Keith Flaherty, MD, Associate Professor of Medicine, Harvard Medical School; Director of Developmental Therapeutics, Cancer Center, Massachusetts General Hospital.

Q: Under what circumstances and to what extent are you willing to take clinical actions on a cancer patient based primarily on preclinical data?
A: There are two scenarios that come to mind when thinking about reliance on preclinical data for treatment decision-making: (1) use of an agent that is an established treatment for a noncancer indication and (2) use of an established cancer therapy outside of the context(s) for which there is known clinical efficacy.
In the first scenario, I am essentially NEVER willing to accept a preclinical finding that suggests efficacy as a basis for prescribing use of such an agent. This perspective comes from a career focused on performing early phase clinical trials with agents that demonstrated promising in vitro and in vivo effects that failed to exert any discernible effect in cancer patients.
The explanations for these failures are numerous, but the most common explanations are inability to achieve the drug concentrations/exposures needed to match those used in preclinical experiments and lack of fidelity of the preclinical model systems for predicting outcomes in patients.
This second category remains a major challenge for many cancer therapeutics in that we simply do not have a repertoire of ex vivo or in vivo model systems that fully recapitulate the complexity of human cancer with regard to the molecular features of the cancer cells themselves, the tumor microenvironment, and an intact immune system. This is a greater or lesser liability for certain classes of cancer therapeutics, but we generally cannot be dogmatic about which mechanisms of action will translate across preclinical and clinical settings.
Regarding the scenario of using a cancer therapy with known efficacy in some context for an off label indication based on preclinical data, I am generally more willing to consider this possibility, though it is infrequent in clinical practice that such an approach trumps direct clinical evidence for a repertoire of therapies in a given cancer indication.
When thinking about specific types of systemic cancer therapy (conventional cytotoxic chemotherapy, oncogene targeted therapy, and immunotherapy) there are very real differences in cancer biology that relate to variable efficacy for each across Cancer types. Several years ago, we had hoped that this would not be true for the activated oncogenes for which molecular targeted therapies have been established as effective and at least one contact. BRAF mutations are, perhaps, one of the best examples here. We know that BRAF mutations are found across the majority of cancer types, though at very low rates in many of them. Going into the first clinical trials with selective BRAF inhibitors, we were equally optimistic regarding potential efficacy in melanoma and colorectal cancer, but came away with enormous enthusiasm in melanoma and essentially no efficacy in colorectal cancer.
Extensive laboratory research subsequently help to explain the relative resistance of BRAF mutant colorectal cancer, but it was not a phenomenon predicted by preclinical models prospectively. In fact, it is this type of example that motivated the NCI MATCH trial which is broadly exploring molecular targeted therapies in cancer patients where the molecular features are the basis for inclusion in a given therapeutic arm, not cancer type.
In other words, we take it as conventional wisdom currently that we do not have a basis for predicting efficacy when exploring these types of approaches across the spectrum of cancer types.
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Y. Tony Yang, ScD, LLM, MPH., Associate Professor, Department of Health Administration and Policy, George Mason University, Fairfax, Virginia. Charles Bennett, MD, PhD, M.P.P., Smart State and Frank P and Jose M Fletcher Chair, Medication Safety and Efficacy, Smart State Center of Economic Excellence, University of South Carolina and the Hollings National Cancer Institute Designated Cancer Center of the Medical University of South Carolina, Charleston, South Carolina.

Q: Are biosimilars the same as generic versions of biologics? Will they be approved by the FDA? Are they safe? Are they cheaper? What about the intellectual property rights of the manufacturer of the reference biologics? If they are only slightly less expensive than the reference biologics, why would anyone prescribe them- particularly if we are not certain that they are as safe as the reference biologic?
A: Biosimilars are NOT generic versions of biologics. Biosimilars are HIGHLY SIMILAR to the reference product they were compared to, but have allowable non-clinical differences. Differently, generic drugs are copies of brand-name drugs, have the identical active ingredient, and are the same as those brand name drugs in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. Biosimilars are produced from a living organism; therefore, it is impossible to produce an exact copy of the reference biologic. Two biosimilars are approved in the U.S. as of July 2016: one is marketed (Zarxio, a Neupogen biosimilar) and the other is involved with patent litigation (a Remicaide biosimilar approved in April). A third and fourth biosimilar received unanimous votes in July of support from FDA’s Arthritis Advisory Committee (a Humira and an Enbrel biosimilar) although patent litigation may occur before marketing is allowed to begin.
For years, biosimilars have been approved and safely used by patients in Europe, Japan, Australia and other countries. While the regulations for approval are similar internationally, Europe has been way out in front on approving biosimilars and the U.S. is just entering this market. The biosimilar approval in developed countries relies on each country’s regulatory agency’s previous findings that the agency-approved reference biologic is safe and effective.
Although biosimilars in the U.S. are not expected to provide the 70-80 percent savings we have seen with traditional generics, biosimilars have historically cost at least 20-30 percent less than the reference product, which can cost over $100,000 per year. Zarxio came to market in the U.S. at a 15 percent lower cost than its reference biologic. That implies the price differential between a biologic and its biosimilar is more likely to approximate the competition in a multi-brand category of drugs rather than between a reference drug and its generic. Nevertheless, these cost savings from biologics help give patients access to these complex drugs. By improving access to biologics through biosimilars, more patients have the potential to receive life-changing treatments. The reduced cost of biosimilars will also lead to substantial cost-savings in the broader healthcare market. Although it remains to be seen as the biosimilar pipeline continues to mature in the U.S., it is estimated that the U.S. health care system has the potential to save up to $250 billion by 2024. These savings create resources to enable access to other innovative treatments, improving the lives of all patients.
Biosimilars were first allowed under the Biologics Price Competition and Innovation Act (BCPIA), a section of the sweeping 2010 Affordable Care Act. The BPCIA acknowledges the significance of promoting innovation, but it also provides a pathway for competition once monopoly protection ends. Biologics can acquire patent protection, which lasts for 20 years from the date the patent application is filed. The BPCIA stipulates a 12-year market exclusivity and a 4-year data exclusivity beginning when the biologic drug secures FDA marketing approval. Each exclusivity can be extended 6 months for pediatric applications. A biosimilar cannot be marketed until the 12-year exclusivity expires. These exclusivity protections are designated to stimulate biologic research and development. However, if the politically controversial Trans-Pacific Partnership between the U.S. and 11 other Asia-Pacific countries is approved, exclusivity could drop to 5 years. Stay tuned and the next few years should be exciting times for biosimilar approvals and uptake in the U.S.
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Brian Klepper, PhD, CEO and Founding Principal of Health Value Direct

Q: Many of us have been touched by the publication of your sensitive but serious criticism of your wife’s care once her ultimately lethal peritoneal cancer had spread. How do you propose that oncologists, patients and their families should best practice “shared decision making”?
A: Sad but true, most cancer patients today unknowingly enter highly conflicted treatment environments where, as a practical matter, the ideal of shared decision making may run counter to the provider organization’s interests. Cancer care is such lucrative business that more than one in four health systems is now building a cancer center. Physicians or the health systems they work for typically profit from the drugs they prescribe, which often lack evidence of efficacy. These vectors often result in care decisions that accrue more to the health system’s than the patient’s benefit.
Patients should assume that their physicians have their best interests at heart but, in complicated, unfamiliar territory, insist on asking hard questions. Doctors are increasingly aware that their role includes making patients aware of their options, but they, like all of us, may also have inherent biases that manifest in what treatments they urge for their patients.
Physicians can be optimistic about outcomes and patients may be unreasonably hopeful, so an honest evidence-based assessment of current realities is critical. What benefits will the treatment realistically buy the patient and how much of an ordeal will it induce? What are the odds of success and what, exactly, is the definition of success in each case? The goal is to arrive at care decisions based not just on abstract notions of what works better, but on results that will be meaningful to the patient’s and family’s lives.
Treatments that buy a few extra days or months may not be worth it if adverse effects make that additional life miserable. And palliative care data over the past few years has shown that stopping after failed 1st or 2nd line chemotherapy often lengthens life by 2-3 months and improves quality of life over conventional therapy.
It would be particularly useful to know whether the vast majority of cancer patients who have gone through aggressive therapy and are about to die believe in hindsight that it was worth it. That voice of experience would be critical new information for patients, and validate or counter many physicians’ arguments that they prescribe all-but-hopeless treatments because many patients demand any chance. Of course, studies are less fundable when they aspire to less treatment and are not in the care community’s financial interests.
In Being Mortal, Atul Gawande MD’s profound and wonderful book, he presents 5 questions for patients at the end of life, developed by Susan Block, a palliative care physician at the Dana Farber Cancer Institute in Boston.

1. What is your understanding of where you are and of your illness?
2. What are your fears about what is to come?
3. What are your goals as time runs out?
4. What tradeoffs are you willing to make?
5. What would a good day look like?

The beauty of these questions is their deep humanity. They clarify the patients’ understanding, worries and priorities for the patient and family, and help clinicians know what matters most to them. My wife Elaine referred to them as “perfect questions.”
In British Medical Journal, Richard Lehman MD sums up the shared decision making problem this way. “We urgently need every paper about a new oncology drug trial to incorporate a comparative infographic, compiled by an independent author from the individual patient data. This could probably be done for the same cost as a single course of the treatment.”
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Valerie Fraser Cancer Research Advocate/­Patient Navigator;
Inflammatory Breast Cancer International Consortium (IBC-IC)
Huntington Woods, Michigan

Q: What are Patient Navigators and why are they sometimes necessary for some cancer patients. How do the best programs work?
A: As precision medicine, information technology and an increasingly savvy internet society merge, there will be a greater expectation that patients be involved, informed and engaged with their healthcare team. Navigators will be pivotal in this process, both those that are within the healthcare system and increasingly those that are lay navigators outside of the system. Lay navigators are often resourceful survivors or caregivers themselves, experienced in research and the health care process, with critical skills, resources and most importantly the “heart connection” that patients will need throughout their cancer experience.
Accessing resources and seeking quality care for those diagnosed with cancer is a demanding and complicated process. A patient’s survival can be impacted by critical decisions, so there’s the pressure to get it right. The reality of receiving a cancer diagnosis begins with an avalanche of emotion, anxiety and uncertainty both for the patient and their family. Many patients will inevitably encounter barriers along the way and face important crossroads critical to their care. Often they will feel buried and paralyzed under the weight of a system focused on time and process and may feel uncomfortable with their ability to question or evaluate the process. With multiple experts and treatments involved, it is often difficult to transition levels of care. Many also experience long term side effects following treatment, impacting their transition from patient to survivor.
Patient navigators are resourceful problem solvers there to guide patients through a difficult experience often never encountered before. They help to prevent and eliminate barriers to quality care and treatment, locate resources and often act as a communication liaison between the patient and the care team. A navigator can help support patient satisfaction through their compassionate guidance, often having first hand experience as a cancer patient themselves, resulting in improved quality of care and overall outcomes. Navigators are also self-advocacy educators and encourage patient empowerment improving a patient’s overall outlook, engagement and quality of life. Studies have shown this is often a win-win for the patient, their care team and their treating institutions.
The best navigation programs are those that are resource and information rich and designed from a patient perspective. A navigation program must be adaptable and broad so as to provide the best information, resources and guidance while at the same time engage and empower patients in the process. Personalized needs assessment and evaluation of patient satisfaction throughout the navigation intervention supports optimal outcomes. As addressed in the landmark 2005 IOM report “From Cancer Patient to Cancer Survivor: Lost in Transition” the key components of delivering high quality cancer care must include patient needs, values, preferences and engagement with the care process.
Cancer is unwanted, unplanned, unscheduled and a very personal experience for those diagnosed. Patients are faced with critical decisions while dealing with overwhelming stress. A navigation plan must be designed around the individual and their unique needs. The best programs will be focused on clearing away barriers and uncertainty while rebuilding a pathway to patient empowerment and survivorship.
Patient Navigation is a rapidly growing and evolving industry especially in cancer care. A patient navigation requirement is now part of the Commission on Cancer institutional accreditation to ensure patient-centered care. Health care institutions and cancer centers developing their programs, often assign nurses to fill these positions who focus on patients at that particular institution. Salaries for Oncology Nurse Navigators can average anywhere from $67,000+ annually . Private/Professional Patient Navigators work independently as consultants with various organizations and individually one-on-one with patients. Their fees are often hourly and can vary based upon the scope of their services, demographics, background and experience, etc..
Patient Navigators are filling important roles in an increasingly complex cancer health care system. Their involvement in patient-centered care will undoubtedly continue to grow and add value to a health care system striving to better serve their cancer patients. However, their real impact will be in the immeasurable value they provide to patients and families on the receiving end of a life threatening cancer diagnosis often overwhelmed and lost in the maze of the cancer experience and process.
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George Lundberg, MS, MD, ScD, MASCP, FCAP, Chief Medical Officer and Editor in Chief, CollabRx, a Rennova Health Company; Editor at Large, Medscape; Executive Adviser, Cureus; Consulting Professor of Pathology and Health Research and Policy, Stanford University; President and Chair, The Lundberg Institute; @glundberg

Q: Did the CollabRx vision of 2008-2010 foretell the 2016 Cancer Moonshot?
A: True history is difficult to confirm. Its representation depends in large part on who recorded “his-story.” Even Socrates, who, amazingly, did not himself write, is known mostly because of the extensive writings by his students.
Did Richard Nixon, in declaring “War on Cancer” in 1972, calling for vast research to find a cancer cure foretell the Obama-Biden 2016 “Moonshot”? Perhaps, since it also was a presidential decree.
It takes many threads to weave a tapestry.
Jay Martin (Marty) Tenenbaum PhD, himself both a former Stanford professor and pioneering internet entrepreneur as well as a metastatic melanoma survivor, founded CollabRx as a privately held, for profit company in 2008.
When Marty conceived CollabRx, he envisioned breaking down the silos of process that inhibited movement of positive research results from “the bench to the bedside” to enable a far shorter time than the extant 16 years. Blending-merging the wonders of advanced information technology and the Internet with the increasing wonders of molecular oncology was to be the method.
The goal was always to “defeat cancer, one patient at a time.”
Jeff Shrager, PhD (still with Cancer Commons) and Smruti Vidwans, PhD (still Chief Science Officer of CollabRx) were early hires.
John Wilbanks (an initial CollabRx Editorial Advisory Board member) is credited with founding “Science Commons” in 2006, as a part of the Creative Commons concept.
Wilbanks and Tenenbaum announced/described “Health Commons” in June 2008.
John Niederhuber, MD, Director of the National Cancer Institute, in the March 17, 2010 issue of JAMA, published “Translating Discovery to Patient Care”, nicely summarizing many of these cancer issues and opportunities. He left the NCI Directorship in July 2010.
From 2004-2011 caBIG was an NCI program that was envisioned to accomplish many of the goals described by Niederhuber and envisioned by Tenenbaum. But after spending >$350 000 000 with little to show for the money, caBIG was replaced.
I joined CollabRx on March 2, 2010.
On April 1, 2010, I participated in an Institute of Medicine program in Washington, DC on “The Learning Healthcare System in 2010 and Beyond”. I mentioned the CollabRx and Cancer Commons concept in my lecture and many people expressed interest.
Tenenbaum, Shrager and I announced Cancer Commons in MedPage Today on July 12, 2010. “The goal of Cancer Commons is to provide patients and physicians with the latest information, tools and resources they need to obtain the best possible outcome and to capture and aggregate the results over all studied patients to improve cancer treatment generally.”
The first real product of CollabRx (in addition to appointing dozens of stellar collaborating editorial board members) was the PLOS ONE paper “A Melanoma Molecular Disease Model” (MDM) on March 30, 2011. This paper portrayed a model describing how to envision cancer by genomes, mutations, and pathways. Harvard’s Keith Flaherty and David Fisher teamed with Smruti Vidwans and other CollabRx authors in this groundbreaking effort.
In order to enable utilization of the new MDM, we harked back to the May 5, 1975 beginning of The JAMA series called “Toward Optimal Laboratory Use” (TOLU) which introduced the concept of algorithms and decision trees and tables to physicians that truly did foretell CollabRx “Therapy Finders.”
Following the TOLU model, CollabRx invented “User Guides” for physicians and patients to use as open access interactive web apps at www.collabrx.com, subset Melanoma Therapy Finder
intended to facilitate shared decision making by patients and physicians together at this most difficult time, dealing with advanced cancer. Lung cancer, colorectal cancer and breast cancer web apps followed. The CollabRx Therapy Finder concept incorporated the new biomarkers, recognized practical therapeutic onco-genomics and was based upon cancer site/organ of origin.
On April 1, 2011, The Scientist Magazine (Sarah Green editor) published my “Thought Experiment” called “Medical Publishing for an N of One.” I, an aficionado of large-scale clinical trials as the gold standard for evidence in medicine, had completely acquiesced to the notion that cancer is thousands of different possibly unique diseases with mutational and other …omic designators.
Parallel to these developments, CollabRx science, led by Vidwans, also invented and built a complex, deep, up to date and highly automated Genetic Variant Annotation (GVA) Service that can be agnostic to organ of cancer origin and utilized a “Pan-Cancer” genomic approach, with a different kind of editorial board called “Pan Cancer” headed by Razelle Kurzrock. The GVA is intended to bridge the interpretation-action gap between the NGS laboratory findings and the practicing physician.
In 2012 CollabRx was acquired by Tegal (which adopted the CollabRx name) and moved to San Francisco. New CEO Thomas R. Mika. Cancer Commons by this time had transitioned from a not for profit initiative into a 501c3 corporation and remained in Palo Alto with Tenenbaum.
By 2014, CollabRx announced a new product, CancerRx, as a mobile app extension of the previously exclusively web-based Therapy Finder apps.
There can be little doubt but that the well funded and widely publicized ASCO product called CancerLinQ formally launched in 2016 after years of planning draws heavily in concept from the early thinking of Cancer Commons.
Listening in person to Vice President Joe Biden exhort the ASCO membership in June 2016 to cooperate, collaborate, break down the silos, share, place beating cancer ahead of promoting your institution, company, career, financial gain, etc. sounded a great deal like Marty and me exhorting the IT planning leaders of ASCO in Alexandria, VA in April 2010, and others subsequently, to help us bring the CollabRx and Cancer Commons visions to reality.
We can all hope that the upshot of the Joe and Jill Biden call to double the rate of progress in the fight against cancer (10 years compressed into 5) has a better outcome for many cancer patients, and not only for the American Cancer Industrial Complex, than did the war declared by Richard Nixon in 1971.
Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.