Evidence Based Medicine (EBM)

Evidence-based medicine refers to applying the best available research to patient-oriented care. It requires integrating evidence with clinical expertise and patient values. 

The following description from BMJ ( British Medical Journal) Best practice explains EBM as below:

Evidence-based medicine refers to applying the best available research to clinical care, which requires integrating evidence with clinical expertise and patient values.  By best available research, we mean clinically relevant (i.e., patient-oriented) research that:

• Illuminates the accuracy and precision of diagnostic tests,
• Highlights the importance of prognostic markers,
• Establishes the efficacy and safety of therapeutic, rehabilitative, or preventive healthcare strategies or
• Seeks to understand the patient experience.

My medical training in the 1960s was a time when patient care was largely based on the opinions, beliefs, and prejudices of senior authoritative medical doctors. Robust clinical evidence to support treatments, whether at an individual or community level, was a rare commodity. This scarcity underscored the necessity and importance of evidence-based medicine, a concept that was yet to be fully realized. 

During my postgraduate training, I had the privilege of studying under the guidance of two pioneering researchers, Professor John Crofton at the University of Edinburgh and Professor Archibald Cochrane at the University of Wales. Their work was not just influential, but instrumental in the application of scientific studies to establish the efficacy of drug treatments, a cornerstone of evidence-based medicine.

The Medical Research Council (MRC) Tuberculosis Unit at the Brompton Hospital, London,  undertook a trial of streptomycin for pulmonary Tuberculosis in 1946,  a milestone in the history of clinical trials. Professor Crofton’s dedication was instrumental in ensuring strict adherence to the admission criteria, proper random allocation, organization of the standard investigations, and diligent completion of the case records of pulmonary tuberculosis patients in Brompton Hospital. This trial demonstrated that streptomycin was highly effective in treating Tuberculosis in the first few months but lost its efficacy in subsequent months due to tubercle bacilli developing resistance to streptomycin. The MRC team’s commitment to finding a solution led to the discovery that a combination of streptomycin and PAS (Para-amino salicylic acid ) proved far more effective than either alone in treating Tuberculosis and reduced the development of drug resistance.  Several randomized landmark trials by MRC in the UK and other developing countries where Tuberculosis was widely prevalent followed streptomycin trials. The MRC researchers provided much evidence for rational treatment policies for drug treatment of pulmonary Tuberculosis.  Indeed, when Archie Cochrane was pondering which of the specialties within medicine had made the most determined efforts to base policies and practices on reliable research results, he had no hesitation in awarding the ‘gold medal’ to the tuberculosis specialists. I should note here that I have written about Archie Cochrane in an earlier chapter, with whom I spent six months at MRC Pneumoconiosis Research Unit in Cardiff, Wales, in 1967.
In a fitting tribute to Dr.Archie Cochrane, who died in 1987,  the Cochrane Collaboration (CC) was initially established in 1993 at Oxford University and later moved to London, U.K. Cochrane’s members and supporters come from more than 190 countries worldwide, a testament to its global reach and impact. The CC does not accept commercial or conflicted funding so that it can generate authoritative and reliable information, working freely and unconstrained by commercial and financial interests.

Fast forward to 1974: When I migrated to Canada in June 1974, I had to do a residency in Internal Medicine to satisfy the requirements for certification in Canada. I was a resident at McMaster University Hospitals from July 1974 to July 1976. I began my Internal Medicine practice in North America in Milwaukee, Wisconsin, in late 1976. Little did I know that this newly minted University in Hamilton, Ontario, Canada, McMaster University, would be made world famous in the emerging field of Epidemiology twenty years after I left McMaster, by Dr. David Sackett.
David Lawrence Sackett, an American-Canadian physician, made a profound impact on the field of medicine. In 1967, he established the Clinical Epidemiology Department at McMaster University, Ontario, Canada, a milestone that marked the beginning of a new era in medical research. His pioneering work in Evidence-Based Medicine, for which he is known as one of the fathers, has reshaped clinical practice. It was his colleague, Gordon Guyatt, who introduced the term. In the early 1990s, Dr. Sackett was appointed the first Chair of the Cochrane Collaborations Steering Group at Oxford University, a testament to the global recognition of his work.
“According to Sackett, the key components to EBM are (1) consideration of the patient’s expectations (wishes), (2) our clinical skills, and (3) the best evidence available to us. In the past, the dogma of “experts” drove clinical practice patterns. To make this point, Sackett would often tell the story behind George Washington’s demise. George Washington was a healthy individual who rode his horse at the robust age of 68. He developed epiglottitis one day, and his physicians and the experts they called upon for advice all suggested treatment with blood-letting (of eight pints or 40% of his blood !!), a treatment that the ancient Greeks used, rather than tracheostomy that would have saved his life. Thus, the American hero probably died from peaceful iatrogenic exsanguination at the hands of experts. Sackett had a poor opinion about “experts”, who claimed clinical expertise based on their experience. Sackett emphasized that truth can only be found in randomized trials when feasible, thus avoiding the influence of bias.”

There is a hierarchy of evidence, and various organizations have adopted a pyramidal structure of this hierarchy.
The levels of the evidence pyramid provide a way to visualize both the quality of evidence and the abundance of evidence available. For example, systematic reviews are at the top of the pyramid, meaning they are both the highest level of evidence and the least common.
The USPSTF (United States Preventive Services Task Force ) guidelines serve as a benchmark of the EBM approach, offering clear paths for making crucial healthcare decisions to physicians world wide.
UNITED STATES PREVENTIVE SERVICES TASK FORCE has 16 volunteer members who are nationally recognized experts in prevention, evidence-based Medicine, and primary care. Their fields of practice and expertise include behavioral health, family medicine, geriatrics, internal medicine, pediatrics, obstetrics and gynecology, and nursing. A chair and two vice chairs lead the panel.
The Task Force’s panel members are from primary care-oriented specialties. Therefore, their recommendations differ from those of expert panels from Specialty organizations like the American Cancer Society or the American Urology Society. One important point,though,is that these guidelines do not incorporate cost-effectiveness.
USPSTF’s Grade A and Grade B recommendations, based on the strength of evidence, provide preventive services with a net benefit that far outweighs potential harm. Their unbiased approach forms a solid foundation for healthcare decisions.
Evidence-based Medicine has undoubtedly lifted standards of medical care worldwide in the last 30 years. It is the bedrock of scientific medical care all over the world.

However, serious problems have arisen with many trials funded by private industry.  The National Institute of Health (NIH) in the USA and academic medical centers are government-funded institutions that design trials and recommend guidelines based on unbiased research. These trials are designed and conducted by the best and brightest researchers in the world, and their findings are more likely to be in the patient’s best interest. 163 NIH-supported researchers have been sole or shared recipients of 96 Nobel Prizes. Among these are individuals who have served as NIH staff scientists. Studies funded and recommended by the NIH, academic medical centers, or voluntary specialty groups (charities) are unbiased, unlike industry-funded trials that are biased toward making a profit. NIH trials are the gold standard for data and are more likely to be in the patient’s best interest. 
New Drug Trials are expensive, and Big Pharma often funds them. In 2014, Big Pharma paid for 6,550 trials, while NIH funded 1,048, according to a study by Stephan Ehrhardt and colleagues published in JAMA. Industry-funded trials, while numerous, are more likely to have publication bias, publishing positive results and suppressing negative results. This potential harm underscores the need for caution and awareness in interpreting research findings.
Leemon McHenry has highlighted these issues in the book “The Illusion of Evidence-Based Medicine: Distorted Science in the Age of Pharma”. Most drug trials published by Big Pharma do not make raw data readily available( lack of transparency). Pharma’s primary focus is marketing, and they spend enormous amounts of money to increase drug sales by having pharmaceutical representatives visit doctors and by direct-to-consumer advertising.
One egregious example of a drug company supported trial is on antidepressants, summarized below:
Study 329, conducted by GlaxoSmithKline (GSK)  in 2001, was designed for the use of an SSRI ( Selective serotonin receptor inhibitor) drug called PAXIL in major depression in adolescents. Two hundred seventy-five adolescents were enrolled, and the study concluded that Paxil was effective. Practitioners wrote 2 million prescriptions after the study’s positive results. After harmful effects emerged, GSK released raw data from the original trial in 2013. Data was analyzed by Restoring Invisible and Abandoned Trials (RIAT). Paxil’s efficacy was not significant, and other inquiries revealed that GSK had hidden the increased risk of suicidal thoughts from Paxil. As a result of this re-evaluation, GSK settled with the Department of Justice and paid $3 billion for damages caused by Paxil’s adverse effects. GSK cited the original trial 600 times, and even after the settlement with the DOJ, there has been no correction, retraction, apology, or comment from GSK or the study’s authors.!
Stuart Ritchie, a researcher from my alma mater, Guy’s-King’s College Hospital, University of London, has written “Science Fictions: How Fraud, Bias, Negligence, and Hype Undermine the Search for Truth.”
Ritchie highlights an issue that can undermine the integrity of research – ‘p-hacking ‘. It is the practice of manipulating statistical analyses to achieve a significant result. It involves trying different analyses or data sets until publishers report a statistically significant result. These published articles can lead to false conclusions and are a form of scientific misconduct. He has also highlighted several recent issues that embellished the integrity of Science and Truth. These range from fraudulent publications accepted even by the most respectable journals like Nature, Science, and Lancet. They publish only positive trials( hiding NULL or inconclusive results), citation biases with three times more citations for positive results, manipulating statistics to attain a significant statistical probability ( p hacking ,as mentioned already, is the technical term),  Hype and spinning of benefits  (e.g., Nutritional Research is full of Hype). There are perverse incentives on the part of academic institutions based on the principles of “PUBLISH OR PERISH” and QUANTITY over QUALITY(of publications). In the epilogue of the book, he quotes timeless words of counsel. The first is the motto of the Royal Society in the UK: “nullius in verba.” The English translation from Latin would be “take nobody’s word for it.” The second was a quote from a Russian poem when President Reagan was negotiating with Mikhail Gorbachev of the Soviet Union during the Cold War-“doveryai, proveryai meaning Trust but Verify.”
Institutional or individual subscriptions are necessary for PUBMED (MEDLINE), BMJ BEST PRACTICE, DYNAMED, and UPDATE. Patients can only access limited information through a short abstract from these websites.
Healthy skepticism (not cynicism) of well-informed patients when interacting with their health providers is tolerated and respected in the current era, unlike in the early years of my medical career. Unfortunately, in countries like Kenya and India, the “Doctors know best” culture is still widely prevalent, and patients feel apprehensive about engaging their providers, who are often brusque and condescending.

If a reader is further interested in a brilliant Indian American researcher and physician who was passionately committed to innovative newer approaches in his own family’s care, read the following fascinating account by a medical journalist at his bedside during the terminal phase of his advanced malignancy.

Innovations in medical science, driven by the unwavering dedication of researchers, have led to several technological advances in patient care. These visionaries, passionate about their work, are the driving force behind disruptive new discoveries. However, caution is necessary to balance the excitement of these advances with the practicality and potential side effects that patients must consider.
Madeline Drexler, Boston-based journalist and visiting scientist at Harvard T H Chan School of Public Health, wrote about Sam Gambhir, a physician-scientist at Stanford School of Medicine.  He was terminally ill with carcinomatosis from cancer of unknown origin. Gambhir pioneered Precision Health and spent 40 years researching early cancer detention. During an interview in 2018, he said most of his research was trying to understand the transition from health to illness by detecting changes at the cellular and molecular levels. Gambhir likened cancer progression to a movie: “We glimpse only a few scattered frames or snapshots near the end. We need the whole movie, including the footage of the very first rogue cells.” His research included imaging techniques, detecting biomarkers, tumor cells, or immune cells in circulation. He continued: “Imagine a cockpit where…..you can see the status of every cell of our trillion cells” -by swallowing a pill, contents of which would enter all of the body’s cells. You detected a signal of a cancer cell. 
As Fate would have it, one tragedy after another struck his family. His wife Aruna battled breast cancer twice, first at age 37 years and second at age 47 years.  Milan, their only son, died from a malignant brain tumor ( Glioblastoma Multiforme) at age 16 years, twenty-one months after his diagnosis.  “ You commit your life and work to science, and then it is almost like religion: how could you fail me now?” – this is the comment Sam made at the time of his son’s diagnosis. Ever a scientist, he snapped out of this melancholy and sent his son’s brain tumor cells to several experts all over the world for expert analysis. Milan had a normal CT Brain scan done at the time of a boating incident when he might have had a concussion nine months before his brain tumor diagnosis. Aruna’s father had died from esophageal cancer in his 50’s. Milan’s tumor cells and Aruna’s genetic analysis established that both had inherited p53 mutation, a characteristic of very rare  Li-Fraumeni syndrome.  Gambhir felt that radiation from the CT scan may have been a trigger to set off the Glioblastoma Multiforme in those who have Li-Fraumeni syndrome. Gambhir researched extensively for any treatment that could help his son’s aggressive brain tumor. Ayurvedic treatment of Ashwagandha plant extract ( subsequently identified as Withaferin A ) had a brain tumor effect; it was too late for Milan.
Gambhir told a colleague: “I am starting a new drug today. I will try to remain optimistic, but this will be a brutal journey now.” He endured severe side effects of chemotherapy before succumbing to his illness. In his last interview with Madeline Drexler,  Gambhir, an atheist and empiricist, said:  “Boy! What would I do to have a peek into what things will be like hundreds if not thousands of years out.!!”
Despite an extraordinarily brilliant scientific career, Sam Gambhir’s adherence in his treatment to the latest and most aggressive treatments available today with their attendant side effects and maintaining optimism, Sam died at the young age of 57 years, almost a year after his diagnosis. 
The story, heartbreaking as it is, reveals the limitations and limits of science. Although the future may be bright in Precision health and early cancer detection, it is helpful to remember Sam’s words: it may take hundreds or even thousands of years!!