Conflict of Interest in Medical Research

In September 2018, Dr. José Balsega, chief medical officer of Memorial Sloan-Kettering Cancer Institute, ignominiously resigned from his position after a scandal engulfed the institution. In a searing article of ProPublica, which conducted the investigative reporting together with the New York Times, he was accused of clandestinely receiving millions from pharmaceutical companies and never reporting it in many scientific articles that he produced as first or secondary author.

Co-authors Charles Ornstein and Katie Thomas said: “ he has held board memberships or advisory roles with Roche and Bristol-Myers Squibb, among other corporations; he had a stake in start-ups testing cancer therapies; and played a key role in the development of breakthrough drugs that have revolutionized treatments for breast cancer…Balsega did not follow financial disclosure rules set by the American Association for Cancer Research when he was president of the group. He also left out payments he received from companies connected to cancer research in his articles published in the group’s journal, Cancer Discovery.” There are no rules for those who make them.

Considering that modern medicine, with its over-reliance in the biological model, has the capacity to sanction or condemn any new drug or treatment based on the opinion and data of the peer-reviewed medical journals, this lack of clarity in the disclosure of financial interests is very serious. For two decades there have been many honest professional efforts to police the rank and file. In April 2009 the Institute of Medicine (IOM) released a report where it recommends to “standardize the content format and procedures for disclosing financial relationships” and at the same time that these policies should be publicly available, preferably in the institution’s official website. In the past ten years, institutions and professionals have been grappling with this still searing issue.

In an article in Neurology Today, Dr. Corey Ford, professor of neurology and dean of research at the New Mexico School of Medicine said that: “a researcher may be required to only enroll patients in a study, but not to analyze the data or have any influence in the output portion.” With these institutional firewalls, the risk of a biased opinion of the whole process is greatly diminished. Another troublesome aspect is the channeling of companies’ payments directly to the researchers’ pockets in the form of the consulting fees, stipends for board memberships, speaking fees, etc. Dr. Kenneth Tyler, from the University of Colorado, said that all the outside activities of physicians must be channeled through the physician practice plan of the institution for a better oversight.

At the University of New Mexico there is a special institutional review board for senior officials above a certain level where all the major donations and gifts of private companies are scrutinized; moreover, all the outside collaborators in any program must fill the disclosure forms as well. The relationship of academia and the industry can be mutually beneficial as the latter can provide skills, technologies, scale and capital for bonafide initiatives that will serve the public at large. But it must be outlined in advance of any implementation in a way that is convenient for public access, rather than the often-cryptic institutional electronic disclosure systems. It must be cloud-based. There is still a long way to go before there is a truly honest, accurate and straightforward exposé of all the significant medical data in our society.

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Age, sex and race discrimination in clinical trials–part I

Clinical research trials are the scientific bellwether to determine the safety and efficacity of the new pharmaceutical products that submit an application for approval to regulatory agencies. However, in the past decade many prominent researchers have questioned the bias against age, gender and race in the selection of individuals that wish to participate in these critical studies. Some good retrospective studies have studied those bias and their consequences in the studies. Most studies use a cohort of middle-aged white men that are progressively less representative of the general population in the USA, which has wide race, cultural and lifestyle differentials now.

Health Equity implies the attainment of fair, equitable access for health care services and the participation in clinical research trials that will determine the future of our modern pharmacopeia. It mandates the reconsideration as a whole of the protracted discrimination against minorities and special age groups in order to develop policy and practice protocols to assure equitable access.

In the USA the elderly population is growing rapidly due to the improved healthcare resources and the Wellness interventions in Baby boomers that consume less alcohol, tobacco, animal fat and other noxious substances that severely limited the lifespan of the previous generations. But the entrance to the third phase of our lives entails the arrival of diseases like high blood pressure, diabetes and arthrosis that do not similarly affect the younger and middle-aged members of society. When an elderly patient is admitted to a hospital , there are usually a few co-morbid conditions. Finally, the expense on elderly care represent the largest share of care budgets in modern societies.

Dr. Jaron Lockett et al. examined the Phase III clinical trials funded by the National Institutes of Health from 1965 to 2015 that studied the major causes of hospitalization or disability in older individuals, which are congestive heart failure, cardiac arrhythmias, coronary atherosclerosis, myocardial infarction, stroke, chronic obstructive pulmonary disease, pneumonia, lung cancer, prostate cancer and osteoarthritis. They found that 33% of these studies had arbitrary age limits that excluded older people and 67% of them had  participants witha median age that skewed younger than the usual age of onset for the clinical condition being studied . The presence of co-morbid conditions like polypharmacy/concomitant medication excluded 37% of the cases and cardiac diseases excluded 30% of the potential participants. This underrepresentation of older individual due to age limits and exclusion of patients with common co-morbid conditions in older age severely limit the usefulness of any novel medication that might target the older population.

Historically women have been largely excluded from the major clinical trials, which has hampered the real usefulness of many medications that do not take into account the biological and cultural differences of women and members of the LGBT communities. The biological differences of women provoke pharmacokinetic and pharmacodynamic variations due to their smaller body size, higher fat and less water content, hormonal variations and varying levels of certain body enzymes. The fluctuating levels of hormones during the menstrual cycle and in pregnancy coupled by the metabolic changes when they use contraceptives must be considered when the effects of study drugs are being assessed by researchers. The particular mental and physical construction of gender and sexuality will influence the feminine lifetime experiences and health outcomes.

Minorities like Blacks and Hispanics have largely been under-represented in clinical trials due to absurd discriminatory guidelines that favored a certain segment of the population. The often-cited excuse that the “minorities do not sign up in good numbers” has been disqualified by the surging participation of them when they are properly, respectfully asked to participate in the clinical trials. Mechanically extrapolating all the scientific results obtained with a largely white middle class population can have disastrous consequences for the future treatment of grave chronic diseases. Three recent studies have highlighted that limitation in critical studies on Alzheimer’s Disease.

Dr. Melissa Murray has been the lead investigator in the seminal “Florida Autopsied Multiethnic” (FLAME) retrospective cohort study that examined the records of 1625 deceased Alzheimer’s Disease patients self-reporting as Hispanic/Latino (n=67) Blacks (n=19) and White Americans (n=1539)  The investigators found that: “Hispanic decedents had  a higher frequency of family history of cognitive impairment (58%), an earlier age of onset ( a median of 70 years).longer duration of the disease 9 a median of 12 years) and lower MMSE proximal to death 9 median of 4 points) Black decedents had a lower Braak Tangle stage ( stage V) and a higher frequency of coexisting hippocampal sclerosis (21%) compared to other groups.” The results seem to suggest that there are clinical differences that might affect the effectiveness of the treating medication.

Dr. Mungas et al. found that Hispanics and Black Americans were more likely than White Americans to have post-mortem neuropathological changes of Vascular Disease; they cautioned that the results must be evaluated with caution as only 67 Hispanics and 19 Blacks were included in this study, compared to 1539 White Americans. However, the suggestion that Vascular Disease may play a bigger co-morbid role in the evolution of AD in Minorities opens the door for the evaluation of opportune care and wellness interventions that would improve the health outcomes for these patients.

The growing use of blood biomarkers for the early detection of Alzheimer’s Disease—before the devastating clinical symptoms appear in a patient—has markedly changed the treatment schedules; the presence of apolipoprotein E4 (APOE4) have been shown to be the strongest genetic risk factor. Sid E. O’Bryant et al. analyzed the serum of 363 Mexican Americans (49 patients with AD and 314 normal controls) and found that AD patients had a lower concentration of APOE4 in blood. How could that be if the presence of that blood biomarker had been singled out as pathognomonic? Perhaps its presence, for still unknown reasons, is not clinically significant for the Mexican Americans. We should determine the biological risks for AD across a larger spectrum of different ethnic groups in order to design efficient therapies to control the disease. We still have much to learn.

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Reform at the NHS England

The recent overhaul of the American health care system, which has been inappropriately referred as “Obamacare” by the media, and the frantic efforts of the new American administration to dismantle it—so far unsuccessful but time will tell—has brought some forced comparison with other care systems; some policy pundits have insolently dubbed it as the “Anglicisation” of our highly fragmented health care delivery system.

Since the health care reforms of Premier John Major—who enacted the “internal market”—and Premier Tony Blair—who instituted the “patient choice”—the health policy experts in the United Kingdom have been talking non-stop about the ongoing “Americanisation” of their venerable National Health Service (NHS). In 1948, the UK authorities created a universal health care coverage for every Briton, who were mostly impoverished after the World War II and the loss of their colonies. Citizens and pundits alike have denounced those modernization drives as a “Trojan horse” to force the entry of the “private sector” in an extremely revered and popular British institution.

What the two health care systems have in common is the following: their citizens live longer and are consuming a higher percentage of public and private financial resources in a technologically-driven medicine. In the USA the Medicare and Medicaid systems have been slowly replacing the fee-for-service system for a more integrated and efficient system of “managed care” that must be accountable. In Britain, the timid introduction of some kind of accountable care has sparked a vivid rebuke of organized citizens groups and the media that have denounced it as illegal because voters had not approved it.

James Meeks wrote in the “London Review of Books” an excellent review of the present reform in the United Kingdom with the forthright description of two universe. “In universe one, the NHS will be upturned to give most of the healthcare people need at home or on their doorstep and admit to the big hospitals only patients with major trauma, or suffering diseases that demand intensive care, or complex surgical or biochemical expertise. Big hospitals are to become centers of research, high technology, rare skills and dramatic, life-saving interventions.” In contraposition to that ideal, clean environment the author describes the other universe. “In universe two a counter-reality prevails: the reality of winter, the reality of need, the reality of an ever increasing number of frail, elderly people converging on the help of last resort, the emergency hospital.”

In the United Kingdom the combination of a providential welfare state and a good universal health care system has led to the marked prolongation of life expectancy for men and women alike. However the entry into an ever older age has brought the emergence of “multiple co-morbidities” in their clinical condition. Nowadays a patient that has a peak of high blood pressure must be treated taking into consideration that he/she might be also diabetic, or suffering form renal diseases, or a neoplasia. As a result, efficient and comprehensive long-term care for the elderly and disabled is a high time and resources-consuming endeavor. Sadly, even though elderly people might elicit compassion and understanding at an individual or family level, they are mostly ignored by the younger generations that work and fill the purse with their salary deductions. That commiseration does not translate into the civic approval of more funding. Younger citizens are usually in a state of “self-denial” about their own future fragility in old age.

Meeks studied the reform in Leicestershire, a miniature expression of modern England: densely populated, a dynamic economy and a younger population, many of them immigrants and students. It’s on the south-eastern rim of the Industrial Revolution of the 19th century, it has three Labor elected representatives and it narrowly voted to stay (Remain) in the European Union. The counties surrounding Leicester are very different as they comprise extremely well-off areas where the country gentlemen live and run-down districts that could not recover from the modernization. It is a whiter, older world where the need for home health services and ancillary support is stronger. The Lansley reform—named after the Conservative health secretary Andrew Lansley—created seven local organizations as the point of delivery in Leicestershire.  The “Clinical Commissioning Groups” (CCG) are aggregation of general practitioners located at the city of Leicester and the east-west ends of the area. The Royal Infirmary Hospital, which has the largest Emergency department in England, is run by the “University Hospitals of Leicester Trust.” The “Leicestershire Partnership Trust” runs all the community care services, including Mental Health and the Prisons.

Meeks found that the authorities of Leicestershire have implemented a virtual system 256 bed “hospital” called “Intensive Community Support” (ICS) where the convalescent patients are being treated by nursing and ancillary personnel in their own residence. There is an integral, holistic approach to the patients that are discharged from the hospital as the home health personnel, social workers and ancillary personnel are being scheduled and supervised by the same administration. The author found that the altruistic objectives—like being able to access a local doctor until 8 PM seven days a week—are not completely attained, with some district areas worse than others. The push for cuts in services that are prodded by the central authorities of the NHS could not prosper.

Considering that the population of Britain is growing in overall number and longevity, there is dire financial need for more staff, more material resources, more distributive planning. Besides the demographic inflation, there is the salaries’ inflation to account for as the health care system is run by persons with increasing needs in a modern economy. In order to compete in a tight labor market for talent and expertise, the health care organizations must offer better benefits and good pay. The “Baumol cost disease”—named after the economist William Baumol—describes the asymmetry between industries like manufacturing that can be automated and require less workers with the ones like health care that cannot be readily automated and still require large number of employees.

Many citizens of modern societies like the UK and the USA (certainly not all and not in the same degree) are enjoying one of the biggest prolongations of their average life spans with an ensuing ability to continue enjoying their activities, including postponing their retirement and working into their late 70s. But they certainly are afflicted by chronic diseases like high blood pressure, diabetes, arthrosis, which require regular medical check-ups and proper long-term treatment. Young people will eventually reach that stage too and if they now refuse to fund the existing long term care services for elderly people, they will be dismantled by myopic bureaucrats that only know how to count beans. Watch out, Millennials. Those services take years to design and put up; they will not be available for you in your golden years if you don’t protect them now with your voices and votes. But there is a positive economic variable at play.  William Baumol considered that the efficiency savings in the manufacturing sector will eventually liberate more funds to invest in health care. Let’s hope that politicians don’t squander those funds.

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Disparities in access to Palliative Care

Access to good, timely and comprehensive Palliative care is one of the great advancements in modern medicine as it has improved the quality of life of patients and their families. However, there are still major disparities in its access, especially for members of vulnerable communities like Minority populations in the USA.

One of the most disseminated and fallacious “truths” circulating in the hospital corridors and medical offices in this great country is that Minorities, i.e. Blacks and Hispanics, do not care much about Palliative Care for socio-cultural reasons. It is true that disadvantaged members of society usually fear, with good reason, that they will be summarily treated and later abandoned by the medical establishment. They view the possibility of Palliative Care as an excuse to withhold necessary care. To complicate matters worse, many minority patients are deeply religious, for which they are confounded by the mixed messages emanating from their traditional churches.

Faigle et al. published an online article where they suggest that the culprit for this glaring inequity of access is actually the systems implemented in certain hospitals, using the data from the ICD-9-CM codes stored in the Nationwide Inpatient Sample (part of the Healthcare Cost and Utilization Project) They found that Minority patients received less PC than whites but also discovered that the same was true for all the patients admitted to largely Minority-serving hospitals.

In predominantly white hospitals., the researchers found that the median rate for the use of Palliative Care in post-Stroke patients was 8.5 per 100 ICH admissions but in mixed or largely Minority-hospitals the median usage rates were 6.3 and 2.5 per 100 ICH admissions respectively. The usage of Palliative Care after Ischemic Stroke was 2.2 per 100 admissions but it lowered to 1.5 in mixed facilities and a dismal 0.5 in largely Minority-hospitals. This data was controlled for demographics, comorbidities, socio-economic factors, hospital features and stages of the disease.

Important variables in the system were the implementation of sound institutional algorithms that could alert the medical personnel that the services were available.

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Medical kits for prenatal care

Sometimes “a little” can mean “a lot” in the daily lives of long ignored, underserved communities.

In under-developed countries the rates of maternal and newborn morbidity and mortality are scandalously high in spite of longstanding intervention by the public and private agencies, especially in the Sub-Saharan countries. The critical factor is to engage the pregnant women at the point of care entry. The lack of adequate supplies of medical kits is of humongous importance.

Pilar Betrán, Bergel et al. designed a pragmatic, stepped-wedge, cluster-randomised controlled trial at ten prenatal care clinics in Mozambique that followed at least 200 pregnant women per year and had specialized nurses. The Public Health interventions were composed of these components:

  1. Component 1: provision of prenatal care kits with basic medicines laboratory supplies and materials approved by the Health Ministry
  2. Component 2: a place to store the kits was provided at each clinic
  3. Component 3: a login sheet was used to register the usage
  4. Component 4: a training session and refresher course for the nurses

Ten practices were chosen initially for primary and secondary outcomes:

  1. Screening for proteinuria
  2. Screening for anemia
  3. Treatment of parasitic women with mebendazole
  4. Screening for high blood pressure
  5. Screening for syphilis
  6. Preventive treatment for malaria
  7. Screening for HIV
  8. Treatment for syphilis

For the three primary outcomes—proteinuria, anemia and parasites—the interventions produced clinically and statistically significant improvements. “5519 (14.6%) of 37826 women were screened for anemia in the control period, compared with 30,057 (97.7%) of 30,772 women in the intervention period…3739 (9.99%) of 37,826 women were screened for proteinuria in the control period compared with 29,874 (97.1%) of 30,772 women in the intervention period…17,926 (51.4%) of 34,842 women received mebendaazole for treatment of parasitic worms in the control period compared with 24, 960 (88.2%) of 28,924 women in the intervention period.” In four of the six secondary outcomes there were also clinically and statistically significant improvements; a small improvement was measured in HIV screening and treatment but it was not statistically significant.

The design and implementation of a woman-centered prenatal supply-chain made a big difference in Mozambique, which sets an example for the rest of Africa.

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The PURE study

In modern nations the importance of consuming fruits and vegetables in order to prevent cardiovascular diseases has been studied extensively. However the same does not hold truth for the rest of the nations until the “Prospective Urban Rural Epidemiology” (PURE) study, a prospective cohort study that involved 135,335 participants aged 35 to 70 years without cardiovascular disease in 18 low, middle and high income countries. Dietary guidelines recommend a minimum of 400g/day of fruits and vegetables but it has not been truly achieved on a global basis due to the cost limitations.

Victoria Miller et al. enrolled participants between January 2003 and March 2103 that responded to standardised questionnaires about socio-economic, lifestyle, personal health and family histories. They studied outcomes like major events related to cardiovascular disease (myocardial infarction, stroke, heart failure) and mortality rates produced by those conditions. Cox models were created to study the association with fruit and vegetables consumption. Potatoes and other tubers, fruit-vegetable juices were excluded; the legumes were beans, black beans, lentils, peas, chickpeas and black-eyed peas.

The authors wrote: “during a median 7.4 years (5.5-9.3) of follow-up, 4784 major cardiovascular disease events, 1649 cardiovascular deaths, and 5796 total deaths were documented. Higher total fruit, vegetable, and legume intake was inversely associated with major cardiovascular disease, myocardial infarction, cardiovascular mortality, non-cardiovascular mortality, and total mortality in the models adjusted for age, sex and centre…Higher fruit, vegetable, and legume consumption was associated with lower risk of non-cardiovascular, and total mortality. Benefits appear to be maximum for both non-cardiovascular mortality and total mortality at three to four servings per day (equivalent to 375-500 g/day)”

The researchers also found that participants that consumed more fruits, vegetables and legumes had higher education, higher levels of physical activity, lower rates of smoking, and higher energy, meat consumption and were more likely to live in urban areas. There was an 11% lower risk of major cardiovascular disease for the highest fruit intake category compared with the lowest category intake; there was a minimum benefit from a higher vegetable input. The authors hypothesized that given that vegetables can be consumed raw or cooked, the latter might have degraded nutrient contents.

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Tuberculosis and HIV

Tuberculosis is one of the leading causes of chronic disability and death in the developing world and is the first one killer of people infected with HIV. The risk of contracting TB increases with HIV, especially after the CD4 counts start to fall and even after the institution of anti-retroviral therapy. Preventive therapy with isoniazid—a cheap and well-tolerated drug—has been instituted for more than five decades with good, measurable results.

Several clinical trials have confirmed the usefulness of the preventive use of isoniazid in people already infected with the HIV virus, even without the availability of proper anti-retroviral therapy for all those patients. A large cohort study in Brazil showed that the use of isoniazid had a synergy effect in patients treated with ART, with a 76% reduction in the TB incidence. However only a million of the approximately eligible people to receive this drug, have been duly treated due to several operational handicaps, including the erroneous perception that it might interfere with the ART efficacy.

Anani Badje et al. published the results of the TEMPRANO study—a randomised clinical trial that focused on the effects of the use of isonaizid in HIV patients with CD4 counts of less than 800 cells per ul but above the threshold for starting the anti-retroviral therapy. The initial results showed that both the use of isoniazid and anti-retroviral therapy reduced the grave clinical consequences of HIV infection and the use of both had the greatest benefits. After 6 months of the use of isoniazid in HIV patients, there was a 37% reduction in the mortality rate that was independent of the ART use.

The results of the TEMPRANO study are encouraging for HIV patients because:

  1. People with high CD4 counts had good survival rates over 5 years
  2. Benefits were noted for people with and without positive tests for TB
  3. Adjustment of baseline covariates did not change the final results
  4. Benefits of the use of isoniazid were independent of the ART

There should be a more forceful design and implementation of isoniazid delivery for the HIV patients who are at high risk of contracting TB and who would benefit the most.

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