Clinical Research: February 2020

Thursday, February 27, 2020

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:

Sunday, February 23, 2020

WHAT CAN WE DERIVE BY HAZARD RATIO INTERPRETATION IN CLINICAL TRIALS ?

comparing the survival time between placebo treatment versus treatment

Suppose you are conducting clinical study for a novel drug or being participated in such trials, you want to know whether new drug is doing better or not. since it is novel drug, there won't be enough data of previous study, you have to see the outcomes of events from the time of enrollment till date in different groups of people getting treatment. Hazard Ratio interpretation provides the backbone of predictions you make to answer this question.

Hazard ratio is the outcome measure used in time to event analysis (survival analysis) which is also called as instantaneous event rate. The term hazard means any bad event in literal sense but for study point of view it can be any end point or event or risk of an outcome after intervention being introduced to the participants.

It is the ratio between hazard in the treatment arm to hazard in the controlled arm.
The term Hazard means instantaneous event rates, which in simple term is the probability of a particular event in any given time.
At the same time, HR gives the rate of progression of disease since it can be plotted against time.

Formula for calculating Hazard Ratio

HR = The ratio between hazard of particular event in intervention group to the hazard of event in controlled group.

Hazard in treatment arm

Hazard in control arm

Bio-statistician calculates HR, but researchers/ Investigators should be able to interpret it accordingly. Here, in this blog we will be discussing about the inferences that can be made based upon the calculated value.

Interpretation of Hazard ratio

HR =1: The probability of having an outcome is same for both treatment arms, i.e. There is lack of associations between the intervention and outcome.

HR =2: The probability of event in treatment arm is twice than that in controlled arm

twice as many patients in treatment arm are having the event proportionally to comparator group

HR = 0.5: At an time half as many patients in the treatment group are having an event proportionally to the comparator group

Why Hazard Ratio is needed instead of Relative Risk ?

Technically these two measures are different since Hazard Ratio can be plotted for events against time whereas relative risk defines the probability of an outcome in two different group regardless of timings.
Hazard ratio is used to interpret the result of intervention in clinical trials as survival analysis whereas Risk Ratio commonly used in observational studies.
This plot of time against an event throughout the study period is called kaplan mier curve. The probability can be calculated from this curve.

Here, since there is death event is happening on each event, survival probability is continuously declining along with the follow ups
Those participants who do not reach the study end-point and lost follow-ups are also included in analysis. Power as well as validity of study can be maintained by analyzing number of survivors at multiples point of time.

Here, in visits 2 to 5,survival probability is constant, since there are no events happen or loss of follow ups
While Interpreting Hazard ratio, Time based parameters like Median time are taken into considerations if possible to know the magnitude of benefit of treatment to the patients.

Can you predict the positive outcome based upon findings of Hazard Ratio

Not exactly. Because Hazard ratio only gives the idea about outcome or event, which can be varied from study to study. For example, if study is ongoing for cardiovascular pathology and end point is determined as stroke or death, then High value of hazard ratio can show study drug not being effective whereas in cancer research if end point is disease free survival, higher the HR value, study drug will be considered better.

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC478551/

https://towardsdatascience.com/kaplan-meier-curves-c5768e349479

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932959/

https://www.youtube.com/watch?v=z1b2hFzXsrU

Sunday, February 2, 2020

Why End Point Analysis is Integral to Clinical Study

End points are the primary outcomes measured in clinical trial to demonstrate the safety and efficacy of the interventions. Based upon the pathogenesis of disease and nature of interventions various end points are measured. For large scale double blinded controlled trials, a group of bio-statisticians will analyse data and verify the the end points by objective evidences. Also physician will determine the efficacy of the treatment given in the form of clinical report and examinations findings. based upon the result obtained through both the means, fate of clinical trial will be determined.

Why End points need to be analysed ?

This is regulatory requirement that authority will check

Validated

whether primary outcome has been analysed or not. Before completing perennial study, end point analysis has to happen when the study was ongoing.
For safety of trial participants, the effect of new treatment or the control i.e. standard treatment or placebo needs to be evaluated in clinical, laboratory and patient experience basis.
Harmony should be maintained between clinical reports prepared by investigators and the analysis made by bio-statistician. End point analysis provides the consideration for the both.
In case disease of study has aggressive pathogenesis, end point analysis help whether to continue the same treatment or to switch the another.

Types of the End points In clinical trials

Some outcomes can be measured by clinicians by clinical examinations to demonstrate the progress of the disease, but in certain situations it has to be measured by analysing the Investigations reports. Former method of analysing end points is called Clinical endpoint and later is known as surrogate endpoint.

Clinical Endpoint: Investigator will determine whether improvement in clinical features of disease shows progressive outcome or not. It includes Improvement in Symptoms, Signs, functional ability of organs and overall improvements. For the study of disease like Myocardial infarction, stroke, trauma, Respiratory and other infections, epilepsy, Gastroenteritis, etc. Clinical endpoints gives the better Understandings.
Surrogate End points: surrogate endpoints is used when direct clinical outcome measurement is not possible and predictions are made from the laboratory investigations. Different Bio-markers are used to predict the disease progression. for example: Random Blood sugar measurement gives the idea of Diabetes progression, urinalysis for Kidney disease, serum cholesterol level measurement for atherosclerosis and so on. All these Surrogate End points should undergo validation by regulatory authority like FDA and only validated one can be employed by investigators.

For most of the Clinical trials, both measurement of clinical and surrogate end point is employed and harmonization has to be established between the findings. Surrogate End points once validated by scientific analysis to be used for that particular clinical study are called Bio-markers. Depending upon disease different Bio-markers can be used like molecular, histologic, radio-graphic or physiologic.

End point in cancer trial

Cancer trial are different than other trials in terms of clinical outcome, where death is the mostly anticipated Clinical outcome. Therefore, survival is considered to be the one of the major positive outcome in such trial. Here are the different types of clinical trial endpoint specially practiced in cancer treatment trials.

Disease free survival (DFS) : Time between completing treatment and recurrences of signs and symptoms of disease.

Progression Free Survival (PFS) : Time measured after treatment up-to further progression of disease, specially used for highly aggressive cancers.

Response Rate (RR) : response of drug by shrinking or disappearing the cancer after treatment. There is no control arm in such trials and response is calculated in percentage.

Overall Survival (OS) : Time between introduction of treatment upto death of patient, irrespective of any cause. Specially in cases of advanced cancer, this is being measured.

Quality of life (QOL) : measurement of drug's impact on sign / symptoms of disease including pain, ability to perform regular activities etc. Such data are taken as patient-reported-outcome and results are subjective to individual experiences.