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.