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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Involving Patients in Their Care Decisions and JAMA Editorial: The New Cholesterol and Blood Pressure Guidelines: Perspective on the Path Forward

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Involving Patients in Their Care Decisions and JAMA Editorial: The New Cholesterol and Blood Pressure Guidelines: Perspective on the Path Forward

Krumholz HM. The New Cholesterol and Blood Pressure Guidelines: Perspective on the Path Forward. JAMA. 2014 Mar 29. doi: 10.1001/jama.2014.2634. [Epub ahead of print] PubMed PMID: 24682222.

http://jama.jamanetwork.com/article.aspx?articleid=1853201

Here is an excellent editorial that highlights the importance of patient decision-making.  We thank the wonderful Dr. Richard Lehman, MA, BM, BCh, Oxford, & Blogger, BMJ Journal Watch, for bringing this to our attention. [Note: Richard’s wonderful weekly review of medical journals—informative, inspiring and oh so droll—is here.]

We have often observed that evidence can be a neutralizing force. This editorial highlights for us that this means involving the patient in a meaningful way and finding ways to support decisions based on patients’ personal requirements. These personal “patient requirements” include health care needs and wants and a recognition of individual circumstances, values and preferences.

To achieve this, we believe that patients should receive the same information as clinicians including what alternatives are available, a quantified assessment of potential benefits and harms of each including the strength of evidence for each and potential consequences of making various choices including things like vitality and cost.

Decisions may differ between patients, and physicians may make incorrect assumption about what most matters to patients of which there are many examples in the literature such as in the citations below.

O’Connor A. Using patient decision aids to promote evidence-based decision making. ACP J Club. 2001 Jul-Aug;135(1):A11-2. PubMed PMID: 11471526.

O’Connor AM, Wennberg JE, Legare F, Llewellyn-Thomas HA,Moulton BW, Sepucha KR, et al. Toward the ‘tipping point’: decision aids and informed patient choice. Health Affairs 2007;26(3):716-25.

Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet. 2005 Jan 1-7;365(9453):82-93. PubMed PMID: 15639683.

Stacey D, Bennett CL, Barry MJ, Col NF, Eden KB, Holmes-Rovner M, Llewellyn-Thomas H, Lyddiatt A, Légaré F, Thomson R. Decision aids for people facing health treatment or screening decisions. Cochrane Database Syst Rev. 2011 Oct 5;(10):CD001431. Review. PubMed PMID: 21975733.

Wennberg JE, O’Connor AM, Collins ED, Weinstein JN. Extending the P4P agenda, part 1: how Medicare can improve patient decision making and reduce unnecessary care. Health Aff (Millwood). 2007 Nov-Dec;26(6):1564-74. PubMed PMID: 17978377.

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Review of Endocrinology Guidelines

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Review of Endocrinology Guidelines

Decision-makers frequently rely on the body of pertinent research in making decisions regarding clinical management decisions. The goal is to critically appraise and synthesize the evidence before making recommendations, developing protocols and making other decisions. Serious attention is paid to the validity of the primary studies to determine reliability before accepting them into the review.  Brito and colleagues have described the rigor of systematic reviews (SRs) cited from 2006 until January 2012 in support of the clinical practice guidelines put forth by the Endocrine Society using the Assessment of Multiple Systematic Reviews (AMSTAR) tool [1].

The authors included 69 of 2817 studies. These 69 SRs had a mean AMSTAR score of 6.4 (standard deviation, 2.5) of a maximum score of 11, with scores improving over time. Thirty five percent of the included SRs were of low-quality (methodological AMSTAR score 1 or 2 of 5, and were cited in 24 different recommendations). These low quality SRs were the main evidentiary support for five recommendations, of which only one acknowledged the quality of SRs.

The authors conclude that few recommendations in field of endocrinology are supported by reliable SRs and that the quality of the endocrinology SRs is suboptimal and is currently not being addressed by guideline developers. SRs should reliably represent the body of relevant evidence.  The authors urge authors and journal editors to pay attention to bias and adequate reporting.

Delfini note: Once again we see a review of guideline work which suggests using caution in accepting clinical recommendations without critical appraisal of the evidence and knowing the strength of the evidence supporting clinical recommendations.

1. Brito JP, Tsapas A, Griebeler ML, Wang Z, Prutsky GJ, Domecq JP, Murad MH, Montori VM. Systematic reviews supporting practice guideline recommendations lack protection against bias. J Clin Epidemiol. 2013 Jun;66(6):633-8. doi: 10.1016/j.jclinepi.2013.01.008. Epub 2013 Mar 16. PubMed PMID: 23510557.

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G-I-N Webinar: Guideline Development & Evidence-based Quality Improvement

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Guidelines International Network Webinar: How to Develop Guidelines Within the Context of a Clinical Quality Improvement Program

Thanks to the Guidelines International Network, a webinar we did for them is available online.  To access the recording and slide show presentation, go to—

http://www.g-i-n.net/activities/g-i-n-na/g-i-n-na-events-activities/webinar-series/delfini

For information about the case study we showcased for our presentation, go to—

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

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Critical Appraisal Tool for Clinical Guidelines & Other Secondary Sources

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Critical Appraisal Tool for Clinical Guidelines & Other Secondary Sources

Everything citing medical science should be appraised for validity and clinical usefulness. That includes clinical guidelines and other secondary sources. Our tool for evaluating these resources— the Delfini QI Project Appraisal Tool—has been updated and is available in the Delfini Tools & Educational Library at www.delfini.org.  For quick access to the PDF version, go to—

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

 

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Canadian Knowledge Translation Website

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Canadian Knowledge Translation Website

The Knowledge Translation (KT) Clearinghouse is a useful website for EBM information and tools. It is funded by the Canadian Institute of Health Research (CIHR) and has a goal of improving the quality of care by developing, implementing and evaluating strategies that bridge the knowledge-to-practice gap and to research the most effective ways to translate knowledge into action. Now added to Delfini web links.

http://ktclearinghouse.ca/

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5 “A”s of Evidence-based Medicine & PICOTS: Using “Population, Intervention, Comparison, Outcomes, Timing, Setting” (PICOTS) In Evidence-Based Quality Improvement Work

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5 “A”s of Evidence-based Medicine & PICOTS: Using “Population, Intervention, Comparison, Outcomes, Timing, Setting” (PICOTS) In Evidence-Based Quality Improvement Work

Much of what we do when answering key clinical questions can be summarized using the 5 “A” EBM Framework—Ask, Acquire, Appraise, Apply and “A”s Again.[1] Key clinical questions create the focus for the work and, once created, drive the work or project. In other words, the 5 “A”s form a scaffolding for us to use in doing EB quality improvement work of many types.

When healthcare professionals look to the medical literature for answers to various clinical questions or when planning comparative reviews, they frequently utilize checklists which employ the mnemonics, PICO (population, intervention, comparison, outcome)[2], PICOTS (same as PICO with the addition of timing and setting) or less frequently PICOT-SD (which also includes study design.[3]  PICOTS (patient population, intervention, comparison, outcomes, timing and setting) is a checklist that can remind us of important considerations in all of the 5 “A” areas.

PICOTS in Forming Key Clinical Questions and Searching

PICOTS is a useful framework for constructing key questions, but should be applied thoughtfully, because at times all PICOTS elements are not needed to construct a useful clinical question. For example, if I am interested in the evidence regarding prevention of venous thromboembolism in hip replacement surgery, I would want to include the population and study design and perhaps key outcomes, but I would not want to limit the question to any specific interventions in case there are some useful interventions of which I am not aware. So the question might be, “What is the evidence that thromboembolism or deep vein thrombosis (DVT) prophylaxis with various agents reduces mortality and clinically significant morbidity in hip replacement surgery?” In this case, I was somewhat specific about P (the patient population—which frequently is the condition of interest—in this case, patients undergoing  hip replacement surgery), less specific about O (mortality and morbidities) and not specific about I and C.

I could be even more specific about P if I specified patients at average risk for VTE or only patients at increased risk. If I were interested in the evidence about the effect of glycemic control on important outcomes in type II diabetes, I might pose the question as, “What is the effect of tight glycemic control on various outcomes,” and type in the terms “type 2 diabetes” AND “tight glycemic control” which would not limit the search to studies reporting outcomes of which I was unaware.

Learners are frequently taught to use PICO when developing search strategies. (When actually conducting a search, we use “condition” and not “population” because the condition is more likely to activate the MeSH headings in PubMed which produces a search with key synonyms.) As illustrated above, the PICO elements chosen for the search should frequently be limited to P (the patient population or condition) and I so as to capture all outcomes that have been studied. Therefore, it is important to remember that many of your searches are best done with using only one or two elements and using SD limits such as for clinical trials in order to increase the sensitivity of your search.

PICOTS in Assessing Studies for Validity and Synthesizing Evidence

When critically appraising studies for reliability or synthesizing evidence from multiple studies, PICOTS reminds us of the areas where heterogeneity is likely to be found. PICOTS is also useful in comparing the relevance of the evidence to our population of interest (external validity) and in creating decision support for various target groups.

PICOTS in Documenting Work

Transparency can be made easier by using PICOTS when documenting our work. You will notice that many tables found in systematic reviews and meta-analyses include PICOTS elements.

References

1. Modified by Delfini Group, LLC (www.delfini.org) from Leung GM. Evidence-based practice revisited. Asia Pac J Public Health. 2001;13(2):116-21. Review. PubMed PMID: 12597509.

2. Richardson WS, Wilson MC, Nishikawa J, Hayward RS. The well-built clinical question: a key to evidence-based decisions. ACP J Club. 1995;123:A12–3.

3. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(12)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. April 2012. Chapters available at: www.effectivehealthcare.ahrq.gov.

 

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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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Divulging Information to Patients With Poor Prognoses

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Divulging Information to Patients With Poor Prognoses

We have seen several instances where our colleagues’ families have been given very little prognostic information by their physicians in situations where important decisions involving benefits versus harms, quality of life and other end of life decisions must be made. In both cases when a clinician in the family presented the evidence and prognostic information, decisions were altered.

We were happy to see a review of this topic by Mack and Smith in a recent issue of the BMJ.[1] In a nutshell the authors point out that—

  • Evidence consistently shows that healthcare professionals are hesitant to divulge prognostic information due to several underlying misconceptions. Examples of misconceptions—
    • Prognostic information will make patients depressed
    • It will take away hope
    • We can’t be sure of the patient’s prognosis anyway
    • Discussions about prognosis are uncomfortable
  • Many patients are denied discussion about code status, advance medical directives, or even hospice until there are no more treatments to give  and little time left for the patient
  • Many patients lose important  time with their families and and spend more time in the hospital and in intensive care units than would be if prognostic information had been provided and different decisions had been made.

Patients and families want prognostic information which is required to make decisions that are right for them. This together with the lack of evidence that discussing prognosis causes depression, shortens life, or takes away hope and the huge problem of unnecessary interventions at the end of life creates a strong argument for honest communication about poor prognoses.

Reference

1. Mack JW, Smith TJ. Reasons why physicians do not have discussions about poor prognosis, why it matters, and what can be improved. J Clin Oncol. 2012 Aug 1;30(22):2715-7. Epub 2012 Jul 2. PubMed PMID: 22753911.

 

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Institute of Medicine CEO Checklist for High-Value Healthcare

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Institute of Medicine CEO Checklist for High-Value Healthcare

In June, 2012 the Institute of Medicine (IOM) published a checklist for healthcare CEOs as a way of encouraging further efforts towards achieving a simultaneous reduction in costs and elimination of waste.[1] EBMers will find the case studies of great interest. Many of the success stories contain two key ingredients—reliable information to improve decision-making and successful implementation.  The full report is available at—
http://www.iom.edu/Global/Perspectives/2012/CEOChecklist.aspx.

Foundational Elements

1. Governance priority—visible and determined leadership by CEO and board

  • Culture of continuous improvement—commitment to ongoing, real-time learning
  • Infrastructure Fundamentals

2. Information technology (IT) best practices—automated, reliable information to and from the point of care

  • Evidence protocols—effective, efficient, and consistent care
  • Resource utilization—optimized use of personnel, physical space, and other resources

3. Care Delivery Priorities

  • Integrated care—right care, right setting, right providers, right teamwork
  • Shared decision making—patient-clinician collaboration on care plans
  • Targeted services—tailored community and clinic interventions for resource-intensive patients

4. Reliability and Feedback

  • Embedded safeguards—supports and prompts to reduce injury and infection
  • Internal transparency—visible progress in performance, outcomes, and costs

References

1. Cosgrove D, Fisher M, Gabow P, et al. A CEO Checklist for High-Value Health Care. Discussion paper. Washington, DC: Institute of Medicine; 2012. http://www.iom.edu/Global/Perspectives/2012/CEOChecklist.aspx (accessed 08/13/2012).

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