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MRC Impact Showcase

How the people and projects we invest in at the Medical Research Council (MRC) are making an impact on our lives and the world we live in.

Our mission at the Medical Research Council (MRC), part of UK Research and Innovation, is to improve human health through world-class medical research. To achieve this, we invest public money into some of the best medical rese arch in the world across every area of health. Our work has led to some of medicine’s biggest breakthroughs – from deciphering DNA’s structure to inventing the MRI scanner and developing the first COVID-19 vaccine. Our scientists have transformed modern medicine, and in turn have been recognised by 32 Nobel Prizes.

The impacts of our work are broad and diverse – benefiting the economy, society, culture, public policy and services, health, the environment, and quality of life for people in the UK and around the world. They are made possible not just through funding science, but also through targeted investment supporting entrepreneurial activity and supporting enterprise. MRC has built up emerging areas and funded world-class ideas, working with stakeholders across all sectors and partners across the world, guided by our vision to accelerate improvements in human health and economic prosperity.

The case studies below showcase just some of the non-academic impacts arising from MRC funding, with examples from higher education institutes (HEIs) and MRC-supported institutes and major investments.

Credit: Dr Daniyal Jafree and Professor David Long, Kidney Development and Disease Group, UCL Great Ormond Street Institute of Child Health

MRC supporting jobs and boosting the UK economy

First gene therapies for haemophilia, and creation of spin-out Freeline Therapeutics

• UCL developed single-dose gene therapy that restores blood-clotting and can be delivered at 1% of the cost of conventional treatment – changing the lives of thousands with haemophilia
• The inherited disorder causes internal bleeding and significantly affects 800,000 affected men and boys worldwide
• Therapies have treated over 300 patients in clinical trials to date, and a spin-out company, Freeline Therapeutics, was launched in 2015 to develop the approach
• MRC funding has supported the underpinning haemophilia research for over 60 years

New cancer therapies insight leads to spin-out companies worth £54m and 326 new jobs

• Research into how cancer cells interact with the immune system has led to new avenues for developing treatments
• Researchers at the Francis Crick Institute – a partnership between MRC, Cancer Research UK and Wellcome – have identified several unique cellular processes involved in driving cancer growth, providing opportunities to develop targeted therapies aimed at disrupting them
• The research has led to several spin-out companies, collectively valued at £54.4m and employing 326 people, with several therapeutic candidates in phase I/II trials for melanoma, solid cancers and leukaemia

Creating the world’s largest retinal gene therapy company

• Gene-therapy research into inherited diseases that cause blindness led to new treatments and the formation of a successful spin-out company
• MRC-funded research at Imperial College London and the University of Oxford pioneered the first clinical trials of gene therapy for the diseases choroideremia and X-linked retinal pigmentosa, which demonstrated significant improvement in vision for some of the patients treated
• Spin-out company Nightstar was created with the novel treatment as its lead programme. Licensing of subsequent research extended the approach to other kinds of retinal pigmentosa, and created the world’s largest retinal gene therapy company

MRC tackling the impact of COVID-19

Global adoption of effective COVID-19 treatments saves lives

• RECOVERY trial (Randomised Evaluation of COVID-19 Therapy) – world’s largest clinical trial into treatments for COVID-19, more than 48,000 participants across 185 sites
• Results found dexamethasone, a cheap, readily available steroid, reduces death rates among seriously unwell patients
• Findings immediately transformed global clinical guidelines and practice
• MRC funding directly supported RECOVERY trial through the COVID-19 Rapid Response Initiative in 2020 with the National Institute of Health Research
• The initiative saved an estimated 650,000 lives by the end of 2020
•   Find out more about the RECOVERY trial

Oxford-AstraZeneca Covid-19 vaccine contributed to 6.3m lives saved

• Oxford-AstraZeneca COVID-19 vaccine contributed to saving 6.3 million lives around the world in the first year of rollout
• More than 11,000 trial participants showed 70% reduced risk of COVID-19 and 100% reduction in risk of hospitalisation or death
• MRC funding supported vaccine’s development – success underpinned by decades of MRC funded research that supported the development of ChAdOx1 platform – an adenoviral vector for vaccines to induce and boost cellular immunity
•   Find out more about our role in developing the vaccine

Coronavirus samples inform national COVID-treatment guidelines

• Sotrovimab was one of the first anti-viral therapies licensed for the treatment of COVID-19 and an essential defence for people who have a poorer response to vaccination. However, by 2022 there was concern sotrovimab may not respond to newer variants circulating
• Led by researchers at the MRC-funded Francis Crick Institute, the Legacy Study utilised a unique bank of more than 400,000 coronavirus samples that had been collected since 2020 to test a variety of therapies
• They were able to show sotrovimab offered protection against newer strains. As a result, NICE issued guidelines for its continued use

UK Biobank provides evidence of COVID-19 brain changes

• Brain scans from UK Biobank – a database established by MRC with genetic and health information from 500,000 UK participants – revealed how even mild COVID-19 infection can cause physical changes to the brain
• The UK Biobank COVID-19 Repeat Imaging study enabled researchers to access brain scans of individuals around three years apart, making it the only study in the world to demonstrate ‘before and after’ changes in the brain associated with SARS-CoV02 infection
• The results showed participants who contracted COVID-19 had a greater reduction in brain size compared to uninfected participants. UK Biobank will be a vital resource in understanding whether these changes are reversible over time

UK Biobank participant undergoing a brain scan as part of the UK Biobank COVID-19 Repeat Imaging study. Credit: UK Biobank

MRC improving UK health and wellbeing

Lifesaving treatments for neuromuscular diseases in children

• More than two million children worldwide are affected by neuromuscular diseases
• Work funded by MRC and medical research charities, in collaboration with biotechnology companies, led to approval of the first effective treatments for the genetic diseases Duchene Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA)
• Researchers from UCL, Royal Holloway and Bedford New College developed Spinraza – the only approved drug for the treatment of SMA in the UK and most of the world – available via the NHS since June 2019, with 300 patients already gaining access
• Two medicines developed for DMD – Exondys 51 and Vyondys 53 – which improve quality of life and life expectancy for at least 20% of patients, approved in the US and benefitting over 1,500 people so far
• These medicines have also generated sales of more than $5.5 billion

Cell discovery offers potential new asthma treatment

• The discovery of a type of immune cell could provide a valuable new tool for treating asthma
• Researchers at the MRC-funded Laboratory of Molecular Biology discovered cells that secrete an inflammatory molecule, interleukin-13 (IL-13), which can trigger a reaction in asthma patients. The release of IL-13 is activated by interleukin-25 (IL-25)
• Scientists developed a therapy to block the action of IL-25, preventing it from activating IL-13 and triggering an asthma reaction. A clinical trial is underway to establish its use in treating asthma. The therapy also has potential in the treatment of colorectal cancer

Microscope images of a mouse intestine showing smaller cancers and a more active immune response when ILC2 immune cells are blocked or removed. Credit: MRC Laboratory of Molecular Biology

Repairing damaged cartilage in knee joints

• Left untreated, defects in cartilage can progress to osteoarthritis. A team of researchers at the University of Keele has developed a cell therapy that helps repair cartilage in knee joints
• An MRC-funded trial provided the evidence and cost-benefit data that led to the therapy, known as autologous chondrocyte implantation, which received NICE approval in 2017. The team also developed a tool to help identify patients who would most benefit from the treatment
• The team are currently investigating a new ‘off the shelf’ cell therapy that uses donor cells, which would reduce cost and improve patient outcomes

MRC improving outcomes for cancer patients

Anti-cancer treatments across the world

• University of Southampton developed anti-cancer monoclonal antibodies. The most advanced are two used to treat leukaemias such as Chronic Lymphocytic Leukemia (CLL) and Follicular Lymphoma (FL) called Ofatumumab and Obinutuzumab
• The patented research was collaboratively developed and licensed to a Swedish biotech firm, resulting in a clinical trial programme that led to a £73 million commercial agreement
• MRC funding has supported this field of research since the 1970s when scientists at the MRC LMB discovered monoclonal antibodies and later developed humanised monoclonal antibodies in the 1990s for which they won Nobel prizes

Trial improves prostate cancer patient health and care

• Research led by the Universities of Oxford and Bristol has changed the way that men with early-stage prostate cancer are diagnosed and treated
• The ProtecT trial compared active monitoring with more invasive treatments, radiotherapy and surgery, finding that patients who did not undergo invasive treatment had the same high survival rates
• The trial also found that the negative impacts of radiotherapy and surgery on urinary and sexual function persist much longer than previously thought – for up to 12 years
• Evidence has changed health policy and clinical practice through updated guidelines and optimised treatment
• MRC funding has supported the underpinning work carried out at the University of Bristol through the MRC ConDuCT-II Hub since 2014

MRC supporting healthy ageing

Preventing falls in older people

• Falls are a significant concern for older people and come at a cost of more than £2.3 billion per year to the NHS
• Home adaptation services – such as stairlifts, grab-rails and ramps – are available for those who want to continue living in their home. However, until now, there has been no evidence to demonstrate their effectiveness
• Researchers from the MRC-funded Health Data Research UK have created a dataset that shows these adaptations can help prevent falls and also identifies those most at risk of falling. The research could help inform policy for proactive interventions

Identifying genetic risk of Alzheimer’s disease

• An international study has identified 75 genes associated with an increased risk of developing Alzheimer’s disease, including 42 new genes that had not previously been implicated
• Researchers at the MRC-funded UK Dementia Research Institute analysed the genomes of 111,326 people diagnosed with Alzheimer’s disease and 677,633 genomes from healthy people, making it the largest genetic study of Alzheimer’s disease to date
• The development of a new genetic risk score could be used when recruiting patients for clinical trials aimed at treating the early stages of the disease, when damage to the brain is minimal

Brain inflammation with microglia that fail to clear debris, causing astrocytes to react. Credit: National Institute on Aging, National Institutes of Health

MRC informing health policy

Big data to improve care and outcomes for millions of people with cardiovascular disease

• UCL researchers used large-scale patient data to shape national and international clinical guidelines for the prevention, diagnosis, and treatment of a range of cardiovascular diseases. This has benefitted care and improved outcomes for millions of patients worldwide
• Evidence from the research informed a major change in guidelines, to lower the blood pressure threshold which defines hypertension, making diagnosis more accurate
• MRC funding has contributed to this research since 2012

Understanding the transmission and control of COVID-19

• Research from Imperial College London and Oxford University provided key data which underpinned recommendations and policies during the COVID-19 pandemic. This included school closure policy, social gatherings and contributed to the recommendation of interventions to protect those living in large households
• The evidence transformed our understanding of the epidemiology of COVID-19 and the measures required to protect public health
• MRC Centre for Global Infectious Disease Analysis (GIDA) scientists have tailored their research focus to COVID-19 to provide rapid, open access, real-time modelling and assessment analysis targeted at the needs of policymakers
• Since its establishment in 2008, MRC GIDA scientists provided insight into previous outbreaks of Ebola and Zika and worked with public health agencies and policy makers to improve preparedness and responses to disease outbreaks

Genome sequencing to inform outbreak response

• Researchers at the University of Birmingham developed rapid whole genomic sequencing methods to transform the management of infectious disease around the world
• The research has improved identification of transmission pathways, evolution of pathogens and sites of persistence. MRC funding supported the team to apply rapid genome sequencing to pathogens such as Ebola, Zika and SARS-COV-2
• In addition, MRC-funded research at the University of Oxford was crucial in the development of the MinION sequence platform – a ‘pocket sequencer’ that enables rapid analysis of data in the field – and the creation of spin-out company Oxford Nanopore Technologies

MRC improving health globally

Protecting human health from infectious disease in low-resource settings.

• Research from the University of Brighton has contributed to reducing human health risk from diseases including cholera, ebola, typhoid, and childhood diarrhoea in regions of Africa, Asia, and South America
• The Brighton team helped the National Institute of Cholera and Enteric Diseases to prioritise effective public health interventions in urban slum districts in India (home to 100,000 people) and the Kenyan Medical Research Institute to protect 1,170 rural inhabitants
• This research was supported by MRC in 2017 in a project which quantified routes of microbial contamination between livestock and drinking water

Improving treatment of meningitis in developing countries

• Cryptococcal Meningitis is a major cause of HIV-related deaths in developing countries, accounting for more than 180,000 deaths per year. Previous treatments involved costly medications and regular monitoring in hospitals
• Researchers at the University of Oxford, Liverpool School of Tropical Medicine, London School of Hygiene and Tropical Medicine and St. Georges, University of London demonstrated the efficacy of low-cost antifungal drug flucytosine. The WHO implemented the findings into their guidelines, which reduced costs, improved access, and led to reductions in mortality
• MRC-funded research supported key clinical trials to determine the optimum combinations of flucytosine, providing the evidence needed for implementing these guidelines
• The findings also led to a $20 million investment from global health organisation UNITAID, benefiting seven African countries

Our mission is to improve human health through world-class medical research. To achieve this, we support research across the biomedical spectrum, from fundamental lab-based science to clinical trials, and in all major disease areas. We work closely with the NHS and the UK health departments to deliver our mission, and give a high priority to research that is likely to make a real difference to clinical practice and the health of the population. Together, we:

• encourage and support research to improve human health
• produce skilled researchers
• advance and disseminate knowledge and technology to improve the quality of life and economic competitiveness of the UK
• promote dialogue with the public about medical research

Further information

Explore more impacts arising from MRC-funded research

Find out more about MRC

The Medical Research Council (MRC) improves the health of people in the UK - and around the world - by supporting excellent science, and training the very best scientists. They are a non-departmental public body funded through the government’s science and research budget.

At the beginning of the twentieth century, tuberculosis was one of the UK’s most urgent health problems. A royal commission, entitled The Royal Commission Appointed to Inquire into the Relations of Human and Animal Tuberculosis, was set up in 1901. It aimed to find out whether tuberculosis in animals and humans was the same disease and whether animals and humans could infect each other. This page describes how, by 1919, the Commission had evolved into the independent Medical Research Council.

In 1911, Parliament passed the National Insurance Act, introduced by David Lloyd George as Chancellor of the Exchequer, which put in place schemes for health and unemployment insurance. One provision – paid for with a penny per working person per year - was sanatorium treatment for cases of tuberculosis and for ‘purposes of research’. This created a national fund for medical research and amounted to £57,000 a year - equivalent to nearly £4 million today.

A committee of the Insurance Commissioners in England, Scotland, Ireland and Wales recommended there be a research organisation with an advisory council and an executive committee.

Mission The heart of the mission is to improve human health through world-class medical research. To achieve this, they support research across the biomedical spectrum, from fundamental lab-based science to clinical trials, and in all major disease areas. They work closely with the NHS and the UK Health Departments to deliver the mission, and give a high priority to research that is likely to make a real difference to clinical practice and the health of the population.

Mission Statement The MRC’s mission, as set out in the  Royal Charter (PDF, 21KB) , is to:

• Encourage and support research to improve human health.
• Produce skilled researchers.
• Advance and disseminate knowledge and technology to improve the quality of life and economic competitiveness of the UK.
• Promote dialogue with the public about medical research.

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Medical Research Council

Learn about this topic in these articles:.

…Brenner began work with the Medical Research Council (MRC) in England. He later directed the MRC’s Laboratory of Molecular Biology (1979–86) and Molecular Genetics Unit (1986–91). In 1996 he founded the California-based Molecular Sciences Institute, and in 2000 Brenner accepted the position of distinguished research professor at the Salk Institute…

In 1962 the Medical Research Council opened its new laboratory of molecular biology in Cambridge. The Austrian-born British biochemist Max Perutz, British biochemist John Kendrew, and British biophysicist Francis Crick moved to the new laboratory. Sanger joined them as head of the protein division. It was a banner…

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The Medical Research Council (MRC) is a national funding agency dedicated to improving human health by supporting research across the entire spectrum of medical sciences, in universities and hospitals, in MRC units, centres and institutes in the UK, and in MRC units in Africa.

The Medical Research Council is a publicly funded organisation dedicated to improving human health.

We support research across the entire spectrum of medical sciences, in universities and hospitals, in our own units, centres and institutes in the UK, and in our units in Africa.

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The MRC’s mission

The heart of our mission is to improve human health through world-class medical research. To achieve this, we support research across the biomedical spectrum, from fundamental lab-based science to clinical trials, and in all major disease areas. We work closely with the NHS and the UK Health Departments to deliver our mission, and give a high priority to research that is likely to make a real difference to clinical practice and the health of the population.

The MRC’s mission, as set out in our Royal Charter is to:

• Encourage and support research to improve human health
• Produce skilled researchers
• Advance and disseminate knowledge and technology to improve the quality of life and economic competitiveness of the UK
• Promote dialogue with the public about medical research

Working with the Science Council

We are working with the Science Council in two ways.

The first is by using their professional registration scheme and making this available to our staff. This gives our staff a clear framework to support them with planning their career development and also a way of getting better recognition for their skills and the important work they do for us.

The second is wider and, as an employer champion especially, is much more about making this publicly known and support the Science Council in their purpose of making sure that the UK Technical workforce continues to thrive and gets the recognition it deserves.

“The technical registration scheme is now part of the strategy or the MRC Harwell Institute to ensure ongoing development and recognition of our talented technical staff. Underpinning all great scientific endeavours is technical excellence from scientists who excel in delivering the resources needed to support research. For genomic studies this includes molecular and cellular biology, pathology, clinical chemistry, phenotyping, genotyping, cryopreservation and importantly animal care. The technical registration schemes charts the success and ongoing development of all of these disciplines through driving CPD, encouraging broader training platforms and most importantly incentivising and motivating our resource teams.” Sara Wells, Director of the Mary Lyon’s Centre, MRC

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Medical Research

Article by Patricia G. Bailey , Judith Miller , Neil R. Morris

Published Online February 1, 2011

Last Edited March 4, 2015

Medical research ranges from fundamental research to clinical and applied technology. Fundamental research involves investigations into biological functions; knowledge thus acquired may then be applied in clinical research to help understand specific diseases and to develop improved treatments, cures and methods of prevention. Applied technologies result from both fundamental and clinical research in the form of vaccines, drugs, instrumentation, diagnostics, prostheses and other health-care products. Physicians, biologists, biochemists, biomedical engineers, chemists, dentists, veterinarians, health economists, nurses, and pharmacists are among the health professionals involved in medical research. The overall objective is the improved diagnosis, treatment, prevention and cure of disease and the delivery of health care to Canadians in the most efficient and economical manner.

The discovery of INSULIN in 1922 by Frederick BANTING , J.J.R. MACLEOD , Charles BEST and James COLLIP stands as the most celebrated event in Canadian medical research history. Its discovery led to the establishment of the SANOFI PASTEUR laboratories (formerly Connaught Laboratories) and the Banting Institute at the University of Toronto.

Since that time, research in Canada has been conducted into areas such as molecular biology, neuroscience, immunology, nutrition and metabolism, biochemistry, reproductive biology, CANCER , behavioural sciences, genetics, cardiology, developmental biology, DENTISTRY , microbiology, pharmacology, OCCUPATIONAL DISEASE , health-care organization, environmental health hazards, and the biology and health of human populations.

Canadian investigators, many of whom are world leaders in their areas, are examining the function and diseases of particular organs and systems such as the skin (dermatology), the blood system (hematology), the kidney (nephrology), the eye (ophthalmology), the ear, nose and throat (otolaryngology), the stomach and intestines (gastroenterology), the endocrine glands (endocrinology), the respiratory system (respirology) and connective tissue disorders.

Current Canadian medical research is addressing a number of key health concerns that range from vaccination to surviving cancer. Microbiologists are developing a new meningitis vaccine through innovative genetic research on mouse animal models that could improve the efficacy of vaccination. Because meningitis symptoms progress rapidly a key issue around vaccination is development of a vaccine that can stop the virus before it infects the patient. Oncologists examine the consequences of surviving cancer treatment on patients. Due to the effects of chemotherapy some people are at greater risk of developing other severe health problems such as heart disease, and tailoring survival strategies by following young cancer patients over the long term will help to improve their chances for a healthy life. Sleep researchers are investigating the connection between a sedentary lifestyle, fluid retention and the development of obstructive sleep apnea. The severity of apnea appears related to the amount of daily sedentary activity a patient engages in, such as sitting. This research could lead to addressing the cause of apnea through a healthier lifestyle, instead of merely treating the symptoms.

The range of accomplishments is impressive. Research in cardiovascular surgery alone has contributed significantly to the overall treatment of blood vessel and HEART DISEASE . Canadians have been responsible for major developments in heart pacemakers, heart-lung machines to oxygenate blood and correct heart defects, and the first coronary care units. Hans SELYE was a world-renowned expert in understanding STRESS , its effects and its management.

International diabetes research was significantly advanced by a group of researchers at the University of Alberta. Led by Dr. James Shapiro, the team developed an innovative technique to transplant pancreatic islet cells into people whose own islet cells had been destroyed by type 1 DIABETES . The technique, called the Edmonton Protocol, has been available for more than 10 years and has treated more than 100 people. The research allowed the patients to live without requiring daily supplemental insulin and significantly advanced the medical knowledge about diabetes and the ultimate potential of genetic research.

In the neurosciences Canadians have made major contributions to the knowledge of the central nervous system and its related diseases. The Montreal Neurological Institute (established in 1934) is an important centre for such research. Its founder, Wilder PENFIELD , not only pioneered the technique of brain-mapping, which is conducive to the better understanding of localized functions of the brain, but also built the MNI into an internationally known training centre.

Research at the MNI has led to improved surgical and nursing techniques for the management of spinal lesions, to the development of electroencephalography (EEG) to treat conditions such as epilepsy, and to a deeper understanding of cognitive and other behavioural changes associated with brain lesions. Noninvasive imaging techniques, such as computerized axial tomography (CAT) and positron emission tomography (PET), in conjunction with a new understanding of neurotransmitters, help researchers understand the way the various parts of the brain and nervous system grow, develop, take on specific tasks, and repair and replenish themselves.

At the University of Western Ontario, Charles Drake has achieved international recognition for developing new techniques for the improved repair and treatment of potentially fatal aneurysms - weakening or ruptures of brain arteries, notably the basilar artery.

The federal government, provincial governments, voluntary agencies and private foundations, industry, business and foreign sources all contribute to the support of biomedical research in Canada, including equipment, operating costs, research training and technical assistance.

Federal Funding Agencies

The CANADIAN INSTITUTES OF HEALTH RESEARCH (CIHR) is the major federal agency responsible for funding health research in Canada. Established by Act of Parliament in April 2000, it consists of 13 institutes that provide partners in the research process. The CIHR was designed to have a comprehensive mandate and the research partners include the funding agencies, researchers and the research institutes. Each health institute has a broad and inclusive focus and sets priorities for research in each topic area. The institutes are led by an advisory board and scientific director as well as the CIHR governing council. The areas covered by the institutes include: Aboriginal people's health, AGING , cancer, circulatory and respiratory health, GENETICS , health services and policy research, infection, musculoskeletal health, diabetes and PUBLIC HEALTH .

The CIHR was developed out of the Medical Research Council of Canada, part of the NATIONAL RESEARCH COUNCIL . The Medical Research Council began as the Associate Committee of Medical Research in 1936, becoming the NRC Division of Medical Research in 1956 and then an autonomous body of NRC in 1960.

The CIHR funds health research and research training in universities, health-care institutions and research institutes. It provides support, on the basis of scientific excellence as determined by national peer review, for research and for training of health-science researchers in the health-science faculties. These include the departments and laboratories of the 17 medical schools, 10 dental schools and 10 pharmacy schools and their affiliated HOSPITALS and institutes across the country.

Health research at CIHR is divided into 4 broad categories: bio-medical; clinical; health services; and social, cultural, environmental and population health research. The CIHR is also responsible for ensuring that the knowledge generated out of health research is translated into findings that reach decision makers, and therefore help to ensure that medical research ultimately works to benefit the health of Canadians.

The CIHR is also mandated to provide researchers with opportunities to participate in international medical research. It cooperates with the CANADIAN INTERNATIONAL DEVELOPMENT AGENCY (CIDA), the International Development Research Centre and HEALTH CANADA in research to improve people's health in Canada and the world.

Research into cancer is led by the Institute of Cancer Research, with the Canadian Strategy for Cancer Control (CSCC) responsible for coordinating all cancer research in the country. The CSCC was created in 1999 and involved the establishment of a research alliance from the groups that were formerly in charge of cancer research - the National Cancer Institute of Canada, the Canadian Association of Provincial Cancer Agencies and Health Canada.

The former major Canadian health research initiatives have largely been maintained and expanded on by the CIHR. Canadian research in genetics is now undertaken by the Institute of Genetics encompassing the work of the former Canadian Genome Analysis and Technology program, which was Canada's participation in the international Human Genome Project. CIHR has research initiatives focused on hepatitis C, HIV/AIDS , antimicrobial resistance, and pandemic H1N1 influenza, among others.

Provincial Funding Agencies

Provincial agencies in Alberta, BC, Manitoba, Ontario, Québec and Saskatchewan contribute to medical research and training through such organizations as the Alberta Heritage Foundation for Medical Research and le Fonds de la recherche en santé du Québec.

Voluntary Funding Agencies

Voluntary agencies, which are generally "disease-specific," also play a major role in medical research. The National Cancer Institute of Canada and the Canadian Cancer Society integrated in 2009 and created the Canadian Cancer Society Research Institute (CCSRI). The CCSRI ensures that cancer research donations fund the most promising Canadian cancer research.

Research costs such as salary support and capital expenses to construct laboratories and animal-care facilities are generally paid by the institutions where the research is conducted. The institutions receive funds for this purpose through provincial governments and private donations.

Structure of Medical Research

Medical research is highly decentralized in universities and teaching hospitals and their affiliated institutions throughout the provinces. Canada is one of a small minority of countries without significant government laboratories devoted to biomedical research. While this decentralization links research with professional training and health-care delivery, it makes it difficult to define or maintain a national focus for concerted programs, especially as health care and education are provincial responsibilities. However, in 1982 federal and provincial representatives identified several health areas of national concern (cancer, accidents, arthritis and joint disorders, cardiovascular and cerebrovascular diseases, maternal and infant health problems, MENTAL HEALTH and respiratory diseases).

In 1983, the federal Cabinet approved a framework for medical research that emphasizes the provision of high-quality training; a balance between basic and applied research, and a balance across regions and disciplines (with special attention to areas of national health concern); and the utilization of new knowledge for improved health care. In 1986 the Medical Research Council of Canada (MRC) adopted an additional objective, to enhance the interaction between researchers in the health sciences and industry by implementing joint university-industry programs. The MRC also placed renewed emphasis on women's health issues and on the inclusion of greater numbers of females in clinical trials, since women traditionally were excluded from clinical trials due to concern over possible effects on monthly hormone cycles and pregnancy.

When the umbrella under which Canadian research is conducted became the CIHR in 2000, the health research mandate was altered to reflect current needs. The research agenda included health services research along with other under-developed areas like population health. In addition, more research has been funded on targeted areas of priority such as diabetes, obesity, aging and infectious diseases. The mandate also expanded to include knowledge translation, whereby the research results can be transformed into policies, practices, services and procedures.

The institutes that comprise the CIHR help determine which medical research studies are conducted in Canada. The institutes fund the Canadian research projects deemed to provide the most benefit to the health of Canadians; the funded topics are myriad.

Issues in Medical Research

Medical research critics claim that advances in medical research have led to little improvement in health status. Some blame this on inadequate communication among workers in the health sector and recommend an increase in the number of clinicians conducting research to improve the introduction of new knowledge into health care and to increase treatment-oriented research. Others charge that the conservative nature of the peer review system precludes progress of innovative science, and they advocate the participation of a greater variety of health professionals in medical research, eg, nurses and pharmacists, who have received less support in Canada than basic and clinical researchers. Canadian researchers and research institutions have worked to improve communication procedures between health-care professionals, and to be more inclusive of the various health professionals in medical research. This has led to a highly diverse group of people working in the field, and is more reflective of the changes in modern Canadian society.

There is also ongoing debate about the appropriate balance between curiosity-driven and targeted research, and between research that is oriented towards costly, technologically sophisticated medical treatments and more broadly based epidemiological and environmental medicine.

Ethics remains a vital issue in health research ( see MEDICAL ETHICS ; BIOETHICS ). The establishment of the CIHR altered the ethical framework for health research in Canada. The MRC helped establish guidelines for the safe and ethical conduct of human experimentation, research with animals and the use of hazardous and infectious agents. However, the guidelines were not law and there was a need to formally address ethics.

The CIHR is mandated by Parliament to adhere to the highest international ethical standards, to apply ethical principles to health research, and to monitor and evaluate ethical issues. Ethics is a shared responsibility among various groups that extend across all levels of the CIHR. The standing committee on ethics identifies emerging ethical issues, while the ethics office develops and implements ethics in research policies. Each institute advisory board has an ethics designate, and the peer review committees that help to determine project funding include a focus on ethics. There is additional support for ethical issues related to research integrity and stem cell research. In addition, the 3 federal research agencies, CIHR, the National Science and Engineering Research Council and the Social Sciences and Humanities Research Council, jointly created the Interagency Advisory Panel on Research Ethics to promote ethical research involving humans in 2001.

International aspects of research are becoming more critical with the increase both in health problems (such as AIDS and pandemic influenza) that face many nations and in multinational studies to examine such problems. New developments, such as cloning and gene identification, present a host of ethical issues. The implications for the misuse of some technologies create what some might view as obstacles to research. The potential uses of cloning have caused the governments of many countries, including Canada, to work toward legislation that will restrict its application. Genetic research, in particular, presents several ethical dilemmas. The ability to identify genomes raises the issues of privacy, confidentiality and autonomy and raises some serious questions for future medical research. Does anyone have the right to genetic information about another individual? Will there be a distinction made between genetic technology for therapeutic purposes and using it to enhance an individual's characteristics? Will such technology change the way we view ourselves and how we define normal/abnormal?

See also HUMAN GENOME PROJECT .

Future of Medical Research

The health-care system in Canada is changing. Developments such as the increased recognition of the contribution of environmental and behavioural factors to mental and physical health, the growing focus on cost containment and the allocation of scarce resources, the significant rise in the number of women in medicine and research, the increased need for chronic-disease care in an aging population, the trend towards home care and away from hospital care, and the increase in hospital-based research institutes have all influenced the nature and extent of medical research.

Many of the discoveries of medical research, such as those that have recently offered new abilities to manipulate genes, to perform in vitro fertilization and embryo experimentation, to transplant organs and to screen for genetic problems, will continue to require excellent research by scientists. However, the growing social and ethical issues raised by such research will necessitate closer co-operation between scientists and the Canadian public. Scientists can help the public understand the implications of new knowledge, and the public needs to exercise its responsibility in guiding the extent, conduct and application of medical research in Canada.

The increase in privatized health-care services across the country will likely influence future medical research. Provincial and federal governments will be challenged in the future to balance the research needs of Canadians against the research wants of corporate profit-based medical care.

Further Reading

Donald Jack, Rogues, Rebels and Geniuses (1981); S.E.D. Shortt, ed, Medicine in Canadian Society (1981); Alison Li, J.B. Collip and the Development of Medical Research in Canada (2003).

External Links

Ebola treatments caught in limbo A brief article on possible roadblocks to generating promising Ebola vaccines. Scroll down for a reference to Canadian involvement in vaccine development. From the scientific journal Nature.

Juvenile Diabetes Research Foundation Canada An authoritative information source about Type I and Type II diabetes. Check out the excellent dietary tips and other recommendations for a healthy lifestyle. Also features a history of diabetes research and a summary of the latest research initiatives.

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Indigenous peoples' medicine in canada, canada's opioid crisis, indian hospitals in canada.

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• A new framework for...

A new framework for developing and evaluating complex interventions: update of Medical Research Council guidance

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• Peer review
• 1 MRC/CSO Social and Public Health Sciences Unit, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
• 2 Medical Research Council Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
• 3 Medical Research Council ConDuCT-II Hub for Trials Methodology Research and Bristol Biomedical Research Centre, Bristol, UK
• 4 Health Economics and Health Technology Assessment Unit, Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK
• 5 Public Health Scotland, Glasgow, UK
• 6 Manchester Centre for Health Psychology, University of Manchester, Manchester, UK
• 7 London School of Hygiene and Tropical Medicine, London, UK
• 8 Faculty of Health and Medicine, Lancaster University, Lancaster, UK
• 9 Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
• Correspondence to: K Skivington Kathryn.skivington{at}glasgow.ac.uk
• Accepted 9 August 2021

The UK Medical Research Council’s widely used guidance for developing and evaluating complex interventions has been replaced by a new framework, commissioned jointly by the Medical Research Council and the National Institute for Health Research, which takes account of recent developments in theory and methods and the need to maximise the efficiency, use, and impact of research.

Complex interventions are commonly used in the health and social care services, public health practice, and other areas of social and economic policy that have consequences for health. Such interventions are delivered and evaluated at different levels, from individual to societal levels. Examples include a new surgical procedure, the redesign of a healthcare programme, and a change in welfare policy. The UK Medical Research Council (MRC) published a framework for researchers and research funders on developing and evaluating complex interventions in 2000 and revised guidance in 2006. 1 2 3 Although these documents continue to be widely used and are now accompanied by a range of more detailed guidance on specific aspects of the research process, 4 5 6 7 8 several important conceptual, methodological and theoretical developments have taken place since 2006. These developments have been included in a new framework commissioned by the National Institute of Health Research (NIHR) and the MRC. 9 The framework aims to help researchers work with other stakeholders to identify the key questions about complex interventions, and to design and conduct research with a diversity of perspectives and appropriate choice of methods.

Summary points

Complex intervention research can take an efficacy, effectiveness, theory based, and/or systems perspective, the choice of which is based on what is known already and what further evidence would add most to knowledge

Complex intervention research goes beyond asking whether an intervention works in the sense of achieving its intended outcome—to asking a broader range of questions (eg, identifying what other impact it has, assessing its value relative to the resources required to deliver it, theorising how it works, taking account of how it interacts with the context in which it is implemented, how it contributes to system change, and how the evidence can be used to support real world decision making)

A trade-off exists between precise unbiased answers to narrow questions and more uncertain answers to broader, more complex questions; researchers should answer the questions that are most useful to decision makers rather than those that can be answered with greater certainty

Complex intervention research can be considered in terms of phases, although these phases are not necessarily sequential: development or identification of an intervention, assessment of feasibility of the intervention and evaluation design, evaluation of the intervention, and impactful implementation

At each phase, six core elements should be considered to answer the following questions:

How does the intervention interact with its context?

What is the underpinning programme theory?

How can diverse stakeholder perspectives be included in the research?

What are the key uncertainties?

How can the intervention be refined?

What are the comparative resource and outcome consequences of the intervention?

The answers to these questions should be used to decide whether the research should proceed to the next phase, return to a previous phase, repeat a phase, or stop

Development of the Framework for Developing and Evaluating Complex Interventions

The updated Framework for Developing and Evaluating Complex Interventions is the culmination of a process that included four stages:

A gap analysis to identify developments in the methods and practice since the previous framework was published

A full day expert workshop, in May 2018, of 36 participants to discuss the topics identified in the gap analysis

An open consultation on a draft of the framework in April 2019, whereby we sought stakeholder opinion by advertising via social media, email lists and other networks for written feedback (52 detailed responses were received from stakeholders internationally)

Redraft using findings from the previous stages, followed by a final expert review.

We also sought stakeholder views at various interactive workshops throughout the development of the framework: at the annual meetings of the Society for Social Medicine and Population Health (2018), the UK Society for Behavioural Medicine (2017, 2018), and internationally at the International Congress of Behavioural Medicine (2018). The entire process was overseen by a scientific advisory group representing the range of relevant NIHR programmes and MRC population health investments. The framework was reviewed by the MRC-NIHR Methodology Research Programme Advisory Group and then approved by the MRC Population Health Sciences Group in March 2020 before undergoing further external peer and editorial review through the NIHR Journals Library peer review process. More detailed information and the methods used to develop this new framework are described elsewhere. 9 This article introduces the framework and summarises the main messages for producers and users of evidence.

What are complex interventions?

An intervention might be considered complex because of properties of the intervention itself, such as the number of components involved; the range of behaviours targeted; expertise and skills required by those delivering and receiving the intervention; the number of groups, settings, or levels targeted; or the permitted level of flexibility of the intervention or its components. For example, the Links Worker Programme was an intervention in primary care in Glasgow, Scotland, that aimed to link people with community resources to help them “live well” in their communities. It targeted individual, primary care (general practitioner (GP) surgery), and community levels. The intervention was flexible in that it could differ between primary care GP surgeries. In addition, the Link Workers did not support just one specific health or wellbeing issue: bereavement, substance use, employment, and learning difficulties were all included. 10 11 The complexity of this intervention had implications for many aspects of its evaluation, such as the choice of appropriate outcomes and processes to assess.

Flexibility in intervention delivery and adherence might be permitted to allow for variation in how, where, and by whom interventions are delivered and received. Standardisation of interventions could relate more to the underlying process and functions of the intervention than on the specific form of components delivered. 12 For example, in surgical trials, protocols can be designed with flexibility for intervention delivery. 13 Interventions require a theoretical deconstruction into components and then agreement about permissible and prohibited variation in the delivery of those components. This approach allows implementation of a complex intervention to vary across different contexts yet maintain the integrity of the core intervention components. Drawing on this approach in the ROMIO pilot trial, core components of minimally invasive oesophagectomy were agreed and subsequently monitored during main trial delivery using photography. 14

Complexity might also arise through interactions between the intervention and its context, by which we mean “any feature of the circumstances in which an intervention is conceived, developed, implemented and evaluated.” 6 15 16 17 Much of the criticism of and extensions to the existing framework and guidance have focused on the need for greater attention on understanding how and under what circumstances interventions bring about change. 7 15 18 The importance of interactions between the intervention and its context emphasises the value of identifying mechanisms of change, where mechanisms are the causal links between intervention components and outcomes; and contextual factors, which determine and shape whether and how outcomes are generated. 19

Thus, attention is given not only to the design of the intervention itself but also to the conditions needed to realise its mechanisms of change and/or the resources required to support intervention reach and impact in real world implementation. For example, in a cluster randomised trial of ASSIST (a peer led, smoking prevention intervention), researchers found that the intervention worked particularly well in cohesive communities that were served by one secondary school where peer supporters were in regular contact with their peers—a key contextual factor consistent with diffusion of innovation theory, which underpinned the intervention design. 20 A process evaluation conducted alongside a trial of robot assisted surgery identified key contextual factors to support effective implementation of this procedure, including engaging staff at different levels and surgeons who would not be using robot assisted surgery, whole team training, and an operating theatre of suitable size. 21

With this framing, complex interventions can helpfully be considered as events in systems. 16 Thinking about systems helps us understand the interaction between an intervention and the context in which it is implemented in a dynamic way. 22 Systems can be thought of as complex and adaptive, 23 characterised by properties such as emergence, feedback, adaptation, and self-organisation ( table 1 ).

Properties and examples of complex adaptive systems

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For complex intervention research to be most useful to decision makers, it should take into account the complexity that arises both from the intervention’s components and from its interaction with the context in which it is being implemented.

Research perspectives

The previous framework and guidance were based on a paradigm in which the salient question was to identify whether an intervention was effective. Complex intervention research driven primarily by this question could fail to deliver interventions that are implementable, cost effective, transferable, and scalable in real world conditions. To deliver solutions for real world practice, complex intervention research requires strong and early engagement with patients, practitioners, and policy makers, shifting the focus from the “binary question of effectiveness” 26 to whether and how the intervention will be acceptable, implementable, cost effective, scalable, and transferable across contexts. In line with a broader conception of complexity, the scope of complex intervention research needs to include the development, identification, and evaluation of whole system interventions and the assessment of how interventions contribute to system change. 22 27 The new framework therefore takes a pluralistic approach and identifies four perspectives that can be used to guide the design and conduct of complex intervention research: efficacy, effectiveness, theory based, and systems ( table 2 ).

Although each research perspective prompts different types of research question, they should be thought of as overlapping rather than mutually exclusive. For example, theory based and systems perspectives to evaluation can be used in conjunction, 33 while an effectiveness evaluation can draw on a theory based or systems perspective through an embedded process evaluation to explore how and under what circumstances outcomes are achieved. 34 35 36

Most complex health intervention research so far has taken an efficacy or effectiveness perspective and for some research questions these perspectives will continue to be the most appropriate. However, some questions equally relevant to the needs of decision makers cannot be answered by research restricted to an efficacy or effectiveness perspective. A wider range and combination of research perspectives and methods, which answer questions beyond efficacy and effectiveness, need to be used by researchers and supported by funders. Doing so will help to improve the extent to which key questions for decision makers can be answered by complex intervention research. Example questions include:

Will this effective intervention reproduce the effects found in the trial when implemented here?

Is the intervention cost effective?

What are the most important things we need to do that will collectively improve health outcomes?

In the absence of evidence from randomised trials and the infeasibility of conducting such a trial, what does the existing evidence suggest is the best option now and how can this be evaluated?

What wider changes will occur as a result of this intervention?

How are the intervention effects mediated by different settings and contexts?

Phases and core elements of complex intervention research

The framework divides complex intervention research into four phases: development or identification of the intervention, feasibility, evaluation, and implementation ( fig 1 ). A research programme might begin at any phase, depending on the key uncertainties about the intervention in question. Repeating phases is preferable to automatic progression if uncertainties remain unresolved. Each phase has a common set of core elements—considering context, developing and refining programme theory, engaging stakeholders, identifying key uncertainties, refining the intervention, and economic considerations. These elements should be considered early and continually revisited throughout the research process, and especially before moving between phases (for example, between feasibility testing and evaluation).

Framework for developing and evaluating complex interventions. Context=any feature of the circumstances in which an intervention is conceived, developed, evaluated, and implemented; programme theory=describes how an intervention is expected to lead to its effects and under what conditions—the programme theory should be tested and refined at all stages and used to guide the identification of uncertainties and research questions; stakeholders=those who are targeted by the intervention or policy, involved in its development or delivery, or more broadly those whose personal or professional interests are affected (that is, who have a stake in the topic)—this includes patients and members of the public as well as those linked in a professional capacity; uncertainties=identifying the key uncertainties that exist, given what is already known and what the programme theory, research team, and stakeholders identify as being most important to discover—these judgments inform the framing of research questions, which in turn govern the choice of research perspective; refinement=the process of fine tuning or making changes to the intervention once a preliminary version (prototype) has been developed; economic considerations=determining the comparative resource and outcome consequences of the interventions for those people and organisations affected

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Core elements

The effects of a complex intervention might often be highly dependent on context, such that an intervention that is effective in some settings could be ineffective or even harmful elsewhere. 6 As the examples in table 1 show, interventions can modify the contexts in which they are implemented, by eliciting responses from other agents, or by changing behavioural norms or exposure to risk, so that their effects will also vary over time. Context can be considered as both dynamic and multi-dimensional. Key dimensions include physical, spatial, organisational, social, cultural, political, or economic features of the healthcare, health system, or public health contexts in which interventions are implemented. For example, the evaluation of the Breastfeeding In Groups intervention found that the context of the different localities (eg, staff morale and suitable premises) influenced policy implementation and was an explanatory factor in why breastfeeding rates increased in some intervention localities and declined in others. 37

Programme theory

Programme theory describes how an intervention is expected to lead to its effects and under what conditions. It articulates the key components of the intervention and how they interact, the mechanisms of the intervention, the features of the context that are expected to influence those mechanisms, and how those mechanisms might influence the context. 38 Programme theory can be used to promote shared understanding of the intervention among diverse stakeholders, and to identify key uncertainties and research questions. Where an intervention (such as a policy) is developed by others, researchers still need to theorise the intervention before attempting to evaluate it. 39 Best practice is to develop programme theory at the beginning of the research project with involvement of diverse stakeholders, based on evidence and theory from relevant fields, and to refine it during successive phases. The EPOCH trial tested a large scale quality improvement programme aimed at improving 90 day survival rates for patients undergoing emergency abdominal surgery; it included a well articulated programme theory at the outset, which supported the tailoring of programme delivery to local contexts. 40 The development, implementation, and post-study reflection of the programme theory resulted in suggested improvements for future implementation of the quality improvement programme.

A refined programme theory is an important evaluation outcome and is the principal aim where a theory based perspective is taken. Improved programme theory will help inform transferability of interventions across settings and help produce evidence and understanding that is useful to decision makers. In addition to full articulation of programme theory, it can help provide visual representations—for example, using a logic model, 41 42 43 realist matrix, 44 or a system map, 45 with the choice depending on which is most appropriate for the research perspective and research questions. Although useful, any single visual representation is unlikely to sufficiently articulate the programme theory—it should always be articulated well within the text of publications, reports, and funding applications.

Stakeholders

Stakeholders include those individuals who are targeted by the intervention or policy, those involved in its development or delivery, or those whose personal or professional interests are affected (that is, all those who have a stake in the topic). Patients and the public are key stakeholders. Meaningful engagement with appropriate stakeholders at each phase of the research is needed to maximise the potential of developing or identifying an intervention that is likely to have positive impacts on health and to enhance prospects of achieving changes in policy or practice. For example, patient and public involvement 46 activities in the PARADES programme, which evaluated approaches to reduce harm and improve outcomes for people with bipolar disorder, were wide ranging and central to the project. 47 Involving service users with lived experiences of bipolar disorder had many benefits, for example, it enhanced the intervention but also improved the evaluation and dissemination methods. Service users involved in the study also had positive outcomes, including more settled employment and progression to further education. Broad thinking and consultation is needed to identify a diverse range of appropriate stakeholders.

The purpose of stakeholder engagement will differ depending on the context and phase of the research, but is essential for prioritising research questions, the co-development of programme theory, choosing the most useful research perspective, and overcoming practical obstacles to evaluation and implementation. Researchers should nevertheless be mindful of conflicts of interest among stakeholders and use transparent methods to record potential conflicts of interest. Research should not only elicit stakeholder priorities, but also consider why they are priorities. Careful consideration of the appropriateness and methods of identification and engagement of stakeholders is needed. 46 48

Key uncertainties

Many questions could be answered at each phase of the research process. The design and conduct of research need to engage pragmatically with the multiple uncertainties involved and offer a flexible and emergent approach to exploring them. 15 Therefore, researchers should spend time developing the programme theory, clearly identifying the remaining uncertainties, given what is already known and what the research team and stakeholders identify as being most important to determine. Judgments about the key uncertainties inform the framing of research questions, which in turn govern the choice of research perspective.

Efficacy trials of relatively uncomplicated interventions in tightly controlled conditions, where research questions are answered with great certainty, will always be important, but translation of the evidence into the diverse settings of everyday practice is often highly problematic. 27 For intervention research in healthcare and public health settings to take on more challenging evaluation questions, greater priority should be given to mixed methods, theory based, or systems evaluation that is sensitive to complexity and that emphasises implementation, context, and system fit. This approach could help improve understanding and identify important implications for decision makers, albeit with caveats, assumptions, and limitations. 22 Rather than maintaining the established tendency to prioritise strong research designs that answer some questions with certainty but are unsuited to resolving many important evaluation questions, this more inclusive, deliberative process could place greater value on equivocal findings that nevertheless inform important decisions where evidence is sparse.

Intervention refinement

Within each phase of complex intervention research and on transition from one phase to another, the intervention might need to be refined, on the basis of data collected or development of programme theory. 4 The feasibility and acceptability of interventions can be improved by engaging potential intervention users to inform refinements. For example, an online physical activity planner for people with diabetes mellitus was found to be difficult to use, resulting in the tool providing incorrect personalised advice. To improve usability and the advice given, several iterations of the planner were developed on the basis of interviews and observations. This iterative process led to the refined planner demonstrating greater feasibility and accuracy. 49

Refinements should be guided by the programme theory, with acceptable boundaries agreed and specified at the beginning of each research phase, and with transparent reporting of the rationale for change. Scope for refinement might also be limited by the policy or practice context. Refinement will be rare in the evaluation phase of efficacy and effectiveness research, where interventions will ideally not change or evolve within the course of the study. However, between the phases of research and within systems and theory based evaluation studies, refinement of interventions in response to accumulated data or as an adaptive and variable response to context and system change are likely to be desirable features of the intervention and a key focus of the research.

Economic considerations

Economic evaluation—the comparative analysis of alternative courses of action in terms of both costs (resource use) and consequences (outcomes, effects)—should be a core component of all phases of intervention research. Early engagement of economic expertise will help identify the scope of costs and benefits to assess in order to answer questions that matter most to decision makers. 50 Broad ranging approaches such as cost benefit analysis or cost consequence analysis, which seek to capture the full range of health and non-health costs and benefits across different sectors, 51 will often be more suitable for an economic evaluation of a complex intervention than narrower approaches such as cost effectiveness or cost utility analysis. For example, evaluation of the New Orleans Intervention Model for infants entering foster care in Glasgow included short and long term economic analysis from multiple perspectives (the UK’s health service and personal social services, public sector, and wider societal perspectives); and used a range of frameworks, including cost utility and cost consequence analysis, to capture changes in the intersectoral costs and outcomes associated with child maltreatment. 52 53 The use of multiple economic evaluation frameworks provides decision makers with a comprehensive, multi-perspective guide to the cost effectiveness of the New Orleans Intervention Model.

Developing or identifying a complex intervention

Development refers to the whole process of designing and planning an intervention, from initial conception through to feasibility, pilot, or evaluation study. Guidance on intervention development has recently been developed through the INDEX study 4 ; although here we highlight that complex intervention research does not always begin with new or researcher led interventions. For example:

A key source of intervention development might be an intervention that has been developed elsewhere and has the possibility of being adapted to a new context. Adaptation of existing interventions could include adapting to a new population, to a new setting, 54 55 or to target other outcomes (eg, a smoking prevention intervention being adapted to tackle substance misuse and sexual health). 20 56 57 A well developed programme theory can help identify what features of the antecedent intervention(s) need to be adapted for different applications, and the key mechanisms that should be retained even if delivered slightly differently. 54 58

Policy or practice led interventions are an important focus of evaluation research. Again, uncovering the implicit theoretical basis of an intervention and developing a programme theory is essential to identifying key uncertainties and working out how the intervention might be evaluated. This step is important, even if rollout has begun, because it supports the identification of mechanisms of change, important contextual factors, and relevant outcome measures. For example, researchers evaluating the UK soft drinks industry levy developed a bounded conceptual system map to articulate their understanding (drawing on stakeholder views and document review) of how the intervention was expected to work. This system map guided the evaluation design and helped identify data sources to support evaluation. 45 Another example is a recent analysis of the implicit theory of the NHS diabetes prevention programme, involving analysis of documentation by NHS England and four providers, showing that there was no explicit theoretical basis for the programme, and no logic model showing how the intervention was expected to work. This meant that the justification for the inclusion of intervention components was unclear. 59

Intervention identification and intervention development represent two distinct pathways of evidence generation, 60 but in both cases, the key considerations in this phase relate to the core elements described above.

Feasibility

A feasibility study should be designed to assess predefined progression criteria that relate to the evaluation design (eg, reducing uncertainty around recruitment, data collection, retention, outcomes, and analysis) or the intervention itself (eg, around optimal content and delivery, acceptability, adherence, likelihood of cost effectiveness, or capacity of providers to deliver the intervention). If the programme theory suggests that contextual or implementation factors might influence the acceptability, effectiveness, or cost effectiveness of the intervention, these questions should be considered.

Despite being overlooked or rushed in the past, the value of feasibility testing is now widely accepted with key terms and concepts well defined. 61 62 Before initiating a feasibility study, researchers should consider conducting an evaluability assessment to determine whether and how an intervention can usefully be evaluated. Evaluability assessment involves collaboration with stakeholders to reach agreement on the expected outcomes of the intervention, the data that could be collected to assess processes and outcomes, and the options for designing the evaluation. 63 The end result is a recommendation on whether an evaluation is feasible, whether it can be carried out at a reasonable cost, and by which methods. 64

Economic modelling can be undertaken at the feasibility stage to assess the likelihood that the expected benefits of the intervention justify the costs (including the cost of further research), and to help decision makers decide whether proceeding to a full scale evaluation is worthwhile. 65 Depending on the results of the feasibility study, further work might be required to progressively refine the intervention before embarking on a full scale evaluation.

The new framework defines evaluation as going beyond asking whether an intervention works (in the sense of achieving its intended outcome), to a broader range of questions including identifying what other impact it has, theorising how it works, taking account of how it interacts with the context in which it is implemented, how it contributes to system change, and how the evidence can be used to support decision making in the real world. This implies a shift from an exclusive focus on obtaining unbiased estimates of effectiveness 66 towards prioritising the usefulness of information for decision making in selecting the optimal research perspective and in prioritising answerable research questions.

A crucial aspect of evaluation design is the choice of outcome measures or evidence of change. Evaluators should work with stakeholders to assess which outcomes are most important, and how to deal with multiple outcomes in the analysis with due consideration of statistical power and transparent reporting. A sharp distinction between one primary outcome and several secondary outcomes is not necessarily appropriate, particularly where the programme theory identifies impacts across a range of domains. Where needed to support the research questions, prespecified subgroup analyses should be carried out and reported. Even where such analyses are underpowered, they should be included in the protocol because they might be useful for subsequent meta-analyses, or for developing hypotheses for testing in further research. Outcome measures could capture changes to a system rather than changes in individuals. Examples include changes in relationships within an organisation, the introduction of policies, changes in social norms, or normalisation of practice. Such system level outcomes include how changing the dynamics of one part of a system alters behaviours in other parts, such as the potential for displacement of smoking into the home after a public smoking ban.

A helpful illustration of the use of system level outcomes is the evaluation of the Delaware Young Health Program—an initiative to improve the health and wellbeing of young people in Delaware, USA. The intervention aimed to change underlying system dynamics, structures, and conditions, so the evaluation identified systems oriented research questions and methods. Three systems science methods were used: group model building and viable systems model assessment to identify underlying patterns and structures; and social network analysis to evaluate change in relationships over time. 67

Researchers have many study designs to choose from, and different designs are optimally suited to consider different research questions and different circumstances. 68 Extensions to standard designs of randomised controlled trials (including adaptive designs, SMART trials (sequential multiple assignment randomised trials), n-of-1 trials, and hybrid effectiveness-implementation designs) are important areas of methods development to improve the efficiency of complex intervention research. 69 70 71 72 Non-randomised designs and modelling approaches might work best if a randomised design is not practical, for example, in natural experiments or systems evaluations. 5 73 74 A purely quantitative approach, using an experimental design with no additional elements such as a process evaluation, is rarely adequate for complex intervention research, where qualitative and mixed methods designs might be necessary to answer questions beyond effectiveness. In many evaluations, the nature of the intervention, the programme theory, or the priorities of stakeholders could lead to a greater focus on improving theories about how to intervene. In this view, effect estimates are inherently context bound, so that average effects are not a useful guide to decision makers working in different contexts. Contextualised understandings of how an intervention induces change might be more useful, as well as details on the most important enablers and constraints on its delivery across a range of settings. 7

Process evaluation can answer questions around fidelity and quality of implementation (eg, what is implemented and how?), mechanisms of change (eg, how does the delivered intervention produce change?), and context (eg, how does context affect implementation and outcomes?). 7 Process evaluation can help determine why an intervention fails unexpectedly or has unanticipated consequences, or why it works and how it can be optimised. Such findings can facilitate further development of the intervention programme theory. 75 In a theory based or systems evaluation, there is not necessarily such a clear distinction between process and outcome evaluation as there is in an effectiveness study. 76 These perspectives could prioritise theory building over evidence production and use case study or simulation methods to understand how outcomes or system behaviour are generated through intervention. 74 77

Implementation

Early consideration of implementation increases the potential of developing an intervention that can be widely adopted and maintained in real world settings. Implementation questions should be anticipated in the intervention programme theory, and considered throughout the phases of intervention development, feasibility testing, process, and outcome evaluation. Alongside implementation specific outcomes (such as reach or uptake of services), attention to the components of the implementation strategy, and contextual factors that support or hinder the achievement of impacts, are key. Some flexibility in intervention implementation might support intervention transferability into different contexts (an important aspect of long term implementation 78 ), provided that the key functions of the programme are maintained, and that the adaptations made are clearly understood. 8

In the ASSIST study, 20 a school based, peer led intervention for smoking prevention, researchers considered implementation at each phase. The intervention was developed to have minimal disruption on school resources; the feasibility study resulted in intervention refinements to improve acceptability and improve reach to male students; and in the evaluation (cluster randomised controlled trial), the intervention was delivered as closely as possible to real world implementation. Drawing on the process evaluation, the implementation included an intervention manual that identified critical components and other components that could be adapted or dropped to allow flexible implementation while achieving delivery of the key mechanisms of change; and a training manual for the trainers and ongoing quality assurance built into rollout for the longer term.

In a natural experimental study, evaluation takes place during or after the implementation of the intervention in a real world context. Highly pragmatic effectiveness trials or specific hybrid effectiveness-implementation designs also combine effectiveness and implementation outcomes in one study, with the aim of reducing time for translation of research on effectiveness into routine practice. 72 79 80

Implementation questions should be included in economic considerations during the early stages of intervention and study development. How the results of economic analyses are reported and presented to decision makers can affect whether and how they act on the results. 81 A key consideration is how to deal with interventions across different sectors, where those paying for interventions and those receiving the benefits of them could differ, reducing the incentive to implement an intervention, even if shown to be beneficial and cost effective. Early engagement with appropriate stakeholders will help frame appropriate research questions and could anticipate any implementation challenges that might arise. 82

Conclusions

One of the motivations for developing this new framework was to answer calls for a change in research priorities, towards allocating greater effort and funding to research that can have the optimum impact on healthcare or population health outcomes. The framework challenges the view that unbiased estimates of effectiveness are the cardinal goal of evaluation. It asserts that improving theories and understanding how interventions contribute to change, including how they interact with their context and wider dynamic systems, is an equally important goal. For some complex intervention research problems, an efficacy or effectiveness perspective will be the optimal approach, and a randomised controlled trial will provide the best design to achieve an unbiased estimate. For others, alternative perspectives and designs might work better, or might be the only way to generate new knowledge to reduce decision maker uncertainty.

What is important for the future is that the scope of intervention research is not constrained by an unduly limited set of perspectives and approaches that might be less risky to commission and more likely to produce a clear and unbiased answer to a specific question. A bolder approach is needed—to include methods and perspectives where experience is still quite limited, but where we, supported by our workshop participants and respondents to our consultations, believe there is an urgent need to make progress. This endeavour will involve mainstreaming new methods that are not yet widely used, as well as undertaking methodological innovation and development. The deliberative and flexible approach that we encourage is intended to reduce research waste, 83 maximise usefulness for decision makers, and increase the efficiency with which complex intervention research generates knowledge that contributes to health improvement.

Monitoring the use of the framework and evaluating its acceptability and impact is important but has been lacking in the past. We encourage research funders and journal editors to support the diversity of research perspectives and methods that are advocated here and to seek evidence that the core elements are attended to in research design and conduct. We have developed a checklist to support the preparation of funding applications, research protocols, and journal publications. 9 This checklist offers one way to monitor impact of the guidance on researchers, funders, and journal editors.

We recommend that the guidance is continually updated, and future updates continue to adopt a broad, pluralist perspective. Given its wider scope, and the range of detailed guidance that is now available on specific methods and topics, we believe that the framework is best seen as meta-guidance. Further editions should be published in a fluid, web based format, and more frequently updated to incorporate new material, further case studies, and additional links to other new resources.

Acknowledgments

We thank the experts who provided input at the workshop, those who responded to the consultation, and those who provided advice and review throughout the process. The many people involved are acknowledged in the full framework document. 9 Parts of this manuscript have been reproduced (some with edits and formatting changes), with permission, from that longer framework document.

Contributors: All authors made a substantial contribution to all stages of the development of the framework—they contributed to its development, drafting, and final approval. KS and LMa led the writing of the framework, and KS wrote the first draft of this paper. PC, SAS, and LMo provided critical insights to the development of the framework and contributed to writing both the framework and this paper. KS, LMa, SAS, PC, and LMo facilitated the expert workshop, KS and LMa developed the gap analysis and led the analysis of the consultation. KAB, NC, and EM contributed the economic components to the framework. The scientific advisory group (JB, JMB, DPF, MP, JR-M, and MW) provided feedback and edits on drafts of the framework, with particular attention to process evaluation (JB), clinical research (JMB), implementation (JR-M, DPF), systems perspective (MP), theory based perspective (JR-M), and population health (MW). LMo is senior author. KS and LMo are the guarantors of this work and accept the full responsibility for the finished article. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting authorship criteria have been omitted.

Funding: The work was funded by the National Institute for Health Research (Department of Health and Social Care 73514) and Medical Research Council (MRC). Additional time on the study was funded by grants from the MRC for KS (MC_UU_12017/11, MC_UU_00022/3), LMa, SAS, and LMo (MC_UU_12017/14, MC_UU_00022/1); PC (MC_UU_12017/15, MC_UU_00022/2); and MW (MC_UU_12015/6 and MC_UU_00006/7). Additional time on the study was also funded by grants from the Chief Scientist Office of the Scottish Government Health Directorates for KS (SPHSU11 and SPHSU18); LMa, SAS, and LMo (SPHSU14 and SPHSU16); and PC (SPHSU13 and SPHSU15). KS and SAS were also supported by an MRC Strategic Award (MC_PC_13027). JMB received funding from the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol and by the MRC ConDuCT-II Hub (Collaboration and innovation for Difficult and Complex randomised controlled Trials In Invasive procedures - MR/K025643/1). DF is funded in part by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007) and NIHR Applied Research Collaboration - Greater Manchester (NIHR200174). MP is funded in part as director of the NIHR’s Public Health Policy Research Unit. This project was overseen by a scientific advisory group that comprised representatives of NIHR research programmes, of the MRC/NIHR Methodology Research Programme Panel, of key MRC population health research investments, and authors of the 2006 guidance. A prospectively agreed protocol, outlining the workplan, was agreed with MRC and NIHR, and signed off by the scientific advisory group. The framework was reviewed and approved by the MRC/NIHR Methodology Research Programme Advisory Group and MRC Population Health Sciences Group and completed NIHR HTA Monograph editorial and peer review processes.

Competing interests: All authors have completed the ICMJE uniform disclosure form at http://www.icmje.org/coi_disclosure.pdf and declare: support from the NIHR, MRC, and the funders listed above for the submitted work; KS has project grant funding from the Scottish Government Chief Scientist Office; SAS is a former member of the NIHR Health Technology Assessment Clinical Evaluation and Trials Programme Panel (November 2016 - November 2020) and member of the Chief Scientist Office Health HIPS Committee (since 2018) and NIHR Policy Research Programme (since November 2019), and has project grant funding from the Economic and Social Research Council, MRC, and NIHR; LMo is a former member of the MRC-NIHR Methodology Research Programme Panel (2015-19) and MRC Population Health Sciences Group (2015-20); JB is a member of the NIHR Public Health Research Funding Committee (since May 2019), and a core member (since 2016) and vice chairperson (since 2018) of a public health advisory committee of the National Institute for Health and Care Excellence; JMB is a former member of the NIHR Clinical Trials Unit Standing Advisory Committee (2015-19); DPF is a former member of the NIHR Public Health Research programme research funding board (2015-2019), the MRC-NIHR Methodology Research Programme panel member (2014-2018), and is a panel member of the Research Excellence Framework 2021, subpanel 2 (public health, health services, and primary care; November 2020 - February 2022), and has grant funding from the European Commission, NIHR, MRC, Natural Environment Research Council, Prevent Breast Cancer, Breast Cancer Now, Greater Sport, Manchester University NHS Foundation Trust, Christie Hospital NHS Trust, and BXS GP; EM is a member of the NIHR Public Health Research funding board; MP has grant funding from the MRC, UK Prevention Research Partnership, and NIHR; JR-M is programme director and chairperson of the NIHR’s Health Services Delivery Research Programme (since 2014) and member of the NIHR Strategy Board (since 2014); MW received a salary as director of the NIHR PHR Programme (2014-20), has grant funding from NIHR, and is a former member of the MRC’s Population Health Sciences Strategic Committee (July 2014 to June 2020). There are no other relationships or activities that could appear to have influenced the submitted work.

Patient and public involvement: This project was methodological; views of patients and the public were included at the open consultation stage of the update. The open consultation, involving access to an initial draft, was promoted to our networks via email and digital channels, such as our unit Twitter account ( @theSPHSU ). We received five responses from people who identified as service users (rather than researchers or professionals in a relevant capacity). Their input included helpful feedback on the main complexity diagram, the different research perspectives, the challenge of moving interventions between different contexts and overall readability and accessibility of the document. Several respondents also highlighted useful signposts to include for readers. Various dissemination events are planned, but as this project is methodological we will not specifically disseminate to patients and the public beyond the planned dissemination activities.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/ .

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Evolution of Clinical Research: A History Before and Beyond James Lind

Dr arun bhatt.

President, Clininvent Research Pvt Ltd, Mumbai, India

The evolution of clinical research traverses a long and fascinating journey. From the first recorded trial of legumes in biblical times to the first randomized controlled of trial of streptomycin in 1946, the history of clinical trial covers a wide variety of challenges - scientific, ethical and regulatory. The famous 1747 scurvy trial conducted by James Lind contained most elements of a controlled trial. The UK Medical Research Council's (MRC) trial of patulin for common cold in 1943 was the first double blind controlled trial. This paved the way for the first randomized control trial of streptomycin in pulmonary tuberculosis carried out in 1946 by MRC of the UK. This landmark trial was a model of meticulousness in design and implementation, with systematic enrolment criteria and data collection compared with the ad hoc nature of other contemporary research. Over the years, as the discipline of controlled trials grew in sophistication and influence, the streptomycin trial continues to be referred to as ground breaking. The ethical advances in human protection include several milestones - Nuremberg Code, Declaration of Helsinki, Belmont Report, and 1996, International Conference on Harmonization Good Clinical Practice guidance. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.

“The charm of history and its enigmatic lesson consist in the fact that, from age to age, nothing changes and yet everything is completely different.” - Aldous Huxley

The evolution of clinical research traverses a long and fascinating journey. The recorded history of clinical trials goes back to the biblical descriptions in 500 BC. The journey moves from dietary therapy – legumes and lemons – to drugs. After basic approach of clinical trial was described in 18th century, the efforts were made to refine the design and statistical aspects. These were followed by changes in regulatory and ethics milieu. This article captures the major milestones in the evolution of clinical trials.

562 BC - 1537: Pre-James Lind Era

The world's first clinical trial is recorded in the “Book of Daniel” in The Bible. 1 This experiment resembling a clinical trial was not conducted by a medical, but by King Nebuchadnezzar a resourceful military leader. 1 During his rule in Babylon, Nebuchadnezzar ordered his people to eat only meat and drink only wine, a diet he believed would keep them in sound physical condition. 1 But several young men of royal blood, who preferred to eat vegetables, objected. The king allowed these rebels to follow a diet of legumes and water — but only for 10 days. When Nebuchadnezzar's experiment ended, the vegetarians appeared better nourished than the meat-eaters, so the king permitted the legume lovers to continue their diet. 1 This probably was the one of the first times in evolution of human species that an open uncontrolled human experiment guided a decision about public health.

Avicenna (1025 AD) in his encyclopedic ‘Canon of Medicine’ describes some interesting rules for the testing of drugs. 2 He suggests that in the clinical trial a remedy should be used in its natural state in disease without complications. He recommends that two cases of contrary types be studied and that study be made of the time of action and of the reproducibility of the effects. 2 These rules suggest a contemporary approach for clinical trials. However, there seems to be no record of the application of these principles in practice.

The first clinical trial of a novel therapy was conducted accidentally by the famous surgeon Ambroise Pare in 1537. 1 , 3 In 1537 while serving with the Mareschal de Motegni he was responsible for the treatment of the battlefield wounded soldiers. As the number of wounded was high and the supply of conventional treatment – oil was not adequate to treat all the wounded, he had to resort to unconventional treatment. He describes,' at length my oil lacked and I was constrained to apply in its place a digestive made of yolks of eggs, oil of roses and turpentine. That night I could not sleep at any ease, fearing that by lack of cauterization I would find the wounded upon which I had not used the said oil dead from the poison. I raised myself early to visit them, when beyond my hope I found those to whom I had applied the digestive medicament feeling but little pain, their wounds neither swollen nor inflamed, and having slept through the night. The others to whom I had applied the boiling oil were feverish with much pain and swelling about their wounds. Then I determined never again to burn thus so cruelly the poor wounded by arquebuses’. 2 However, it would take another 200 years before a planned controlled trial would be organized.

1747: James Lind and Scurvy Trial

James Lind is considered the first physician to have conducted a controlled clinical trial of the modern era. 1 – 4 Dr Lind (1716-94), whilst working as a surgeon on a ship, was appalled by the high mortality of scurvy amongst the sailors. He planned a comparative trial of the most promising cure for scurvy. 1 – 4 His vivid description of the trial covers the essential elements of a controlled trial.

Lind describes“”On the 20th of May 1747, I selected twelve patients in the scurvy, on board the Salisbury at sea. Their cases were as similar as I could have them. They all in general had putrid gums, the spots and lassitude, with weakness of the knees. They lay together in one place, being a proper apartment for the sick in the fore-hold; and had one diet common to all, viz. water gruel sweetened with sugar in the morning; fresh mutton-broth often times for dinner; at other times light puddings, boiled biscuit with sugar, etc., and for supper, barley and raisins, rice and currants, sago and wine or the like. Two were ordered each a quart of cyder a day. Two others took twenty-five drops of elixir vitriol three times a day … Two others took two spoonfuls of vinegar three times a day … Two of the worst patients were put on a course of sea-water … Two others had each two oranges and one lemon given them every day … The two remaining patients, took … an electary recommended by a hospital surgeon … The consequence was, that the most sudden and visible good effects were perceived from the use of oranges and lemons; one of those who had taken them, being at the end of six days fit for duty … The other was the best recovered of any in his condition; and … was appointed to attend the rest of the sick. Next to the oranges, I thought the cyder had the best effects …” (Dr James Lind's “Treatise on Scurvy” published in Edinburgh in 1753)

Although the results were clear, Lind hesitated to recommend the use of oranges and lemons because they were too expensive. 3 It was nearly 50 years before the British Navy eventually made lemon juice a compulsory part of the seafarer's diet, and this was soon replaced by lime juice because it was cheaper.

Lind's Treatise of 1953, was written while he was resident in Edinburgh and a Fellow of the Royal College of Physicians, contains not only his well known description of a controlled trial showing that oranges and lemons were dramatically better than the other treatments for the disease, but also a systematic review of previous literature on scurvy. 5

In 2003, Royal College of Physicians established The James Lind Library to commemorate 250 th anniversary of publication of Dr Lind's pioneering contribution “Treatise on Scurvy”. The James Lind Library ( www.jameslindlibrary.org ) was created to improve public and professional general knowledge about fair tests of treatments in healthcare and their history. 5 This library is a website ( www.jameslindlibrary.org ) that introduces visitors to the principles of fair tests of treatments, with a series of short, illustrated essays. In 2003, Scientific American awarded the Library a Sci/Tech web award. The publicity and popularity of the James Lind Library has made 20 May to be designated International Clinical Trials Day, because James Lind's celebrated controlled trial began on that day in 1747. 5

1800: Arrival of Placebo

It took another century before the emergence of another important mile stone in the history of modern clinical trial: the placebo. The word placebo first appeared in medical literature in the early 1800s. 1 Hooper's Medical Dictionary of 1811 defined it as “an epithet given to any medicine more to please than benefit the patient.” However, it was only in 1863 that United States physician Austin Flint planned the first clinical study comparing a dummy remedy to an active treatment. He treated 13 patients suffering from rheumatism with an herbal extract which was advised instead of an established remedy. In 1886, Flint described the study in his book A Treatise on the Principles and Practice of Medicine. “This was given regularly, and became well known in my wards as the ‘placeboic remedy’ for rheumatism. The favorable progress of the cases was such as to secure for the remedy generally the entire confidence of the patients.”

1943: The First Double blind Controlled Trial - Patulin for Common Cold

The Medical Research Council (MRC) UK carried out a trial in 1943-4 to investigate patulin treatment for (an extract of Penicillium patulinum) the common cold. 6 This was the first double blind comparative trial with concurrent controls in the general population in recent times. 6 It was one of the last trial with non-randomized or quasi-randomized allocation of subjects. 6 The MRC Patulin Clinical Trials Committee (1943) was chaired by Sir Harold Himsworth, and its statisticians were M Greenwood and W J Martin. This nationwide study enrolled over a thousand British office and factory workers suffering from colds. This was quite a challenging endeavor in wartime,

The study was rigorously controlled by keeping the physician and the patient blinded to the treatment. The treatment allocation was done using an alternation procedure. A nurse allocated the treatment in strict rotation in a separate room. The nurse filed the record counterfoil separately, and detached the code label for the appropriate bottle before asking the patient to visit the doctor. 6 The statisticians considered this an effective random concurrent allocation. .However, the outcome of the trial was disappointing as the analysis of trial data did not show any protective effect of patulin. 6

1946 First Randomized Curative Trial - The Randomized Controlled Trial of Streptomycin

The idea of randomization was introduced in 1923. However, the first randomized control trial of streptomycin in pulmonary tuberculosis was carried out in 1946 by MRC of the UK. 6 , 7 The MRC Streptomycin in Tuberculosis Trials Committee (1946) was chaired by Sir Geoffrey Marshall, and the statistician was Sir Austin Bradford Hill and Philip Hart, who later directed the MRC's tuberculosis research unit, served as secretary. Marc Daniels, as the “registrar” coordinated the clinicians at the participating hospitals. The trial began in 1947. As the amount of streptomycin available from US was limited, it was ethically acceptable for the control subjects to be untreated by the drug—a statistician's dream. 6 This trial was a model of meticulousness in design and implementation, with systematic enrolment criteria and data collection compared with the ad hoc nature of other contemporary research 8 A key advantage of Dr Hill's randomization scheme over alternation procedure was “allocation concealment” at the time patients were enrolled in the trial. Another significant feature of the trial was the use of objective measures such as interpretation of x-rays by experts who were blinded to the patient's treatment assignment. 8

Sir Bradford Hill had formed his allocation ideas over several years (with randomisation replacing alternation in order to better conceal the allocation schedule), but had only tried them out in disease prevention. Dr Hill instituted randomization – a new statistical process which has been described in detail in the landmark BMJ paper of 1948. 7

“Determination of whether a patient would be treated by streptomycin and bed-rest (S case) or by bed-rest alone (C case) was made by reference to a statistical series based on random sampling numbers drawn up for each sex at each centre by Professor Bradford Hill; the details of the series were unknown to any of the investigators or to the co--coordinator and were contained in a set of sealed envelopes, each bearing on the outside only the name of the hospital and a number. After acceptance of a patient by the panel, and before admission to the streptomycin centre, the appropriate numbered envelope was opened at the central office; the card inside told if the patient was to be an S or a C case, and this information was then given to the medical officer of the centre. Patients were not told before admission that they were to get special treatment. C patients did not know throughout their stay in hospital that they were control patients in a special study; they were in fact treated as they would have been in the past, the sole difference being that they had been admitted to the centre more rapidly than was normal. Usually they were not in the same wards as S patients, but the same regime was maintained

Sir Bradford Hill had been anxious that physicians would be unwilling to give up the doctrine of anecdotal experience. However, the trial quickly became a model of design and implementation and gave a boost to Dr Hill's views and subsequent teaching, and resulted, after some years, in the present virtually universal use of randomised allocation in clinical trials. 6 The greatest influence of this trial lay in its methods which have affected virtually every area of clinical medicine. 8 Over the years, as the discipline of controlled trials grew in sophistication and influence, the streptomycin trial continues to be referred to as ground breaking. 8

Evolution of Ethical and Regulatory Framework

The ethical framework for human subject protection has its origins in the ancient Hippocratic Oath, which specified a prime duty of a physician – to avoid harming the patient. However, this oath was not much respected in human experimentation and most advances in protection for human subjects have been a response to human abuses e.g. World War II experiments.

The first International Guidance on the ethics of medical research involving subjects – the Nuremberg Code was formulated in 1947. Although informed consent for participation in research was described in 1900, the Nuremberg Code highlighted the essentiality of voluntariness of this consent. 9 In 1948, Universal Declaration of Human Rights (adopted by the General Assembly of the United Nations) expressed concern about rights of human beings being subjected to involuntary maltreatment. 9 The brush with thalidomide tragedy helped the U.S. pass the 1962 Kefauver-Harris amendments, which strengthened federal oversight of drug testing and included a requirement for informed consent. 10

In 1964 at Helsinki, the World Medical Association articulated general principles and specific guidelines on use of human subjects in medical research, known as the Helsinki Declaration. The Helsinki Declaration has been undergoing changes every few years the last one being in 2008. However, the use of placebo and post-trial access continue to be debatable issues.

In 1966, the International Covenant on Civil and Political Rights specifically stated, ‘No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment. In particular, no one shall be subjected without his consent to medical or scientific treatment.’ 9 Dr. Henry Beecher's 1966 study of abuses and the discovery of human exploitation of Tuskegee study in the 1970s reinforced the call for tighter regulation of government funded human research. 10 The US National Research Act of 1974 and Belmont Report of 1979 were major efforts in shaping ethics of human experimentation. In 1996, International Conference on Harmonization published Good Clinical Practice, which has become the universal standard for ethical conduct of clinical trials.

In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. The FDA was founded in 1862 as a scientific institution and became a law enforcement organization after the US Congress passed the Food and Drugs Act in 1906. After that, legislation progressively demanded greater accountability for marketing food and drugs and the need for testing drugs in clinical trials increased. The regulatory and ethical milieu will continue to evolve as new scientific disciplines and technologies become part of drug development.

Evolution of Clinical Trials in India

India has recently been recognized as an attractive country for clinical trials. But the country's journey in clinical research field has a long history. India has a rich heritage of traditional medicine – Ayurveda. The classic ayurvedic texts contain detailed observations on diseases and in-depth guidance on remedies. It is likely that these descriptions are based on direct observations made by the ancient ayurveda experts. However, there is no recorded documentation in the ancient texts of any clinical experiments. Hence, one has to fall back on current history of medical research in India.

The major historic milestones of the Indian Council of Medical Research reflect, in many ways, the growth and development of medical research in the country over the last nine decades. First meeting of the Governing Body of the Indian Research Fund Association (IRFA) was held on November 15, 1911 at the Plague Laboratory, Bombay, under the Chairmanship of Sir Harcourt Butler. 11 At the 2nd meeting of the Governing Body in 1912, a historic decision was taken to start a journal for Indian Medical research. Between 1918--20, several projects on beriberi, malaria, kala azar and indigenous drugs were initiated. In 1945, a Clinical Research Unit – the first research unit of IRFA attached to a medical institution- was established at the Indian Cancer Research Centre, Bombay. In 1949, IRFA was redesignated as the Indian Council of Medical Research. Over next 60 years, ICMR established many national research centers in the fields of nutrition, tuberculosis, leprosy, viral disease, cholera, enteric disease, reproductive disorders, toxicology, cancer, traditional medicine, gas disaster, genetics, AIDS etc.

The Central Ethical Committee of ICMR on Human Research constituted under the Chairmanship of Hon'ble Justice (Retired) M.N. Venkatachaliah held its first meeting on September 10, 1996. Several subcommittees were constituted to consider ethical issues in specific areas e.g., Epidemiological Research; Clinical Evaluation of Products to be used on Humans; Organ Transplantation; Human Genetics, etc. The committee released Ethical Guidelines for Biomedical Research on Human Participants in 2000 which were revised in 2006. 9

Schedule Y of Drugs and Cosmetics Act came into force in 1988 and established the regulatory guidelines for clinical trial (CT) permission. The schedule did force the industry to conduct Phase III clinical trials for registration of a new drug and supported growth of a predominantly generic Indian pharmaceutical industry. However, this schedule only permitted clinical trials at a phase lower than its global status. This phase lag obstructed integration of India in global clinical development.

The next major step has been revision of Schedule Y in Jan 2005. 12 As compared to Schedule Y 1988, which had narrow and restrictive definitions of clinical trial phases, the amended Schedule Y 2005 provided pragmatic definitions for Phase I to IV. 12 The definitions and guidelines for clinical trial phases are broad and rational. The earlier restrictions on number patients and centers in early phases stipulated in Schedule Y 1988 were removed allowing the sponsor company freedom to decide these in relation to protocol requirements. The phase lag requirements gave way to acceptance of concurrent Phase II-III as part of global clinical trials.

Schedule Y 2005 legalized Indian GCP guidelines of 2001. This schedule stipulated GCP responsibilities of ethics committee (EC), investigator and sponsor and suggested formats for critical documents e.g. consent, report, EC approval, reporting of serious adverse event. These amendments in Schedule Y have been a major step forward in direction of GCP compliant trials and have provided the much-needed regulatory support to GCP guidelines.

Since the Scurvy trial, clinical trials have evolved into a standardized procedure, focusing on scientific assessment of efficacy and guarding the patient safety. As the discipline of drug development is enriched by novel therapies and technologies, there will always be a continuing need to balance medical progress and patient safety. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.

Strategy of MRC

Read the MRC’s strategic delivery plan 2022 to 2025 .

Our vision is to accelerate improvements in human health and economic prosperity for everyone, regardless of background, place or upbringing, by supporting world-class biomedical research and innovation, and strengthening partnerships within UKRI, across the UK and around the world.

In our new strategic delivery plan, we have renewed our commitment to supporting excellent fundamental discovery science to advance the frontiers of knowledge and maintain the breadth of expertise that allows us to respond rapidly to current and future challenges.

We will work across UKRI, with national and international partners, and industry to address health and societal challenges. This includes targeted support for those set out in the strategic themes of the UKRI strategy, focusing on securing better health, ageing and wellbeing and tackling infections, in support of the government’s Life Sciences Vision.

The MRC strategic delivery plan sets out our key priorities across the next 3 years. It was developed within the framework of the wider UKRI strategy and is 1 of the suite of UKRI strategic delivery plans which showcases the part each council will play in delivering the wider UKRI mission and vision.

Last updated: 2 December 2022

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