Care at Lower Cost: The Path to Continuously Learning Health Care in America

“If home building were like health care, carpenters, electricians, and plumbers each would work with different blueprints, with very little coordination.”

“If airline travel were like health care, each pilot would be free to design his or her own preflight safety check, or not to perform one at all.”

The Institute of Medicine (IOM) has just released this latest “state of our health care” report which is well worth reading. [1]  We have a long ways to go before we have a health system. The report, released September 6, 2012, concludes that our dysfunctional health care system wastes about $760 billion each year. Much of the waste is due to inefficiencies and administrative duplications, but $210 billion of the waste is due to unnecessary services (e.g., overuse, unnecessary choice of higher cost services) and $55 billion is wasted on missed primary, secondary and tertiary prevention opportunities.

Here are just a few of the interesting points and recommendations the 18 authors make:

  • The volume of the biomedical and clinical knowledge base has rapidly expanded, with research publications having risen from more than 200,000 a year in 1970 to more than 750,000 in 2010;
  • We can achieve striking improvements in safety, quality, reliability, and value through the use of systematic evidence-based process improvement methods;
  • We need digital platforms supporting real-time access to knowledge;
  • We need to  engage empowered patients;
  • We need full transparency in all we do;
  • We need improved decision support; improved patient-centered care through tools that deliver reliable, current clinical knowledge to the point of care; and, organizations’ support for, and adoption of, incentives that encourage the use of these tools.

The pre-publication issue of this IOM report is currently available free of charge at this URL.[2]



[1] Smith M, Cassell G, Ferguson B, Jones C, Redberg R; Institute of Medicine of the National Academies. Best care at lower cost: the path to continuously learning health care in America. http://iom.edu/Activities/Quality/LearningHealthCare/2012- SEP-06.aspx.

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Critical Appraisal Matters

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Critical Appraisal Matters

Most of us know that there is much variation in healthcare that is not explained by patient preference, differences in disease incidence or resource availability. We think that many of the healthcare quality problems with overuse, underuse, misuse, waste, patient harms and more stems from a broad lack of understanding by healthcare decision-makers about  what constitutes solid clinical research.

We think it’s worth visiting (or revisiting) our webpage on “Why Critical Appraisal Matters.”

http://www.delfini.org/delfiniFactsCriticalAppraisal.htm

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Dr. John Ioannidis on Clinical Trials Issues, Cost and Inappropriate Care

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Dr. John Ioannidis on Clinical Trials Issues, Cost and Inappropriate Care

Since 1949, the NIH has provided a biweekly newsletter for employees of the National Institute of Health. Mostly the NIH Record announces talks to be given on-campus, but also summarizes some of the talks. In a recent issue the Record summarized a recent talk on bias in healthcare trials, delivered by  Dr.John Ioannidis, director of the Stanford Prevention Research Center. Some of his key points are quite thought-provoking and relate to our our huge problem of costly and  inappropriate care. Here is some food for thought from Dr Ioannidis:

  • Most statistically significant findings are not real at all—they’re just false positives
  • Many of these false positives are revealed when larger-scale studies attempt to replicate the findings of smaller studies
  • One of every four such trials is refuted when a larger trial is conducted
  • Journal editorial policies are responsible for much of this trend— editors want to see research that is novel and will have a large impact on the field. This generally means that editors are looking for papers that report very large, statistically significant effects.
  • An important safeguard is “repeatability” of positive findings
  • Individuals with a track record for doing high quality research should be recognized and given priority in publishing.

To read the entire entry go to:

http://nihrecord.od.nih.gov/newsletters/2012/05_11_2012/story2.htm

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