Revolutionary Events in Clinical Research and Consequences

Healthcare Industry is  one of the most stringently regulated domain all over the world. Pharmaceutical industry occupies major portion of healthcare in terms of cost, regulation and public health impact. Pharma industry has  made a long path of offering new therapeutics to existing as well as potential illness, significantly impacting life span and quality of life of people throughout the globe. Beside scientific and technical regulation, Heath-care has adopted various administrative as well as Legal procedures including legislation, Bills, guidelines etc. Behind this Meticulous management, a huge lesson is learnt from mistakes, misconducts, and conflict of interest  happened in the past. Here I'm going to discuss some of the major Incidents happened in the past along with their consequences till date. 

     Tuskegee Syphilis Study (1932)

Back in 1930s, syphilis was disease of higher prevalence, specially among black communities. There was not evident treatment available and scant of information on the natural history of disease created fear in affected individuals. A group of doctors from US public health service took advantage of intimidation and innocence of those community where infection rate was significant and enrolled them for a study to treat 'Bad Blood' in their own term. In 1932, study was initiated at Tuskegee Alabama, with number of 601 black male (among them 399 were infected with syphilis and 201 were not) without taking consent and providing information about the study. The treatment was offered with Aspirin and vitamin supplementation which has nothing to do with actual disease. Real intention behind the study was to know progression of disease, it's complications and associated morbidity as well as mortality.  This so called study continued for 40 yrs till 1972. Penicillin was declared as the first line of treatment for syphilis 1947, which was not offered to these people, because researchers wanted to track them till death. The brutality of study was exposed by Peter Buxton, PHS venereal disease investigator in mid 1960s.  Finally US national press started to write about the trial and it came into scrutiny and after a series of investigations, conflicts and conspiracy, study was forced to close by 1972. 

As a lesson for this unethical conduct of study, national research act was formed in United state at 1947,  which led to formation of the 'Institutional review Board and National Commission for the protection of human subjects and behavioral research'. The major Role of these committee is to protect the right, safety and integrity of Human participants in any clinical study. 

    Elexir Sulphanilamide Tragedy (1937)

Sulphanilamide was being manufactured by S.E massengil company in tablet form which was used for various kinds of infections right from Common respiratory infection to Gonorrhea. Company thought of producing the same drug in liquid form and prepared liquid Sulphanilamide by mixing a sweetener called "Diethylene glycol", which noways used as antifreeze. This dilutional agent chose was poison, but till then there was no law for safety testing of drug and came into market after basic testings like: appearance and fragrance. in September 1937, This newly prepared Elixir was distributed in 15 different states at the same time. Drug was prescribed by physician for sore throat but immediately death cases started reporting from various places. Among various toxicity reported, acute kidney failure was the major cause of death of  105 consumers in total. News  became a big sensation of that time drawing attention of scientific as well as political community.

As a result, Congress responded the public outrages by passing '1938 Food, Drug and Cosmetic Act' with the provision that every pharmaceutical companies are required to perform safety test for their product and data needs to be submitted to FDA before approval of marketing. Till date, this FDA food, drug and cosmetic act is on frontier of pharmaceutical regulations after a number of revisions.

  Doctors Trial and Nuremberg Code (1945)

During the time of second world war, a group of German doctors conducted a brutal trial known as Nuremberg trial, which involved experiments in group of people in the concentration camp. Since, the way Germans were treating the minorities withing the country was Inhuman, this trial can not be expected to be conducted with consents and with scientific manner. They categorized a group of people as not fit for living for those having trauma, mental illness and disabilities. Within the time period of almost 5 months of experiment, many brutal incidents happened to participants such as

• High altitude experiments: people are forced to stay inside  chamber without oxygen which duplicates the environment of 68,000 ft. from the ground. 
• Section removal of a bone, muscle or nerve  from one person to transplant the same on other victims. Sometimes whole leg used to resect and experimented
• Creating artificial wound and exposure to mustard gas
• Experimenting two artificial wounds in same human with or without antibiotics treatment.
• Intramuscular injections of fresh thymus
• Collection of skeleton by defleshing from live Jewish inmates. 

Once war came to an end, those doctors were brought into investigation,  All the Activities performed within the concentration camp were scrutinized on the  basis of available documents and witnesses. Taking the reference of this devastating event, a A group of American judges authored regulatory guideline called "Nuremberg Code" in 1948 which introduced "Informed Consent" of research participants before conducting any trial on them.

                Thalidomide Disaster (1960)

One of the major change that Clinical Research industry adopted was after the event in United states in 1960, known as thalidomide disaster. Since it's discovery in 1954 in Germany, Thalidomide was being used as sleeping tablet till 1957 specially in Europe and America. Since this was post war time, Use of thalidomide was prominent specially in this region. Along with sedative effect people also felt betterment in nausea.  Women started taking Thalidomide to treat Morning sickness in early stage of pregnancy also based upon their personal preferences. In 1956, first case of was reported. New born baby affected with phocomelia have underdeveloped limbs and short stature. Since, drug was affecting pregnant women and developing fetus, it took almost one year to know this toxic effect of the drug. By the end of 1961, doctors from Germany and Australia were able to make link between the drug intake and outcome in newborn baby. Almost 20,000 babies were expected to born with defective limbs because of this drug. Immediately, drug was withdrawn from the market and  suspected fetuses were killed wherever possible. Almost 40 % of those affected babies were died within first year of life. Regulatory bodies all over the affected region were triggered with this event and a new level of discussion started taking place within research communities also. 

Currently practiced Major Research Guidelines

Declarations of Helsinki: Developed by World Medical Association in 1964, Considered as the first significant effort of the medical community to regulate itself which is the statement of ethical principles to provide guidance to physicians and other participants in Medical research involving human beings (Download full text from https://www.wma.net/wp-content/uploads/2016/11/DoH-Oct2013-JAMA.pdf)

The Belmont Report: Published in 1979, stated the major ethical principles and Guidelines for the protection of Human subjects of Research. Written by US National commission, it talks in detail about the core ethical principle: Respect for the persons, Beneficence and Justice. (Read in detail from here: https://www.hhs.gov/ohrp/sites/default/files/the-belmont-report-508c_FINAL.pdf) 

ICH GCP Guideline: International council of Harmonization of technical requirement of pharmaceutical for human use was established in 1990 by three major powerhouse of the wold US, Japan and European Union. Adopting the major provisions of declarations of Helsinki and Belmont report, ICH developed four major Guidelines such as Quality, Safety, Efficacy and Multidisciplinary (QSEM). Good Clinical Practice (GCP) is one component of efficacy guideline which talks about ethical and scientific way of conducting research and generation of credible data. ICH GCP consists of thirteen major principles along with other major responsibilities of Different stakeholders in Clinical Research. (Download all the ICH guidelines from https://www.ich.org/page/efficacy-guidelines)

CIOMS International Ethical Guideline

Council for international organizations of Medical Sciences (CIOMS) was established in 1982 and developed guidelines for Biomedical Research. Core of this organizations consists of 21 guidelines with commentaries, which undergoes amendments and updates on regular basis with the Need of scientific community. (Download the full text from https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf)

                                                             Thank You !!!

References: 

• https://cioms.ch/shop/product/international-ethical-guidelines-for-biomedical-research-involving-human-subjects-2/
• https://blogs.findlaw.com/free_enterprise/2016/02/regulation-nation-what-industries-are-most-carefully-overseen.html
• https://www.history.com/news/the-infamous-40-year-tuskegee-study
• https://www.the-scientist.com/foundations/the-elixir-tragedy-1937-39231
• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1323276/
• https://www.sciencedirect.com/topics/medicine-and-dentistry/pharmaceuticals-regulation