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Clinical trials are one of the most complex and resource intensive processes which healthcare & the life science industry undertakes.There are over 370 thousand studies registered on ClinicalTrials.gov, of which, over 120 thousand are held in the U.S. alone. Based on this data what we see is that even though the complexity of clinical trials have increased, the number of clinical trials have also increased significantly over the last decade. There has been a lot of innovation in this space and we can certainly attribute digitalization of clinical trials as one of those innovations which has made it much easier for the sponsors to manage complexity involved in this process.

To better under the complexity involved in a clinical trial, we are going to look at the critical path of the clinical trial and deep-dive into digital transformation which has made this complexity manageable. To do that, we will step-by-step uncover each stage of the critical path of the clinical trial evaluating software solutions addressing the challenges in each of these stages. There are quite a few primers on how to design and run a clinical trial published by the FDA [0] and the NIH [1]. We are going to be leaning heavily on these resources as a baseline process. These primers are usually a guideline and each organization adapts the process based on the available resources and their coporate standard operating procedures (SOPs).

For this series of articles, we are going to take a snapshot of one of the processes (figure 1) and deep-dive into individual stages to translate those into software solutions available in the marketplace today. In this post we are going to explore the overview of the critical path of the clinical trial and list key activities which take place during each of these stages. In the subsequent series of articles, we are going to focus on breaking key activities for an individual stage into functional requirements and map those requirements to commercial-off-the-shelf (COTS) or software-as-a-service (SaaS) solutions. 


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Figure 1. The critical path of the clinical trial

 

Below are the list of all stages in the critical path of the clinical trial and the corresponding key activities taking place during each stage. Listing key activities will help us narrow the scope of the solution we can evaluate and trace back the requirements to an individual solution.

 

1. Planning

Planning a clinical trial efficiently helps to avoid any possible delays. The complexity of planning can increase quite a bit depending on the design of a trial. Understanding and anticipating the problems arising in the critical path of the clinical trial is key in timely and successful completion.

Some of the key activities which are undertaken during clinical planning stage are:

  • Project & portfolio management
  • Cross-functional collaboration
  • Management of multiple projects across multiple business units
  • Contingency planning
  • Time and cost estimation
  • Evaluation of regulatory and marketing requirements
  • Observe and identify problems and potential solutions
  • Manage and track treatment or class of treatment
  • Manage and track literature and available evidence
  • Manage therapeutic models
  • Track rough budget estimates
  • Track key metrics like rough sample size
  • Manage and define the study target population
  • Provide synopsis of the trial
  • Track the original hypothesis & rationale
  • Choice of control treatment
  • Expected size of effect

2. Clinical Trial Study Protocol

A clinical trial study protocol is a document used to define and manage the trial. It is prepared by a panel of experts. All study investigators are expected to strictly observe the protocol. The protocol describes the scientific rationale, objective(s), design, methodology, statistical considerations and organizations of the planned trials. 

Some of the key activities which are undertaken during study protocol design stage are:

  • Trial design
  • Preparation of draft protocol
  • Inclusion/Exclusion criteria
  • Eligibility criteria
  • Definition of end-points 
  • List of critical events
  • Duration of follow-up
  • Treatment(s): dosage, presentation
  • Follow-up schedule 
  • Sample size
  • Planning of multicenter study
  • Setting up steering committee
  • National, regional, and/or institutional boards
  • Planning ethics committee and regulatory approval
  • Planning and finalization of study protocol
  • Tracking & managing revision history
  • Selection of investigators
  • Investigators eligibility criteria
  • Clearance of all participants
  • Patient Consent form
  • Selection of key data to be shared with the patients
  • Study organization
  • Operating manual and procedures
  • Data collection, circulation & control
  • End-point validation procedure
  • Overall quality assurance and control
  • Operating manuals and procedures
  • Monitoring procedures
  • Management procedures
  • Fund seeking
  • Public funds

3. Case Report Form 

A case report form (CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The case report form is the tool used by the sponsor or the clinical trial to collect data from each participating patient. All data on each patient participating in a clinical trial are held and/or documented in CRF, including adverse events.

Some of the key activities which are undertaken during design of Case Report Forms (CRFs) stage are :

  • Design Case Report Forms
  • Adhere to study protocol
  • Timely and efficient data entry 
  • Input from investigators
  • Input from statisticians
  • Reduce monitoring time
  • Checking and correction
  • Cost effective study
  • Track revision history

4. Regulatory/IRB Approval

An institutional review board (IRB) is a type of committee that applies research ethics by reviewing the methods proposed for research to ensure that they are ethical. Such boards are formally designated to approve (or reject), monitor, and review biomedical and behavioral research involving humans. They often conduct some form of risk-benefit analysis in an attempt to determine whether or not research should be conducted. The purpose of the IRB is to assure that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in a research study. 

Some of the key activities which are undertaken during regulatory and ethics approval stage are:

  • Institutional Review Board (IRB) approval
  • Good Clinical Practice (GCP)
  • Ethics Committee
  • Identify areas of delays
  • Adequate preparation & forward planning
  • Collaboration Tools
  • Identify suitable investigators and principle investigators during planning stages of the study
  • Steering Committee for the study
  • Submit investigators’ names to the regulatory authorities
  • Early submission for the final protocol to an independent review board or ethics committee 
  • IRB from each site/center
  • Each IRB adheres to GCP 

5. Trial Documents and Supplies

The study documents like consent forms, patient information packs, case report forms, investigator brochure, finished pharmaceutical dosage form that is suitable for administration and dosing to humans in clinical trials should be prepared as early as possible in the path of the study. Most of the delays take place due to the sites waiting for the supplies or instruction about how to administer the dosage. 

Some of the key activities in preparing Trial Documents and Supplies are:

  • Preparation and printing of study documents
  • Consent forms
  • Patient information packs
  • Case Record Forms
  • Investigator brochures 
  • Inform the pharmacist in the trial supplies department
  • Quantity of medication required
  • How the material are to be packed
  • Labelling
  • Preparation of the trial material
  • Result of poor communication and exchange of information
  • This process is under the control of sponsor to avoid an delays
  • Identify delays caused in the planning and preparation of the study
  • Identify excessive workload
  • Inadequate identification and management of priorities
  • All personnel at all levels are in agreement with the time schedules and strategy
  • Critical Path Analysis
  • Time schedule of the study
  • Avoid early delays which may have significant effect on the motivation of the investigators
  • Internal administrative tasks to be performed by site personnel before patient recruitment
  • Frequent contact with the investigator by the monitor
  • Planning to avoid lengthy delays leading up to the start of patient recruitment
  • The period between protocol finalization and the start of patient recruitment is critical to perform training and trial material preparations
  • Investigator to identify suitable patients
  • Determine more accurately the anticipated recruitment rate
  • Get sites ready to a state where upon IRB and regulatory approval recruitment of patients to the study may begin

6. Investigator Selection

One of the keys to the success of the clinical trial is the selection of the study investigator. Timely selection of investigators helps in onboarding the site so that when the IRB is approved, the patient recruitment can start.

Some of key activities which are undertaken during investigator selection process are:

  • Identify potential investigators
  • Known investigator list
  • Previous history with the sponsor or other clinical research
  • Recommendation from colleagues, other investigators
  • Review of published literature may be used to identify investigators
  • Ability to do correspondence test
  • Evaluate response time 
  • Investigator's ability to respond in reasonable time, providing the information you have requested
  • Effectiveness assessment of investigator
  • Prior performance may not be a good indicator of future performance
  • Copy of Curriculum Vitae
  • Academic Credentials
  • Companies can help by providing a standard form for completion of CV
  • Ability to check Medical Directory
  • Names of staffing assisting the investigator
  • Ability to check unsuitable/debarred investigators by regulatory authorities

7. Site assessments

Assessing a site helps to ensure that selected investigators have the necessary facilities and resources & motivation to conduct the study. 

Some of the key activities undertaken during site assessments are: 

  • Site assessment
  • Ensure selected investigators have the necessary facilities
  • Potential number of Patients
  • Time to spend on the trial
  • Motivation and resources to undertake the study
  • Site monitor visit
  • Keep Trail critical path in mind to avoid delays
  • All centers should be visited by site monitors or regional site monitors (RSMs)

8. Site Startup 

Site Startup is a stage where a monitor visits a site to undertake a pre-study briefing providing details around the type of patient to be recruited, timely data entry and the handling of the trial supplies. For a multicenter study a regional site monitor (RSM) does the site visit and reports it back to the sponsor. 

Some of the key activities undertaken for site startup are: 

  • Pre-study briefing 
  • Group or Individual briefing
  • Detailed discussion of the type of patient to be recruited
  • Completion of record forms
  • Administrative procedures to be followed
  • Understanding of the study protocol
  • His/her obligation during the study
  • Likely recruitment rate should be performed 
  • Targets for patient recruitment should be agreed
  • Verification of data obtained in the study
  • Payments must be discussed and agreed upon
  • A course of action agreed before the study commences

 9. Patient Recruitment

Once the IRB is approved, the sites can start recruiting suitable patients without any delays. First patient first visit (FPFV) is one of the key milestones for trial sponsors as it sets up the ground for other activities which have to be undertaken for timely completion of the trial. Poor recruitment is a common problem and is usually due to inaccurate predictions about the number of patients an investigator can recruit. 

Some of the key activities in preparation for patient recruitment are:

  • Ability to provide prediction of suitable patients has been accurate
  • The study protocol is appropriate
  • Inclusion and Exclusion of patient
  • Process of patient recruitment
  • Avoid poor recruitment practices
  • An accurate prediction of the number of patients an investigator can enroll
  • The total number of patients with a particular condition known to them
  • Some patients will not wish to participate in the study
  • 50-60% of initially predicted patients may actually enroll in the study
  • Shortfall against the total planned number
  • Allow bench test to test the methodology and protocol
  • Monitoring of patient recruitment should be carried out
  • Study protocol is being properly followed
  • Record forms are correctly completed
  • Patients enrolled soon after the start of recruitment should be carefully evaluated
  • Misrepresentation of entry criteria in the planning stages of the study
  • Too rigorous inclusion criteria
  • Lack of interest, motivation, time and resources by investigator site
  • Establish special clinics for patients in clinical trials
  • Recruitment may be improved by scanning an age-sex register
  • Writing to potentially suitable patients 
  • Having a poster in the surgery offering a special study clinic
  • Screening all patients who have the surgery
  • Informed consent
  • Number of centers required
  • Number of patients per center should be carefully determined with this in mind
  • Including an overage for dropouts
  • Withdrawals
  • Unsuitable patients
  • Sufficient number of centers should be kept in reserve in case unforeseen problems occur once recruitment has started

10. Periodic Monitoring 

Periodic monitoring by site monitors and regional site monitors (RSMs) help in checking the progress of the study. Regular visits to sites by the monitors help in mitigating any risks which may cause delays as the study comes to closure. Depending on the length of the study these visits can be every two-six weeks.  

Some of the key activities during periodic monitoring are:

  • The monitor should visit each investigator every two to six weeks
  • Monitor should periodically check on study progress
  • Patient entry in accordance with the study protocol should be checked
  • Completion of the CRFs should be checked
  • Standard Operating Procedures describing how frequently the monitor should visit each investigational site
  • SOP should have description of checks and tasks that should be performed at each visit
  • Ensure that the study is conducted according to GCP guidelines
  • Validation checks on the data collected by the investigator should be performed
  • Good Clinical Practice guidelines now require the monitor to perform “direct source data verification”. This is where the monitor compared data written in the CRF with source data (eg. patient files, print-outs of laboratory results and automated instruments, etc)
  • Check the reliability of data collected
  • The monitor also checks the CRF to ensure it has been fully completed and the data are legible
  • All alterations and errors in the CRF need to be initiated and dated by the investigator
  • Completed and checked record forms may be collected by the monitor at each visit and passed on to the data monitor for further checking before processing of data entry
  • To conserve time, data entry may be undertaken whilst the study is in progress. 
  • This also enables testing and verification of the database in plenty of time to meet future deadlines

11. Database Lock 

When the last patient has the last last visit (LPLV) among all recruited patients across all sites the study comes to a close and all remaining trial materials, including unused medication, used patient packs, record forms and other forms, should be collected by the monitor. The monitor diligently checks the CRFs as the study progresses avoiding any delays in data management at the end of the study.  

Some of the key activities undertaken during study lock are: 

  • As each center completes the study, all remaining trial materials, including unused medication, used patient packs, record forms, code breaking envelopes and other documents, should be collected by the monitor
  • The investigator should retain consent forms and the register of names of patients who took part in the study, as well as copies of study results, the protocol and correspondence
  • The study closure phase may also include clarification of inconsistencies and missing data revealed as a result of data monitoring and quality assurance

12. Data Entry 

For the data entry having the statistician involved in study planning early on helps in speedy and efficient collection of data during and once the study has finished. Delays in data entry are often the result of lack of communication regarding the date CRFs will be available. 

Some of the key activities involved during data entry are: 

  • Early involvement of statistician in study planning
  • Ensure data entry is undertaken speedily and effectively once the study has finished by involving statistician from early on
  • Delays in data entry are often result of lack of communication regarding the date CRFs will be available
  • Delays due to poor CRF design giving rise to data entry difficulties
  • Delays due to poor monitoring giving rise to numerous queries requiring attention before the database is complete

13. Statistical Analysis 

Quality assurance checks should be made at all stages of data entry and analysis. Double data entry helps minimise errors and a manual check on a certain percentage of the data 10-20%, is usually performed by the statistician before final analysis. Two to three months is typically necessary for data entry and analysis, depending on the size and complexity of the study. A source of great irritation to investigators and monitors alike is the long delay in receiving study results, especially if the investigator has been “hurried along” to meet deadlines only for the analysis to take a very long time to perform. 

Some of the key activities involved during statistical analysis are: 

  • The project team should ensure that the statistician has allocated time to the project as data becomes available
  • Collaboration, progress reports during the study and cooperation by all parties can help avoid unnecessary delays at the end of the study
  • Most time is taken up in data entry; the analysis and preparation of the statistician report is relatively quick if a computerized database is set up
  • Quality assurance checks should be made at all stages of data entry and analysis
  • Double data entry helps minimize errors and a manuals check on a certain percentage of the data
  • Two to three months is typically the time necessary for data entry and analysis, depending on the size and complexity of the study

14. Clinical Study Report

The clinical study report (CSR) is a scientific document addressing efficacy and safety, its content is similar to an academic paper. It is prepared from the protocol, record forums and statistical report and is a comprehensive description of the methods and results of the study, interpretation of the findings, and tabulation and full listings of all data collected. The final Report may be written in addition to the statistical report or fully integrated with it as a single document.

Some of the key activities involved in creation of Clinical Study Report are:

  • The Final Clinical Study Report is prepared from the protocol
  • Record forms
  • Statistical report
  • Comprehensive description of the methods
  • Results of the study
  • Interpretation of the finding
  • Tabulation
  • Full listings of the data collected
  • The final clinical study report may be written in addition to the statistical report or fully integrated with it as a single document
  • Delays are usually caused by the need for numerous in-house reviews and approval
  • The investigator should also be asked to review the Final Clinical Study Report and show his approval of the final document by signature
  • Data presented in the Final Clinical Study Report are likely to be submitted to the regulatory authorities to support a product license application
  • The results will be reported to the authorities for information purposes
  • All patients entered into the study are accounted for 
  • No inconsistencies occur between tables and text

15. Regulatory Submission 

The final stages of the critical path of the clinical trial are those of preparing common technical documents (CTDs) or electronic common technical documents (eCTD) submission to be submitted to the regulatory agencies to support a product license application. These eCTDs can be submitted for Investigational New Drug (INDs), New drug applications (NDAs), Abbreviated new drug application (ANDAs), biologics license applications (BLAs). 

Some of the key activities involved in creation of regulatory submissions are: 

  • Preparing a paper or electronic publication 
  • The presentation of the study at a meeting or congress
  • Submission to journal 
  • This ensures the results of the study are used effectively whilst the data are still current
  • Study Data Standard
  • Controlled Terminology Standard
  • Comply with CDISC Standard
  • Adhering to ICH standards

To that end, the stages outlined here is a single snapshot based on the guidelines, every organization is going to adapt based on the resources and exerptise they have in-house. What this represents is the minimum steps required to bring drugs & medical devices safetly to market at the same time complying to ICH-GCP standards. In the next part of this series we are going to start diving deeper into each stage to find software solutions which can in running a clinical trial.

 

 

Resources: 

[0] https://www.fda.gov/media/78814/download

[1] https://pubmed.ncbi.nlm.nih.gov/25624092/