A Call to Action on Breast Cancer: How Management Science Can Improve Performance Outcomes (October 23, 2013)

Summary – To address the increasing incidence of breast cancer, we all must rally around a realistic objective such as reducing by 1,000,000 women the projected levels of breast cancer by the year 2023 and, during the same time period, increasing the 10-year survival rates of those afflicted to 95%. Once these objectives are set, detailed plans should be put in place for each type of breast cancer including plans for education, prevention, detection, research, regulation, benchmarks, reporting, allocation of resources and recognition programs.


Introduction

Breast cancer isn’t a pink issue, or even a women’s issue, and increased awareness is not enough to achieve sustained improvements. Rather, we all need to rally around a challenging yet realistic set of objectives – and a plan to achieve those objectives.

An effective place to start would be a concerted call for a 1,000,000 reduction in the number of women who otherwise would have experienced breast cancer by the year 2023, and an improvement in the 10-year survival rate to 95% of those afflicted. After setting the bar at this level, current health care resources should be aligned to achieve these objectives, as described herein.

A Case Study

Anecdotal evidence can sometimes have important implications. My introduction to the treatment of breast cancer was through a friend, whose mother and aunt had died of breast cancer and ovarian cancer, respectively. Out of fear, she chose not to have a genetic test. Instead, relying on the promise of early detection, she had annual mammograms from age 35 as advised by her gynecologist.

At the age of 49, a new gynecologist sent her to a breast specialist, who suggested an MRI despite the absence of any symptoms. The MRI revealed a cancerous tumor and soon thereafter she was confirmed as having a BRCA1 mutation.

The patient followed her physician’s advice and opted for aggressive treatment, undergoing double mastectomy, oophorectomy, radiation treatment and chemotherapy. Chemotherapy consisted of eight cycles of Adriamycin, Cytoxan and Taxol (ACT), as advised by her oncologist given her categorization as a “triple negative” patient.

Despite a Stage I diagnosis and the aggressive treatment, the cancer metastasized to her lung, and she underwent lung tumor excision. But the cancer appeared in the lung again, this time near to the heart where surgical removal was deemed to be too risky. Given her condition and the state of approved treatments, she effectively was given a death sentence by two leading breast cancer physicians. Nonetheless, she was encouraged to go into a clinical trial.

By the time she was able to identify and get into a PARP inhibitor and carboplatin Phase I trial at the National Institute of Health, her tumor had grown to 5 cm. Nevertheless, within a few months, the tumor had shrunk to less than 1 cm and a year later, there was no longer any evidence of cancer.

While this trial outcome may come as a surprise to most, it is consistent with both theory and clinical research going back more than five years. Sadly, women are not provided an opportunity to pursue this approach with their oncologists. Rather, the medical guidelines call for a regime of ACT chemotherapy. However, upon closer examination, ACT chemotherapy has minimal empirical support for the subcategory of breast cancer patients with the BRCA1 mutation.

The question we need to ask is whether this case represents an isolated instance or is it part of a larger pattern of practices that leave breast cancer victims underserved.

Key Facts About Breast Cancer

About 1 in 8 women will develop breast cancer in their lifetimes. [1] There are about 2.8 million women with a history of breast cancer in the United States. [2] Each year, approximately 40,000 victims will lose their battle [3], but they are replaced with another 230,000 newly diagnosed patients. [4]

The current five-year survival rate for women with breast cancer is 86%. The current ten-year survival rate is 76%. These rates include women at all stages or levels of severity of breast cancer. [5]

A woman with cancer that has not metastasized – that is, the cancer has not moved to the lymph system or other parts of the body – has a five-year survival rate of 96%. Women whose breast cancer has metastasized to other parts of the body have a five-year survival rate of about 20%. [6]

From 1976 and 1997, there was an improvement in the five-year breast cancer survival rate from 75% to 86%, largely the result of improvements in the detection of breast cancer at early stages although advances in the treatment of breast cancer had also contributed. [7]

While we are forty years into the war on cancer, basic facts relating to the cost of treating breast cancer are still not well-documented. For example, one can find estimates for lifetime costs that range from $20,000 to upwards of more than $100,000. [8] Chemotherapy typically adds about $20K to $30K to the overall cost. [9] The direct costs to society from treatment alone amount to over $17 billion of dollars per year. [10]

Moreover, the cost of many new drugs is steep, exceeding $100,000 per year. [11] With a typical co-pay of 20%, this expense is prohibitive for many women. Yet increased costs for health care do not necessarily lead to improved patient outcomes. [12]

Genetic predisposition to breast cancer is a factor in approximately 5% of its victims, with certain mutations carrying a life-time expectation of up to an 80% chance of getting breast cancer. [13] However, according to a study by researchers at the University of Pennsylvania, only about half of newly diagnosed breast cancer patients who were at high risk of carrying a BRCA1 or BRCA2 mutation, based on age, diagnosis and family history of breast or ovarian cancer, reported that their doctors urged them to be tested for the defective genes. [14]

Once diagnosed with breast cancer, more than 40% of the victims will progress to metastatic cancer. [15]

The cost to treat metastatic cancer represents more than half of the lifetime costs attributable to breast cancer, with cumulative costs over $100,000 for patients receiving chemotherapy. [16]

Typical Treatments for Breast Cancer

Breast cancer is a heterogeneous disease that is managed with a range of treatment modalities. Treatments must be approved by the FDA before they can be prescribed by a practitioner.

Approximately two-thirds of breast cancer tumors are hormone-receptor positive (i.e., express estrogen and/or progesterone receptors) [17] , and endocrine therapy is advised for these patients.

Between 20% and 30% of patients with breast cancer have tumors that express HER-2/neu (HER-2), a tyrosine kinase growth factor receptor located on cell membranes. [18] Targeted therapy with the monoclonal antibody, trastuzumab (Herceptin®), or the dual tyrosine kinase inhibitor, lapatinib (Tykerb®), in combination with hormonal and/or conventional chemotherapy, improves response rates in these patients. [19]

Chemotherapy is the main treatment option for patients with tumors that do not express hormone receptors and those with HER-2 negative tumors. [20] It also is the primary treatment modality for patients with rapidly progressive visceral disease and those with hormone-receptor positive tumors that do not respond or have become resistant to endocrine therapy. [21]

Despite its discovery almost 20 years ago, the FDA does not recognize patients with BRCA mutations as a separate category for testing in clinical trials. [22] As such, drugs are not necessarily being tested against the correct patient target, which is a contributing factor to the lack of an approved approach specifically for this type of cancer (as opposed to the broader category of triple negative patients).

Once a woman’s initial tumor has metastasized in any of the categories of breast cancer, there are no known cures. Patients are often encouraged to participate in a clinical trial. However, there is no accredited or reliable assistance to sort through and analyze the best approach for that particular patient (although a list of trials along with descriptions is available).

Further, the support that women with breast cancer receive is inconsistent at best. An excellent model is provided by Life with Cancer in Fairfax, Virginia, which provides patients with a program that includes education, support, and the information needed to live with a cancer. The staff is assisted by a team of more than 90 volunteers. [23]

Research

Research into the causes, prevention, and treatment of breast cancer is conducted in many medical centers throughout the world.

While there is always a desire for more research resources, a substantial amount of research has been conducted or is underway. For example, the ClinicalTrial.gov website lists over 5000 trials if one searches its database with the keywords “breast cancer”. [24] Likewise, there are over 1000 studies referenced on Google Scholar relating to the BCRA1 mutation alone. [25]

However, there is no coordinated game plan across research projects nor is there an effort to ensure follow-through on promising research. For example, researchers found that platinum-based drugs such as Cisplatin have a profound effect upon patients with the BRCA1 mutation over five years ago. [26]

Additionally, in 2009, researchers published statistics showing the pathological complete response for Cisplatin at four times higher than the level of the next best regimen, including that for Anthracyclines such as Adriamycin, Cyclophosphamides such as Cytoxan, and Taxanes such as Taxol (ACT). [27]

Despite these findings, ACT remains the chemotherapy of choice for BRCA1 patients because these patients are treated by the FDA as part of the category of triple negative breast cancer patients.

Lastly, the federal and state governments have discretionary funds for research which can be targeted to certain approaches that the private sector is not pursuing due to cost or other factors. For example, the National Cancer Institute allocates about 13% of its $5 billion annual research budget to breast cancer. [28] Additionally, the Department of Defense has an annual research budget exceeding $100 million which it allocates to trials relating to vaccines designed to prevent breast cancer or its recurrence. [29]

Relevant Trends

Several major transitions are underway in the health care industry that will shape the quality and cost of breast cancer care in the future, including: 1) the movement toward the deployment and utilization of digital technology [30] ; and 2) the opportunity for increasingly personalized medicine given advances in genomics and proteomics, completion of the human genome map, and development of “targeted” diagnostics and therapeutics. [31]

Even within the four major types of breast cancer, individual tumors appear to be driven by their own sets of genetic changes, implying that a wide variety of drugs will most likely need to be developed to tailor medicines to individual tumors. [32]

Although digitalization and the advent of personalized medicine are expected to improve health care, the current drug approval process is not set up to be able to drill down to small niches on an economically viable basis to test a multitude of candidate treatments.

Assessment of the Current Situation

Any assessment of breast cancer care will vary depending upon the lens from which it is viewed. From a management perspective, we can observe that:

1) There are no recognized champions or leaders in industry or the government who are laying out a strategic vision for an overall approach to breast cancer. Nor is there a roadmap for each of the various types of breast cancer. That is, no one “owns” the relevant problems facing women and society as a whole.

2) The resources devoted to breast cancer generally are not coordinated nor prioritized along the path of the strategic vision (or any specific path). And these resources are substantial. Approximately $6 billion a year is committed to breast cancer research and awareness campaigns, including contributions to non-profit associations.

3) Faculty at medical centers and research institutions around the country are expected to publish in scholarly journals, not to participate in industry-wide joint planning or development on a particular approach or objective.

4) There are no recurring report cards for the costs of care, particularly categorized by stage of cancer, age of patient, etc.

5) There are no recurring report cards for the performance outcomes of treatments, including how performance relates to the cost of treatment.

6) There are no recognized benchmarks or objectives for consumer education, prevention, treatment, care or the cost of treating breast cancer.

7) There is no clear objective or objectives for management of the disease whether the statistic relates to the overall incidence of breast cancer, the 5 or 10 year survival rates, the percentage of primary cancers that progresses to metastasis, the number of women currently undergoing treatment, or the mortality rate of all victims or by category.

Overall, the number of women with a history of breast cancer will increase from 2.8 million today to approximately 4 million in 2023, given current trends. From a mathematical perspective, the only way to effectuate a meaningful increase in the overall survival rates of this group of people would be for the percentage of women progressing to metastatic cancer to decrease or the survival rate of metastatic breast cancer patients to increase, or both. But relatively little focus is being given to metastatic breast cancer at the present time.

One would also observe that the government applies the same practices and procedures across a range of very disparate circumstances. For example, the FDA procedures for clinical trials are identical whether the compounds being tested are for metastatic or primary cancers despite the entirely different trial design objectives. Similarly, safety concerns are weighted as heavily for metastatic cancer patients in advanced age as for the participants in all other clinical trials.

More troubling than inflexible trial procedures, the process for approving drugs at the FDA is fraught with long delays and the imposition of excessive costs. [33] And some would argue that the process is subject to manipulation by the industry participants in a manner that does not serve the public interest. [34]

The FDA would say that its procedures ensure the safety of the drug whether it is introduced into trials or for commercial usage. And it takes flack when safety isn’t protected in trials. [35] But the FDA rules do not conform to conventional risk/reward analysis. For example, it does not consider the cost and anguish of delay that its procedures impose on existing patients. Nor does it consider the astronomical costs that its procedures impose on new drugs. Nor are the debilitating side effects of chemotherapy such as ACT weighed against the relatively light side effects of alternative treatments.

Finally, some of the federal government’s current approaches to breast cancer are based upon historical practices and outdated knowledge. For example, the vast majority of deaths and costs for cancer are attributable to metastatic cancer, yet only 8% of the National Cancer Institute’s research budget is targeted to metastatic cancer. And the FDA’s procedures, in effect, are even more onerous for metastatic cancer than for primary cancers, leaving many new promising compounds sitting in the lab without proceeding to clinical trials. [36] Yet promising research is now finally underway for metastatic breast cancer and new approaches could bring much progress if more tailored regulatory procedures are employed. [37]

In a nutshell, the FDA looks at its trial procedures horizontally and applies similar regulation across all categories. That is a flawed approach, particularly for breast cancer given its modalities.

Recommended Changes to Meet the Challenge

Management science tells us that when performance improvement is desired, leaders must focus on the relevant item(s) that needs improvement, develop a strategic plan to address these items, organize the resources necessary to execute the plan, track progress against the plan’s objectives and make adjustments to the plan when needed. [38]

Additionally, given that various organizations address breast cancer research and care, the principles of matrix management must also be incorporated into the process such as employing extensive communications and collaborative techniques. [39]

In particular, the following nine changes would significantly increase the productivity of the resources dedicated to breast cancer and significantly improve the patient outcomes resulting from the disease:

1) Reordering of the roles, responsibilities and organizational structure of the existing federal government resources.

a. The federal government should reorganize its existing resources into virtual pyramid structures organized around the types of breast cancer (as well as a catch-all group for identifying new categories of breast cancer). Cancer resulting from BRCA1 mutations should be recognized as a separate category immediately, along with the four other long-established categories.

b. The National Cancer Institute should appoint a qualified individual to the top of each virtual pyramid as the Executive Director for “managing” that type of cancer (as described below).

c. A Board of Advisors should be constituted for each major type of breast cancer consisting of the Executive Director as Chair, a member from the FDA, a member of the National Comprehensive Cancer Network (NCCN), a member of the lay public, a member from the large pharmaceutical companies, a member from the biotech industry, a member from the insurance industry, and a member from a non-profit association. These assignments should rotate every two years.

d. Each Executive Director (and that person’s staff) would be responsible for developing the strategic plan for his/her category of breast cancer. The Board advisors could issue dissenting or concurring opinions on the guidelines and plans issued by the Executive Director. The strategic plans would have to be approved by the NCI Director.

e. Each Executive Director would also be responsible for identifying benchmarks and budgetary requirements for the education, detection, prevention, research, regulation and care of his/her assigned category of breast cancer along with benchmarks and reporting (as described below). While the FDA would remain a separate agency, its objectives for breast cancer-related therapies would be set by the NCI including the procedures affecting the cost burdens and timeliness of clinical trials relating to each type of breast cancer.

2) Education. Each Executive Director should assess the need for public awareness and the associated communications budget for his/her assigned type of cancer. For example, this need would be different for families who have an incidence(s) of breast cancer.

3) Detection. Each Executive Director should outline the imperative for detection and the plan to achieve early detection. This could vary for the different types of breast cancer. For example, for women with the BRCA1 mutation, regular mammograms at a relatively young age have been shown to increase the incidence of cancer. [40]

4) Prevention. Each Executive Director should assess the ability to prevent his/her assigned type of cancer and what actions should be taken and at what cost. For example, the requirements and expectations relating to Department of Defense’s research into vaccines should be documented and included in the strategic plan.

5) Research. Each Executive Director should select and use a modern electronic collaborative tool to codify and track all basic and applied research relating to his/her assigned type of cancer. This tool should be used to identify promising tracks that are either not being sufficiently pursued or that are underfunded. The repository of information affecting each type of cancer would be categorized and made available to the public. The capability for researchers to collaborate online should be provided. The NCI budget should have an objective of filling in funds for promising research where an outreach to private funding sources does not produce the desired result. Progress should be reported on a regular basis through electronic conferences. Finally, the NCI should encourage an industry research organization to offer a new service that provides an analysis of the clinical trials relevant to a victim’s particular condition.

6) Regulations. Each Executive Director would review the FDA generic regulations for clinical trials and devise adjustments for the trial procedures for his/her assigned type of cancer to be approved by the NCI Director. For example, the FDA’s stringent requirements for safety in Phase I trials may not be appropriate for trials testing the efficacy of treatments for metastatic breast cancer. Similarly, trials for patients with personalized defects should be recalibrated to fit the situation.

7) Benchmarks and Reporting. Each Executive Director should establish the current benchmarks and future objectives by date to be achieved for his/her assigned type of cancer. These targets would include benchmarks for improvements in the incidence of the disease, the percentage and average length of time to progression to metastatic cancer, the longevity, mortality rates, and the costs to treat the disease in each phase.

8) Recognition. The NCI should adopt a recognition program to provide annual awards to the medical centers and research institutes that are most helpful in the joint planning and coordinated research efforts of the national breast cancer priorities by type of cancer.

9) Allocation of Resources. Overall, the NCI Director should allocate resources across the various categories of breast cancer to meet the overall objectives. Reports on progress of the key statistics should be released on an annual basis. Corrective actions should be implemented if and when any interim objectives are missed.

Selecting the Proper Criteria for Setting the Overall Objective

Breast cancer negatively impacts women and society in a number of ways. The initial incidence of breast cancer is one such way. The progression of the disease to higher stages compounds the cost and the side effects of treatment. And the mortality rates give an indication of the effectiveness of treatments over time, or lack thereof.

In turn, selecting one of these parameters as an objective will influence the focus of research going forward. For example, if the goal were to decrease the incidence of cancer by 2023, research would focus more heavily on prevention possibly including more research on vaccines.

If survival rates of women with any type of breast cancer were the primary objective, early detection might attract more focus and resources.

If the cost to society of treating breast cancer were the primary issue, methods to prevent cancers from progressing to metastasis might be the focus of attention.

To maximize women’s health and to minimize the cost to society, the objectives should be to decrease the incidence level of breast cancer and to increase the 10-year survival rates of those afflicted by all types of the disease.

Conclusion and Recommendations

The traditional methods of addressing breast cancer often have been ineffectual given their hit or miss approach. The existing trends imply that there will be 4 million women alive by 2023 who will have experienced breast cancer. And the costs to treat breast cancer in 2023 will have grown to $25 billion per year.

Of course, we should not be so naïve as to think the large pharmaceutical companies will lead of us out of this cruel trajectory given that they benefit from the development and sale of expensive drugs. Similarly, because the national breast cancer organizations are dependent on pharmaceutical companies for funds, they also are not likely to support effective change.

Rather as a first step out of this conundrum, we all must rally around a call to action to reduce the incidence of breast cancer by 1,000,000 women from projected levels in the year 2023 and, during the same time period, to increase the 10-year survival rates of those afflicted to 95%.

Once these objectives are set, plans can be put in place to effectuate the desired outcome as outlined herein.

Pink ribbons are fine, but breast cancer awareness ornaments would be much more effective with identical objectives on each one of them – and a commitment and plan to meet those objectives.

[1] SEER Stat Fact Sheets: Breast. National Cancer institute, National Institutes of Health. http://seer.cancer.gov/statfacts/html/breast.html

[2] Breast Cancer Risk in American Women. National Cancer Institute, National Institutes of Health. http://www.cancer.gov/cancertopics/factsheet/detection/probability-breast-cancer

[3] U.S. Breast Cancer Statistics. BreastCancer.Org. http://www.breastcancer.org/symptoms/understand_bc/statistics

[4] Ibid.

[5] Warren, B. (2002) Diet and Lifestyle and Survival from Breast Cancer. Cornell University, College of Veterinary Medicine. http://envirocancer.cornell.edu/factsheet/diet/fs44.survival.cfm

[6] Ibid.

[7] Ibid.

[8] Campbell, J.D. & Ramsey, S.D. (2009) The costs of treating breast cancer in the US: a synthesis of published evidence. Pharmacoeconomics 27, 199-209.

[9] Ibid.

[10] The Cost of Cancer. National Cancer Institute, National Institutes of Health. http://www.cancer.gov/aboutnci/servingpeople/cancer-statistics/costofcancer

[11] In 2012, 11 out of the 12 new cancer drugs approved by the FDA were priced at well over $100,000 a year. How Drug Companies Price What Your Life is Worth.

http://www.cancerdefeated.com/how-drug-companies-price-what-your-life-is-worth/1266/

[12] For example, researchers at the Yale School of Medicine found that… “there was no relation between screening expenditures and the detection of advanced cancers.” JAMA Internal Medicine, Published Online Jan. 7, 2013.

[13] High-Penetrance Breast and/or Ovarian Cancer Susceptibility Genes. National Cancer Institute, National Institues of Health. http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional/Page2 – Section_2264

[14] Nearly Half of Breast Cancer Patients at High Risk of Carrying BRCA Mutations Do Not Receive Genetic Testing Recommendations from Physicians. ScienceDaily, LLC. http://www.sciencedaily.com/releases/2013/04/130408133016.htm

[15] New Test May Predict Breast Cancer Metastasis. http://www.sciencedaily.com/releases/2009/03/090327152403.htm

[16] Vera-Llonch, M., Weycker, D., Glass, A., Gao, S., Borker, R., Qin, A. & Oster, G. (2011) Healthcare costs in women with metastatic breast cancer receiving chemotherapy as their principal treatment modality. BMC Cancer 11, 250.

[17] Glass, A.G., Lacey, J.V., Jr., Carreon, J.D. & Hoover, R.N. (2007) Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 99, 1152-1161.

[18] Rastelli, F. & Crispino, S. (2008) Factors predictive of response to hormone therapy in breast cancer. Tumori 94, 370-383.

[19] Higgins, M.J. & Wolff, A.C. (2008) Therapeutic options in the management of metastatic breast cancer. Oncology (Williston Park) 22, 614-623.

[20] Isakoff, S.J. (2010) Triple-negative breast cancer: role of specific chemotherapy agents. Cancer journal 16, 53-61.

[21] Conlin, A.K. & Seidman, A.D. (2008) Beyond cytotoxic chemotherapy for the first-line treatment of HER2-negative, hormone-insensitive metastatic breast cancer: current status and future opportunities. Clin Breast Cancer 8, 215-223.

[22] Questions About the BRCA1 and BRCA2 Gene Study and Breast Cancer. National Human Genome Research Institute, National Institutes of Health. http://www.genome.gov/10000940

[23] Life with Cancer. http://www.lifewithcancer.org/

[24] 5262 references for: “breast cancer”. National Library of Medicine and National Institutes of Health. http://clinicaltrials.gov/ct2/results?term=%22breast+cancer%22&Search=Search

[25] Google Scholar. http://scholar.google.com/scholar?hl=en&q=brca1&btnG=Submit&as_sdt=1%2C49&as_sdtp=

[26] Byrski, T., Gronwald, J., Huzarski, T., Grzybowska, E., Budryk, M., Stawicka, M., Mierzwa, T., Szwiec, M., Wisniowski, R., Siolek, M., Narod, S.A., Lubinski, J. & Polish Hereditary Breast Cancer, C. (2008) Response to neo-adjuvant chemotherapy in women with BRCA1-positive breast cancers. Breast Cancer Res Treat 108, 289-296.

[27] Byrski, T., Gronwald, J., Huzarski, T., Grzybowska, E., Budryk, M., Stawicka, M., Mierzwa, T., Szwiec, M., Wisniowski, R., Siolek, M., Dent, R., Lubinski, J. & Narod, S. (2010) Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J Clin Oncol 28, 375-379.

[28] Cancer Research Funding. National Cancer Institute, National Institutes of Health. http://www.cancer.gov/cancertopics/factsheet/NCI/research-funding

[29] Breast Cancer Research Program Idea Award, Funding Opportunity Number: W81XWH-12-BCRP-IDEA. U.S. Army, Department of Defense. http://cdmrp.army.mil/funding/pa/12bcrpidea_pa.pdf.

[30] Top Three Healthcare Technology Trends: Big, Personal, Social. Accenture, Incorporated.

http://www.accenture.com/us-en/Pages/insight-top-three-healthcare-technology-trends.aspx

[31] The new science of personalized medicine. PricewaterhouseCoopers International Limited. http://pwchealth.com/cgi-local/hregister.cgi/reg/personalized-medicine.pdf

[32] Study Divides Breast Cancer Into Four Distinct Types. The New York Times Company. http://www.nytimes.com/2012/09/24/health/study-finds-variations-of-breast-cancer.html?_r=0

[33] Dyax, United States Securities and Exchange Commission, Form 10-Q. Dyax Corporation. http://investor.dyax.com/secfiling.cfm?filingID=1104659-09-30425&CIK=907562 “Government regulation of drug development is costly, time consuming and fraught with uncertainty, and our products in development cannot be sold if we do not gain regulatory approval”.

[34] Downing, N.S., Ross, J.S. & Krumholz, H.M. (2012) Generic competition in a flawed system: pill them, bill them-reply. Arch Intern Med 172, 1522-1523.

[35] Madden, B.J. The Problem with the FDA Drug Approval Process. The Heartland Institute. http://news.heartland.org/newspaper-article/2007/06/01/problem-fda-drug-approval-process. See also: Friedman, M. & Friedman, R. Free to Choose, (Harcourt Brace Jovanovich, New York, 1979).

[36] Steeg, P.S. (2012) Perspective: The right trials. Nature 485, S58-59.

[37] Saxe, C. (2013) Unlocking the Mysteries of Metastasis. American Cancer Society. http://www.cancer.org/cancer/news/expertvoices/post/2013/01/23/unlocking-the-mysteries-of-metastasis.aspx.

[38] Peter Drucker, five basic principles of management. Summary available at: http://www.blacksacademy.net/content/3648.html

[39] Dancer, J. & Raine, J. (2010) The idea of the ‘Matrix Organisation’ has caught on in recent years, but what is it exactly, and what are the essential skills and principles required to operate successfully within one? Pharmafile.com, Samedan Ltd. http://www.pharmafile.com/news/making-matrix-work

[40] Norris, J. (2009) Mammograms Bad for Young Women with Breast Cancer Genes? University of California, San Francisco. http://www.ucsf.edu/news/2009/03/8163/mammograms-bad-young-women-breast-cancer-genes