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. 

                                            Thank You !!!

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.
                                                        Thank You !!!
                                                    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”. 

                                                        Thank You !!!

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

How To Find Appropriate Literatue In PubMed

               Basic steps of literature search  

1.     Learning the steps of literature search process

2.     Understanding MeSH

3.     Determining the database searching techniques

4.     Conducting an advance search in PubMed

5.     Accessing the literature

     Essential terminologies for literature searches

ü Keyword: These are the words or phrases that researcher types in search engine/database. Keywords defines the questions/concepts we are searching about, and results are displayed accordingly. Narrower (specific) the keyword is, higher the chance of getting appropriate results. 

üMeSH (Medical subjects headings) is the national library of medicine-controlled vocabulary thesaurus, used for indexing articles for the MEDLINE/PubMed databases. Each article citation is associated with a set of MeSH terms that describes contents of citation. MeSH terms are organized in a tree with sixteen main branches such as anatomy, organisms, disease, publication characteristics and so on. Searching with MeSH is preferred over keyword searching.

           Stepwise methods of searching literature

1.     Break down the search topic into different steps:

ü Depending on types of data we are searching, keywords are also constructed accordingly.

ü Generally our search topics for experimental study results contain intervention, diagnosis and outcome keywords.

Eg: chemotherapeutic agents for breast carcinoma. Here four major keywords are used (chemotherapy, agents, breast and carcinoma)  

2.     Gathering keywords

üFor gathering keywords, Google, Google scholar and Wikipedia are used

ü Google search shows thousands of results for any keywords, including journals, official and personal websites, blogs and patient information sites. most of information by random searching are of no use. Results can be limited by directing googles algorithms to particular types of sources like site.gov, site.edu, site.org at the end of keyword.  Generally limiting .gov is preferred one to get more relevant results (governmental agencies provides data on .gov. country shortcut)

Here,  keyword 'peptic ulcer' is typed by applying two methods- random searching and specifying the algorithms. Former search showed large number of sites designed to provide  general information and later displayed only governmental sites with authentic results. 

ü Wikipedia is preferred to get background information, and references & external websites. But, content itself is not preferred in scientific communities.

ü Google scholar provides scholarly information like books, Journals articles and patents. One special characteristic of google scholars is it shows results in order that higher the article is sited for, higher will be the rank-older articles are prone to be ranked high.  

3.     Search the concepts separately in PubMed

ü Once we done with gathering keywords, we now search that particular keyword in PubMed search box.

ü Relevant MeSH terms (medical subjects headings) are searched. It’s the set of controlled vocabulary terms used by national library of medicines. In pubmed, articles are assigned in subject specialists who read over the article and determines the subjects contents. Applying MeSH term ensures that articles in same subjects are grouped together regardless of the vocabulary used by author. MeSH descriptors are arranged in a tree structure that allows to search the different level of specificity 

 Here, firstly the search icon was changed to MeSH, then keyword is typed, total of 15 major MeSH were displayed, Each  heading again contains subheadings arranged in a typical tree format. 

4.  Apply additional Database search techniques

   

I.  Truncation

ü Addition of symbol using an asterisk at the end of word stem to find variant of root word and this is very useful to find synonyms. Eg: incubat* (incubator, incubation, incubating, incubated, incubates)

II  Quotation Marks keep terms together and in order. Eg: cervical cancer metastasis contains three keywords which can be represented as one by “cervical cancer metastasis”.

III.Parentheses: allows users to combine the concepts. They are used in the same manner that are being used in mathematics equation and allows ordering the set of terms. Eg oesophageal carcinoma (adenocarcinoma).

IV.  Boolean operators

ü They are used to narrow the search and helps to find the relationship between the search terms when searching in electronic databases.

ü Three Boolean operators are AND, OR and NOT.

ü AND narrows the search by combining together two separate topics. Putting treatment And outcome Helps to find the article which contains both these concepts. Eg: child* AND “head injury”. Quotation marks is used to keep two words as a phrase and * to find the variants on this word.

ü Using OR Boolean operators broaden the search and this is often used with synonyms child* OR paediatrics OR infants* OR adolescence*.

ü Using NOT will narrow the search. It helps to remove the terms we want to exclude. Eg: childhood diarrhoea NOT rotavirus.

here, I searched for Tamsulosin and 'benign prostatic hyperplasia', by applying AND & OR. former showed 838 results where both the terms are being used, and later showed 14359 results where either of these two terms are used. 

use of NOT is dependent on knowledge & understanding of researcher.

5. Apply filter:

Filtering article according to our wish is available in pubmed, on the left hand side of the result. Applying filter reduces the number of articles significantly and increases the accuracy. 

also, literatures can be filtered by author name. After entering keyword/MeSH, authors short name in this bracket […] will show exact literature you are searching for..

                                                                    Thank You !!!

References: 

1. https://www.nlm.nih.gov/bsd/disted/meshtutorial/themeshdatabase/index.html
2. https://www.youtube.com/watch?v=0lill6yUmk8&t=543s
3. https://www.nlm.nih.gov/mesh/intro_trees.html
4. https://www.youtube.com/watch?v=0lill6yUmk8&t=543s