Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

21st Century Cures Act, Societal Net Negative or Positive?

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Daniel R. Hoffman, Ph.D., Health Care Consultant in Glenmoore, PA.

Q: Many people are praising the recently passed 21st Century Cures Act. But there are also critics. What are some of the downsides that the American public might experience from this important piece of legislation?

A: On December 13 President Obama signed into law the 21st Century Cures Act, a piece of legislation that the blogosphere has called the “21st Century Giveaway Act” and “Obama’s Gift to Biopharma.” While such appellations suggest the windfall the new law represents for pharma and other health care manufacturers, they fail to hint at its likely harm to public health and safety.
As the price for continuing to fund the National Institutes of Health and various exotic programs such as the cancer “moonshot,” pharma extracted a major step at deregulation that sets back oversight of the nation’s approval and use of medications.
Even as a funding measure, the Cures Act is skewed in favor of pet projects such as Joe Biden’s cancer initiative, while it reduces support for less glamorous public health programs such as immunizations and tobacco prevention.
But the 21st Century Cures Act distinguishes itself by setting back the regulatory process that protects public safety. It does that by relaxing the standards the FDA currently uses for approving new drugs. The entire status of prospectively designed, placebo-controlled, double-blind studies as the gold standard for approving new drugs and devices is now weakened in favor of the deceptive euphemism, “real world evidence” (RWE) defined in the Cures Act as “data regarding the usage, or the potential benefits or risks, of a drug derived from sources other than randomized clinical trials.”
The concept and definition from the Cures Act is not yet precise. Several authors of an article in the December 8 New England Journal, including FDA Director Rob Califf, claim that the agency is currently “developing guidance” on what constitutes RWE and how it may be used. Until such definition and operational use are precisely defined, several writers in clinical studies, public health and pharmaceutical marketing have chimed in on how the practice of including RWE in regulatory approval is likely to play out. The Pharma Marketing Blog contends the 21st Century Cures Act will permit pharma companies to include “the experience of their KOLs with their patients” as evidence to support a submission.
Section 3022 of the Cures Act about RWE requires FDA to evaluate the use of real world evidence to help support the approval of a new indication for a previously approved drug and to help support or satisfy post-approval study requirements. Health care reporter Julia Belluz in Vox notes that researchers with whom she discussed RWE consider it as “just observations about things that are already happening, not experiments with placebo controls.” According to experienced clinicians, the practice opens the door to “data dredging” that makes it impossible to tell whether a drug is really safe or effective.
So unless the FDA’s eventual guidelines come out with requirements that appear entirely at odds with the relaxed standards that are at the core of the legislation, the practice of RWE will be open to a range of abuses.
The phrase “real world evidence” is one of those semantic sleights of hand typically used by corporate shills in support of egregious giveaways to multinationals and the wealthy. For example, instead of using the term “estate tax,” which most Americans support because it suggests a justifiable tax on the wealthy, they concocted the term, “death tax,” which people in surveys and focus groups considered a penalty on the children of every working person who passes away.
“Real world evidence” involves using observational studies that lack the rigor of current standards. Anyone who has ever done any clinical or survey research knows that crosstabs can be sliced and diced to yield correlations that appear impressive but, upon further analysis, result from intervening and confounding variables. Yet the Cures Act permits drug makers to present precisely such statistical damned lies as proof their products work. One point of reference is Merck’s Vioxx.
Snigdha Prakash studied the Vioxx situation and its ensuing litigation in her book, All the Justice Money Can Buy. She stated she was really “shocked” by “the extent of the scientific…and clinical trial data manipulation” routinely practiced by pharma companies. “I couldn’t believe,” she said, that “a company of Merck’s stature could be doing that.” The 21st Century Cures Act and its relaxed standards involving RWE make such manipulation more likely and potentially more dangerous to public health. FDA epidemiologist Dr. David Graham concluded that Vioxx was responsible for causing 30,000 to 55,000 deaths and 88,000 to 139,000 heart attacks, 30-40% of which were fatal. How many more products are likely to be approved and used with similar or worse adverse consequences?
Equally appalling, the new law will allow the FDA to rely upon “qualified data summaries” to support new indications for a drug, thereby allowing pharma companies to submit their own reviews as the basis for securing label modifications and expansions.
In return for pharma not reprising the infamous “George and Martha” ads in 2009-10 that helped sink Hillary Clinton’s health care initiative in 1993-94, Barack Obama has repaid the predatory pharmaceutical industry many times over. He beat down an initiative to permit drug re-importation, he appointed a pharma functionary as director of the FDA, and he championed the Trans Pacific Partnership, which would abrogate national sovereignty by using secret courts to overturn drug-pricing decisions made in signatory countries. The 21st Century Cures Act represents the final installment in the health care extortion of U.S. consumers that Obama and a compliant Congress engineered.
The previous Democratic administration under Bill Clinton dismantled many of the public safeguards that the New Deal enacted on the banking industry, thereby enabling the 2008 financial meltdown and the worst recession since the 1930s. Obama’s 21st Century Cures Act is motivated by the same neoliberal ideology and, for that reason, it sets U.S. public health on a destination that predates The Jungle and adulterates patent medicines.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Role of the NCQA in Advancing Cancer Care

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Margaret E. O’Kane, MHA. Founder and President, National Committee for Quality Assurance (NCQA) Washington, DC.

Q: Under your visionary leadership, the National Committee for Quality Assurance (NCQA) has established and enforced quality standards for much of American medicine for >25 years. What is the current major role of NCQA in caring for patients with advanced cancer?

A: We at NCQA (National Committee for Quality Assurance) are proud of our role in helping drive better performance in health care. Since 1993, when HEDIS (Healthcare Effectiveness Data and Information Set) measures were first publicly reported, we have seen substantial improvement in colon cancer screening rates, diabetes and blood pressure control. This comes as a result of HEDIS measures driving pay for performance Medicare stars and a variety of rating and reward systems. These gains translate into better quality of life—and even longer life—for the people to whom the measures apply.
In NCQA’s Accreditation and Recognition programs, plans and practices are rated on whether they are organized for quality through structure and process measures. In patient-centered medical homes and specialty practices, we look at whether access is adequate, whether there are systems to follow up on abnormal test results and whether practices “talk to each other” to ensure that patients benefit from an unbroken chain of coordinated care. Study after study has shown that practices “organized for quality” do better on quality and patient experience and have lower rates of hospital and emergency department use.
We have been working on cancer care from a number of different angles. For me, this is personal: I lost my father to cancer and a number of my family members have struggled with it. NCQA is partnering with Dr. Ezekiel Emanuel and the Center for American Progress to focus on two issues: adherence to treatment guidelines and management of patient symptoms. There will be needless deaths unless life-saving knowledge is disseminated to patients as it is generated, so adherence to guidelines matters. If patients’ symptoms are managed carefully, suffering, needless emergency room visits and hospitalizations can be avoided—along with the attendant risk of infection and avoidable costs.
Parallel to those efforts, we have worked for a number of years with forward-looking oncology practices to certify that they are organized for quality. Dr. John Sprandio, for example, brought his oncology practice through our PCMH (Patient-Centered Medical Home) Recognition program before we had a specialty practice program. Work has continued on a project involving a number of oncology practices in Pennsylvania, with funding from the Patient-Centered Outcomes Research Institute. So far, 35 oncology practices have earned Patient-Centered Specialty Practice Recognition. And we are evolving that program to be more cancer-specific, with the collaboration of Dr. Barbara L. McAneny, who has made groundbreaking efforts on the organization of cancer practices.
In addition, we were recently awarded a grant by the Gordon and Betty Moore Foundation to focus on patients who are at the end of life from illnesses such as cancer. Watching a loved one suffer is never easy, and when there is unnecessary suffering due to defects in the system of care, it is particularly difficult. Cancer treatment is often very difficult, particularly in advanced stages, where the rigors of treatment can actually cause harm. We must learn to engage with patients more effectively—to give them information about a treatment’s potential risks and harms and, when treatment is futile, to give them emotional and personal support.
NCQA is proud of the course we have charted to improve the quality and outcomes of cancer care. Much remains to be done, and much good remains to be achieved.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Clinical Trial Matching for Patients with Molecularly Characterized Tumors

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Smruti Vidwans, PhD, Chief Science Officer at CollabRx

Q: Clinical Trials is such an important topic, but it is so broad. Is there a way to provide better matching for Clinical Trials involving cancer patients, especially those whose cancers may have the added diagnostic information of molecular profiling?

A: Clinical trials provide cancer patients, especially those whose cancer has progressed beyond standard of care, access to potentially promising investigational therapies or novel combinations of approved therapies. Yet only a small fraction (less than 5%) of the 1,700,000 Americans diagnosed annually with potentially lethal cancer participate in clinical trials. A growing number of cancer patients now have their tumors profiled molecularly and there is real opportunity to use that information in better matching them to clinical trials. Below I outline the CollabRx approach to this problem.
Most clinical trials for cancer seek patients based on criteria such as tissue of origin and/or histological characteristics of the tumors. But with hundreds of targeted therapies now approved or under development, there are a growing number of clinical trials looking for patients based on the molecular characteristics of their cancer. Of note are genomically-driven trials such as basket and umbrella trials that match patients to therapies based on the individual molecular profiles of their individual cancers.
While such trials are a natural fit for patients whose tumors have been molecularly characterized, they are not easy to identify in clinicaltrials.gov. For example, a search for the gene ‘BRAF’ identifies trials for patients with BRAF mutations as well as those without. This issue can be resolved only with careful annotation and structuring of trial inclusion and exclusion criteria from sources.
Some trials without explicit molecular criteria may ALSO be relevant to patients with certain molecular profiles. What are these trials and how can physicians and patients identify them?
A patient whose cancer has a certain molecular profile (defined as having a particular set of variants) may benefit from participating in a clinical trial if the trial therapy can be “associated” with one or more individual variants in the patient’s molecular profile. For example, if:

  • The therapy either directly mitigates the oncogenic effect of one or more variants in the patient’s tumor or a downstream component of a relevant biological pathway
  • There are published data suggesting that one or more variants are predictive of response to therapy
  • Clinical experience of oncologists/cancer centers call for use of therapy for a patient with a certain molecular profile

At CollabRx, we use ‘treatment strategies’ to match cancer patients with trials. Treatment strategies explicitly connect a drug or drug class to a variant or variant class and a diagnosis. For example, a treatment strategy for ‘BRAF activating mutations’ in thyroid cancer could include ‘BRAF inhibitors’ (drugs that directly target BRAF) and, say, ERK inhibitors (if published data were to suggest efficacy of ERK inhibitors in BRAF-mutated thyroid cancer). We then match any trials evaluating BRAF inhibitors or ERK inhibitors to patients with BRAF activating mutations, even if those trials don’t have “BRAF activating” molecular criteria.
We believe that matching patients to clinical trials using this two-pronged approach–using molecular inclusion criteria AND using strategically relevant therapies–could identify treatment options for patients that they may not have considered otherwise.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Complementary/Alternative Approaches in Advanced Cancer

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Marc S. Micozzi, MD, PhD, Editor of Fundamentals of Complementary & Alternative Medicine, 5th ed. (2015), Elsevier Health Sciences, 759 pp; Editor of Complementary and Integrative Medicine in Cancer and Prevention: Foundations and Evidence-Based Interventions (2007), New York: Springer, 478 pp. www.drmicozzi.com

Q: Many, even millions, of Americans are living with advanced cancer. You are the author of the definitive text “Fundamentals of Complementary and Alternative Medicine,” now in its 5th edition. What forms of complementary and alternative medicine might be most useful for patients with advanced cancer?
A: In cancer treatment trials, both treatment and control groups receive treatment. Likewise, standard oncological treatments are not directly compared to various complementary/alternative (CAM) therapies. Rather CAM treatments are added, or not, to the standard oncological protocol. Thus, in research conducted, they are truly “complementary” as adjuncts to cancer treatment. Some trials on commonly occurring cancers have allowed observations of improvements in both survival times and quality of life in patients with advanced cancer. The most direct analogies to mainstream cancer treatments for research trials are dietary supplements (vitamin and mineral micronutrients, and botanicals) since they can be administered the same way as drug treatments.
Vitamin D shows strong clinical evidence of anti-cancer activity. In a recent study by Garland et al, people in the highest quantile of serum vitamin D had 17% less risk of developing advanced lung cancer compared with the lowest quantile. Men with blood serum vitamin D levels less than 30 ng/ml had 2.6 times greater likelihood of having an advanced form prostate cancer at time of diagnosis. People with lower vitamin D were four times more likely to develop aggressive melanoma. Women with malignant melanoma took in only 311 IU Vitamin D per day, about half the RDA of 600 IU/day. (Garland recommends 4000 IU daily; very few foods contain Vitamin D). In several clinical trials, women with advanced breast cancer administered Vitamin D dietary supplements showed significant improvements in quality of life and prolongation of survival time.
For Vitamin C, a key observation is that intravenous infusions are necessary to achieve the higher, steady state blood levels observed to benefit cancer patients. Clinical data suggest that high-dose Vitamin C infusions improve survival in advanced cancer patients. A study on IV vitamin C for cancer, conducted in 2012, focused on the inflammatory component of cancer. When cancer tumors are growing, there’s typically an inflammatory response in the local area. Elevated inflammation can worsen prognosis and shorten survival times in many forms of cancer. The researchers treated 45 patients with lymphoma or prostate, breast, bladder, pancreatic, lung, thyroid, or skin cancers with high-dose, IV vitamin C. In three-quarters of the patients, vitamin C treatment resulted in decreased levels of tumor markers which suggests that, over the long term, treatment with IV vitamin C would improve prognosis and survival rates in cancer patients. The study also tells us that it is probably impossible to achieve blood levels of vitamin C high enough to treat cancer by taking oral supplements.
Some cancer treatment studies had been conducted with Vitamin A (and analogue carotenoids and retinoids), which were limited by toxicity. Preliminary clinical studies suggest that micronutrients in combination are more effective than single ingredients.
A few botanical remedies, appropriate to consider this holiday season, include Boswellia, commonly known as Frankincense. It appears to distinguish cancer from normal cells, which could be helpful in targeting treatments, and avoiding toxicity of chemotherapy in advanced cancer. One study showed that frankincense could reduce the effective dose needed for cancer chemotherapy drugs. Its has been clinically demonstrated to reduce chronic inflammation, a sign of increased aggressiveness in advanced cancers. In a recent clinical trial, frankincense significantly reduced brain swelling in patients with advanced glioblastoma.
Mistletoe, or Iscador ®, is administered only by direct injection into or near the tumor site in advanced cancer patients. It is currently practiced in Germany and Switzerland, where over 80,000 patients have been treated over the past century. The evergreen tree, Pacific yew, from which the drug Taxol was derived, is used clinically for its activity against advanced breast and ovarian cancers.
Various mind-body therapies, such as biofeedback, hypnosis, mindfulness, meditation and yoga, have improved survival (through effects on cancer progression, primarily mediated by immune system), and quality of life (primarily through reduction of anxiety, depression, pain and stress, and side effects of chemotherapy), in advanced breast, prostate, and other cancers in multiple trials.
Clinical practice has yet to establish standard cancer treatment protocols routinely incorporating natural remedies, but available evidence suggests the value in CAM for advanced cancer. As Dr. George Lundberg says: what works is not ‘alternative,’ or ‘complementary;’ what works is just good medicine.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Best Use of Palliative Care in Cancer Patients

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Malinda Bell, MD, Associate Professor Michigan State University College of Human Medicine; Clinical Associate Professor Western Michigan University Dept of Emergency Medicine

Q: Many, even millions, of Americans are living with advanced cancer. You are a board certified Emergency Physician and also boarded in Palliative Care. Please explain the fundamental premises, promises, and practices of palliative care for cancer patients.
A: “Quality of life” defies a singular, concise definition and thwarts researchers’ attempts to be measured. It is easier to express a personal definition of what isn’t quality of life i.e. “Don’t ever put me in a nursing home,” or “I never want to be kept alive by machines.” A cancer diagnosis changes everything and ever after. In best-case scenarios involving serious illness, “quality of life” becomes less about negatives and more about individualized, ongoing, informed conversations. Such communication happens when a Palliative Medicine (PM) specialist is invited to collaborate in cancer care.
When a cancer outpaces a prescribed oncology regimen, it is not uncommon for the patient to feel hopeless. The oncologist, “battling” cancer, may be reluctant to transition to a treatment plan focusing on quality rather than quantity. This is fertile ground for PM; it’s our wheelhouse in anydisease that is life limiting. A patient should never hear: “There’s nothing more we can do.” Such words are the greatest disservice and opinion any physician can deliver. When cure is no longer possible, PM replaces despair with a new road map—“Let’s get you where you want to be.”
Scrupulous symptom management is a primary focus of PM. Pain, dyspnea, nausea, even constipation can be bothersome but depression, anxiety, grief, and spiritual distress are under-recognized comorbidities that are often managed successfully by PM. We don’t have more time than other physicians, but our consultations offer the expertise of a multi-disciplinary team to benefit our colleagues, patients and families.
Administrators want PM involved “early” because more visits garner more reimbursement. Discharge planners want us involved under the guise of “care coordination” but we must not be confused with case managers. Some PM physicians promote same-day consultation for newly diagnosed cancer as “low hanging fruit” or “job security.” As a boots-on-the-ground specialist, I believe PM can be introduced too early. Our oath is Hippocratic, not bureaucratic. Adding one more specialist in this immediately vulnerable time creates undue stress and is likely to be confused with “hospice,” our closely related cousin.
A properly timed PM consult is an invitation to board a moving train: even if we can’t change the direction, destination, or timetable, our presence can address or alleviate many common fears such as dying in pain. PM physicians typically have a series of conversations with patients and families to help get “affairs in order.” Facilitating a “life review,” we often unpack decades of emotional baggage that foster understanding and healing opportunities that might otherwise be missed.
Do we extend life? Studies suggest “perhaps” or “no.” Do we reduce the cost of care at end-of-life by reducing ICU days? Sometimes. Do we excel in symptom management? Absolutely. PM is not available everywhere and fellowships are few but it can still be studied and practiced. I observed physician mentors, who may not have had all of the answers but didn’t hesitate to enter the sacred space with a patient who had been given difficult news. One of my patient’s daughters summarized the role of PM when someone asked, “What does Dr. Bell do exactly?” She replied, “She heals hearts.” We certainly try.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Will Advanced Computing Help Eradicate Cancer?

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Helen Sadik, PhD, Scientific Knowledge Engineer, CollabRx

Q: Computers and artificial intelligence show both great progress and great promise in many fields. Can “Big Data”, A.I., and the Watson ilk devise a way to end cancer?
A: In 2011, a young and emotionless Watson grabbed the tech industry’s attention by dominating Jeopardy’s two greatest champions. That night, the show was not at all about the $1 million prize. Instead all eyes were on the one-of-a kind contestant: Watson, IBM’s supercomputer. Watson had just proved that intelligent machines can understand, process, and respond to questions posed in human language.
A few years later, artificial intelligence (AI) exploded into many information-intensive industries with its market expected to reach $47 billion by 2020. But young Watson had one main career in mind since its inception: healthcare. It entered medical school in 2011 and graduated in 2 years.
So how can AI change the oncology field? According to a paper published by Michael Schatz in the journal PLoS Biology, genomic data is likely to generate the most raw data in the next ten years–data which holds answers to many health questions. While understanding and finding patterns in this enormous amount of data might seem impossible for the human brain, cognitive computing capable of ingesting data that analyzes and self-learns without forgetting might hold the key to uncovering the answers.
AI can therefore revolutionize oncology care, save doctors time, and save patients’ lives. Because supercomputers store millions of oncological records which they can rapidly analyze and cross-reference, their deep learning ability has the potential to:

  • understand the genetic profile of a patient and offer evidence-based, personalized treatment options
  • provide accurate interpretation of medical images, faster diagnosis, and appropriate treatment options
  • treat rare cancers
  • advance resistance research
  • improve and accelerate new drug discovery
  • optimize patient identification and clinical trial matching
  • assist in health management and remote patient monitoring
  • democratize access to healthcare, and expand knowledge from one specialist to any doctor

It is important to emphasize that the success of AI and deep learning relies heavily on the existence of a large, accurate training dataset, which in turn, relies on human input and effort. Therefore strong collaboration and data sharing between supercomputer developers and healthcare systems are essential. Not surprisingly, for instance, IBM Watson Health is partnering with more than a dozen leading cancer institutes to develop Watson for Genomics.
As the excitement of using AI in healthcare grows, the concerns about AI will grow as well. These concerns display a general lack of trust in machines and include patient record privacy and confidentiality, effective analysis of precarious studies, and the potential for human replacement. The latter fear is augmented by warning from experts such as Stephen Hawking who caution that AI could evolve faster than the human race, and that “…success in creating AI would be the biggest event in human history. Unfortunately, it might also be the last.”
Although this point is beyond the scope of this article, it is worth mentioning that caring for a patient involves more than just finding a diagnosis and administering a cure. It is about evolving continuous relationships between the patient, the doctor and the health care team. Even if Watson and similar robots are starting to learn to act more human by analyzing emotions, tone, and personality, machines won’t be able to replace meaningful relationships between patients and practitioners because AI still lack real human feelings and morals.
Back to the main question: Can AI devise a way to end cancer?
AI is still in its infancy. Its biggest promise is to amplify human ability and augment their intelligence. It has the potential to become the doctor’s closest advisor, providing better and faster diagnostic and treatment tools to improve patient care and quality of life. But will it find an end to cancer? Only the future can tell. The hope is that it will speed up discovery and put us closer to the finish line.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

The Essential Value of the International Committee of Medical Journal Editors (ICMJE)

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Catherine D. DeAngelis, MD, University Distinguished Professor Emerita, Johns Hopkins University School of Medicine; Professor of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health; Editor in Chief Emerita, JAMA

Q: The internet has produced mass democratization of information provision and access with little quality control. You represented JAMA at the International Committee of Medical Journal Editors (ICMJE) for over 10 years. How important is the ICMJE in protecting quality and ethics?
A: Since 1978, when a group of high impact medical journal editors representing several countries first met, the ICMJE has played a major role in setting standards for the ethics, preparation, and formatting of biomedical manuscripts. The current membership consists of thirteen medical journal editors and representatives of selected related organizations including the National Library of Science and the World Association of Medical Editors (WAME). These individuals work together to improve the quality of medical science and the reporting of such science.
The ICMJE publishes recommendations for the conduct, reporting, editing and publication of scholarly work in medical journals. These guidelines, primarily for authors, reviewers and editors, are available on line for anyone. ICMJE developed these recommendations to review best practices and ethical standards for the conduct and reporting of research and other material published in medical journals. The recommendations also help authors, editors, and others involved in peer review and biomedical publishing create and distribute accurate, clear, reproducible, and unbiased medical journal articles. These guidelines have also provided useful insights into the medical editing and publishing process for the media, patients and their families, and general readers.
One example of the important role the ICMJE has played in helping to assure the ethical publication of sound research occurred in September 2004 when the editors published a joint editorial regarding the registration of randomized clinical trials. At that time the law in the United States required that all clinical trials be registered in clinicaltrials.gov as soon as the first patient was enrolled. Very few such trials were registered because no one enforced the law. This put editors in a quandary because they had no idea if the submission of a manuscript that described a trial accounted for other trials using the same intervention (often a drug or medical device). In addition, editors looking at a manuscript’s trial did not know the results of those other trials or if the other trials were performed in different populations.
The joint editorial by the ICMJE editors announced that they would not publish any unregistered trials. This essentially meant that they also would not even review such manuscripts. The editors gave investigators a year to enroll the ongoing trials, but after September 2005 no unregistered trial would be published. This caused a great kerfuffle especially among the pharmaceutical and medical device manufacturers. However, the ICMJE prevailed and since September 2005 essentially all published clinical trials have been registered.
The numerous journals that follow the ICMJE recommendations are listed online and allow authors, reviewers, the media and others to know if the journal to which they plan to submit a manuscript or to review a publication follows the ethical and scientific guidelines.
The ICMJE has no legal jurisdiction. However, the respect shown for its leadership and the influence it has had on medical journalism for the past thirty-eight years cannot be questioned. The importance of having guidelines to assure honest reporting is more important than ever with the expanding use of online and print, non peer-reviewed publications by foundations and other institutions.
Hopefully the influence of the ICMJE will continue for as long as medical publications in any form exist.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Making Cancer Care Great Again

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Michael L. Millenson, President of Health Quality Advisors LLC and an Adjunct Associate Professor of Medicine at Northwestern’s Feinberg School of Medicine

Q: Donald Trump’s campaign for the presidency included a promise to repeal “Obamacare” in its entirety. If he succeeds in fulfilling that promise, what impact can we expect on American cancer prevention and cancer treatment?

A: Donald Trump, emboldened by eliminating ISIS, ending illegal immigration and energizing the economy, will eradicate cancer. Or at the very least, I predict, he will append it to his list of promised achievements as president.
Our current chief executive, dubbed “No Drama Obama” by his staff during the 2008 campaign, couldn’t resist the heady promise of a cancer “moonshot.” Trump, who’s declared, “I will take care of ISIS,” “close up those borders” and “jump-start America,” will likely rev up the rhetoric back to Nixonian “War on Cancer” levels.
A candidate whose campaign centered on his personal pledge to “make America great again” will surely be galvanized by the chance to make cancer care “great,” too.
The current Cancer Moonshot initiative, featured in President Barack Obama’s last State of the Union Address, is codified in a presidential memorandum of Jan. 28, 2016 and placed within the Office of the Vice President. While fighting cancer was of deep personal interest to Vice President Joe Biden, Vice President-elect Mike Pence was governor of Indiana, where pharmaceutical giant Eli Lilly has a major portfolio of oncology products. Coincidentally, Lilly in October introduced a new version of its PACE Continuous Innovation Indicator (CII), a customizable, online tool to review progress against cancer in order to inform public policy and accelerate innovation.
The current executive director of the Cancer Moonshot initiative, Greg Simon, was an aide to former Vice President Al Gore. But Simon is also a cancer survivor and entrepreneur who once worked for New York City-based Pfizer. He came to his current post from FasterCures, a foundation whose work has strong support among Congressional Republicans.
Whether enthusiasm for anti-cancer combat entails increased funding remains to be seen. However, a Trump administration may downplay cancer prevention. Recent research among a population of mostly white Americans aged 25 to 79 found that lifestyle changes related to smoking, drinking, diet and physical activity can reduce the risk of dying from cancer by 14 to 61 percent. Given the central role played in Trump’s electoral triumph by a working class population more prone to those behaviors, I wouldn’t expect a lot of new government nagging.
And while the Centers for Disease Control and Prevention has recommended that pre-teens be vaccinated against the HPV virus, linked to a series of cancers transmitted through sexual activity, I wouldn’t expect this to be an area where President Trump speaks out publicly, either.
Some current cancer patients are reportedly “frantic and scared” that Trump’s vow to ax Obamacare (a/k/a the Affordable Care Act) will sweep away its ban on lifetime dollar limits on coverage and its protection against denying coverage to those with pre-existing conditions. Trump has said he plans to keep both those prohibitions, but those who are sick remain worried. If the provisions are repealed, said a 32-year-old mom with breast cancer, “I can’t afford treatment and I die.”
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

How to Control American Drug Costs

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Brian Klepper PhD, Health Care Analyst, CEO of Health Value Direct and an advisor to The Lundberg Institute

Q: Many newer (as well as many older) drugs are of great value in treating many diseases. But the prices charged seem very high and rising, causing serious concern for many. Is there anything the United States can do to control these costs?

A: We can do a lot to control drug costs, but success will take the cooperation of Congress and the legislatures, which are fundamentally in the drug industry’s pocket.
The industry lavishes money on Congress to buy that favor. Open Secrets data show that the pharmaceutical/health products sector, the most politically influential industry, gave Congress $3.3 billion in campaign contributions between 1997-2015. That largess averages out to $183 million annually over that 18-year period, or a stunning $343,000 per legislator per year. Within these dynamics, every relevant law and rule is spun to favor the interests of the drug industry over those of the American people.
In an excellent recent JAMA article on the sources of US drug pricing, Kesselheim et al. point out that influence over policy has translated into two core problems: “granting government-protected monopolies to drug manufacturers, combined with coverage requirements imposed on government-funded drug benefits.”
Consider Congress’ prohibition against Medicare negotiating drug prices. Millions of patients’ medications are subsidized by Medicare, which pays whatever price is demanded. It’s hard to imagine a better deal than the purchaser allowing the manufacturer to set any price, with the guarantee that the bill will be paid.
These dynamics translate to harsh realities. Federal programs are required to cover most products – including those with sub-optimal performance – priced at whatever the market will bear. To a large degree, the commercial health plan sector follows suit. No rational market rules guide the way we currently buy drugs. We don’t require pricing to be tethered to what’s paid in other industrialized, international markets, or tied to the value delivered in care avoided or Quality-Adjusted Life Years gained.
For perspective, consider a 2015 JAMA Int Med study showing that between 2008-2012, 86 percent of the drugs approved with surrogate endpoints and 57 percent of cancer drugs approved by the FDA “have unknown effects on overall survival or fail to show gains in survival.” In other words, the authors write, “most cancer drug approvals have not been shown to, or do not, improve clinically relevant end points.” Realizations like this make clear the need to identify the measurable improvements that existing or new drugs represent. That would provide a rational way to value and price a drug.
Recently efforts have been afoot to tie pricing or purchasing decisions to known value. For example:

  • The American Society of Clinical Oncology recently unveiled its drug value framework, which evaluates new cancer therapies based on clinical benefit, side effects, and improvements in patient symptoms or quality of life in the context of cost.
  • The Center for Health Policy and Outcomes at Memorial Sloan Kettering Cancer Center is also focused on the price and value of drugs, under the belief that more rational pricing could increase patient access to important medications while driving innovation.
  • The Institute for Clinical and Economic Review (ICER) independently assesses the value of new drugs, guided by four questions:
    1. How well does the drug work?
    2. How much better is it than what we already have?
    3. How much could it save us?
    4. How much would it cost to treat everyone who needs it?

In other words, methodologies to achieve value-based drug pricing are well within reach, but the industry will resist with all its power and influence. Secretary Clinton is focused on this area, and believes that leadership can mobilize the agents of reform to make meaningful change achievable. That is what it will take.
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.

Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

Expanded-Compassionate Use of an Investigational Drug

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Vivek Subbiah, MD, Assistant Professor, Department of Investigational Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

Q: You have exhausted surgical, radiation, and standard chemotherapy options for a patient with an advanced epithelial malignancy. Yet the patient has a strong will to live and to advance science during palliative care.  No active clinical trial is available. How would you evaluate pre-clinical data to try to identify an investigational drug for “expanded-compassionate” use?

A: Thank you for the question. This is a challenging situation. It is subjective and complex.
My answer – “it depends”. Let me give you 2 scenarios.
Scenario A: A 30-year-old surgeon, recently married with the love of his life who has just graduated from a neurosurgery residency, is expecting his first child and diagnosed with Stage IV non-small cell lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. Has a strong will to live.
Scenario B: An 85-year-old man, who has a wife in the nursing home and a son in California and another son in Australia has been diagnosed with Stage IV non-small lung cancer. Has exhausted radiation, surgery, and standard chemotherapy. He lives alone and has a declining PS with multiple co-morbid conditions.
In the first case, yes, as an experimental investigator I would go to any lengths to try to provide investigational drug for expanded-compassionate use.
In the second case, I would likely arrange a family meeting to discuss the reality and lean towards providing best supportive palliative care.
Breakthroughs in oncology or any other field infers that successful outcome in the face of what was considered impossible. We all live in the future. If we do not take risky experiments, breakthroughs cannot be made. It could be argued that there is a 1 in 100 chance that the investigational agent for expanded compassionate use works. I would say that the chance is ONE and not zero. For his mother, father, wife and future child it is HOPE. It is with this hope that we live in.
How do I evaluate the pre-clinical and/ or clinical data for justifying compassionate use?
I refer you to the webpage of Personalized Cancer Therapy at MD Anderson. Here there are quite a few resources to define actionability of a gene. I am highlighting the main aspects from that site as below:
Actionable Gene: A gene is deemed actionable if 1) there are clinically available drugs that directly or indirectly target tumors with genomic alterations in the gene of interest with minimally preclinical evidence of their use in tumors with alterations in the gene of interest, and/or 2) there are clinical trials specifically selecting for patients with tumors harboring genomic alterations in the gene of interest.
Actionable Variant: A variant is deemed actionable if all of the following criteria are met: 1) the variant occurs in a gene deemed actionable, 2) the alteration type (mutations, amplification, etc) for that gene is deemed actionable, and 3) there is either published literature or data from the MD Anderson Zayed al Nahyan Institute for Personalized Cancer Therapy (IPCT) functional genomics platform that the alteration is likely to be tumor promoting (e.g. activating mutation in an oncogene or inactivating mutation in a tumor suppressor), or there is evidence that the variant confers sensitivity or resistance to a clinically available therapy.

Table 1
Precision oncology decision support level of evidence classification: level of evidence for drug effectiveness in a specific tumor type harboring a specific biomarker*

Level 1
1A | Drug is FDA-approved for the same tumor type harboring a specific biomarker.
1B | An adequately powered, prospective study with biomarker selection/stratification, or a meta-analysis/overview demonstrates a biomarker, predicts tumor response to a drug or that the drug is clinically effective in a biomarker-selected cohort in the same tumor type.
Level 2
2A | Large-scale study demonstrates a biomarker is associated with tumor response to the drug in the same tumor type. This could be a prospective trial where biomarker study is the secondary objective or an adequately powered retrospective cohort study or a case-control study.
2B | Clinical data that the biomarker predicts tumor response to drug in a different tumor type.
Level 3
3A | Single or few unusual responder(s), or case studies, show a biomarker is associated with response to drug, supported by scientific rationale.
3B | Preclinical data (in vitro or in vivo models or functional genomics) demonstrates that a biomarker predicts response of cells to drug treatment.
Bottomline, is that clinical studies provide highest level of evidence and pre-clinical studies lowest level of evidence (but at least provide some evidence for hope in the face of nothing).
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.