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Potential Problems with Clinical Trials
Clinical trials serve as the bridge between medical research and real-world patient care. They represent essential steps in evaluating the safety, side effects, and effectiveness of potential new treatments. However, the very nature of the complex, multi-factor problems and questions that clinical studies aim to answer means that the clinical research process is usually quite complicated on numerous different fronts. The exploratory nature of investigating new drugs, stringent legal and regulatory frameworks and oversight (which differ between regions), and the need to maintain strong ethical standards in order to ensure the safety of volunteer subjects (who aren't always easy to find) all contribute to the complexity of clinical research.
Thus, sponsors and research sites are often faced with various challenges when undertaking clinical trials. Common aspects of trials that may be particularly difficult to navigate include:
- Choosing a methodology and designing the trial in a way that sets it up for optimal scientific validity, while still being feasible
- Patient recruitment and retention
- Upholding ethical standards and safeguarding participant safety while still producing insightful data
- Maintaining research integrity and avoiding conflicts of interest
- Navigating regulatory landscapes
- Adapting to the globalization and decentralization of clinical trials
- Projecting and adhering to trial timelines and budgets
1. Methodological challenges - optimizing study design
Designing rigorous clinical trials that are optimized for generating results of high scientific value and quality requires careful planning. We have written a dedicated article on the art of clinical trial design; have a look for a deeper dive into this topic. Briefly, some of the main steps involved include:
- Selecting an appropriate study design
- Selecting a suitable control group/treatment/placebo
- Deciding whether or not to use randomization, as well as blinding
- Establishing inclusion and exclusion criteria, in a way that facilitates recruitment yet controls sufficiently for confounding variables
- Calculating the necessary sample size to detect the expected effects
- Determining a meaningful outcome measure
Some of these points will be explored in more detail in the next sections. But to begin, it’s important to explain the fact that many aspects of the study are predetermined in the finalized study protocol, and making changes may or may not be permitted (this is also part of study design, which is relevant for example in adaptive-design clinical trials). Thorough planning is therefore vital, as most aspects should be consciously thought-out before even recruitment efforts begin. Experienced trial sponsors may have streamlined systems in place for determining optimal trial designs, whereas others may even contract a CRO as early as the trial planning/design stage, to draw upon their expertise in previous trials.
The sponsor has to decide on what to compare the intervention under study against. Is there a standard of care already established? In that case, would it be ethically permissible to use a placebo instead of the standard of care, in consideration of the severity and urgency of the condition being studied? How many study arms are needed, and what randomization schedule will be used to assign participants to these study groups? Should participants be blinded or is there an explicit reason why they might need to know what group they’ve been assigned to? Should investigators also be blinded to prevent any bias in patient care decisions and/or study outcomes? All of these questions have multiple dimensions that should be carefully considered, both to set the trial up for success as well as to prevent unexpected problems after it starts.
Next, what does the demographic of people with the condition being studied look like? Is there a dominant age range, or does it affect one sex more than the other? Are there lots of people with the condition living around the study area? Are there certain characteristics or conditions that would make it particularly dangerous or unethical to give the study treatment to that individual? Are there significant lifestyle factors or habits that would confound study results, such as smoking or being obese? Deciding on eligibility criteria is an art of balancing between promoting accessibility to a wider population and obtaining results that are more generalizable versus leaving too much room for variability in confounding factors that would make it difficult or impossible to determine a drug effect. As per the study design, the ideal sample size should also be determined, which will then allow the sponsor to determine if the study can be conducted locally or how many sites (and which) might need to be involved. Or, perhaps, it would be more feasible to conduct the trial remotely – i.e., a decentralized clinical trial – in order to access a more dispersed population, which might be particularly relevant for studies on rare diseases.
The research hypothesis must also be formulated, which could be done before the above parameters are set (thus guiding those decisions so they support answering the research question) or afterward (i.e., formulated after determining the most feasible way to investigate the intervention in the specific context). Finally, what is the quantitative or qualitative metric (or metrics) that will be used to prove or disprove the study hypothesis? Choosing a primary (and maybe secondary) outcome measure is a vital step for ensuring that the right data is collected, and in such a way that it supports researchers in making conclusions about the safety or efficacy of the intervention (or both). Will that data be collected by a study physician at periodic study visits, or does it require constant monitoring, warranting the use of a connected device? Is it something that patients could reliably report themselves, thus supporting the use of ePRO?
In general, ensuring validity (does the data actually support the conclusions in consideration of all of the parameters of the study?) and reliability (were procedures and regulations followed strictly, and would repeated studies be likely to yield similar results?) is not an easy task, as human bodies are complex systems and there are almost innumerable factors that can affect study data and outcomes.
2. Patient recruitment and retention challenges
Recruiting sufficient eligible participants who are willing to voluntarily consent to participate in the trial is one of the major hurdles faced by clinical trial sponsors. We have written a few articles dedicated to this topic; check them out for more thorough discussions, approached through different angles:
Three Clinical Trial Recruitment Challenges and Strategies to Overcome Them | Power
Enrollment in Clinical Trials: Statistics and Patient Recruitment Strategies | Power
9 Clinical Trial Recruitment Tools to Try in 2023 | Power
As a general guideline, the concept of patient centricity can help sponsors ensure that their trials are as attractive as possible to prospective participants, and in general this trend is helping to ensure that trials are addressing the real needs of the patients who are awaiting new treatments.
Putting Patients First: A Guide to Patient Centricity in Clinical Trials | Power
An important underlying theme in trial recruitment is diversity. Clinical research has classically been characterized by unequal representation of diverse populations. This is a problem because, beyond not supporting equal access to participation opportunities (although largely unintentional), a lack of diversity in participant characteristics leads to results that may not be generalizable (applicable) to the broader community with the condition. Recruiting diverse populations ensures that researchers can get an idea of how various populations may respond differently to treatments.
Once enrolled and consented, retaining these volunteers can also present a challenge, especially over longer periods of time. High drop-out rates, also known as attrition, may cause delays, demand additional interim recruitment, or even render trial results inconclusive. It is generally thought that a certain degree of attrition is essentially unavoidable, particularly for longitudinal studies or studies researching morbid conditions. However, there are strategies that sponsors and sites can adopt to try to encourage patients to stay in the study and thus minimize attrition – see 5 Simple Yet Highly Effective Patient Retention Strategies | Power.
3. Upholding ethical standards to safeguard participant safety
Issues around obtaining informed consent
Since clinical trials are experiments with living human participants as the research subjects, ethical considerations are the number-one priority. The concept of ethics has a few dimensions – clinical researchers must consider what is fair, what is safe, what is legal, what level of risk is acceptable, and how participants’ well-being and first-hand experience will be affected throughout the trial. Ethical standards in clinical research are generally established at international, national, and maybe also regional levels, and are set forth and enforced in order to ensure the rights, well-being, and safety of participants are protected.
One of the central mechanisms for guaranteeing the ethical treatment of human research subjects is informed consent. The research sponsor drafts an informed consent form (ICF) – a document that compiles all of the details of the study, explicitly outlining the nature of the study, what is expected of the participant, and what risks are involved. This document is priorly reviewed (along with the study protocol and other study documentation) by an independent entity responsible for verifying that the study is ethical – in the US, an institutional review board (IRB) confirms that the study adheres to FDA guidelines, while in the EU, these are typically called independent ethics committees (IEC). The consenting process also involves an active discussion between the investigator and the participant, to ensure that the participant acknowledges that they fully understand the study's purpose, procedures involved, and its risks and benefits.
The digitalized version of consenting, known as eConsent, is increasingly being used, especially in remote or decentralized trials. With eConsent, different types of media can be employed (i.e., videos, interactive questionnaires, etc.) to verify the patient’s comprehension, and offers certain logistical benefits for both sponsors and participants as they can consent from home. However, obtaining informed consent remotely brings a new set of challenges related to confirming participant identity and confirming their willful acceptance of the document contents. The authenticity of eConsent is upheld by various types of electronic signatures, which offer differing levels of identity verification and security.
Another challenge with consent is the prevalence of medical jargon in the clinical sphere, and the differing learning styles and capacities for comprehension between participants. As such, it is important for ICFs and other study documentation to be written in accessible language – study information should be presented thoroughly and in a clear and concise manner, replacing medical jargon with layman terminology and providing further explanation for complex concepts in ways that are easy to understand. Researchers can ask themselves the question “would I understand this had I never been involved in the clinical or medical fields?” We’ve written an article on patient engagement that touches on the topic of clear communication in clinical trials. Our discussion on health literacy also goes over some considerations that may prove to be useful.
Challenges pertaining to privacy and confidentiality
Another aspect of clinical research ethics relates to privacy and confidentiality, for patients as well as their personal data. Researchers must balance the requirements of data sharing for research purposes with preserving individuals' privacy, and there are various regulations that come into play here, such as the GDPR and CTR in the EU or HIPAA in the US. Refer to our article on data privacy in clinical trials for a deeper dive into this topic. Respecting patient privacy is also an important aspect of clinical trial recruitment advertising that can’t be overlooked; see our guides to recruitment advertising on Facebook and through Google for examples of how privacy regulations rule how sponsors are allowed to target potential participants.
The ethics of placebo-controlled trials
Finally, there is an ongoing debate around the ethics of placebo-controlled trials, particularly in cases where an existing treatment is already available. Depending on the severity of the condition being studied and the urgency of receiving treatment for different patients, it could be entirely unethical to withhold a standard treatment in favor of a placebo for research purposes.
On the other hand, there are ethical debates regarding certain types of trial designs in general. For example, some argue that open-label extensions (OLEs) do not give participants sufficient information (with regard to their allocation in the prior study) to allow them to make an informed decision to participate. Further, some believe that OLEs don’t meet the definitions and criteria of a research study, and that these may be better described as marketing or compassionate use programs disguised as clinical research. In general, ethics is a prominent consideration in trial design, for example influencing the decision to utilize an adaptive-design trial such that those assigned to the control group can later be switched and receive the study treatment if interim results seem to indicate that it is providing therapeutic benefit.
4. Maintaining research integrity and managing conflicts of interest
Alongside ensuring the ethical treatment of research participants, clinical trial sponsors must also uphold standards of scientific research integrity. Research integrity involves the accurate, transparent, and honest collection, processing, and interpretation of study data, such that results can be considered trustworthy and scientifically valid. However, another core component of this is avoiding conflicts of interest – or at least acknowledging their potential when one exists. In clinical research, a conflict of interest usually means that an individual or entity funding a clinical trial has a vested interest in the investigational product being approved. For example, if a trial is entirely sponsored and conducted by the pharmaceutical company who already spent millions of dollars developing a new potential therapy, then there is a potential conflict of interest. In other words, that company has a strong interest in the drug being approved; to the contrary, they could have spent millions on developing a drug that can never be used or marketed, either due to being unsafe or ineffective for its proposed use. As you might already be thinking, this situation is quite common in clinical trials due to the very structure of pharmaceutical development and clinical research. Thus, it has been argued that eliminating conflicts of interest in clinical research may not be feasible, and that instead the focus should be on their transparent disclosure and management to ensure that the study is still conducted – to the extent it’s possible – from a place of neutrality and honesty.[1]
Conflicts of interest can also exist in regulatory boards (via personal or institutional affiliations), or in investigators (who could be affiliated with a sponsoring organization, whether openly or not). For the sake of transparency and research integrity, all potential conflicts of interest should be disclosed, and sponsors should make sure not to engage in any form of bribery or coercion, whether internal or external, as this could spell heavy penalties including fines and revocation of licenses/authorizations if exposed, not to mention the potential for tragic consequences for human participants.
Bias
Relatedly, there are numerous ways in which bias can be introduced into a clinical trial, which has the potential to skew results and negatively impact the integrity of the research. Bias can be inherent in a study design that was not properly thought-out, or could be introduced (usually unintentionally) via the personal beliefs, preconceptions, or hopes of researchers, investigators, or statisticians.
At the same time, there may be strong pressure on investigators to publish positive results. This pressure could arise from the sponsoring organization or elsewhere, and may be especially prevalent in highly competitive research fields or those wherein drug development is even more costly than in others. Investigators and sponsors alike have an ethical, moral, and scientific responsibility to be as neutral as possible throughout the clinical research process. While simple to state, this may be a daunting feat. Addressing this issue is part of the reason why there are so many external checks and balances in place – independent auditors, ethics committees, federal agencies, and international guidelines are all in place to provide a level of oversight to counteract the potential for bias and coloring of research results, whether intentional or not. Common results of uncontrolled or unchecked bias would be the overestimation of a drug effect, treatment benefit, or safety profile, or underestimation of harms or confounding variables – all of which have the end result of hampering research integrity and the validity of study results in terms of making real advances toward improving healthcare for patients in need.
Overall, many aspects of clinical research should be transparent (with the exception of facets that obviously need to be kept private, such as proprietary steps in drug discovery and protocol factors such as blinding and allocation assignments), supporting trust within and in relation to the clinical research industry. A lack of transparency can augment confusion or mistrust in certain communities, which was identified as a factor in the lack of diversity in trial participation.
5. Navigating regulatory landscapes
Clinical trials are conducted under stringent regulatory frameworks, which are in place to maintain high standards of patient safety, legal accountability, and ethical conduct. Unfortunately, legal and regulatory landscapes can differ (sometimes significantly) between geographical regions. On the national scale, different states across the US may have divergent state laws that need to be considered when operating trial sites in multiple states. However, the variation becomes even greater when dealing with international trials, which are becoming increasingly prevalent, as we will explore in the next section. Thus, navigating different, complex, and sometimes overlapping or directly conflicting regulatory frameworks and guidelines presents specific challenges to the trial sponsor. In some cases, sponsor organizations conducting international trials may contract local professionals in the different countries in which a trial is being conducted, or may even have an internal team dedicated to managing the unique regulatory and logistic considerations of international trials.
The unification and standardization of clinical research regulations across jurisdictions is a dream of some researchers, sponsors, and even regulators, but is currently far from being a reality. While this could someday be a reality that facilitates cross-border research and opens up new possibilities, in the meantime sponsors need to understand and comply with applicable regulations in each jurisdiction involved in each trial.
It should be mentioned that while there are international guidelines, these are not necessarily rules/standards that are enforced internationally. For example, the ICH GCP (Good Clinical Practice) is an international quality standard which can be adopted/drawn upon by regulatory bodies in different regions. GCP standards are not legally binding in the US, although they have been incorporated heavily into the FDA guidelines, which are enforceable.
6. Adapting to the globalization and decentralization of clinical trials
As clinical trials become increasingly globalized, sponsors face an expanding set of novel challenges. In the previous section we discussed the complexity of navigating different regulatory landscapes, but there are further nuances involved in conducting research internationally. For example, conducting studies in developing nations may require particular consideration of socio-economic constraints (i.e., access to internet or routine medical care). Patterns of disease prevalence can differ significantly between regions and across ethnic subgroups of the population, due to a combination of genetic, social, economic, and environmental factors. Cultural diversity adds another layer of complexity to designing and executing global trials, as cultural sensitivities, customs, and nuances may heavily impact the feasibility of studies as well as the receptivity of the local population to participating. Study documentation may need to be re-written to account for cultural norms, or protocols may even need to be adapted for specific regions. There are numerous factors that can play into this, such as religious customs and observations, tradition and convention, societal norms, and political structures (to name a few).
Potentially significant differences in genetic and environmental factors across diverse populations should also be accounted for when interpreting study data and formulating conclusions. The generalizability of results depends on the characteristics of the sampled population, and researchers should make attempts to recognize and account for these differences in such a way that the conclusions include these nuances in a transparent manner. It should be mentioned, however, that the inclusion of diverse populations and the strengthening of international collaborations in healthcare research has the potential to provide significantly deeper insights as well as results that are more generalizable, and which may even be suitable for informing healthcare policy at an international level – but only when these factors are consciously and honestly considered when interpreting study results.
7. Projecting and adhering to trial timelines and budgets
Last but not least, it is common for researchers to run into delays and setbacks, as well as to stick to research budgets. Thorough planning is vital, but projected budgets and trial timelines should be approached with some degree of flexibility, such that minor setbacks or divergence from plans does not throw the trial entirely off track. In other words, while it is important to plan, part of that planning is likely to include acknowledgement that things don’t always go as planned, and to be prepared and equipped to absorb such deviations in order to continue moving forward with the trial. Common sources of delay (which can carry associated monetary losses) include patient recruitment and enrollment, regulatory submissions and approvals, and site selection, including negotiating clinical trial agreements. High attrition rates may also occur unexpectedly, and in general, it is wise to accept the fact that some drugs simply prove to be unsafe or ineffective, and that failures may be part of the research process. With the right mindset, sponsors and investigators can use setbacks and failures as learning opportunities in order to improve in subsequent trials.
Conclusion
In conclusion, sponsors face a diverse range of challenges in conducting clinical trials. Beginning with planning and trial design, there are numerous factors that have to be considered in order to generate a protocol that is scientifically robust yet respectful of patient rights and safety and compliant with all applicable regulations. Establishing eligibility criteria that strike the right balance between inclusivity and control of confounding factors, calculating the required sample size, and then actually recruiting the required population – on time and within budget – is the next challenge. Keeping them engaged and thus retaining them in the study is a separate concept entirely which must also be addressed.
Ethical considerations underlie almost all aspects of clinical research, from selecting a fair trial design to ensuring patients are thoroughly informed to maintaining patient and data privacy and confidentiality. On top of this, research integrity must be upheld, which involves managing conflicts of interest as well as adhering to high quality standards and complying with legal regulations. The coordination of multinational trials can be particularly tricky in terms of ethics and regulations. The evolving trend towards decentralized and global clinical trials adds its own set of complications, as sponsors must maintain these high standards across diverse socio-political and economic environments.
Since clinical trials are a necessary step in bringing new treatments and drugs to patients who need them, there is no choice but to work through the challenges that clinical research presents. Although there are numerous and diverse challenges and problems with clinical trials that sponsors need to manage and navigate, many of these originate in the need to ensure the protection of patient rights and well-being. Regulations have become stricter over the years, often in response to tragic occurrences which provided the necessary fuel for making changes toward improving safeguards for patients. Along this same logic, we can take the point of view that challenges are exactly what propel innovation. As clinical research continues to evolve, sponsors and researchers will continue to craft clever solutions. With this feedback loop, the industry will continue to become better equipped for investigating today's health mysteries and bringing life-saving treatments to patients, while ensuring the utmost protection of the rights and well-being of the human volunteers who make these advances possible.