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Designing clinical trials for maximum efficacy: obstacles and opportunities

By understanding trial design challenges and the opportunities to overcome them, better strategies and methodologies can be implemented to ensure the highest chances of success.  

26 April 2023 9 minutes

Designing clinical trials for maximum efficacy: obstacles and opportunities

Clinical trial design entails the process of planning and structuring a clinical trial in order to test the safety, efficacy, or other aspects of a medical intervention, such as a drug or device. The design process of a clinical trial is a crucial and requires time, resources, and considerable effort to ensure that a trial is set up for optimal outcomes and maximum efficacy. However, designing clinical trials for maximum efficacy can be a complex and challenging task, especially considering the various factors that must be taken into account, such as patient populations and regulatory requirements. 

In this blog post, we will explore the fundamentals of clinical trial design for each phase and discuss key challenges faced by those working within the realm of trial design, such as clinical trial designers, data scientists, clinical project managers, and clinical data managers. By understanding these challenges and the opportunities to overcome them, better strategies and methodologies for designing clinical trials can be implemented to ensure the highest chances of success.  

Fundamentals of clinical trial design 

Clinical trial design is the process of planning and structuring a study to assess the safety and efficacy of a new drug, medical device, or treatment in humans. The main objectives of clinical trial design are to: 

  • Determine the appropriate sample size and study population
  • Select the best control group and randomization method
  • Establish primary and secondary endpoints and methodology
  • Determine the study duration and follow-up period
  • Set up data collection, monitoring, and analysis methods  

The clinical trial process typically consists of several phases: 

  • Phase 1 Clinical Trials: evaluating safety, tolerability, and pharmacokinetics

    Phase 1 of a clinical trial is the first stage in the testing and evaluation process of a new drug or treatment. It is a crucial step in the development of any novel intervention. Evaluating the safety, tolerability, and pharmacokinetics (how the drug is absorbed, distributed, metabolized, and excreted) of the investigational drug are the main goals of a Phase 1 trial.   


    The main components of a designing a Phase 1 clinical trial are: 


    Study type and method: Phase 1 trials are often designed as open-label, non-randomized, and non-controlled studies, meaning that both the investigators and participants are aware of the treatment being administered, and there is no control group receiving a placebo or standard treatment. Some Phase 1 trials may use a single ascending dose (SAD) or multiple ascending dose (MAD) design, where the drug is given at gradually increasing doses to different groups of participants to assess safety and tolerability.

    Patient population: Phase 1 trials usually involve a small number of participants, typically ranging from 20 to 100. The participants are generally healthy volunteers, although in some cases, patients with the targeted condition may be enrolled, especially if the drug carries a significant risk or if the condition is rare and severe.

    Data collection and analysis: Throughout the trial, data is collected on the safety and tolerability of the investigational drug, as well as its pharmacokinetic properties. This data is carefully analyzed to identify any patterns or trends that may influence the design of future trial phases, as well as to determine the maximum tolerated dose (MTD) or the no-observed-adverse-effect-level (NOAEL).

    Phase 1 clinical study duration: Phase 1 trials are typically shorter in duration than later-phase trials are, usually lasting a few months to a year. 

  • Phase 2 Clinical Trials: assessing preliminary efficacy and further evaluating safety

    Phase 2 focuses on assessing the preliminary efficacy and further evaluating the safety of the investigational drug in a larger group of participants with the targeted condition. Determining the optimal therapeutic dose, refining the dosing schedule, and establishing proof-of-concept for the investigational drug's effectiveness are some main Phase 2 objectives. Often, potential biomarkers or patient characteristics can be refined that ensure response to the treatment. 


    Some relevant components of designing a Phase 2 clinical trial are: 


    Study type and methods: Phase 2 trials are generally designed as randomized, controlled studies, where participants are randomly assigned to either the investigational drug group or a control group. The trials can be single-blind, in which only the participant is unaware of their treatment assignment. Trials can also be double-blind, in which both the participant and the investigator are unaware of the treatment assignment.  

    Patient population: The number of participants in a Phase 2 trial usually ranges from several dozen to a few hundred. These participants are patients with the targeted condition, as opposed to healthy volunteers, allowing for a more accurate assessment of the drug's effectiveness and safety in the intended population. 


    Endpoints: Endpoints are used to assess the drug's effect on the disease progression, symptoms, or other relevant outcomes. Phase 2 trials often use surrogate endpoints or intermediate clinical endpoints. 


    Data collection and analysis: As in a Phase 1 trial, throughout a Phase 2 trial, data is collected on the efficacy, safety, and tolerability of the investigational drug, as well as any relevant biomarkers or patient characteristics. This data is carefully analyzed to identify trends or patterns that may influence future trial phases and to determine whether the investigational drug has demonstrated sufficient promise to warrant further investigation in a Phase 3 trial. 

  • Phase 3 Clinical Trials: further assessing efficacy, effectiveness, and safety

    A Phase 3 clinical trial focuses on evaluating the effectiveness and safety of the investigational drug in a larger and more diverse population of patients with the targeted condition. Phase 3 trials are critical for obtaining the necessary data to support regulatory approval for marketing and commercialization of the drug. 


    Some important components of designing a Phase 3 clinical trial are: 


    Study type and methods: Phase 3 clinical trials are generally designed as randomized, controlled, and double-blind studies. Both the participants and the investigators are unaware of the treatment assignment. The study design may include parallel-group or other specialized designs depending on the research question. 


    Patient population: The number of participants in a Phase 3 trial is significantly larger than in Phase 1 or Phase 2 trials, usually ranging from several hundred to several thousand. These participants are patients with the targeted condition. The larger sample size allows for a more accurate assessment of the drug's effectiveness and safety across various subpopulations.


    Endpoints: Phase 3 trials often use primary and secondary endpoints to assess the drug's effectiveness. Primary endpoints are the main outcome measures used to determine the drug's effectiveness, while secondary endpoints provide additional information on other aspects of the drug's effects.


    Phase 3 trial duration: Phase 3 trials are typically the longest of all clinical trial phases, lasting from several months or years, up to even a decade. 

  • Phase 4 Clinical Trials: post-marketing surveillance

    Phase 4 of a clinical trial is also known as a post-marketing surveillance trial or a post-approval study. It is the final stage in the testing and evaluation process of a new drug or treatment and is conducted after the investigational drug has received regulatory approval and is available for use in the general population.  


    Some important components of a Phase 4 clinical trial are: 


    Study Type and methods: Phase 4 trials can be designed as observational or interventional studies, depending on the research question and objectives. Observational studies involve monitoring the drug's use and outcomes in a real-world setting without controlling the intervention, while interventional studies involve assigning patients to different treatments or strategies to assess their effects.


    Patient population: Phase 4 trials involve a large and diverse population of patients who are prescribed the drug as part of their standard care. The number of participants in these trials can range from several hundred to several thousand or more, depending on the drug and the specific study design.


    Data collection and analysis: As with other trial phases, data is collected on the safety, effectiveness, and tolerability of the investigational drug. Data is also collected on any relevant subpopulation characteristics and real-world usage patterns. This data is carefully analyzed to inform the drug's benefit-risk profile and guide updates to the drug's label or prescribing information.


    Trial duration: Phase 4 trials are typically long-term studies, lasting from several years to indefinitely, depending on the drug.  


    Throughout the course of a Phase 4 trial, the data collected may lead to updates in the drug's label or prescribing information, or even result in the withdrawal of the drug from the market if significant safety concerns are identified.  

Overcoming challenges and designing clinical trials for maximum efficacy 

Approximately only 14% of all drugs undergoing clinical trials eventually get FDA approval. The reasons for failure or delays are numerous, but more often than not, they have to do with misunderstandings of key biological and/or drug development principles or patient population scoping, leading to inadequate study design, inappropriate efficacy markers, and more.   

While there are steps to be taken to help ensure a clinical trial’s design is as optimized for success as possible, life sciences companies are increasingly facing more and more challenges when trying to do so, making trial success harder and harder to achieve. Below, we have detailed three of the top clinical design challenges that might compromise designing a study for maximum efficacy. We are also detailing some strategies to help overcome these challenges. 

Clinical trial patient recruitment 

One of the most significant challenges in clinical trial design is ensuring optimal patient recruitment. A well-designed clinical trial requires a sufficient number of participants to guarantee that the study results are statistically valid and reliable. However, recruiting the right patient population and keeping them enrolled can be difficult tasks.  

 The success of every clinical trial hinges on its ability to enroll a set of patients according to a highly specific set of criteria. Further, when designing a clinical trial, certain trial design decisions can impact recruitment and retention rates. Around 85% of clinical trials fail to retain enough patients, while 11% of study sites fail to enroll even a single patient. Unsurprisingly, patient recruitment and retention are widely recognized as major bottlenecks in the clinical trial process – and some of the costliest. Slow or insufficient recruitment can delay the study and increase costs, while high attrition rates can compromise the validity of the results. 

For example, for a phase 3 clinical trial design for a rare disease, finding enough eligible patients can be particularly challenging due to the limited number of individuals affected by the condition. Additionally, competition from other ongoing trials targeting the same patient population may further complicate the recruitment process. 

How to overcome patient recruitment and retention challenges  

To overcome recruitment challenges, clinical trial designers may employ strategies such as developing a strong patient outreach program or collaborating with patient advocacy groups. 

To target patient retention issues, trial designers may consider incorporating patient-centric design elements, such as flexible visit schedules, the use of digital devices for remote data collection, and patient-reported outcomes, to improve participant engagement and retention. 

Even before employing such strategies, trial designers and researchers can turn to historical data to assist them in the clinical trial design process. Utilizing historical data may reveal crucial insights that can help overcome or mitigate future recruitment and retention roadblocks.  

By having a look at data points from similar studies in the past, such as 

  • Number of patients recruited  
  • Number of patients that have dropped out 
  • Recruitment start dates
  • Enrollment duration
  • Enrollment per country or site
  • Inclusion/exclusion criteria
  • Endpoint and outcomes 

 trial designers can make informed, data-driven decisions regarding site selection, endpoint selection, and more when in the trial design process. Armed with this data, trial design can be optimized for patient recruitment and retention later on.  

Clinical trial data challenges 

While utilizing historical data to help drive optimized patient recruitment and retention is indeed a solution to mitigate recruitment and retention issues, collecting and consolidating this data (and other relevant data for trial design optimization) for use remains in itself a challenge.  

Finding accurate and relevant data to use can be difficult for study designers, researchers and data scientists. While there has never been more information available as there is currently, never has such a large fraction of that data been so intangible. Bits and pieces of relevant data are scattered across registries, companies, departments, databases and many other siloes. The overall stream of information isn’t just too vast to plow through manually, it’s also fragmented and exists in too many hard-to-digest formats. 

 Utilizing public data sources for clinical trial design 

Despite this challenge, utilizing data from public data sources like or EudraCT remains essential when designing a new clinical trial for maximum efficacy. Reviewing data from previous trials allows researchers and trial designers to learn from past experiences and gain insights into what worked and what did not. This knowledge can help them design more effective and efficient trials, avoid potential pitfalls, and build on existing evidence.  

Public data sources can also provide information on the standard of care, interventions, and methodologies used in previous trials to help researchers and designers design their clinical trial in line with the best practices and adopt the most appropriate study design. And as mentioned above, assessing the recruitment strategies and eligibility criteria used in past studies can help researchers and designers optimize their own recruitment plans and select a suitable study population. This can improve the generalizability of the trial's findings and increase the likelihood of successful participant enrollment. 

 However, to get a comprehensive overview of current and past clinical studies for a specific condition, time period, or a combination of other search criteria, all public clinical data registries must be consulted. Unfortunately, consolidating the data in these databases is time consuming and often requires manual work. 

Clinical trial design patient recruitment data ONTOFORCE DISQOVER

Utilizing internal data for optimized clinical trial design 

In addition to consulting public data sources, leveraging internal data sources is just as essential when aiming to design for maximum efficacy. Analyzing past clinical trial data can help identify trends, patterns, and potential areas of improvement. This can lead to more efficient trial designs that minimize potential pitfalls or challenges faced in previous trials. 

 Regarding patient recruitment challenges, utilizing data from an organization's previous clinical trials provides valuable information on patient demographics, enrollment rates, retention rates, and treatment outcomes. This historical data can help inform the design of new trials, ensuring that they are well-suited to the target population and address the needs of the patient population being studied. 

 However, when consulting internal data, getting a comprehensive overview of all relevant data can be difficult due to silos and governance challenges. Moreover, it can be difficult for a designer or researcher to know what data even exists within their organization let alone where or how to access it.  

On top of that, consolidating and consulting both public data and internal data at the same time for an even more informed overview can be practically impossible due to some organizations’ data management infrastructures and lack of interoperability.  

To overcome the difficulties around consolidating and consulting public data and historical internal data, data management tools that enable integration from multiple sources and that allow for smart search and filtering are an ideal solution.  

Challenges with selecting endpoints 

In clinical trial design, an endpoint is a predetermined outcome that is used to measure the effectiveness of a new treatment or intervention being tested. Endpoints are critical to the design of clinical trials, as they help to determine whether a treatment is safe and effective, and whether it should be approved for use by patients. Choosing the right endpoints is essential to ensuring that clinical trials are meaningful and provide accurate information about the treatments being tested.   

While selecting the appropriate endpoints is crucial for the success of a clinical, it can be difficult to identify which endpoints are relevant to the disease being studied and clinically meaningful, while also being measurable. Moreover, selecting the wrong endpoints can lead to inaccurate results and can affect the treatment's approval and use in the population. 

Additionally, once the endpoints are chosen, it is essential to define them precisely, including how they will be measured and analyzed. Ambiguity or lack of clarity in endpoint definitions can lead to inconsistent interpretation of data across the study sites, which can affect the trial's validity. 

To ease the challenges associated with endpoint selection during the clinical trial design process, research teams can conduct a thorough literature review, engage with patients and clinicians, consult with regulatory authorities, use established and validated endpoints, and consider the practicality of the endpoints. Further, looking into historical clinical trial data may reveal alternative endpoints to consider that could help to quicken approval times.  

While consulting literature and data about endpoints is indeed an important step in order to ensure optimized trial design, it can still be a difficult and time-consuming task. Compiling a comprehensive overview of literature and data for endpoint selection requires consolidating heterogenous data and information from across sources. Just as with consolidating internal and public data for patient recruitment purposes, utilizing a data management tool that allows for integration from multiple sources is essential. On top of that, a tool with advanced filtering and search capabilities will be ideal so that researchers and designers can quickly narrow down the information that is explicitly relevant to the study they are designing.  

Data: a north star for designing clinical trials for maximum efficacy 

Designing a clinical trial for maximum efficacy is a complex and challenging process, with numerous factors to consider and obstacles to overcome. However, consulting relevant datasets and sources can considerably lessen trial design challenges, especially when it comes to tackling patient recruitment and retention obstacles. Utilizing data management and analysis tools to consult such data can further simplify the trial design process by enabling data-driven decision design and set-up.