Your session is about to expire
10 Key Factors for Successful Clinical Trials: What Every Professional Should Know
Successful clinical trials begin before they begin, right at their inception. In other words, the entirety of trial operations could run smoothly and perfectly, but if the trial protocol was not set up for success from the get-go, the results simply won’t be optimal.
Many of the challenges that sponsors and investigators run into during clinical trials can be managed in a much more efficient and prepared way (or even prevented altogether) with thorough and intensive efforts in planning and risk identification and management before the trial starts. Understanding the fundamental principles of successful clinical trials provides sponsors a strong theoretical basis for ensuring that everything is well thought-out and planned to a T before launching the trial. In this article, we provide an overview of 10 key factors determining successful clinical trials, so sponsors can do just that.
Factor 1 - Formulate a robust research hypothesis
Everything begins with a well-worded research question. A clinical trial aims to answer a question about an investigational intervention, but that question needs to be clearly defined such that the whole experimental design can be set up to generate the right data that allows researchers to answer it. Further, the research question – or questions – should be relevant and important; the clinical trial should aim to answer a health question that would bring real benefit to patients and to healthcare at a broader level.
A good research hypothesis will meet the following attributes:
- Practical (it can feasibly/realistically be answered within the means available to the sponsor organization and researchers)
- Relevant (it should answer a question that has relevance to patient care)
- Specific (it should describe exactly what is to be studied)
- Clear (it should not be vague or open to differential interpretations)
- Robust (it should support the generation of useful data even if unexpected problems are encountered; in other words, it should not rely too delicately on one specific thing)
Dedicate time to formulating robust research questions and objectives, and you will have a strong foundation for the next steps of trial design.
Factor 2 - Map out the trial’s organizational structure and assign roles
Clinical trial operations involve a myriad of entities and people working both separately and together, in different institutions and on different timeframes, all interconnected through contracts and electronic systems, and united in the common goal of carrying out the clinical trial. It could be a useful step to graphically map out all of the actors involved in the trial, noting things about each relation such as specific agreements/contracts involved, timelines, contact information, etc. Keeping track of all of these dynamic interactions is important for ensuring the trial runs smoothly, and that any issues can be addressed efficiently should they arise.
Mapping out the logistical and organizational structure of the trial’s operations can come in very handy for study monitoring. In order to do this, some decisions and arrangements need to be finalized. Some of the questions to be answered in this stage include:
- Will the study be remote/decentralized, or will study sites be involved? In that case, how many sites? Where should they be located? (See Factor 4)
- What aspects of the trial operations will be outsourced? Which service providers will be contracted for those services? If many operations will be outsourced, can they be tasked to the same company offering an integrated/end-to-end solution?
- How many investigators are needed? In a broader sense, how many people will be involved in the trial? Trial manager(s), data manager(s), study coordinator(s), principal investigator(s), clinical research associate(s), statistician(s), study nurse(s) and/or physician(s), pharmacist(s), monitor(s), medical monitor(s), etc. should all be considered and eventually identified/appointed.
- What is the hierarchy among these positions? In other words, who should report to whom in case of discrepancies or issues? Who oversees which operations? Who is responsible for making decisions and solving different types of problems?
- Which software systems are to be used? If the sponsor does not already have established workflows, then time should be dedicated to researching and identifying the tools and solutions that best fit the trial’s needs.
- Are any intermediary services needed? Which carrier(s) will be used to distribute drug supplies? Does the investigational product require specific storage/handling conditions? Will samples need to be sent to laboratories?
While it could seem like a lot of work, having all of these dynamics mapped out can significantly streamline monitoring and oversight and support the sponsor in keeping everything on track. All of these connections need to be formalized before beginning the trial anyway, so having them mapped out somewhere is a small additional step that could go a long way. Successful clinical trials are well-organized.
Factor 3 - Choose the right trial design
Developing a robust clinical trial protocol involves making a few decisions about how to set up the experiment to best answer the research question. The main aspects involved in study design include those listed below – when all of these parameters are well-selected, the trial will be optimized for gathering useful data that leads to accurate and useful insights.
For an in-depth look at all of these factors together, consult the article we have written dedicated to clinical study design. For more information on individual factors, follow the links in the list below.
a. Decide what the study intervention will be compared against – i.e., will there be a control group, and will the control receive a standard treatment or placebo?
b. Decide whether the investigational intervention will be compared to the control under the lens of a comparative, equivalence, or non-inferiority study.
c. Will participants be randomized to the study arms? If so, which randomization method will be used?
d. Is an open-label trial appropriate, or will any parties need to be blinded to minimize the risk of bias? If so, will only the participants be blinded (single-blind study), or will the investigators and staff also be blinded (double-blind study)? In very sensitive cases, the statisticians who analyze the study data may also be blinded (triple-blind study). Under what circumstances should unblinding be performed?
e. Decide if a fixed design is best, or whether an adaptive study design might improve the ability to reveal a drug effect or address ethical concerns.
f. Calculate the necessary sample size to achieve good statistical power
g. Decide on the primary outcome measure and any secondary outcome measure(s) which will be followed to assess patients’ health outcomes and answer the research question(s)
h. Determine which statistical analysis methods will be used to reveal the effects of the treatment, and what level of statistical confidence will be necessary/desired to demonstrate this effect
Factor 4 - Select high-performing sites and carry out any required training
Remote or decentralized trials may not involve study sites at all, in which case this factor can be skipped!
For trials that will be conducted at one or more study sites, there are a few steps involved in establishing the network of sites that will carry out the study visits and collect patient data. Some sponsors and many CROs already have a network of sites they’ve worked with, so depending on the level of prior experience or any partnerships with CROs, some of these steps may be omitted.
- Determine the number of sites needed, based on the required sample size, the capacity of each site, and the geographical spread of participants who will need to access a study site
- Site identification - Identify sites in a preliminary manner based on certain criteria (location, specializations, etc.)
- Site selection - Select from amongst identified sites by narrowing down the criteria, which could be facilitated by sending out site feasibility questionnaires (SFQs), and eventually open discussions with promising sites to reach an agreement
- Visit the sites in-person to confirm suitability, inspect facilities, SOPs, compliance and training records, etc., if necessary
- Formalize clinical trial agreements (CTAs) with selected sites
- Perform site initiation visits (SIVs), and…
- …conduct any staff training required in relation to trial-specific procedures/tasks, electronic systems used by the sponsor, GCP, etc.
As sites are essentially partners who collect the bulk of the actual study data, it is important to establish good relationships with sites and ensure your trial is in reliable and trustworthy hands.
Factor 5 - Develop the trial budget and proposed timelines
Once the bulk of external agreements are in place and the trial design is formalized, the clinical trial budget and timeline should also be updated. It’s likely that both a timeline and a budget were involved in regulatory approval steps earlier on in the conception of the trial, but by this time it should be more feasible to create refined versions reflecting additional details that have been worked out.
A tip that may help prevent headaches in regard to budgeting and timelines is to assume that things won’t go 100% according to plan. Flexibility is a great asset, since clinical trials are notorious for running into setbacks. Some of the most common sources of delays in clinical trials include regulatory approval steps, patient recruitment, and site selection/activation, since all of these are directly reliant on third parties. Being prepared to absorb the effects of delays and unexpected expenses to some extent and then move forward graciously (rather than these ‘blowing up’ and leading to further problems or even early termination) will significantly support the trial’s overall success. A risk assessment will be a great help for identifying the potential delays or setbacks that are most likely to occur.
Factor 6 - Create a data management plan (DMP)
The principal outcome and objective of clinical trials is not curing patients or getting a drug approved - it’s simply the collection of data. This data then forms the basis for drawing conclusions about the safety and/or efficacy of the intervention, for informing patient care, and for regulators to make decisions about whether or not to approve a new treatment. Robust data does not materialize from thin air; it is the result of meticulously planned, designed, and executed trials. The part of trial operations responsible for ensuring the clinical trial data is healthy is known as clinical data management (CDM). The ‘master plan’ for how data is to be collected, handled, and analyzed throughout a trial is usually set forth in a data management plan (DMP).
A trial will typically have a data manager responsible for creating, implementing, and monitoring adherence to the DMP (or for managing a data management team dedicated to that purpose). Creating the DMP requires the consideration and formalization of:
- Roles and responsibilities for everyone involved in data handling, including its collection, organization, sharing, validation, and analysis
- Software solutions to be used, such as a clinical data management system (CDMS), electronic data capture (EDC) or eCOA or ePRO tools
- User permissions for these software tools
- Appropriate training for all users of data management tools, including training site staff on data collection methods, or even patients in the case of patient-reported outcomes (PRO), wearable devices, or direct-to-patient (DTP) trials
- Document management, tracking, and audit trails
- Data privacy considerations
- How blinding of the data will be maintained throughout all operations
- Statistical analysis methods to be applied
- Conditions for database lock (both soft lock and hard lock)
- Reporting
Factor 7 - Set up for efficient patient recruitment and enrollment
As mentioned previously, patient recruitment and enrollment is a common source of delay due to the myriad factors involved, many of which are beyond the control of the sponsor. After establishing the required sample size, for some trials wherein high attrition rates are expected (i.e., longitudinal studies, studies on diseases with high morbidity, studies involving high patient burden), oversampling may be a good strategy to prevent delays resulting from patient drop-outs. For rare-disease studies and other studies where it seems difficult to find the required number of patients, timelines should be extended to allow sufficient time for recruitment.
We have written an extensive piece dedicated to clinical trial recruitment, which further links to other articles we’ve written on sub-topics related to patient recruitment and retention. Here, we provide an overview of the main considerations to keep in mind, as thorough planning can go a long way toward supporting successful clinical trial recruitment.
Part 1. Eligibility criteria
The first step is to establish eligibility criteria – inclusion and exclusion criteria – in a critical manner, achieving a good balance between overly relaxed criteria (leading to exaggerated variability in confounding factors) and being overly strict (unnecessarily limiting the eligible participant pool, causing problems with accessibility, or leading to results that are weakly generalizable to the broader population with the condition).
Part 2. Diversity considerations
Genetic and lifestyle factors in the sampled population should be considered, in order to provide the right context for the results. For example, if the disease is significantly more prevalent in women than in men, it would not make sense to conduct the study on a sample consisting of 75% men. Of course, sometimes it’s simply not realistic to account for such factors.
Relatedly, it is important to capture a reasonable degree of diversity in the study population, not only for ethical reasons of inclusivity and accessibility, but also to capture the natural variability in genetics and lifestyle factors between people and groups of society. This ensures that results are more likely to be relevant to the real-world population of people with the condition being studied. In extreme cases, the risk of overlooking this is approving treatments that are ineffective or even seriously unsafe for particular groups who were not included in the research studies.
Part 3. Outreach and advertising
The bulk of recruitment and enrollment efforts center around outreach and advertising, unless there are solid patient databases already established and accessible to the sponsor, in which case it could be a simpler matter of reaching out to invite eligible participants directly. Trials are increasingly moving to digital platforms for patient recruiting, and sponsors may use a combination of various approaches, depending on the characteristics of the target population. We have covered this topic extensively, so rather than fill this article with the same information, we will keep it brief and provide links to useful resources we’ve compiled about all aspects of patient recruitment, enrollment, and retention:
Recruitment challenges and statistics
Enrollment in Clinical Trials: Statistics and Patient Recruitment Strategies | Power
Three Clinical Trial Recruitment Challenges and Strategies to Overcome Them | Power
Broad recruitment strategies and tools
Clinical Trial Recruitment 101: How to Recruit Participants for a Study | Power
9 Clinical Trial Recruitment Tools to Try in 2023 | Power
Specific recruitment platforms and media
Designing Effective Social Media Clinical Trial Recruitment Campaigns in 2023 | Power
Google Clinical Trial Advertising: Getting the Most Out of Google Ads for Recruitment | Power
Research Recruitment Flyer | Power
Outsourcing patient recruitment
Top 10 Patient Recruiting Companies for Clinical Trials in 2023 | Power
Resources on patient retention
Measuring Patient Retention in Clinical Trials | Power
5 Simple Yet Highly Effective Patient Retention Strategies | Power
Factor 8 - Decide on a monitoring plan
Monitoring fulfills multiple functions and is essential for a variety of reasons:
- Ensuring patient adherence to study visits and dosing schedules
- Keeping an eye on patient safety and identifying adverse effects
- Upholding data integrity throughout the data lifecycle
- Ensuring consistency across study sites and adherence to protocol
- Continually assessing and addressing risks
- Verifying accuracy of data between source documents and electronic records
- Maintaining quality standards
- Demonstrating continued regulatory compliance
Monitoring can be performed under a few different models/approaches, each of which is described further in the dedicated article linked for each monitoring style:
- On-site monitoring: Study monitors or CRAs visit sites in-person to verify source documents, verify compliance, etc.
- Remote monitoring: Monitoring is largely performed from a central location (can also be called centralized monitoring), with connected electronic systems and a dashboard overseeing operations comprehensively. May be complemented with on-site visits to resolve certain queries or issues.
- Risk-based monitoring: A type of centralized/remote monitoring that takes an approach of risk identification to prioritize monitoring of high-risk areas/operations, on a dynamic basis as the trial progresses
A related concept is that of a medical monitor, whose role is specifically to ensure that patient care decisions are made from a place that is sufficiently informed by professional medical knowledge. This individual may also perform other functions of monitoring, such as checking data to ensure that protocol is being followed, particularly in relation to protecting patient safety and well-being.
Establishing strict monitoring practices is key to successful clinical trials, as it will ensure that you stay on top of trial operations as they proceed, being equipped to respond quickly and proactively to any concerns or issues with safety, quality, or compliance.
Factor 9 - Quality assurance (QA) and quality control (QC)
Closely related to monitoring, strong quality control (QC) and quality assurance (QA) protocols should be in place to maximize the chances of a smooth and successful trial. These might form part of the monitoring plan, or may be separate functions conducted by the sponsor or also by neutral (or at least external) third-party auditors or review boards. QC and QA can infiltrate nearly all aspects of the trial, from manufacturing the study drug to software validation and maintenance and data validation. It is up to the sponsor to identify risk areas and undertake appropriate quality control measures to minimize risks to quality and safety.
Quality control measures are also important for maintaining the integrity and reliability of trial data and results, as they support transparency by providing records of continued and targeted oversight of different aspects of the trial. The role of properly trained personnel in quality-assurance cannot be understated. mitigating potential risks and promoting trial success.
QA and QC practices can be based on internal protocols developed by the sponsor, or on external regulations and guidelines, such as the ICH Good Clinical Practice (GCP) guidelines for upholding standards of ethics, quality, and patient safety. Often, a combination of both internal and external frameworks are used to monitor and maintain quality in a way that is adapted to the specifics of the trial at hand.
There are, of course, dedicated tools for helping sponsors and sites manage the realm of quality control, such as electronic quality management systems (EQMS).
Factor 10 - Promoting transparency and communication
Since all of the interconnected parts that coordinate to run a successful clinical trial are run by (or maintained or overseen by) people, clear and effective communication is absolutely vital for:
- Facilitating collaborations, most of which are dynamic and involve multiple parties
- Supporting troubleshooting of issues
- Keeping stakeholders informed
- Enabling informed and effective decision-making
- Supporting efficient resolution of disputes
- Keeping operations efficient and streamlined
A related aspect is transparency, which could be thought of as a form of open communication between the interior world of the trial and the broader community (the public as well as researchers, healthcare policy-makers, government institutions, etc.) who were not involved in any way. Focusing on being transparent – in regard to why the study was conducted, who was involved, how it was done, and especially in reporting the clinical trial results (including when they are negative!) – offers many benefits, particularly:
- It enables the trials results to be used for generating wider impacts (i.e., informing policy or being utilizable in meta-analyses, real-world evidence studies, etc.).
- It supports trust in clinical research among the general public, where they may be prevalent negative perceptions and misperceptions, especially within certain communities who have been underrepresented or treated unfairly in the past.
- It promotes health literacy and health-informed citizens, as publishing results in a transparent way involves using layperson language so results are accessible to a wider audience, which…
- …can help increase awareness about developments in healthcare, as well as about clinical research in general, helping to dispel myths or negative perceptions arising from suspicions or a simple lack of understanding about clinical research.
In this sense, the idea of communication within a clinical trial should also strongly consider the patients. Clear communication, beginning with recruitment advertising and continuing through informed consent and every study visit, helps make sure patients are properly informed and that they feel safe, comfortable, and valued for their contribution. In this regard, it’s important to train any staff who interact directly with patients on topics of compassion, empathy, and respect. Patients voluntarily participate in trials, for various reasons, but many are experiencing difficult life situations and do not want to be treated as research subjects before they are treated as fellow human beings. Remember that patients have the basic right to leave the study at any time, for any reason, and without explanation – so, besides the obvious motivation of treating them with decency, it’s in the best interest of the trial to ensure they feel appreciated and seen. For more reflections on this topic, see our article on patient-centricity in clinical trials.
Conclusion
We hope that these 10 ideas (which in reality encompass many more topics!) come in handy as a sort of comprehensive overview of key factors for successful clinical trials. We suggest it could be used as a checklist to confirm that various essential aspects have been thought out adequately before launching a trial. While it’s never realistically possible to guarantee success, the secret is in detailed, thorough, proactive planning. When the trial is set up to be successful on all of these pillars, the chances of success – and of generating tangible and positive developments for patients – are maximized.
As a closing note, make sure to always take lessons from past trials – both successes and failures – as experience is always the best teacher.