Charles Bennett, MD, PhD, MPP, 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. William Hrushesky, MD, FACP, Founder and Chief Scientific Officer Rythmalytics LLC (Cicada Circadian Coach), West Orange NJ; Chief Medical Officer Ambulatory Monitoring Inc., Ardsley, NY.

Q: Prescription drugs are a big ticket item in American Money Driven Medicine. Since the initiation of pharmacy benefits management (PBM) in 1968, the growth and proliferation of functions of this “middle-man managed care” concept has been so successful that PBMs now control not only pricing, discounts, and drug selection for >250 million Americans, they threaten to become “the prescriber.” Is this a good thing?
A: You and I naively imagine that medical care responsibility logically devolves to the doctor who cares for the patient, diagnoses their condition, and provides accountability for management, treatment, and outcomes. Guess again. Since medicines have grown in cost and costs continue to skyrocket, profit-oriented businesses have muscled the patient and the doctor out of the way. Pharmacy Benefit Manager (PBM)’s plans now replace physician choice in many settings, and if the physician’s choice is expensive, they replace it with less expensive alternatives. These PBMs then profit from the resultant savings.
What is a Pharmacy Benefit Manager (PBM) and how did they get here? PBMs were developed to act on behalf of insurance carriers, self-insured employer plans, Medicare Part D plans, Federal Employees Health Benefits Program, and state government employee plans to maintain or reduce prescription costs while concurrently trying to improve outcomes. These “middle men” corporations are now principal players in our health care system, controlling at least 80% of drug benefits for 260 million Americans.
The initial goals that were instrumental in PBM development seem to have gone astray. The system which put PBMs in place was done with good intentions, but it has now resulted in increased cost to health plans and adverse health outcomes. PBMs restrict access by excluding products from formularies, delaying access through prior authorizations, developing step-by-step care algorithms, defining disparate pricing, and establishing lengthy and complicated paperwork. A recent studyusing Medicare data showed that a switch to a less expensive medication for non-medical reasons, termed as non-medical switching, leads to increased annual medical payments of $6,254 to $13,127 and a higher rate of secondary switching (this time for medical reasons) to another medication. Patient care also suffered.
Anthem health plans’ current $15 billion lawsuit against the PBM Express Scripts seeks to recover rebate funds, and Anthem’s withdrawal from its PBM raised public awareness of the lack of transparency about actual discounted costs of expensive drugs.  Express Scripts is willing to accept Anthem’s withdrawal from their plan and lose 14% in sales revenues, to protect against having to share rebate dollars with health plans and their members. This lack of transparency has recently been addressed by Alan Lyles PhD of the University of Baltimore, College of Public Affairs, who questions PBM value in the healthcare system. Similarly, consumers are suing their insurers for “bait and switch” claims. This action is pressuring states to consider adopting state legislation that limits insurer’s ability to control pharmaceutical formulary decisions.
Traditionally, physicians prescribed medicines that they felt were most likely to help their patients based on clinical judgment rather than cost alone.  PBMs have stepped beyond their historical role and are making formulary decisions that control access to which drugs physicians can prescribe without regulatory oversight or the benefit of clinical experience. What started as a value-based strategy, using clinical guidelines to define a stepwise process of drug selection based on best clinical evidence, yet allowing for individual case decision exceptions, has morphed into blatant cost-based guidelines selecting from a restricted list of drugs to be offered (the formulary) based on the lowest cost and highest profit to the PBM. Lowering pharmaceutical costs in the United States is essential. This must be the purview of professional societies and other healthcare patient and provider groups rather than PBMs profiting directly for every dollar saved.
From a practical perspective of the physician, the laborious prior authorization and step therapy processes used to gatekeep expensive FDA approved drugs are onerous and cost a great deal of time and effort that could be better directed to patient care. This modus operandi also leads directly to inordinately high copays for PBM non-preferred drugs, further influencing decisions without any responsibility or accountability for patient care. Authority without responsibility is an extremely bad practice which will lead to a range of bad outcomes. In essence, the PBM has become the physician without training, knowledge, medical license, or knowledge of the individual and their illnesses.
PBMs have adopted new approaches to control formularies and, thereby drug costs. They remove an existing and generally well-tolerated drug on a formulary and replace it with another less expensive and less validated drug because of better pricing for the new, now “preferred” drug (non-medical switching). This is particularly worrisome for oncology, as biosimilar trastuzumab and biosimilar rituximab are expected to enter the US market soon. It’s possible that PBMs may switch out branded rituximab and trastuzumab despite the absence of a proven 20-year safety history.  Similar concerns apply to persons with a range of complex medical illnesses, such as diabetes. Because of the possible absence of drugs’ proven effectiveness, non-medical switching has potentially important and adverse implications for both the patient and their doctor.
Dr. Elaine Nguyen, a Health Economics and Outcomes Research Fellow at Hartford Hospital, applied macro-analysis to multiple studies looking at the broader implications of non-medical switching on patient clinical and economic outcomes, healthcare utilization, and medication-taking behavior. The study found that non-medical switching is associated with significantly more negative effects upon care than benefits, and negative care effects were even more substantial when non-medical switching occurs among patients who are stable and doing well on their current treatment regimens.
This practice is especially damaging to patients with diabetes, as diabetes is a complex progressive disease. Diabetes requires self-management skills and a positive working doctor-patient relationship. The condition also needs continual fine-tuning of medication, formulation of a diet and exercise regimen, and attending to diabetes-related stress. When non-medical switching is required, it is disruptive to an individual’s current management routine.
The solution to the problem requires a concerted effort among those most impacted (patients and providers), encouragement of conversations, and collaborative problem-solving. Physician and patient groups have begun to work together to voice concerns about PBM practices and to advocate for action. PBMs could help by having a streamlined, universal Prior Authorization process (as supported by the AMA Coalition), publishing coverage policies consistent with the insurer’s medical benefit policies, and providing a list of alternative options when a prescribed option is not available. Coalitions have worked for state legislation to define step therapy and prior authorization but many states still need legislation. Physicians and patients can increase communication with employers, providing details about the impact of their PBM policies on workers. In addition to discussing the interference with disease control and function, the details should also include the topics of worker productivity, absenteeism, and decreased attentiveness when at work to encourage better decision-making when selecting insurers and PBMs. The ultimate goal is to position the physician as the ultimate authority on patient care once again.
As Dr. Seth Baum, CMO of Excel Medical Clinical Trials, eloquently expressed: “What is the cost, and the value, of a life? How do we measure this intangible and all-important metric? I can’t answer this question. I can tell you though that withholding medications from those who might benefit would exact a price I’m unwilling to pay: my personal ethos and professional integrity.”
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.

Richard J. Ablin, Ph.D., D.Sc. (hon), Dr. h.c. Professor, Department of Pathology, University of Arizona College of Medicine, The Arizona Cancer Center and BIO5 Institute, Tucson, AZ 85724. Ronald Piana, Freelance Science Writer, Huntington, NY 11743

Q: The new draft USPSTF recommendations for rapid comment on use of PSA for screening represent a big change from 2012. They now read: “The decision about whether to be screened for prostate cancer should be an individual one. The USPSTF recommends that clinicians inform men ages 55 to 69 years about the potential benefits and harms of prostate-specific antigen (PSA)–based screening for prostate cancer” and much more. Shared patient-physician decision making. What do you think? (For last week’s answer to the same question see here)

A: In a troubling reversal of its previous Recommendation against the use of prostate-specific antigen (PSA) screening, the US Preventive Services Task Force has issued a Draft Recommendation that doctors should have a meaningful conversation with male patients between the ages of 55 and 69 about the risks and benefits of undergoing PSA screening. This is a bad public health decision that will only increase the use of an intrinsically flawed test that—as formally noted by the Task Force—does far more harm than good.
Screening to identify preclinical and asymptomatic disease in a population at risk is one of the cornerstones of preventive medicine. However, the success of a screening program depends on the specificity of the test for the disease in question and early identification of these patients must convey a clinical (treatment) advantage. Screening for prostate cancer generally begins with a PSA test, which is specific for a protein in the prostate gland but not for cancer. Moreover, there is no level of PSA diagnostic for prostate cancer; PSA cannot distinguish a harmless, slow-growing cancer from an aggressive one. It’s important to note that prostate cancer is an age-related disease and upward of 80% of men screened will have asymptomatic cancer irrespective of their PSA level, which leads to overdiagnosis and unnecessary treatments that to date have left countless millions of men incontinent and impotent, not to mention the healthcare costs and emotional turmoil that a positive PSA test introduces.
The Task Force’s new Draft Recommendation centers on a doctor-patient informed-decision conversation about PSA screening, across all social and demographic lines. Given the complexity of this issue, it is not feasible for a busy community doctor to elucidate the full spectrum of detailed clinical issues involved in PSA screening.1 Inequities and variability will abound, as is borne out by data. For example, a new study2 that looked at 200,000-plus men found that 37 percent were told only of the advantages of PSA compared with 30 percent who were advised of advantages and disadvantages. More striking, 33 percent were not informed of either. These men were more likely to be Hispanic, not high school graduates, and of low income. Basing a potentially life-changing medical decision on incomplete information will have profound consequences for men across the country.
The Task Force indirectly suggests that doctors and patients should revisit the decision to screen (or not screen) in a Table presented in the Draft Recommendation of estimated effects of PSA-based screening for prostate cancer on men observed in the ERSPC trial. A relevant caveat here3is that the ERSPC trialists have yet to de-identify patient data and make it available for independent review. Without examining individual patient data, it is impossible to confirm any benefit of PSA screening or the validity of the data.
Before the Draft Recommendation goes into effect, doctors across the country need specific guidance from the Task Force on how to conduct informed-decision-making conversations with their patients about PSA testing. It is recommended that the Task Force create a discussion summary similar to the Table included with the Draft Recommendation. Thereby all patients will receive consistent information so that they can make their own assessment of the potential benefits or harms resulting from the PSA test.

• 1) Brett AS, Ablin RJ. NEJM, 365, 1941, 2011
• 2) Turini et al. Urology, http://www.goldjournal.net/article/S0090-4295(17)30246-7/fulltext (accessed 10 April 2017) Download Turini III et al. Urology Preprint 2017
• 3) Haines I. et al. BMJ, 353, i2574, 2016

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.

Jeff Shrager, PhD, Director of Research, Cancer Commons; Adjunct Professor, Symbolic Systems Program, Stanford University

Kathryn A. Phillips, PhD, Professor of Health Economics and Health Services Research; Founding Director UCSF Center for Translational and Policy Research on Personalized Medicine; Dept. of Clinical Pharmacy; Institute for Health Policy Studies; Comprehensive Cancer Center
University of California, San Francisco

Q: Adoption and insurer coverage for precision oncology may require evidence that it can improve patient outcomes. The current situation is confusing for many. What are some practical next steps that workers in the field can take to improve clinical evidence and consistency of payment?

A: It’s been said that the greatest challenges facing genomic medicine are not scientific, but economic. Much has been written about the need for improved clinical evidence and consistent reimbursement policies, but there have been relatively few studies that illuminate what steps can be taken to address them. Two new studies from the University of California San Francisco Center for Translational and Policy Research on Personalized Medicine (TRANSPERS) address these questions.
A newly published study in Genetics in Medicine combines insights from TRANSPERS collaborators and leading genomic medicine experts to identify evidence gaps in genomic medicine that comparative effectiveness research can address, with direct relevance to precision oncology. For genomic/precision medicine to fulfill its potential, it must be (1) evidence-based and (2) consider a full range of patient outcomes. Does the literature to date suggest that these objectives have been met? TRANSPERS and experts from multiple institutions addressed this question. This is the first study that uses a systematic structured literature review (combined with expert input) to provide an overarching assessment of comparative effectiveness research for genomic medicine. We found that all included reviews (N=21) identified potentially important clinical applications of the genomic medicine interventions. Most had significant methodological weaknesses and there were few studies of conditions other than cancer. There were only a few analyses examining a broad range of patient-centered outcomes. Our findings provide next steps about where to focus future research activities and policy initiatives by identifying conditions, tests, and interventions where comparative effectiveness questions may be appropriate for study. We also discuss the limitations of prior research and how they could be addressed.
Specifically for precision oncology, we found that studies are needed to measure whether tumor sequencing tests lead to better clinical outcomes than alternative prognostic methods in different stages of common cancers. Additionally, studies are needed for cancer risk assessment panels that examine the consequences of testing for individuals and families including acceptability to patients, adherence to screening, delivery of genomic testing, and models to estimate the incremental net benefit of testing and optimal testing intervals.
Another recent publication from TRANSPERS identifies opportunities to resolve reimbursement challenges of genetic panel tests for cancer risk assessment. This study, published in the Journal of the National Comprehensive Cancer Network used data from payers themselves to address not only reimbursement challenges but also opportunities for resolving those challenges. Hereditary cancer panels – testing for multiple genes and syndromes – are rapidly transforming cancer risk assessment but are controversial and lack formal insurance coverage. Our study of private payers found a number of barriers to coverage for hereditary cancer panels including poor fit with coverage frameworks, insufficient evidence, and departure from pedigree/family history-based testing toward population-based genetic screening. Opportunities for addressing these challenges includes refining target populations, developing evidence of actionability and pathogenicity/penetrance, and creating infrastructure and standards for informing and re-contacting patients. We also need to separate research from clinical use in the hybrid clinical research setting and adjust coverage frameworks. Our findings have particular relevance to the NIH’s Precision Medicine Initiative, which will assemble and study an unprecedented cohort of one million or more volunteers who will contribute genomic, clinical and lifestyle data to accelerate genetic science.
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.

by Dr. George Lundberg

Searching for Truth in Cancer Clinical Trials

Richard E. Horowitz, MD, Clinical Professor of Pathology, Keck School of Medicine at USC; Emeritus Professor of Pathology, UCLA School of Medicine; Consulting Pathologist, Los Angeles Veteran’s Affairs Medical Center

Q: Who has been among the strongest supporters and most constructive critics of CollabRx (since 2010) and Curious Dr. George (since 2016)?
A: American pathology lost one of its greatest leaders (and I lost one of my best friends) when Richard Horowitz died on March 15, 2017 in Los Angeles, California. Still of sharp mind and keen humor, he died with dignity and grace, in a manner of his own choice during home hospice care, of metastatic non-small-cell adenocarcinoma of the lung.
Richard and I met across an autopsy table at the old LA County General Hospital in summer 1967. We bonded and remained colleagues and friends who shared many professional beliefs based on personal experiences for 50 years.
Richard was born in Vienna, Austria on May 17, 1931. He left Austria with his parents to flee Hitler’s scourge in 1939.
His college was UCLA, medical school UCSF, internship at Los Angeles County General Hospital, and pathology training (after 2 years in the US Army at Walter Reed doing germfree research) at Mount Sinai in New York. Richard was one of those rare individuals who could keep one foot in academia and one foot in private practice in perpetuity and perform brilliantly in both.
Richard’s “real world” pathology practice management writings and teachings exerted wide influence. But his “tour de force” was always the irreplaceable medical learning uniquely gleaned from his legendary “Organ Recitals” at USC, UCLA, and especially the Wadsworth Veterans Administration Hospital.
Richard achieved many positions in organized pathology, wrote numerous articles, chapters and books, and received many awards.
Family life was very important to Richard; he leaves his lovely and dedicated wife Nona, 3 daughters, and 4 grandchildren.
Richard’s total course of illness after initial diagnosis (malignant pleural effusion discovered at a routine annual medical checkup with established widespread metastases) was 9 months. He tried “Precision Oncology”; his cancer was found to harbor an EGFR mutation, so he was begun on erlotinib. He experienced adverse effects of such severity that he decided to decline further “curative” therapy of any sort and quickly moved into palliative home-hospice care.
Richard’s last publication in a primary source medical journal was in February 2017 in the Archives of Pathology and Laboratory Medicine. Co-authored with Dr. Sarah Bean, it was entitled “Pathology’s Stepchild”, all about the dilemma of Clinical Chemistry and what to do about it.
His final (of many) contributions to the CollabRx discussion group posted on February 25, 2017. It reads:
Sirs & Madams:
You are making pronouncements and decisions based on insufficient knowledge.  Until the use of autopsies becomes the standard of whether the new therapy worked or how the new therapy’s side effects caused the death, we do not have adequate data.  I previously sent the following:

1. A letter sent to the Wall Street Journal (Published on Sep 23, 2016)
   . . . The autopsy is credible outcome measure; nothing else can attest as convincingly to the accuracy of a diagnosis or the efficacy of a therapy.  Few, if any, clinical trials utilize the autopsy to test their hypotheses . . . .
2. A short composite of the many autopsies I have personally done:
   The patient has Stage IV lung cancer; all standard therapy has failed.  The patient is coerced into treatment, first with targeted therapy and later, with immunotherapy.  Soon he experienced diarrhea – the oncologist “handles” that with loperamide which results in annoying constipation. Then after a few days, there is marked increase in dyspnea – is it a progression of the disease, perhaps carcinomatous pneumonia or therapy related (auto-immune) interstitial pneumonitis? Well, that can certainly be treated with steroids.  Oh, the oncologist forgot to tell the patient that he needs CNS radiation because of brain metastases.  So the patient is given a course of radiation therapy – unfortunately, there is significant cerebral edema.  Again the oncologist ameliorates that with steroids, however, the cognitive impairment and confusion persist.  About the same time there are some cardiac arrhythmias – are they due to metastases to the heart or due to “auto-immune” myocarditis?  No worry, add some more steroids.   Regrettably a mixed bacterial and fungal pneumonia develops and that, of course, is treated with powerful antibiotics.  Within a brief period of time another bout of diarrhea, this time due to C.difficile, develops and progresses into a dire megacolon that appears about to perforate.  The patient is taken to surgery, the colon has, in fact, perforated and a segment is resected.  In the surgical ICU the early signs of sepsis appear, soon septic shock ensues and the patient dies after prolonged intensive, but futile, care.  The surgeon requests an autopsy, the oncologist does not attend the autopsy and does not answer the call when informed of the Cause of Death.

In September 2015 the National Academy of Sciences/IOM released their Report “Improving Diagnosis in Health Care”. The report listed eight Goals and multiple recommendations. Goal 4 was to develop and deploy approaches to identify, learn from, and reduce diagnostic errors and near misses in clinical practice and Recommendation 4C was that HHS should provide funding…to conduct routine postmortem examinations on a representative sample of patient deaths. It is incumbent on oncologists to obtain autopsies – then they will know if their “magic bullet” worked or killed.
R.E. Horowitz, MD
George Lundberg, MD
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.