The Cochrane Collaboration is a not-for-profit organization that produces and maintains systemic reviews of the effects of healthcare interventions.

ARCHIE COCHRANE

During my long walks during the Covid-19 pandemic, I listened to various educational healthcare podcasts. From Bloomberg Organization, Barry Ritholtz interviews exciting people and asks his hosts at the end of each podcast about their mentors who impacted their careers most. Reflecting on my medical career after my medical career ended in 2018, Archie Cochrane was the mentor who made the most impact on my medical education and career.
Who was Archibald Cochrane?
SMITH & NEPHEW PHARMACEUTICAL COMPANY awarded six fellowships for graduate training in tuberculosis and chest diseases for doctors from developing countries. I was fortunate to be one of the recipients from Kenya. During the Fellowship year in 1966, I spent six months at the U.K. Medical Research Council  Pneumoconioses Unit ( under the auspices of Cardiff University School of Medicine) in Wales, U.K. Professor Archibald Cochrane was the head of MRC Pneumoconioses Unit, and our Course Director. He was a great teacher and a brilliant world-acclaimed medical researcher. He pioneered modern clinical epidemiology and evidence-based medicine in the U.K.  He describes his first successful “randomized trial” from Salonika, Greece. He was in charge of German Prisoners of War Camp during WW II. There was a high incidence of ankle edema in prisoners. To test his hypothesis that this might be “wet beriberi “( Vit B complex deficiency) in a prison population on a meager subsistence diet of 400-500 Calories, he divided 20 prisoners into two groups of 10 prisoners each. Group 1 received yeast, and Group 2 received vitamin C.  Group 1 soldiers rapidly improved their ankle edema within four days of therapy!  This Salonika trial was probably the first randomized controlled trial in Epidemiology. Professor Austin Bradford Hill, Professor of Statistics at the London School of Tropical Medicine and Hygiene, proved a correlation between smoking and lung cancer. Professor Hill influenced Professor Cochrane. In his landmark book “Effectiveness and Efficiency- Random Reflections on Health Services,” he says: “Randomize till it hurts” – to accumulate reliable evidence to provide the best medical care.

While Archie was a visiting professor at Henry Phipps Clinic in Philadelphia in 1947, he gained valuable insights into observer error in interpreting Chest X-rays for the diagnosis and prognosis of T.B. patients. One of the most impactful lessons I learned from him was the demonstration of significant intra-observer and inter-observer variations in reading T.B. skin tests and chest X-rays. It was eye-opening to see that the same observer had a substantial variation in the interpretation of tests. He forcefully taught us to be skeptical of interventions and treatments not proven by robust, large-scale, randomized studies. The phrase “healthy skepticism” caught my attention recently when Dr. Jon Jureidini (coauthor with Dr. Leemon McHenry of the book “The Illusion of Evidence-Based Medicine – the Crisis of Credibility in Clinical Research”) strongly cautioned healthcare consumers to approach medical treatments not cynically but with healthy skepticism.

I reviewed Archie Cochrane’s life history. I learned much about Archie Cochrane from Alan Cassels, a health policy researcher at the University of Victoria, Canada. His Book Title itself was intriguing: “The Cochrane Collaboration – Medicine’s best kept secret.” In the Preface, the author poses a question that is often asked: “Is there anywhere I can go for reliable, trustworthy information about how to treat my condition?” In Cochrane Collaboration, 30,000 people worldwide, primarily volunteers, collect and summarize research on healthcare interventions. Cassels says: Think of healthcare interventions in thirds; the first third works and is underpinned by reliable evidence. This pie is evidence-based. The second third needs more studied interventions, and the proof is unknown. So, we need evidence that the benefits exceed the harms. The final third is harmful interventions, as per available evidence, which medical practitioners should eliminate.

Cochrane was born in a small town south of Edinburgh, Scotland, in 1909 and died in 1988. He had his undergraduate education at King’s College, Cambridge, and medical education at University College, London. He was a great teacher, a wonderful human being, and a great humanist. He arranged a reception in his country home in 1966 in Penarth,Wales ,when I spent six months doing a D.T.C.D ( Diploma in Tuberculosis and Chest Diseases)
All of the fellows and other postgraduate students were staying in a hostel. He arranged for a bus transportation to his sprawling estate. Archie was a lifelong bachelor. His butler had laid out the most sumptuous spread, and we had the privilege of tasting some of the rarest wines and champagne from his cellar. It was an evening hard to forget as we all returned to the bus in an inebriated state and staggered back to our rooms in the hostel.

Cochrane Collaboration was created by his peers five years after he died in 1988. Cochrane’s jibe in 1979 to Sir Iain Chalmers was the impetus for the establishment of Cochrane Collaboration. The jibe: “It is surely a great criticism of our profession that we have not organized a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomized controlled trials”. Archie wrote a foreword to Iain Chalmers’s 1500-page treatise on Effective care in Pregnancy and Childbirth, representing “a real milestone in the history of randomized trials and the evaluation of care.” Archie had another jibe: “Other specialties should copy what Iain and his colleagues had done.” The Collaboration is a non-profit international organization of more than 30000 scientists from 100 countries worldwide. They have more than 5000 systemic reviews. The Collaboration is a database of systemic reviews. Dr. Muir Gray had an interesting perspective in Cassel’s book. Toyota’s CEO attributed Toyota’s success to it being a knowledge business rather than a car business. He says health care is a knowledge business, and Cochrane Collaboration provides the framework for this knowledge. The advent of the Internet supplied a bit of luck in establishing systematic reviews online, and data could be accessed conveniently by anyone worldwide. The library’s electronic infrastructure allows for updates and periodic reviews.

Chalmers notes in his Foreword to Alan Cassel’s Book that one of Collaboration’s precious features is its tradition of self-criticism. In the early 1990s, high-dose chemotherapy with autologous bone marrow transplantation HDC/ BMT was in vogue for breast cancer. Breast cancer advocacy groups agitated for the treatment’s approval. Numerous women received this highly toxic therapy. One of them was a dear friend of ours, the wife of a physician. She was diagnosed with breast cancer at age 50. Unfortunately she had the most horrific side effects and died within one month of getting this treatment. Subsequent randomized trials showed that women fared considerably worse with this treatment when compared with those who had conventional therapy. The book “FALSE HOPE: BMT FOR BREAST CANCER” documents in detail the sorry saga of not only a highly toxic treatment; it was enormously expensive. Kay Dickersin ( Director of the US Cochrane Center) says that EBHC(evidence-based health care) is one of the most critical milestones in the history of medicine. Kay, a breast cancer survivor herself, accepts the Cochrane Collaboration’s systemic review of screening mammography: 2000 women over age 50 would need to be screened for ten years to prevent only one dying from breast cancer. This approach also highlights the potential harm of unnecessary treatments, making us more cautious and aware. To unpack this harm Kay said that ten completely healthy women out of 2000 would be diagnosed and treated unnecessarily (with potential harm to their physical and emotional health). So the risk benefit ratio is ten women being harmed for the benefit of one person.

Gotzsche, a Danish radiologist who has done extensive research on this subject, agrees that the benefit is a lot smaller as compared to harm. Additionally there is considerable harm from overdiagnosis of breast cancer. Screening mammography is a highly emotional issue, and Gotzche’s recommendations for abandoning screening mammography will not get much support in the USA and Europe. He recommends that developing economies like China, India, and Brazil should prioritize many other essential health services and discourage universal mammography as currently offered and practised in developed economies. Prostate cancer is much less controversial than screening mammography. American Cancer Society and American Society of Urology still recommend prostate cancer screening until age 75( provided that expected life expectancy of a subject is morethan ten years.) USPSTF (United States Preventive Services Task Force) no longer recommend PSA screening in the USA.

Hilda Bastian was Cochrane Collaboration’s first consumer advocate .She instituted Plain Language Summaries (PLS) for consumers and established the CC Network (CCNet). One of the statistical “distortions” Maryann Napoli (Hilda Bastian’s successor ) points out is the example of alendronate (Fosamax), a widely used drug for osteoporosis. The FDA approved Fosamax after a trial in elderly women (considered at “high risk” for fractures) with participants randomly assigned to a placebo or Fosamax. The authors reported a “50% reduction in risk of hip fracture for women taking the drug compared to placebo. She points out that a 50% reduction is a relative risk reduction. When one looks at absolute risk reduction, 1%  of the Fosamax group had a hip fracture at three years, compared to 2% who had the placebo. So 97 % of women had no fractures, 2% of the placebo group had a hip fracture as compared to 1% of the Fosamax group having a fracture. To emphasise the point further, two out of one hundred women benefited from avoiding a hip fracture as compared to one out of one hundred women taking a placebo. Unfortunately, T.V. advertisements, medical journal articles headline 50% risk reduction as compared to one additional woman taking a thus grossly overestimating benefits. The advertisements also minimized side effects in small print.

Archie Cochrane published “Effectiveness and Efficiency: Random Reflections on Health Services.” He tracked Welsh coal miners for over 20 years and kept meticulous records with the help of disabled miners helping him with data collection. Archie was a maverick; even as a medical student, he rallied to establish the National Health Service in the U.K. He scrawled his slogan on a banner during demonstrations in favor of the National Health Service (NHS) in the UK: “All effective care must be free.”Alan Cassels offered this modification for current times: “All free care must be effective.” These slogans should be an excellent lesson for those clamoring for Medicare for All. In a world of finite resources, Medicare for All can only be possible if health care and benefits are restricted to treatments and interventions that meet the strictest criteria of robust evidence for their efficacy. For instance, treatments like insulin for diabetes or interventions like vaccination for preventable diseases have robust evidence for their efficacy.  The ultimate Cochrane question is: ‘How can we have a rational health service if we don’t know which of the things in it are helpful and which are useless or possibly even harmful?” No wonder during the debates for Medicare for All in 2020’s, astronomical figures like 30-40 trillion dollars over ten years were the price tag floated in the media. I believe that these figures were postulated and based on healthcare practised and delivered currently. As per gold standard Cochrane Collaboration criteria, half of the currently delivered healthcare, can be cut out if only high-value effective care were covered as per gold standard Cochrane Collaboration criteria. 

Tamiflu (oseltamivir) was approved by the U.S. Food and Drug Administration for the treatment of influenza in 1997 after Roche published a trial showing the drug’s effectiveness. Subsequently, the WHO recommended stockpiling the drug in preparation for the influenza pandemic. Dr.Tom Jefferson was involved in an independent review of Tamiflu for the Cochrane Collaboration. When he asked for all trial datasets, he found out that more than half the data from over 100 trials was unpublished. With its open data project, the British Medical Journal (BMJ) joined the fight by Tom Jefferson and his team and has published extensive correspondence between Cochrane authors and Roche( http://www.bmj.com/tamiflu). Based on the Cochrane team’s review of complete clinical trial data, the conclusion was that the benefits of Tamiflu do not outweigh the harms. BMJ’s International Editor, Kamran Abbasi ,summed up the Tamiflu saga in April 2014, highlighting the financial impact of the missing data: “The incomplete information cost $ 20 billion!! “ He further stated the correspondence with the CDC and WHO  was also aimed at understanding the evidence they relied on to make recommendations for stockpiling the drug and their thoughts regarding the independent review of  Cochrane authors.

After intense internal debates about funding challenges for the Collaboration’s review activities, it’s worth noting that Cochrane Collaboration has made a significant decision to avoid funding from private profit-making companies, demonstrating their commitment to unbiased research. They are mainly financed by Government entities.
Alan Cassels summarizes the predicament well expressed by Professor Alfirevic, a Cochrane editor for Cochrane OB-GYN review group: We as a medical profession are absolutely in love with the treatments, with anything that kind of works or is statistically significant, and can’t cope when something close to our heart does not work, or somebody dares to say there is not much evidence for it. When the evidence from a systemic review is often controversial, one’s tendency to attack or praise the CC will depend on your existing beliefs and prejudices.”

Archie Cochrane, a brilliant scientist, a great teacher with humor and humility, a passionate humanist, and an advocate of social justice, has left an indelible mark on my psyche. His work has inspired generations and continues to shape the healthcare landscape today.
A new medical building at the University of Cardiff was named after  Cochrane so that “students would always remember the principles of academic excellence and equality and equity in health care for which he stood.”
Although circumstances in my life changed and I did not pursue the field of epidemiology and public health, I wonder what Archie Cochrane would think of the current delivery of care with hundreds of guidelines and pathways, many of them forged by consensus and expert opinion only and in many instances not supported by robust evidence from large scale randomized clinical trials. Unlike professional organizations and societies, I am not constrained by guidelines and pathways as an individual physician who is no longer practicing. I have directed my effort to educate and empower patients and patient advocates so that they can evaluate some of the controversial recommendations made by some guidelines.  Indeed, Dr.Adam Cifu, coauthor with Dr.Vinay Prasad of the book “Ending Reversal,” makes the same point that patients should arm themselves with questions during their interactions with healthcare providers so that they can make informed decisions in alignment with their values and preferences. For genuine patient autonomy, a physician who so often is under pressure to make recommendations -based on “Quality” (of care) guidelines created by “committee  consensus”- “should not be the sole “decider” and “influencer.”