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)

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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

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

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. 

                                           

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ADVERTISEMENT OF CLINICAL TRIAL, IS IT LEGAL ? TO WHAT EXTENT ?

Have you ever seen any pamphlet or   hoarding sign board on public places requesting to participate for any Clinical study ? Do you think asking publicly to participate in trial of drugs for some pharmaceutical company is legal ? answer is YES. It's absolutely OK asking publicly to participate in any study being conducted  on drug for patients of particular disease. In fact, public request is less likely to have conflict of interest than asking personally in clinic or sending mail. 

Patient recruitment is the integral part  of study, which should be completed within time range defined by protocol, recruited one should be fit for study based upon inclusion and exclusion criteria  and most importantly needed to be retained throughout the study period for the sake of quality data and reproducible outcome. Every  Clinical Study and their investigators finds it hard to get enough patient and retain them throughout. Study findings says that about 50 % of studies conducted  in Unites states faces higher the cost than expected because of delay in patient Recruitment. Hence, Advertisement of study is the most commonly employed method of subjects recruitment which is endorsed by FDA also. 

Criteria to be filled for Advertisement by any hospital or site

Objective: Advertisement, content used for this purpose  should only be oriented to recruiting subject for the study. 
Approval: any content going to be publicized should be  reviewed and approved by Ethics committee of the  institution. 
Claims: there should not be any claims of curing disease or prolonging life span of participants or any fanciful commitment for that matter. Moreover study drug should not be declared as superior than any available or established treatment. 

Safety: Since there is paucity of enough evidence regarding  the safety of new drug or combinations of existing drugs being studied, advertisement should not claim any products to be safe, effective , equivalent or superior than any other treatment .

Commonly employed Methods of Advertisement

Different recruitment models can be employed in the form of advertisement in different country in the as  per the social and environmental circumstances, these are the common methods employed: 

• Broadcasting through Local Radio or television  channel
• Giving pamphlets on social places or people gathering in huge numbers
• Advertisement on Local or National newspaper
• Database search of relevant patients and sending personal mails
• Organizing health camps and gathering patients  intended to treat
• Peripheral referring from hospitals, polyclinics and other Hospital to Research site by informing the patient
• Mouth publicity 

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The Needs and Practice of Adaptive Clinical Trial Design

Since introduced by FDA in 2004,  Adaptive Clinical Trial Design is the extensively practiced model of clinical trial throughout the globe in spite of its technical and execution related complexities. Adaptive Clinical Trial is the method of modification of pre-specified procedural aspects of clinical trials like statistical analysis, sample size while the trial is ongoing . Decision is taken mainly based upon the raw data generated trough the study in order to prioritize the accelerated innovative drug development process. By inspecting  the positive outcomes related to this design, EMA ( European medicine agency) also pursued adaptive clinical trial design in 2006.

The sole purpose of introducing  adaptive clinical trial design is to provide flexibility for identifying  optimal clinical benefits of  test drug without compromising ethical and scientific aspects of research. 

          Benefits of Adoptive Clinical Trial

1. Research question getting answered: by embracing the modification in research protocol, chances of research question getting answered is enhanced even in unanticipated unfavorable situation. But, it doesn't guarantee any positive outcome. 
2. New drug development becomes less time consuming with improvement in overall success rate
3. Combats the common difficulties during drug development like low success rate, specially pharmaceuticals funded trials, procedural complexity, rapid escalation of cost, decreased willingness of bringing new candidates forward by the existing one and so on. 
4. Overall process becomes more flexible, efficient and less time consuming

Methodology of Adaptive Clinical Trial Design

 Planning for adaptation is normally made before the data was examined in unblinded manner, but process actually starts once interim analysis completes with data in hand (Interim analysis is generally performed when 50 % of research work is completed).
Notably, changes in research design as well decision not solely based in internal reason is not considered to be adaptive at  all.
Obtained Data is transferred to Data Safety Monitoring Board (DSMB) for analysis, they check for major or minor discrepancies, if present, impact on future study result, study participant and possible legal threats are also analysed. Message is circulated to sponsor, with the prior notification to ethics committee. Final decision on making protocol amendments and giving the shape of adaptive trial design is  performed by Sponsor.
Protocol amendment consists mainly of two procedure viz. trial procedure and statistical procedure. Trial procedure includes Eligibility criteria, study dose, treatment duration, study endpoint, laboratory testing procedures, diagnostic procedures criteria for evaluation and assessment of clinical responses.  Whereas Statistical procedure includes Randomization, study design, hypothesis, sample size, data monitoring and interim analysis, methods of data analysis.

    Types of Adaptive designs in Clinical Trials

Though there are various models used as adaptive methods in clinical trial, the most commonly used one in clinical trial are as follows: 

1. Adaptive Randomization Design: Randomization process is not fixed so that probability of treatment assignment changes over time considering previously enrolled patient. There should be recalculation of treatment assignment probability, but it is predetermined and no changes are entertained  in fixed randomization. 
2. Group sequential design:  Sample size of the patient is not previously fixed, can be added, reduced or suspended based upon the result of interim analysis. Considerations are made on the basis of efficacy and safety reports of trial participants. Data Safety Monitoring Board (DSMB) plays the key role for suggesting sponsor to make such changes or in extreme finding trial can be terminated prematurely. For example: In Oncology setup, number of participants are added over time following sequential pattern like 3 + 3. 
3. Drop the loser Design: Here, subjects receiving inferior treatment can be dropped by adopting new treatment arm. Again decision is made on the basis of interim analysis report, such model is commonly applied for phase-II clinical development study. 

Conclusion

Adaptive Clinical Trial Design is progressively advancing and widely accepting model,  found to be effective in terms of reducing the time and cost of large scale Drug development Research with enhancing the scientific pragmatism of study. With considering various factors like statistics, research ethics, business need and benefits of trial participants, various Regulatory authorities has been adopted the model to make the Research Process more beneficial to needy ones and Rational to the  scientific communities. 

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References:


https://newonlinecourses.science.psu.edu/stat509/node/68/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941608/
https://www.eupati.eu/glossary/group-sequential-design/
https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-018-1017-7

Rationality behind banning Ranitidine

Last September passed with sensation of banning and Recall one of  most commonly used  anti hyper-acidity drug, named Ranitidine and its major brand Zantac. News went viral worldwide, immediate action was taken by United States food and drugs administration (FDA), followed by respective authority of Canada, Europe, India and so on. Ranitidine is completely banned to be used by hospital, selling by pharmaceuticals and product was recalled to manufacturer throughout the country as summoned by regulatory body. 

Here, the question is :  how seriously people were being affecting before the news came out ? what are the supporting evidences ? and finally, is matter as serious as claimed ? or being exaggerated ? 

 According to official notice published by FDA and EMA (European medicine agency), a potentially threatening chemical called N-nitrosodimethylamine (NMDA) was detected in Ranitidine, which based upon animal study is carcinogenic. Crucial finding here is that, no any cancer cases are being reported so far in human beings neither during study nor clinical practice. Most importantly, the findings are derived from animal study, which may or may not reproduce in human population exposed to NMDA. Hence, getting triggered t make sense, but the fact is not serious enough for intimidation. 

In fact, NMDA is found to be present more commonly in other daily consumption like meat, Dairy products, vegetables, but  amount present is significantly negligible to cause negative  health impact. 

Evidence behind the claims

Among the negative multi-system  health impact of NMDA, liver is the  most susceptible organ, which can lead to chronic damage and tumorous changes on long term exposure. Risk associated is not only limited to long term use of medications like Ranitidine but also with food products like cured meat. Among various chemical structural of NMDA, B2NMDA is suspected to be hazardous to human organs and tissues like Liver, kidney, lungs, blood platelets. 

Summery

Firstly, public should not use banned product even if they are yet to be recalled. Secondly, care should be taken by industrial workers from rubber, fannery, fish processing, dye, surfactant production industries, where NMDA is used extensively in numerous forms. 

Contaminated water, habit of smoking cigarette should be avoided along with the industrial precautions and regular health check up ( blood and Urine sample) is recommended for individual with relatively high risk.  

Designer Babies: Technological progress vs Ethical Dilemma

The unravelling of the human genes viz. human genome project and the potential it provides has accentuated the likelihood of human genomic editing. This has allowed scientists to look into possible ways for restructuring the genes. Previously this modification – even in humans – had been tried through selective breeding, radiation, and DNA interpolation agent. These were methods of wholescale editing and more so than often resulted in unwanted diseased traits and even death. Recent advances in genomic editing techniques allow for precision and possibilities.

Are evidences supporting Positive outlook ??

Zinc Finger Nucleases (ZFNs), Transcription activators like effector nucleases (TALENs) and the gene that has scientists most enthused Clustered regularly interspaced short palindromic repeats (CRISPR) are some of the methods in and around which lays the promise for future. CRISPR a family bacterial DNA along with enzyme Cas9 acts like scissors and glue for cutting DNA at a specific point and replacing it with a new sequence. This allows for treatment of mutations in genes that cause disease. CRISPR-Cas technology has shown potential in the treatment of cancer, hemophilia, cystic fibrosis, beta-thalassemia, infections, and heart disease.

In 2016 FDA has approved a clinical trial in which CRISPR would be used to alter T cells and after engineering specific genes would be administered back into those same people. Similarly, a trial that began in 2019 utilizes CCR5-modified CD4+ T cells (using ZFN) for treatment of HIV infection. These trails are bound to make an impact on what the future holds for human genetic engineering. But an even bigger impact came in late 2018 when Lulu and Nana, Chinese twin girls, became the first germline genetically engineered babies (Designer babies). The CCR5 genes of parental DNA had been modified such that these babies were resistant to HIV infection.

Contradiction of Opinion and Ethical Dilemma

The scientific world emblazoned with this advancement has searched for what the future might hold for these babies. Was the genetic modification too early for these babies? CCR5 modification in these twins might result in cancer due to off-target effect and reduced lifespan. Also, research in mice with germline modified CCR5 shows that it may result in increased cognition and better recovery from stroke. And speculations have been flying that this might be the case in these babies as well. And the answer to this will come with time. Similarly, the scientific community has raised concerns over whether or not there was even CCR5 modification. Some pointing to only one gene modification in Lulu, thus not acquiring HIV resistance and Nana being a genetically mosaic.

CRISPR-cas9 besides being used in a clinical scenario offers myriad of possibilities especially when combined with preimplantation genetic diagnosis (PGD) allows for selection of traits best suited for the baby or in an ethically inconsiderate view – the parent. Promises of babies who are intelligent on par with adults, who are beautiful and stay beautiful in adulthood by societal standards, and who live on to be 150 without any disease or deformity bothering them are some of the promises shown by this technology. Thus these babies are colloquially termed as “designer babies”.

However, the ethics surrounding “production” of these babies befuddles the ethics surrounding human experimentation. The tenets of pricipalism - autonomy, beneficence, non-maleficence, and justice – have to be ignored for these experimentations. The possible instrumentalization of these babies is always of concern. A concern in and around Kantian ethics which states that “a human being can never be used as a means only and must be treated and end in itself”. Similarly, with any experimentation, the issue of informed consent will always be of concern. Also, the risk vs. benefits of such human experimentations without prior knowledge of what these testing might result in is of concern. Lulu and Nana if they knew they would have a shorter life span with the only benefit of having resistance against acquiring HIV, probably would not have opted for these experiments upon them.

lastly, 

These ethical concerns should and need to be answered before any human experiments are carried out. The only possibility comes out of mapping phenotypic changes with changing genotypes (reverse genetics). Similarly, this idea of having a child with heightened phenotypic changes might also be a cauldron for heightened societal disparity and social turmoil with the technology being availed to certain influential and economically advantaged people.
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                                                    Dr. Samyam Aryal

New Drug Approved For Tuberculosis: Golden Gem for XDR and MDR TB

 According to notice published on its official website, FDA has approved a new drug named pretomanid tablet in combination with bedaquiline and linezolid  for the treatment of extensively drugs resistant tuberculosis of lungs. FDA principle deputy commissioner Amy Abernethy, M.D., Ph.D stated that threat of antimicrobial-resistant infection is key challenge faced as a public health agency. This new treatment is claimed to be highly Potent than any other treatment options available till date

Key features of New Regimen

#   This combination contains a new drug Pretomanid which is  combined with bedaquiline (Approved in 2012 as combination therapy for multidrug resistant bacterial TB/MDR-TB) and linezolid (already marketed drug for treatment of multidrug resistant including streptococcus and methicillin resistant staphylococcus aureus) in  tablet form. 

# This combination is for limited adult patient with extensively drug resistant treatment intolerant or nonresponsive multidrug resistant

# Before approval, clinical trial was conducted in 109 patients with extensive drug resistant, treatment intolerance and non-responsive multi drug resistant TB of lung. All the efficacy and safety data were assessed and found to be satisfactory according to regulatory requirements with typical success rate of 95 %. (whereas the previously available treatment has only 34% in XDR and 55 % in MDR TB)  

#    Duration of treatment for this new drug combination is total of 6 months, much shorter than the available one (18 -24 months).

# Adverse drugs reaction profile is also considerable weighing risk-benefit ratio. Demonstrated reactions were peripheral neuropathy, hyperamylasaemia, mild hepatic enzyme elevation, hypoglycaemia, anaemia and general gastrointestinal upset.

Approval was taken from a special regulatory guidance under FDA called ‘limited population pathway for antibacterial and antifungal drugs’ by providing priority review and orphan drug designation which provides special incentives to encourage the development of drugs for rare disease.

Why new drug is appreciable over existing one?

According to WHO, in spite of availability of treatment and aggressive TB eradication programmes worldwide, by the end of 2016, the estimated number of  new cases of MDR TB was 4,90,000 from 123 WHO member states countries and the reliable data suggested about 6.2% of those are XDR-TB. The real scenario might be more intimidating than data suggested, because most of countries with low-socioeconomic status do not have proper detection facility.

This new treatment will be more fortunate for the countries like India which accounts for more than 9,000 XDR TB cases, second highest after Russia throughout the world.

Long duration of treatment and high side effect profile is One big reason of failure of previously available treatment. Behind Mere success rate of bedaquiline treatment, Patient withdrawal was the major reason. Practitioners stated, “retention of patient throughout the duration is more challenging than anything else.”

Behind high patient withdrawal rate, excessive side effect profile is major contributing factors. As of now, the available evidences suggest that this new treatment is going to fill this gap. 

What actually XDR and MDR TB means?

When two most powerful anti-TB drugs isoniazid and Rifampicin are resistant during treatment, that is referred as MDR TB and along with these two drugs if resistance to any of fluoroquinolone (ciprofloxacin, levofloxacin, moxifloxacin etc.) and at least one of three injectable second line anti tubercular drugs (amikacin, capreomycin and kanamycin), such condition is referred as extensively drug resistance  (XDR-TB).  Both MDR and XDR TB takes longer duration of treatment than drug susceptive TB with low success rate and high mortality.

Sources of development of such TB is mainly because of improper treatment of susceptible TB. Condition might have resulted from faulty prescription or improper regimen of prescribed treatment. On other side people with MDR and XDR TB can transmit the resistant disease pathogen.

Total of 19 XDR Tb cases were reported in Nepal in 2017; number is much higher for MDR. This available new treatment may be an golden opportunity to “stop TB in Our lifetime”. 

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References: 

1. https://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/ 
2. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-resistant-forms-tuberculosis-affects-lungs
3. https://www.ghdonline.org/ic/discussion/issues-and-threats-of-tuberculosis-in-nepal/
4. http://tbonline.info/posts/2018/5/5/managing-mdr-tuberculosis-nepal/
5. https://www.ncbi.nlm.nih.gov/books/NBK138752/
6. https://www.who.int/tb/areas-of-work/drug-resistant-tb/xdr-tb-faq/en/

Qualitative Research, Understanding of Focus Group Discussion and Personal Interview

There is the practice of occult spiritualism for treatment of various ailments in tribal community of Nepal, specially in rural area. Such practices are not only limited in rural places but outreached to urban area also. They have their own treatment methods, defined centres, practitioners and people following them regularly. Let’s say researchers are interested to know the factors behind its existence and peoples belief toward these practice even at the time of scientifically stablished conventional treatment system. What methodologies will researcher follow? How data will be collected? what should be the purpose of study? 

                     Exploratory research

As in above-mentioned real-life scenario, the prime purpose of researcher is to know something about this unknown and unexplored practice. Such studies are termed as exploratory research, where we search for new concepts, idea, belief, attitude, and impact on society etc. which has not been explored before. For the future research, the collected data and conclusion of study, will be the foundation for descriptive research, which will dig deep with defined questioner, sample size, statistical methods to get more concrete information over the facts established by exploratory research. Exploratory research always probes to gets answer of ‘what’ and ‘why’ and methodology followed is obviously qualitative research method.

               Qualitative research method

This is method of enquiry, that helps in-depth understanding of problems or issues or our matter of interest in their natural setting by non-statistical methods. The whole research process is dependent upon experience of investigator with the participants regarding that particular research question. Different methods are being employed to collect data such as focus group discussion, in depth interviews, ethnographic research, text analysis and case study research. Here, former two methods -the most commonly used will be discussed

                              In depth interviews

v Patients are enrolled from one particular treatment centre who

are participating already in our concerned subject matter 

v Questioners mainly asked why they are using this particular treatment

vSemi-structured questioner is used with intent of getting information on disease, psychology, socioeconomic and other confounding factors

v Before reaching to patients/participants, consent has to be taken from those hospital/healer/practitioners to use their patient after explaining the objectives of the study

v Inclusion/exclusion criteria is varied according to objectives. Generally, for in depth interview, investigator as well as participants should know the vernacular language.

v Number of Participants recruited be determined by the information they are providing. Unless there is no new information given by the participants, recruitment continues.

v Interviews are conducted in private room, where participants feel comfortable to share their personal belief, experiences and any confidential information.

v Generally, one investigator conducts the interviews and 1or 2 assistant will help by collecting data. 

                       Focus group discussion

v Conducted to know the general view of community toward that particular treatment or researcher problems.

v Generally peoples who are well known about the topics are gathered together in different groups and a moderator will facilitate the discussion within the group members.

v Again, semi-structured questioner is employed to know peoples view and every idea are appreciated. Experience of moderator will play vital role to get more interesting facts by throwing probing questions.

v Number of groups can be variable according to demographic distribution of community. 

   Different approach of data analysis 

The collected information need to be organized and analysed in qualitative study also but different approach is employed. There is no any predefined data analysis methods. Here nature and extent of information collected during FGD and personal interview will determine what approach will be appropriate for data analysis. These are the basic steps of data analysis in qualitative research. 

v Transcribing all data: converting the data into textual format.
v  Organizing data: a tedious process which demand great effort.   Finally clean data will be obtained according to research objectives
v Coding: expression of data into understandable format for software. 
v  Data validation: accuracy and reliability of data is validated throughout the process. 

v Conclusion of data: Finding the research outcome according to objectives. 

Applicability of Qualitative research 

v In general, this method is extensively applied in Market research related to consumer satisfaction and impact of the product on market demand.

v In epidemiology, impact of any treatment, health care service, new health governance and its impact on social structure, traditional belief in community etc. can be studied.

v In clinical research scenario, qualitative methods helps in advancement of healthcare system. Eg: novel monitoring of COPD via mobile-health technology.

v  In psychology, qualitative research has been extensively used to know human social behaviour and cultures. Social phenomenon like experiences, perception, behaviour and aspect related to it can best understood in natural setting rather than experimental.

v Library and information system (LIS) can use this method to expand their horizon. 

                                                 Thank You !!!

    

   References For Further Reading 

1. https://www.questionpro.com/blog/what-is-research/
2. https://www.cambridge.org/core/journals/the-psychiatrist/article/qualitative-research-its-value-and-applicability/51B8A4C008278BA4BA8F518060ED643C
3. https://keydifferences.com/difference-between-exploratory-and-descriptive-research.html 
4. https://www.youtube.com/watch?v=FlBFdEgrTBM