Thomas P. Stossel, MD, American Cancer Society Professor of Medicine, Harvard Medical School; Senior Physician, Hematology Division,
Brigham & Women’s Hospital, Boston, MA; Visiting Scholar, American Enterprise Institute; Secretary, Options for Children in Zambia

Q: Your recent book “Pharmaphobia:—–” about conflict of interest “Myths” drew great attention to what you and David Shaywitz earlier called the “Pharmascolds” hazard. How do you see that phenomenon impacting the current national movement toward “Precision Oncology”?
A: The public’s dread of cancer engenders electric excitement every time something new comes along to combat the disease. The latest example of such a development is “precision oncology:” using the specific genetic makeup of a patient’s malignancy to target therapy against it or else engineering a subject’s immune system to recognize and destroy tumors based on their unique composition.
Over my five decades in health care new anti-cancer strategies have, for the most part, incrementally brought cancer mortality to its all-time low. Therefore, in theory the public’s enthusiasm for these novel approaches ought to be justifiable.
But one serious impediment threatens to squelch such optimism. I call this obstacle “pharmaphobia”: demonization of the industries that produce medications and medical devices. The current political fallout of this attitude is to demand drug price controls.
Underlying pharmaphobia is profound ignorance of fundamental facts. One is that the maligned industry is responsible for healthcare — including cancer treatment — being far better today than in the past.
Another is that developing new drugs is incredibly difficult and expensive. An FDA drug approval costs eighty times more today compared to 50 years ago. It’s because even small increases in testing stringency the FDA imposes on drug development disproportionately exacerbate a high disappointment rate: nine out of ten drugs that seem promising in test tubes and animal studies crash in clinical trials. Therefore, every drug brought to market has to pay for the nine that fail. In no other enterprise does the cost of developing a product bear so little relationship to its present value or production costs. Only profitability addresses the long odds by enabling taking more chances.
What motivates pharmaphobes? Academics gain promotions by attacking industry. Lawyers profit by teaching regulatory compliance – so the more regulations the better. The media attracts readership by ginning up faux scandals, and demagogue politicians garner attention. Medical journals demonize industry marketing to brand themselves as fonts of “trustworthy” information. But the truth is practicing physicians get far more accurate practical information from FDA-regulated company marketing than from unregulated medical journal articles or health center propaganda.
But what about those huge fines medical products’ companies pay for alleged misconduct? These penalties are not smoking guns for corruption but rather manifestations of a federal extortion racket. Physicians often and rightly prescribe FDA approved products “off-label” for unapproved indications. Prosecutors twist the definition of a “false claim” — billing the government for unperformed services – to allege that devious corporate marketing that physicians can’t resist coerced them to prescribe off-label. These cases never go to trial, because conviction for one indictment confers a penalty called “debarment.” A debarred company cannot sell to the government, the major purchaser of its products. To avoid this draconian punishment, companies always settle.
Pharmaphobia has slowed or prevented research relationships, limited or eliminated worthwhile activities (such as providing product samples to patients) and compromised medical training. Most importantly, it diverts scarce resources from medical innovation and education. Unchecked, pharmaphobia will sabotage the promise of precision oncology.
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.

Erica Frank, MD, MPH, Professor and Canada Research Chair, University of British Columbia; Founder and President, NextGenU.org; Founding Member, CollabRx Editorial Advisory Board

Q: What is Next Gen U and how does it approach the prevention of cancer?
A: NextGenU.org is essentially the world’s first free university; uniquely global for credit, for free. Founded in 2001 with a focus in the health sciences, NextGenU’s accredited courses span from college-level pre-health sciences and community health worker training through medical and public health graduate training, residency programs, and continuing medical education.  The courses are competency-based, and include online knowledge transfer, a web-based global peer community of practice, and local and remote skills-based mentorships. Our accredited partners, North American universities that are outstanding in each particular course topic, give individual learners credit for this training (or institutions can adopt them and use them with their students). We collaborate with leading universities, professional societies, and government organizations including the American College of Preventive Medicine, CDC, Grand Challenges, Harvard Institute for Lifestyle Medicine, NATO Science for Peace, and WHO.
We now have more than 3,000 registered users in over 130 countries, and expect to achieve our ultimate outcome this year:  the world’s first free degree, a Master’s in Public Health.  We globally launched our first full course in March 2012, Emergency Medicine (EM) for Senior Medical Students, in partnership with Emory University’s WHO Center for Injury Control, the International Federation of EM, and the Society of Academic EM — with this and other NextGenU courses now demonstrated to imbue students in North America and beyond with as much knowledge gain and greater satisfaction than with traditional courses.  NextGenU’s educational system will soon span from expert-created competencies, through learning resources and activities, and multiple choice and mentor, peer, and self assessments, to recommending Continuing Medical Education based on the outcomes of trainees’ patients’, and will encompass a community of practice of former trainees who have learned to interact globally and meaningfully.
What do we offer that is specifically useful to CollabRx Curious Dr. George readers and their colleagues and constituents? We produce courses with components that can help with broadly ranging aspects of cancer prevention, diagnosis, and treatment, including:

• Alcohol, Tobacco, and other Substance Use Disorders in Primary Care
• Alcohol, Tobacco, and other Substance Use Disorder Screening (for community health workers)
• Community-Oriented Primary Care
• Emergency Medicine
• Environmental Health (the MPH core course)
• War and Health

In addition, we will soon be launching these cancer-relevant trainings:

• All Core MPH courses
• Breastfeeding
• Family Medicine Residency
• Oral Public Health
• Pediatrics Residency
• Public Health Nutrition
• Practice Support
• Prevention and Treatment of Alcohol Use Disorders
• Prevention and Treatment of Tobacco Use
• Preventive Medicine Residency

And one last piece to offer — we would love to work with volunteers (from medical and graduate students through residents, practitioners, and professors emeriti) to co-create further cancer-related trainings, and organizations with which we could co-sponsor these educational offerings globally.
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.

Robert Orlowski, MD, PhD, Florence Maude Thomas Cancer Research Professor and Professor of Medicine (Lymphoma/Myeloma) and Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX

Q: Some writers have characterized 2015 as a year of great progress in the treatment of Multiple Myeloma. What advances in Myeloma treatment in 2015 do you consider to be the most important and why?
A: Five new drug approvals for patients with relapsed and/or refractory multiple myeloma mark 2015 as a year of great progress against this disease. Proteasome inhibitors were full with three new regimens:

1. 1. Panobinostat with bortezomib and dexamethasone
   2. Carfilzomib with lenalidomide and dexamethasone
   3. Ixazomib with lenalidomide and dexamethasone and these were complemented by a pair of antibodies:

      –Daratumumab

      –Elotuzumab with lenalidomide and dexamethasone.

All of these are exciting developments that will help further improve myeloma patient outcomes. Panobinostat, an oral deacetylase inhibitor, is the first agent in its class to be approved for myeloma. It showed activity with the proteasome inhibitor bortezomib and dexamethasone in patients after at least two prior therapies, including bortezomib and an immunomodulatory agent, based on the PANORAMA-1 study. The ASPIRE trial demonstrated that proteasome inhibition with carfilzomib was safe and tolerable when added to the immunomodulatory drug lenalidomide and dexamethasone. Importantly, the three-drug regimen induced deep and durable responses, with little added toxicity. Ixazomib was found by the TOURMALINE-1 investigators to improve outcomes in combination with lenalidomide and dexamethasone for patients with at least one prior therapy. Notably, this proteasome inhibitor is orally dosed, and thereby enhances convenience and could reduce costs by avoiding the need for injections. Next, the SIRIUS study found that the anti-CD38 monoclonal antibody daratumumab was active in patients with three or more prior lines of therapy. This agent’s approval made it the first in its class, providing another new mechanism of action for our therapeutic armamentarium against myeloma. Finally, following shortly thereafter, the anti-SLAMF7 antibody elotuzumab was approved in combination with lenalidomide and dexamethasone. Supported by results from the ELOQUENT-2 study, patients with one to three prior lines of therapy can now receive this immunostimulatory combination.
Since patients with myeloma often receive several different types of therapies, additional studies will be needed to understand whether using these options in certain sequences is ideal. Also, it may be possible to identify biomarkers that could predict in advance whether some patients would most benefit from one or another of these strategies. In the meantime, patients with one prior therapy can receive either carfilzomib-, ixazomib-, or elotuzumab-based regimens, while patients who have been more heavily treated could receive these, as well as either daratumumab or panobinostat in its combination. Use of panobinostat- or antibody-based therapies could be sensible if patients have disease that is progressing through a proteasome inhibitor. Conversely, if progression has been seen on an immunomodulatory drug, therapy incorporating panobinostat or daratumumab could be reasonable. However, it is important data also show that use of sequential proteasome inhibitor- or immunomodulatory drug-based therapies can be effective in some settings, especially with addition of other, novel agents.
Moving forward, many of these drugs will be evaluated in earlier lines of therapy, including in patients with newly diagnosed disease, and it is likely that their activity in those settings will be enhanced as myeloma is then less chemoresistant. The proven track record of proteasome inhibitors make carfilzomib and ixazomib attractive candidates in this regard. While antibodies are still new kids on the block, their relative lack of added toxicity beyond first-dose infusion reactions contribute to their appeal as well. Also, it may also be possible to construct four-drug regimens with a proteasome inhibitor, immunomodulatory agent, monoclonal antibody, and corticosteroid that will achieve optimal cytoreduction. Most importantly, in playing these new therapeutic cards against myeloma, a push is no longer likely, and we are consistently getting the high hand, and coming closer to a cure for this disease.
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Arthur L Caplan, PhD Director, Division of Medical Ethics, NYU Langone Medical Center. Amrit Ray MD, MBA, Chief Medical Officer, Janssen Pharmaceutical Companies of Johnson & Johnson.

Q: What is the ethical basis for compassionate use of investigational drugs; and what are some practical considerations in making such use reality?
A: In seeking relief from the burden of disease, some patients face a lack of satisfactory treatment options from the range of available, government regulatory authority approved medicines. In these circumstances, patients often turn to investigational medicines, or “pre­approval access.” The main avenue for pre­approval access is for patients to enter clinical trials. When clinical trials (and related expanded access programs) are already fully enrolled or otherwise unavailable, individual patients – particularly those facing serious and life­ threatening conditions – may seek “compassionate use.”
Clinical trials are geared to deliver the evidence thresholds that allow regulatory approval in order that medicines can become widely available to all patients who need them, or regulatory denial where benefit­ risk is inadequate. In order not to undermine the clinical trials process and its potential to benefit all patients, individual compassionate use grants need to be evaluated using a clear process including pre­defined ethical criteria. The unbridled access to investigational drugs for all individual compassionate use requests could undermine the clinical trials process. An example would be in clinical trials where patients may feel uncomfortable with being randomized to investigational medicine or placebo, when they could instead obtain certain access to investigational medicine through compassionate use requests. An unlimited number of compassionate use grants might thus undermine the benefit to the many that comes from clinical trials supporting the approval of a new medicine. Conversely, when a potentially beneficial therapy is being studied, the absolute denial of all compassionate use requests may overlook the plight of patients in dire circumstances with no other avenue for potential relief. Therefore, a balance is needed to meet both the needs of the many awaiting new approved medicines then or in the future, and the needs of the few who are out of currently available treatment options.
In order to secure fairness, a balanced policy should lay out processes and ethical criteria that will give equitable opportunity to all patients’ requests. Further, the balance should seek to eliminate sources of bias that could result in unfairness based on morally irrelevant criteria such as celebrity or social standing.
We have proposed a mechanism to achieve this balance and are currently conducting a pilot through the use of a Compassionate Use Advisory Committee (CompAC) [The Ethical Challenges of Compassionate Use, Caplan AL, Ray, A. JAMA, 2016; 315(10): 979­-980]. The CompAC insists on anonymizing individual requests to prevent undue influences from wealth, celebrity or other similar factors. We recommend the systematic application of a number of pre­specified ethical criteria, such as do no harm and the requirement to consider current evidence with respect to benefits and risks. Further, we propose that the criteria be evaluated by an independent, objective committee that includes the voices of physicians, ethicists and patients.
The intent of these proposals is to minimize potential bias and allow the equitable consideration of each request for compassionate use. By offering clear information, a transparent request process, including pre­defined ethical criteria and an objective evaluation by those with broad expertise, we believe that the many awaiting new approved medicines and the few seeking compassionate use will each receive a fair chance at the potential benefit from the development of investigational drugs.
COI Disclosure
Caplan serves as the non­voting, unpaid Chairperson of the Compassionate Use Advisory Committee (CompAC), an external, expert panel of internationally recognized medical experts, bioethicists and patient representatives formed by NYU School of Medicine, which advises the Janssen Division of Johnson & Johnson about requests for compassionate use of some of its investigational medicines.
Ray is a full time employee of Janssen Research and Development, LLC.
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.