Avastin and the Meaning of Evidence

September 9, 2011

By Antonella Surbone MD PhD and Jerome Lowenstein MD

The recent hearings at the Food and Drug Administration regarding the revocation of approval for the use of Avastin in the treatment of breast cancer [1,2,3] bring into sharp focus several very important issues in medicine today.

The pharmaceutical industry, armed with powerful new tools for deciphering the signaling mechanisms and mutations responsible for the development and progression of malignancies, has developed new therapies for treating cancer and other malignancies. The cost of development of each new drug and the cost of carrying out controlled trials to evaluate the efficacy and safety of each new agent is very great, usually hundreds of millions of dollars. Once a drug is approved, the pharmaceutical industry makes tremendous profit, which in the case of Avastin has been estimated to be about 6.8 billion dollars in 2010 from its sale for the treatment of breast cancer alone.

There is pressure from oncologists and patients to move new treatments “through the pipeline”. Avastin received such “accelerated approval” for the treatment of breast cancer in 2008, after studies showed that bevacizumab added to paclitaxel yielded a 5.5 month increase in median progression-free survival over paclitaxel alone.[4,5] Subsequent studies have not confirmed the same effectiveness of Avastin, showing more limited progression-free survival benefit of only 1.2 to 2.9 months. [6-10] Furthermore, several serious side effects have been reported, leading to the present hearing, before the FDA, to reevaluate the use of Avastin in breast cancer.

The FDA’s role in approving/disapproving new treatment agents through intense scrutiny and ‘tough decisions’ is the best safeguard for sick and vulnerable patients against the risk of being treated with ineffective or dangerous drugs, though some decisions may be questioned and, eventually, reconsidered by the Agency. The recent Avastin hearing has pitted the drug’s manufacturer, Genentech, and a number of women who feel they have benefited from Avastin, against a panel of experts who have decided that the drug should be disapproved for this indication. The decision of the panel will be submitted to the FDA commissioner, Dr. Margaret Hamburg. This final FDA decision will be an important consideration in the decision whether Medicare, and major health plans in the US will cover the cost of treatment of breast cancer with Avastin. Medicare has already announced that it will continue to reimburse for the use of Avastin (11), but this decision is probably susceptible to “revisions and revisions which a minute will reverse”.

This very current issue is, we submit, the tip of a large iceberg. The decision regarding Avastin will hinge on the analysis of several large, randomized treatment trial which form the cornerstone of “evidence-based medicine”, a new discipline heralded since 1992 as de-emphasizing “intuition, unsystematic clinical experience and pathophysiologic rationale“(12).  Randomized double blind clinical trials (RCTs) which have greatly contributed to progress in oncology, are seen as the “gold standard” for clinical decision-making

Randomization, a keystone in the holy grail of evidence based-medicine, assures that treatment groups are closely matched for all identifiable important variables, however, within each treatment group there is always considerable patient-to-patient variability. The finding that the frequency of beneficial or desired effects does not differ between or among treatments in a RCT does not necessarily mean that the patients who respond demonstrate a “non-specific” or placebo effect. In any study, there may be a subset of patients who are “responders” because they carry a specific gene mutation, are exposed to specific environmental influences, or have differing underlying causes of their identifying disease. If such a subset makes up only a small proportion of the test group, the overall findings of a randomized trial might be judged as “not significantly different”, when in fact, some participants have truly responded. A simple example: if a trial of vitamin B12 in the treatment of anemia had been undertaken before the relatively uncommon cause, pernicious anemia, was recognized, it might well be that this highly effective, specific treatment would have been disapproved by the FDA. Today, would Gleevac have been approved if we didn’t know about the specific tyrosine kinase mutations that identify the subsets of patients who benefit from this specific therapy?A reasonable argument can be made that some women who “respond” to Avastin do so because they have a genetic polymorphism that makes them susceptible. This appears to be the case for patients with the BRAF mutation that makes metastatic melanoma more responsive to a kinase inhibitor. This is an important issue that will need to be pursued with many new drugs, including chemotherapy and others. It is an extension of what we already practice in avoiding some drugs in patients who are G6PD deficient or patients sensitive to CYP 450 inhibition. Simply randomizing patients with a given disease, or a given stage of a disease is no longer an adequate way to adduce evidence.

However, we see additional scientific and ethical problems related to the application of “evidence-based medicine” to the determination of approval or disapproval of Avastin for the treatment of advanced breast cancer. First, it is clear that the overall conclusions regarding efficacy (or toxicity) seen in a treatment trial, can never be applied to each single individual in that trial, as subsets of patients may have responded even in a “negative” trial. Subset analysis, however,is of little value unless a subset of responders or non-responders can be identified with certainty.Beyond this, there are several ethical issues related to potential differences among patient subsets. If some patients are recognized as “true responders”, wouldn’t the withdrawal of approval, and the consequent likely cessation of coverage of the cost of the treatment, conflict with the ethical principles of beneficence and of “do no harm”(to those who have responded and to future patients who may also be responders)? As many have remarked, the use of a drug such as Avastin in breast cancer would end up being limited to those who can afford to pay more than $ 80,000 yearly: hardly an ethical solution.Should we not therefore invest more research and funds in finding out , on a scientific basis, why some patients responded?  For example, Gelmon and colleagues just reported PARP inhibitors’ activity also in non-BRCA ovarian cancer – a new finding that might benefit all women with ovarian cancer [13, 14] Hua and colleagues have reported an association between VEGF polymorphism and survival in breast cancer, which might be explored in relation to treatment responses.[15]

Surely, it is important to place restrictions on the prescription of drugs (expensive or not) of doubtful efficacy, while avoiding the scientific and ethical issues that such restrictions may raise. Finding appropriate and just solutions is not easy, yet we wish to offer two possible strategies for consideration by all involved parties, based on all the evidence derived from a given trial and not limited to its global results. At the conclusion of a clinical trial, judged to show overall evidence of “no efficacy”of a drug under investigation, it might be decided that those patients (now termed “patients” rather than “participants”) who meet scientifically sound, pre-determined criteria defining a beneficial effect be enrolled in a follow up study to examine the duration and magnitude of the “beneficial effect”. The duration of such follow up study might depend on the clinical response, and the drug would have to be provided free of charge by the pharmaceutical industry.  During this follow up phase, the drug might be classified as “conditionally approved”.  Patients currently being treated with Avastin, who are judged to have benefited, might be similarly enrolled in a “follow up study.” This solution would only apply to those cancer patients who have already proven to be responders in the trial. Since the reason for response to Avastin in some women on the trial is not yet known, it would be “on the safe side” to assume that there might be a specific genetic reason.

The second solution is, therefore, intense investigation of genetic and/or environmental factors that make some patients likely responders. Coupled together, these could be relatively simple steps toward a sound, more equitable, approach to all patients on RTCs.

Indeed, in the era of patient-centered personalized medicine, we need a reappraisal of the notion of “evidence” to include new objective data, based on genomic assessment and pharmacogenetics (16-19), as well as quality of life and psychosocial considerations [20]. Only by abandoning a narrow perspective of what constitutes “evidence”, we can consider and treat each patient in her/his uniqueness.  This is very much the way the best physicians cared for patients before the advent of “evidence-based medicine” i.e. a treatment was initiated, based on the physician’s knowledge and experience and continued or discontinued depending on the response of the patient.  Evaluating evidence is especially difficult in patients with advanced cancer (8), yet today the old approach can be supported by embracing a broader, holistic, notion of evidence. The value of our proposed solutions, viewed from the perspective of science and the ethical practice of medicine, might be substantial.

Dr. Antonella Surbone, is the Ethics Editor, Clinical correlations

Dr. Jerome Lowenstein is a Professor of Medicine, Division of Nephrology, NYU School of Medicine

References:

1. Pollack A. Cancer Survivors Appeal to FDA over Avastin . NY Times 6/28/2011

2. Pollack A. FDA Panel Rejects Use of Avastin in Breast Cancer. NY Times 6/29/2011.  http://prescriptions.blogs.nytimes.com/2011/06/29/f-d-a-panel-still-sees-no-benefit-of-avastin-for-breast-cancer/

3. Ratner M. FDA panel votes to pull Avastin in breast cancer, again. Nat Biotechnol 2011;29:676.

4. Carpenter  D, Kesselheim  AS, and Joffe  S.Reputation and Precedent in the Bevacizumab Decision. New Eng. J Med 365, e3, July 2011  http://www.ncbi.nlm.nih.gov/pubmed/21707383

5.Miles D, Chan A, Romieu Get al.Randomized, double-blind, placebo-controlled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer (MBC): AVADO. J ClinOncol 2008; 26(suppl):43s, abstr LBA1011

6. O’ Shaughnessy J, Miles D, Gray RJ et al. A meta-analysis of  overall survival data from three randomized trials of bevacizumab (BV) and first-line chemotherapy as treatment for patients with metastatic breast cancer (MBC). J ClinOncol 2010: 28 (Suppl 15s) abstract.  http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/1005

7. Miller K, Wang M, Gralow Jet al.Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med2007 ;357:2666–2676.

8.Robert NJ, Diéras V, Glaspy J et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer.J ClinOncol. 2011; 29:1252-60.

9. Ray R, Bhattacharya S, Bowden Cet al. Independent review of E2100: A phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J ClinOncol 2009; 27:49664972.

10.Ocaña A, Amir E, Vera F, Eisenhauer EA, Tannock IF. Addition of bevacizumab to chemotherapy for treatment of solid tumors: similar results but different conclusions. J ClinOncol 2011; 29:254-6.

11. Pollack A. Medicare Will Pay for Avastin in treating breast cancer NY Times 6/30/2011

12. Lowenstein J. “Shaky Evidence” in The Midnight Meal and other Essays about Doctors, Patients and Medicine, Yale University Press 1997, University of Michigan Press 2005  http://press.umich.edu/pdf/9780472030842-fm.pdf

13. Gelmon KA et al. Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: A phase II, a multicenter, open-label, nonrandomized study. Lancet Oncol 2011; 12: 852-861.

14 -Telli ML. PARP inhibitors in cancer: moving beyond BRCA. Lancet Oncol 2011; 12: 827-828.

15. Hua, L et al. Association of Genetic Polymorphisms in the VEGF Gene with Breast Cancer Survival Cancer Res 2005: 65:5015-5019

16. Jubb, A.M. and Harris, A.H. Biomarkers to predict the clinical efficacy of bevacizumab in cancer. Lancet Oncol2010; 11, 1172-83.  http://www.ncbi.nlm.nih.gov/pubmed/21126687

17. Ashley EA, Butte AJ, Wheeler MT et al. Clinical assessment incorporating a personal genome. Lancet 2010; 375:1525-1535.

18. Ormond KE, Wheeler MT, Hudgins L, et al. Challenges in the clinical application of whole- genome sequencing. Lancet 2010;375:1749-1751.

19. Samani NJ, Tomaszewski M, Shunkert H. The personal genomeandthe future of personalized medicine? Lancet 2010;375:1497-1498.

20. Surbone A, Baider L, Weitzman TS et al.on behalf of the MASCC Pychosocial Study Group Psychosocial Study Group at www.massc.org. Psychosocial care for patients and their families is integral to supportive care in cancer: MASCC position statement. Supp Care Cancer 2010;18:255-63.

2 Responses to Avastin and the Meaning of Evidence

  1. e mandell on September 12, 2011 at 1:44 pm

    Dear Dr. Surbone & Dr. Lowenstein:

    Having just read your article on the Clinical Correlations website please allow me to thank you for capturing and communicating so quintessentially the core spirit that should inform both the clinical hands on approach to patient care, as well as the conceptually nuanced schema when considering research to benefit patients. To constantly conceive of the patient as an individual in their unique human presentation with….. “specific gene mutation, are exposed to specific environmental influences, or have differing underlying causes of their identifying disease.”

    Yes, statistical methods are valuable and not to be discounted, but must always be placed in perspective as primarily referring to groups and secondarily and approximately to the individuals in those groups. Whatever general guidance statistical methods and models grant, we should not allow their power to blur our vision of the individual patient. In the article, with specific reference to the case of Avastin, you’ve captured that point poignantly. And furthermore, you’ve gone ahead with proposals to refine that insight in continuing rather than precluding patient centered research by focusing on those statistical outliers who very well may belong to a different subset, and may benefit from treatment. You’ve used your humanity to inform your science, and your science to inform your humanity.

    With this Avastin case in point, and the more wide ranging insightful discussion (i.e, Gleevac and pernicious anemia) which followed in its wake you could devise a teaching module for 3rd or 4th year students.

    Thank you both for taking the time making the effort for composing this Clinical Correlations editorial which I wish had an even wider audience.

    Sincerely,

    E Mandell (M.D.)

    I extracted some quotes below from the article which I felt were particularly telling.

    In any study, there may be a subset of patients who are “responders” because they carry a specific gene mutation, are exposed to specific environmental influences, or havediffering underlying causes of their identifying disease

    If such a subset makes up only a small proportion of the test group, the overall findings of a randomized trial might be judged as “not significantly different”, when in fact, some participants have truly responded. A simple example: if a trial of vitamin B12 in the treatment of anemia had been undertaken before the relatively uncommon cause, pernicious anemia, was recognized, it might well be that this highly effective, specific treatment would have been disapproved by the FDA. Today, would Gleevac have been approved if we didn’t know about the specific tyrosine kinasemutations that identify the subsets of patients who benefit from this specific therapy?

    It is an extension of what we already practice in avoiding some drugs in patients who are G6PD deficient or patients sensitive to CYP 450 inhibition. Simply randomizing patients with a given disease, or a given stage of a disease is no longer an adequate way to adduce evidence.

    First, it is clear that the overall conclusions regarding efficacy (or toxicity) seen in a treatment trial, can never be applied to each single individual in that trial, as subsets of patients may have responded even in a “negative” trial. Subset analysis, however,is of little value unless a subset of responders or non-responders can be identified with certainty

    Only by abandoning a narrow perspective of what constitutes “evidence”, we can consider and treat each patient in her/his uniqueness. This is very much the way the best physicians cared for patients before the advent of “evidence-based medicine”

  2. Antonella Surbone on September 13, 2011 at 2:01 am

    We deeply thank Dr. Mandell for his comments in appreciation of our piece.
    The issues at stake are very complex and the solutions difficult to be found and applied. Yet, there is only one correct approach, as Dr. Mandell eloquently says: humanity must inform our science and science must inform our humanity.

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