Advancing Clinical Research in Nepal: Urgent Calls for Regulatory Framework Upgrades

In recent days, Nepal has been involved in a number of clinical trials specially after the hit of COVID-19 pandemic. Most of such trials were developed on some other countries, imported and implemented here in Nepal. Rise of COVID-19 has certainly given an opportunity for a burning mind of the country in order to involve in a global movement of developing a new therapy or vaccine. This movement has been facilitated from two major government organization - Nepal Health Research Council (NHRC) and Department of Drug Administration (DDA). But In order to make country self-dependent on developing and implementing new trials, there must be few upgrades in the regulation and infrastructure in both of these organizations. 

Nepal Health Research Council (NHRC) provides both ethical review support for all the trials registered and also acts as implementation body for any new trial conducted by or in collaboration with other organizations. In 2019, NHRC has published 'National Ethical Guideline for Health Research in Nepal' which provides direction to perform clinical trial activities anywhere within the country in the most ethical manner possible. All in one, NHRC works as regulatory body as well as implementation body combinedly. for this purpose, it has made collaborations with many national and international organizations working in the field of human health research such as Indian Council of Medical Research (ICMR), International Vaccine Institute (IVI), Oxford University Clinical Research Unit (OUCRU). 

Similarly, Department of Drugs Administration (DDA) is the national licensing authority of the country which reviews and authenticate the documents submitted by clinical trialist / individual or an institute. Based upon the favorable opinion and round of reviews, it provides certificate for conducting research. DDA approval is needed only if you are conducting trial / research on a specific drug or medications but not for other kind of therapies or observational research. After submitting documents physically to 'Administration' section, it will move to the respective department and reviewal process will start. There are multiple departments within DDA for different activities like registration of pharmaceutical company, a pharmacy, import / export of drugs, approval / registration of a medicine, registration of trial etc. 

Problems and Immediate Changes Needed in DDA 

• A new researcher coming to DDA in order to register his / her trial will demotivated by too many windows to queue, lots of Paperworks, ambiguous comments and lack of clarity among the review members themselves. But actually, review process is much simpler than it seems to be. In short, if review and approval process is made via online platform, all the activities will run smoothly in less time-consuming manner which will ease the whole process itself. Though DDA is the national regulatory authority where national as well as international delegates come for different purpose, DDA functions like any other government offices which should be changed immediately. Adapting online platform is mandatory for any office sooner or later. If appropriate arrangements are made in place needed to implement online registration, reviewal and approval process, research activities will be completed more smoothly. 

• Guideline and regulations should be updated enough to make them relevant with the time. Most of the legal obligation under which we are working currently are older than researcher themselves. Getting an approval and being regulated from those outdated guideline is another frustrating experience for a researcher. As for example, if you register a clinical trial which is adaptive in design, once the trial is approved and implemented, there might be multiple amendments to the protocol based upon current scenarios and the requirements. It is not possible to receive new approval license from DDA each time with the protocol amendment. DDA does not have such regulations in place to regulate such trials whereas adaptive design is the most commonly employed model of clinical trial throughout the world on recent times. Similar experiences are there with trials being conducted on emergency health situations like COVID-19 pandemics. 
• Other changes also carry some importance such as administrative, infrastructure wise and for smooth experience of visitors. Such arrangements may not directly affect much the integrity of the functions of DDA. 

                Immediate Changes Needed at Nepal Health Research Council (NHRC)  

Being a part of organization, I may be biased on reviewing functioning of Nepal Health Research Council (NHRC). If you are an independent researcher or have acquainted with the functions of NHRC from any other organizations, your review and experience will matter more than that of mine. Anyway, these are the changes that 'NHRC' should address at the earliest in order to foster research culture in Nepal. 

• Establishing an independent clinical research unit. A separate unit which is completely dedicated for reviewing new clinical trials proposals, conducting meetings and conferences with other different organizations for collaborations, continuation and daily implementation of the trials on the implementation phase and for capacity building of the clinical trials experts in the country. Such unit should be led by an expert working in relevant field. For clinical trial culture to foster in the country, it demands a lot of discussions, trainings and implementation. NHRC only can and should provide such platform for all the researcher working inside and out of the country. 
• Separating ethical review support from routine activities of NHRC. Since NHRC is working both as ethical review board as well as trial implementation body, there is chances of conflict of interest and functions of one can be hindered by the other. Ethical review board of NHRC should be independent not only on provision but also in physical and real sense. Ethical Review Board (ERB) and its activities must be independent from routine NHRC functions which includes multiple meetings, implementation of an observational trials, training and so on. All those activities will definitely hinder the ERB functions and international communities may not consider its activities with higher integrity. 
• Developing an online central information system. If any researcher working here in Nepal or any part of the world wants to make an query about the current situation of health research status or particular evidence, NHRC should be able to respond them online and such system has to be established available for public domain. All in all, NHRC should function as center of evidence generation and dissemination. 
• Strengthening research activities on other institutes. NHRC cannot and should not function all the health research activities on its own. Only if every medical college and hospitals of Nepal involve in evidence generation by themselves, research culture of the country will be upgraded. NHRC should be center of facilitation for other research institutes as well. 

If you have any other viewpoints about how research and clinical trials should be regulated / promoted in the country, please give your opinion on the comment box below.

                                                                        Many Thanks !!!!

PRECIS Tool - Critical Analysis to Pragmatic Trials

https://www.bmj.com/content/350/bmj.h2147

Pragmatic Explanatory Continuum Indicator    Summary (PRECIS) is the tool designed by clinical trials specialist in order to help other clinical trialist to design a trial that best fits on pragmatic platform. Since most of the pragmatic trials being implemented in the recent days are self-declared, their design and implementation may not best fit with the global standard set for conducting pragmatic trials. Here we will discuss about the PRECIS-2 tool and its different domains. 

History of PRECIS tool 

The original PRECIS tool was developed in 2005 - 2008 by 25 international trialists and methodologists with the prime objectives of helping other trial specialists to make their better decision while designing a trial by allowing them to test the questions they are seeking answer for. PRECIS tool was used widespread between 2009 to 2013 by various researchers. Later this tool received a lot of criticism for having unclear face validity, inter rater reliability, the lack of scoring system, redundancy in PRECIS domain etc. After addressing all of those criticism and comments, an updated version was released in 2013 with the name of PRECIS-2 tool. This updated version is still being used globally and been cited around 1100 times from https://www.bmj.com/content/350/bmj.h2147 as per Sep 2022. 

Domains of PRECIS-2 Tool 

There are nine different domains in the PRECIS-2 tool which help trialist to think of the trials design decision considering the future reproducibility of the trial result. 

     1. Eligibility

• Are Participants recruited in the trials similar to the future intended population? 
• Higher the similarity between the people in trials and those in usual care settings, higher the score would be. 
• Excluding people with less adherence to treatment, based on laboratory tests results, having less responsive to the treatment, excluding people who have difficulties in completion of trials like old, aged population and children 
• If Inclusion / Exclusion criteria is more stringent by including many laboratory tests before drug administration, trial will incline towards explanatory design from pragmatic one. 
• Highest score that trial will get from this criterial would be Five. 

     2. Recruitment

• Was there the similarity of effort being made to recruit participant with that for a patient to engage into the treatment process? 
• In an extremely pragmatic settings, patient will be informed of the study in usual care settings and recruitment will be made based upon their interest. 
• Sometimes an extra effort needs to be made by additional human resources or by enhancing knowledge about the trial among potential participants via different communication tools such as mailing invitations letters, Radio / Television advertisement etc. The only concern is potential participants should not be over influenced by the information provided.
• Recruitment from usual hospital settings without additional effort is scored as '5'. 

     3. Settings

• How similar / different is the trial settings from usual care?
• In this domain, trialists are encouraged to match their settings proposed for a clinical trial with the hospital setting where patients are being treated on regular basis. 
• While designing a pragmatic trial, various characteristics of a settings are to be considered such as: geography, healthcare system, socioeconomic and cultural background of that particular country / community and other nuances of the population trial is being intended to apply on. Higher the matching between them, trial will be considered more pragmatic. 
• Sometimes the same socioeconomic constrains of a particular setting can be of no issue rather supportive in different settings. 

     4. Organization

• How different are the resources, provide expertise and the organization of delivery in the intervention arm of the trial from those available in the usual care settings. 
• This domain specifically focuses on resources and human expertise available in a particular healthcare setting. If service provided to a trial participant is from highly skilled and trained personnel in well-equipped setting but regular visitors are not receiving the same degree of care and treatment from healthcare center, trial will lose its pragmatism and will incline towards being an explanatory. 
• A highly pragmatic trial will receive score '5' and highly explanatory one will receive score of '1'

     5. Flexibility (Delivery) 

• How flexibly intervention is being administered in trial setting than usual care setting. 
• In order to make a trial more pragmatic, trialist should anticipate the future of that particular intervention post trial in the same hospital / study site and the flexibility on how to introduce an intervention should be provided accordingly.
• If protocol does not dictate rigidly how to deliver an intervention for a trial participant, there will be similarity in the between patient admitted and treated in the hospital and the trial participants. The most flexible study will score maximum of '5' which means trial is most pragmatic. 
• If trialist wants study to be descriptive in nature, he should be very rigid about dose, time-schedule, person and method of delivery of that particular intervention. But this methodology will score the trial least in this PRECIS-2 score system. 

     6. Flexibility (Adherence) 

• This domain check if the protocol adherence and monitoring techniques are compatible with the real-life scenario or not. 
• Encouragement to take intervention in its defined dose and time is mandatory both in clinical trial as well as clinical practice. But physician can only encourage and convince patient about the adherence to the treatment in usual care settings but in clinical trial there might be need of monitoring tools to be applied just to verify that adherence to treatment is ensured.  
• If trialist apply monitoring tools for protocol adherence to treatment, trial will be inclined to explanatory and will score close to '0' in PRECIS-2 tool. Whereas, if there involve only the instructions and encouragement from researcher / physician for trial participants without applying any monitoring tools, that study will score close to '5' in PRECIS-2 tool. 
• Monitoring tools may include pre-screening evaluation of adherence, withdrawal of participants based upon cut-off value of intervention adherence, scheduling discussions and repeated questioning to study team etc. this approach leads study to be descriptive from pragmatic. 

     7. Follow Ups 

• This domain focus on the how different are the follow ups procedure set by trialist from that being practiced at the hospital / site on routine usual care settings. 
• If the trial is very pragmatic, there won't be any scheduled follow up for participant after being discharged. But measuring an outcome of an intervention may be difficult if it could not be derived from electronic means, medical records and registries. Those trials which have no or minimal follow ups and no additional information to be collected during follow ups are considered to be more pragmatic trials. Such trials tend to score close to '5' as per PRECIS-2 tools. 
• In explanatory trials like blinded study of vaccine candidates, there would be frequent scheduled follow ups, follow up visits may affect primary outcomes and there would be extensive study of various biological markers from blood and other samples. 

    8. Primary Outcomes

• This domain emphasizes if primary outcome expected from clinical trial is directly relevant to participant or not
• While designing the pragmatic trial, outcome set by the trial should solve the problem of the people attributed from disease or condition being studied. For example, if a trial aims to reduce mortality from disease, its primary outcome should be the number of death events among enrolled participants in the defined time period. Same applies if primary outcome is based upon biological marker or a surrogate marker. 
• In the best-case scenario, the drug or a therapy used in pragmatic trial in particular sites will be the standard of care in future globally. Those trials with an obvious importance to the participants, score highest (close to '5') in PRECIS - 2 whereas studies whose outcomes are not the part of routine care scores lowest. Such trials are considered to be more explanatory than pragmatic.

    9. Primary Analysis

• This domain typically considers if all the data generated via trials are being considered during analysis phase or not
• Almost all the pragmatic trials use Intention-to-treat analysis model where all the participants enrolled into the trial are equally considerable for statistical data analysis regardless of whether they received full treatment, meet the primary outcome or loss to follow up. Intention-to-treat model typically follows 'Once Randomized, Always Analyzed' hypothesis which provides them very high reproducibility than per protocol analysis trials. 
• It is not possible for all the trials to follow Intention-to-treat model, where they will consider only those data which has reached data integrity benchmark as set by the protocol for statistical data analysis. Such trials are considered to be explanatory which serves the propose of being high specificity when used in the mass scale. For example, during the time of COVID-19 pandemics, therapy trials followed pragmatic approach and vaccine trials majorly followed explanatory models. 

When should the PRECIS - 2 Tool Be Applied? 

Keeping it simple, PRECIS - 2 tool is designed for trialist to be implemented while developing the trial protocol. All the domains of tools are applicable only when there is sufficient room to anticipate the future scenario of usual care post trial and implement the study protocol accordingly. But sometimes, for knowledge purpose, PRECIS - 2 tool can be applied for those trials which are already in implementation phase. Findings from such studies can be inculcate by making an amendment to the protocol if study allows adaptive clinical trial design. 

How to Use PRECIS - 2 Tool? 

Trialist can visit and register their trial from official website of PRECIS - https://www.precis-2.org/. After receiving confirmatory email response from university of Aberdeen, they can move forward to follow the scoring system. 

   

      Thanks!!!