Mathumai Govindarajan

Abbreviations

Adverse Drug Reaction (ADR); Clinical Trials Authorization (CTA); FDA Adverse Event Reporting System (FAERS); Food and Drug Administration (FDA); Medicines and Healthcare Products Regulatory Agency (MHRA); New Drug Application (NDA); Non-small Cell Lung Cancer (NSCLC); Overall Survival (OS); Population, Intervention, Comparator, Outcomes (PICO); Progression-free Survival (PFS); Randomized Clinical Trials (RCT); Therapeutics Goods Administration (TGA)

Glossary

Adjuvant therapy; Anaplastic thyroid cancer; Antineoplastic; Antiviral; Atezolizumab; Assay; Bioavailability; Brivanib; Chemotherapy; Clinical trial; Corticosteroids; Double-blind design; Drug tolerance; Efficacy; FDA; Gingival; Half-life; Hemorrhage; Hepatocellular carcinoma; Hypertension; Immunotherapy; in vitro; in vivo; Metabolism; Metastatic; Opioid; Osteonecrosis; Osteoporosis; Paclitaxel; Pazopanib; PD-L1; Pharmaceutical; Pharmacodynamics; Pharmacokinetics; Pharmacovigilance; Phase I; Phase II; Phase III; Phase IV; Physiochemical; Radiation therapy; Rheumatism; Scurvy; Side effect; Signaling pathway; Thyroid cancer; Toxicology; Vaccine

Introduction

Between 2021 and 2022, there was a consistent rise in the number of prescription medications dispensed in the community of England. The total number of items dispensed during this period was 1.14 billion, which reflects a 2.58% increase from the previous year’s figure of 1.11 billion [1]. The pharmaceutical industry experienced a surge in demand for medications, particularly in the wake of the COVID-19 pandemic. Statistical evidence indicates that the net pharmaceutical market is projected to increase by $500 billion over seven years as a result of the pandemic [2]. During that period, clinical trials played a crucial role in the rapid development of therapeutic interventions, vaccines, and diagnostic modalities. The evidence provided enabled the researchers to evaluate the safety and effectiveness of potential treatments in response to a pressing demand for novel medical interventions, thereby contributing to the enhancement of public health outcomes [55]. This article will explore the history and background to clinical trials, the distinct phases of clinical trials, and how the evidence-based approach underpinning the basis of clinical trials enhances the quality of healthcare.

What are clinical trials?

Clinical trials are research investigations designed to analyze the effects of medical or behavioral intervention in human subjects. These studies are carried out to assess the comparative efficacy and safety of novel medicines tested on patient volunteers [3]. The primary objective of these investigations is to systematically examine and provide answers to specific questions concerning the safety and efficacy of a designated therapeutic intervention. The clinical trials aim to investigate various specific research concerns regarding a potential treatment, including the potential harm that the treatment may cause to individuals, the possible side-effects that may arise, and the treatment’s efficacy for a particular patient population [4]. The PICO framework, which comprises population, intervention, comparator, and outcomes, needs to be explicitly established in the overarching research inquiry [4]. In addition to identifying potential long-term effects of the medication, the clinical trials also collect data regarding the pharmacodynamics of the treatment. The evaluation of clinical trial results holds significant weight in the decision-making process of regulatory bodies such as the United States Food and Drug Administration (FDA) concerning the authorization of a new medication [5].

The drug discovery process

The evaluation of a new medical treatment or drug typically involves a four-phase clinical trial process. The primary objective of Phase I is to assess the safety of the new treatment, followed by subsequent phases that aim to evaluate its efficacy and potential side effects. Phase II and III clinical trials entail the administration of the medication to a larger cohort of patients, while Phase IV is conducted after the clinical trials, following the drug’s approval [23]. In general, the procedure of formulating a novel medication may span over numerous years and encompass various phases of investigation, experimentation, and validation, as illustrated in Figure 1. The process involves an initial stage of discovery, during which a target molecule or prospective therapy is identified for the treatment of a specific medical condition [7]. Preclinical investigation and experimentation involve animal and laboratory-based research that is aimed at identifying potential pharmaceutical agents and assessing their safety and effectiveness [8]. This stage can take up to three to five years. Following the identification of a potential drug candidate, an application is submitted to the FDA for approval and subsequent review. Upon submission of the application, the FDA conducts a comprehensive evaluation to ascertain the safety profile of the drug, thereby determining its suitability for clinical trials involving human subjects. It is only after obtaining this approval, that clinical trials can be conducted [9].

Figure 1 Flowchart illustrating the drug development process from drug discovery to post-marketing surveillance. A patent is lodged at the stage of Discovery and authorization for conducting clinical trials is given once preclinical testing has been approved. Image taken from Encyclopaedia Britannica, Inc. 2020

A brief history of clinical trials

Throughout history, clinical trials have faced numerous ethical and scientific challenges. The inaugural randomized clinical trial was performed by Scottish physician, Dr. James Lind in 1747 [13]. The surgeon, serving aboard a vessel, was struck by the elevated incidence of mortality due to scurvy among seafarers [10]. Scurvy is a pathological condition resulting from a deficiency of vitamin C, characterized by gingival edema, lethargy, and brittle gingival tissues that demonstrate an inclination to hemorrhage [12]. The clinical study covered a cohort of 12 representative cases of severe scurvy, who were all confined to a common infirmary, subjected to uniform dietary provisions, and administered diverse pharmacological interventions. In the study, five pairs of subjects were administered cider, elixir, vinegar, and seawater for two weeks. Meanwhile, the sixth pair was given a daily dose of two oranges and one lemon for six days [10, 13]. Upon completion of the six days, it was observed that the individuals who had consumed the oranges and lemons exhibited the most significant recovery and were able to resume their respective duties [12]. Lind’s experiment, being the first controlled trial, brought about a fundamental shift in the domain of clinical research. Lind’s Treatise, published in 1953, not only provided a comprehensive evaluation of scurvy but also presented evidence supporting the efficacy of citrus fruits as a treatment for the condition [10].

Figure 2 Dr James Lind’s controlled trial with citrus fruit, reportedly one of the first clinical trials in medical history [34]. Image taken from the History of Medicine, 1959.

The placebo was first introduced in the year 1800, roughly a century later. In 1863, American physician Austin Flint commenced the initial clinical trial that compared a placebo to an active treatment. Flint administered a herbal extract to 13 rheumatism patients as a substitute for a recognized treatment. As per the physician’s account, the herbal extract was described as a “placebic remedy” for rheumatism [10].

The common cold treatment underwent the first controlled experiment with a double-blind design in 1943-1944, with patulin as the subject of the study [10]. The investigation was conducted by Commander W A Hopkins. Historically, there was a belief that patulin, a harmful compound synthesized by certain molds that commonly grow on fruits such as apples, possessed antiviral properties and could potentially serve as a remedy for the common cold [14]. The study involved the participation of healthy volunteers who were subjected to random allocation to receive either patulin or a placebo. The treatment allocation was blinded, with both the subjects and the researchers being unaware of the treatment administered until the study’s conclusion [11]. Following the exposure to the common cold-causing virus, the participants’ symptoms were observed. According to the results of the study, there was no observable distinction between the groups that received patulin and placebo in terms of the severity or duration of the symptoms [10, 11]. The implementation of a double-blind controlled trial ultimately facilitated the establishment of the efficacy of novel treatments through the utilization of rigorous and dependable scientific methodologies. Consequently, double-blind trials have become a customary procedure in clinical research [56].

The standardization of clinical trials has resulted in a process that prioritizes the assessment of both efficacy and patient safety. This is largely due to the strict protocols implemented during the initial stages of these clinical investigations. Future advancements in the field of medicine are anticipated to necessitate modifications to the ethical and regulatory framework of clinical trials [57].

Pre-clinical research

The earliest stage is the discovery of the drug, in which a target molecule, pathway or potential therapy that can be used to treat a particular disease or condition is identified. Drug discovery screening assay techniques include target validation, compound screening, secondary assays, and in vivo analysis [7].

Pre-clinical research involves conducting extensive laboratory tests and studies on cells, computer data analysis, tissues, and animals before clinical trials are conducted to assess the safety and effectiveness of prospective novel medicines [63]. The most crucial objective of preclinical research is to find feasible drug molecules or therapies that have the potential to be marketed as drugs or other treatments. Evaluating the efficacy, pharmacokinetics, mechanism of action, and safety of these potential treatments is necessary. Preclinical research known as in vitro tests potential therapies on lab-grown cell cultures to see if they have the anticipated effect on target cells [15]. Locating and validating a target is the initial stage in preclinical drug discovery development. These can be ranging from receptors and enzymes to specific intracellular signaling pathway events. The next phase is the creation of an activity assay where novel drugs can be evaluated. This allows for the removal of inactive compounds [16]. 

The evaluation of treatment safety in pre-clinical research involves the utilization of toxicology and in vivo animal model studies. The process can involve the administration of the medication to non-human subjects, monitoring their reactions, and documenting any unfavorable outcomes. In vitro investigations utilizing cell lines [17], as seen in Figure 3, are also included within this scope. The study of toxicology requires an analysis of the impact of the drug on the animal’s organs and tissues. Drug candidates undergoing examination must possess specific desired characteristics, including distinct chemical and pharmacological properties [8]. Ensuring the stability and selectivity of a molecule is of paramount significance, particularly in its ability to bind with high affinity to the target binding site and exert an active impact on the target receptor molecule in vitro. In addition to evaluating the drug’s bioavailability and half-life, it is imperative to assess its pharmacokinetics, safety, and and toxicity. It is also crucial to determine if the drug exhibits any apparent toxicity in animal studies [18].

Figure 3 Pre-clinical testing involves studies both in vitro and in vivo in animal models. Once this round of animal testing has been completed, the drug is then studied in humans in clinical trials [15]. Created with BioRender.com.

The oral bioavailability of drug candidates can be predicted with the aid of a set of guidelines called Pfizer’s Rule of Five, which was proposed by Pfizer scientist Lipinski [19]. The guidelines presented are founded upon the physicochemical attributes of low molecular weight drugs that are anticipated to impact their distribution and integration within the body [20]. As per the “Rule of Five” principle, a potential drug candidate is deemed to possess favorable oral bioavailability if it fulfils the subsequent criteria: a molecular weight not exceeding 500 Daltons, a partition coefficient (log P) that does not exceed 5, a maximum of five hydrogen bond donors, and a maximum of ten hydrogen bond acceptors [21]. According to Pfizer, drug candidates failing to comply with one or more of these regulations are believed to be associated with reduced oral bioavailability [58].

Upon identification of prospective drug therapy, the next step of action requires the submission of an application to regulatory bodies to obtain clinical trial authorization (CTA). The drug regulatory agencies exhibit differences across nations, including the renowned FDA in the United States, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom, and the Therapeutic Goods Administration (TGA) in Australia [45].  The application provides a comprehensive account of the drug candidate, consisting of its chemical composition, pharmacological properties, toxicological profile, and manufacturing process [22]. The evaluation of medicines is subject to the distinct procedures of each country’s regulatory organization. For instance, in the UK, researchers have the option to assess whether their study necessitates approval from the MHRA through the work of an online algorithm. This algorithm determines whether the substance being tested qualifies as a medicinal product and whether the trial is classified as clinical. Questions posed in the algorithm refer to the substance’s medicinal properties and its pharmaceutical form, its utilization for comparative pharmacodynamics and adverse reactions, and its intended administration via human blood cells, plasma, food products, or medical devices [46]. Upon submission of the application, the regulatory agency conducts a thorough review to verify the safety of the drug before its administration in humans. In the case that the proposed treatment appears promising and receives approval from the regulatory agency, the formulation and manufacturing of the drugs will take place during this phase. The CTA gives authorization for the production of the treatment on a large scale, allowing it to be used in human clinical trials [59].

The Phases of the Clinical Trials

Clinical trials frequently consist of several phases, each with a particular aim to achieve. The significance of safety has been emphasized by the FDA. Therefore, the initial four stages of clinical trials serve to evaluate the effectiveness and appropriate dosage of the proposed medication, as well as its pharmacokinetics, pharmacodynamics, and potential drug-drug interactions [23].

Phase 0 is recognized as an investigatory trial aimed at evaluating the safety and pharmacokinetics of the drug, with a specific focus on the treatment’s half-life and bioavailability. In certain instances within the framework of clinical trials, the initial stage of Phase 0 may be excluded, and the trial may commence directly with Phase I. Phase 0 clinical trials typically include a limited cohort of around ten participants. At this stage, the dosages administered are minimal. The design of Phase 0 was initiated by regulatory bodies to minimize drug exposure during initial human trials, thereby reducing any potential risks to human subjects [24].

Phase I

Phase I clinical trials typically involve the administration of varying doses of the investigational treatment to a small cohort of healthy volunteers (ranging from 20 to 100 individuals) to assess its efficacy. Additionally, the efficacy of the medication is evaluated during this phase. These trials are not controlled. Phase I clinical trials aim to conduct a comprehensive evaluation of the drug’s safety and tolerability in both single-dose and multiple-dose settings. Furthermore, it provides a comprehensive summary of the medication’s potential safety profile and recommended dosage range [25]. The aforementioned phase is expected to be completed within approximately one year or less. In a review conducted by Muglia and DiGiovanna, the distribution of phase I clinical trials by study phase was analyzed across five European countries. The findings indicated a marked discrepancy in the number of Phase I trials carried out in comparison to Phase 0/early Phase I and Phase I/Phase 2. The UK exhibited the highest number of phase I trials, with a total of 1592. The data was sourced from ClinicalTrials.gov, in which the total count of registered clinical trials was categorized based on study phase and country. Figure 4 depicts a graphical representation of the data gathered [47].

Figure 4: The distribution of phase 1 clinical trials according to the study phase. The total number of phase 1 clinical trials registered on ClinicalTrials.gov was broken down by country and research phase, with the countries France, Germany, Italy, Spain, and the UK and the period ranging from 1 January 2012 to 31 December 2021. The p-value = 0.0192 for early phase 1 vs. phase 1; p-value = 0.0003 for early phase 1 vs. phase 1/phase 2 [47].

Phase II

Upon successful completion of Phase I clinical trials, the drug candidate proceeds to Phase II, wherein it undergoes testing on a larger cohort of patients afflicted with the specific condition or disease while maintaining stringent selection criteria, as a randomized and controlled trial. The cohort comprises individuals ranging from 100 to 300 in number, who have the same medical condition. The objective of Phase II is to evaluate the pharmacodynamics, pharmacokinetics, optimal dosage, and potential adverse drug reactions (ADRs). The efficacy of the drug in the affected population is assessed [23]. These assessments are additionally devised to establish a clinical endpoint, indicating the point at which a treatment exhibits sufficient promise for efficacy or if the intervention provides a benefit. The primary endpoint of choice in the majority of Phase II trials has been progression-free survival (PFS). PFS is characterized as the duration of time that a patient has the condition, during and after treatment, without experiencing any deterioration [48].   PFS is considered a favorable endpoint due to its shorter follow-up duration in comparison to the overall survival (OS) endpoint. While this is the case, the use of OS is also advantageous in various manners, such as in diseases with poor prognosis or lacking salvage therapies [48]. The primary endpoint in NRG/RTOG 0912 (NCT01236547) was overall survival (OS). Given that the trial investigated the integration of pazopanib into intensity-modulated radiation therapy alongside paclitaxel for anaplastic thyroid cancer, time-to-event endpoints are appropriate for assessing the potential efficacy of pazopanib treatment.  Subsequently, this current stage of clinical trials holds significant value in determining the cost of medication. It facilitates an initial evaluation of the drug’s potential and indicates the projected outcome of Phase III. [26]. At present, the medication is not believed to have any therapeutic effects, and its duration of action is estimated to be 2-3 years.

Phase III

Upon demonstrating favourable outcomes during Phase II, the drug candidate advances to Phase III, where it is subjected to further review in a more extensive and diverse patient population to validate its safety and efficacy [27]. The sample size for this study ranges from 300 to 3000 participants. This phase requires a prolonged duration of multiple years and involves the recruitment of numerous individuals exhibiting the same specific condition. This phase is also responsible for identifying any potential ADRs that may arise upon administration of the drug to a larger population over an extended duration [23]. This stage determines the therapeutic efficacy of the drug and is anticipated to have a clinical impact on the patients. This phase of the study typically spans 3-5 years.

Phase III trials encompass various trial designs, among which placebo-controlled trials are the most prevalent. This highlights the distinction between the intervention group receiving a specific treatment and the control group receiving either a placebo or conventional medical treatment.  It has been argued that acute symptoms may be exhibited by trial participants, which may eventually reduce as the trial progresses, emphasising the significance of the participants’ particular circumstances as a constituent of external validity [23]. An additional type of phase III clinical trial is the equivalency trial, which aims at assessing whether the new therapeutic intervention is comparable to its comparator, as per the investigator’s predetermined criteria, and excludes the administration of a placebo. The intervention is considered to be equivalent to the comparator, as long as the variances between the two remain within the specified criteria [49]. Phase III clinical trial designs generally incorporate various features such as randomization, stratification, and blinding strategies. These measures help in maintaining treatment allocation balance to compare treatment effectiveness and reduce subjective outcome assessment bias [23].

What about Phase 4 and longitudinal studies?

The fulfilment of the established objective by the researchers marks the declaration of a successful clinical trial. Key components of a successful clinical trial include the discovery of an identifiable difference in the data between the experimental drug and the placebo, as well as a clear demonstration of the medication’s metabolism in a specific subset of the general population. A significant difference is key as the greater degree of differentiation between the two cohorts directly correlates with the extent to which the effects of the medication can be attributed. Researchers need to have a comprehensive understanding of the medication’s tolerance among distinct subgroups of the intended population to successfully finalise a new drug application (NDA) [50].

After the successful completion of Phase III clinical trials, the drug developer may proceed to submit an NDA to regulatory agencies, including the FDA [31]. The NDA comprises a detailed description of the drug candidate, covering the results of clinical trials, manufacturing details, and proposed labelling. Upon submission of the NDA, the FDA conducts a thorough evaluation to ascertain the safety and efficacy of the drug for its intended use. Additional information or studies may be requested by the FDA before deciding [32].

Upon approval of the NDA by the FDA, the medication may be made available for commercial distribution and administration to patients. Post-marketing surveillance is a mandatory requirement for drug developers to oversee the safety and efficacy of the drug in real-world scenarios. In the event of safety concerns, the FDA reserves the right to require supplementary studies or enforce restrictions on the drug’s use. This is alternatively referred to as Phase IV [33].

The benefits of participating in clinical trials

Despite the old-age questions of potential side effects and risks, clinical trial participation may provide several advantages. Most significantly, it facilitates access to state-of-the-art and cutting-edge therapies and treatments that are not yet offered to the general public. You can gain access to novel treatments that may eventually lead to improved health outcomes by taking part in clinical trials [35]. Atezolizumab, an immunotherapy drug marketed under the brand name Tecentriq by Roche, has demonstrated successful results in clinical trials. The clinical trial IMpower010 (NCT02486718) yielded remarkable results for the drug, resulting in its approval for the treatment of metastatic non-small cell lung cancer (NSCLC). The conducted research was a randomized, multicenter, and open-label study that involved the participation of 1280 patients. Out of these, 1269 patients were administered adjuvant chemotherapy, wherein 1005 patients were randomly assigned to receive either atezolizumab or best supportive care [51]. In patients with tumors expressing PD-L1 on 1% or more of tumor cells, the drug demonstrated improved disease-free survival in comparison to the administration of best supportive care. In summary, the use of atezolizumab following adjuvant chemotherapy showed a PFS benefit. These findings suggest that atezolizumab could serve as an advantageous therapeutic route for patients with early-stage NSCLC [52]. Involvement in clinical trials from patients assists in the progress of medical research and enhances future patients’ options for therapy. Being involved in clinical trials ensures that patients receive the most pioneering medications possible. The public may have a significant role in shaping the future of healthcare, and participation can result in the development of innovative and successful therapies. Participating in clinical trials can also be empowering and give hope to many patients [37].

Clinical trials are a type of biomedical data, along with biomarkers and pharmacological analysis, which are cutting-edge approaches to analyzing “healthcare big data” and, ultimately, generating knowledge to enhance patient care [36]. Additionally, clinical trials are frequently conducted by qualified medical professionals who are committed to providing participants with the best treatment possible. As a result, individuals may receive medical care that tends to be more individualized and attentive than what they could have in a traditional healthcare setting [35]. Some clinical trials provide financial compensation to participants in exchange for their time and effort. According to a study conducted by Fisher et al, the median pay received from 1001 clinical trials completed at 73 research institutes over a period of three years was $3070 [60]. The research indicates that there is no apparent restriction on the compensation amount for healthy participants in phase I trials. However, research findings suggest that these individuals can potentially get compensation ranging from a few hundred dollars to more than $10,000, depending upon the duration of the study [61]. Compensation in the context of clinical trials is commonly understood to include various forms of remuneration, such as reimbursements for expenses related to meals, babysitting, and transportation to and from the research site [62]. It is important to note that compensation is not generally considered to constitute a benefit of participation in clinical trials. Concerns have been raised in countries that are developing regarding the potential exploitation of individuals who participate in activities solely for financial gain [62]. Compensation payments covering factors such as time, pain, and inconvenience are often difficult to measure accurately.  Examples contain long periods spent at the research facility, investigations necessitating pap smears, blood extractions, and invasive procedures, as well as assuming potential risks associated with the administration of experimental medication, even in spite of immediate personal benefits [62]. Any injuries sustained during a trial would additionally be compensated. Due to potential covert motives, this can pose ethical issues regarding its influence on clinical research [38].

Risks associated with participating in clinical trials

There are some risks associated with participating in a clinical trial. Adverse events such as side effects and ADRs, patient discomfort influencing study participants, and difficulties concerning inconvenience are among the concerns that patients may encounter. Side effects include undesired or unforeseen symptoms or sensations that arise alongside the intended therapeutic impact of a medication. These effects can vary in intensity from mild to severe and might require medical attention [70]. Instances of these side effects encompass symptoms such as nausea and vomiting, drowsiness, a dry mouth, digestive problems such as constipation or diarrhea, dizziness, and headaches [70]. ADRs, in contrast, refer to the undesired effects of a medication that go beyond its intended therapeutic effects and arise throughout the course of clinical usage. This covers both physical and psychological pain in addition to loss of function. It is a response to a medicinal product which is noxious and unintended, and outside terms of marketing authorization [64]. The classification system for ADRs, known as ABCDE, comprises augmented, bizarre, continuous, delayed, and end of use reactions [65]. As an instance, an augmented reaction is an exaggeration of the drug’s normal pharmacological actions when given at a usual therapeutic dose. It is typically dose-dependent and is identified in clinical trials. A specific example of an augmented adverse effect is respiratory depression when opioids are administered [66]. Bizarre reactions are novel responses that aren’t expected from known pharmacological actions of drug [66]. Antibiotic-induced skin rashes, characterized by unpredictability and immune-mediated mechanisms, serve as an example of this particular reaction [67]. Continuous ADRs persist for a relatively long period of time after discontinuation of the medication and are independent of the half-life of the medication. One instance of this is the occurrence of osteonecrosis of the jaw as a result of the administration of bisphosphonates or corticosteroids, which can subsequently contribute to the development of osteoporosis [68]. Delayed ADRs become apparent after some use of medication and the timing makes them more difficult to detect. An example of this leucopoenia which occurs up to 6 weeks after dose of lomustine or chemotherapy leading to infertility [69].

 Figure 5 Patient outcomes for reports in FAERS from 2006 until the first quarter of 2015. The serious causes, denoted in blue, result in one or more of the following outcomes: death, disability, a congenital defect, and hospitalization [39]. The figure is taken from FDA.gov, 2019.

The side effects of an investigational product are one of the most main risks associated with clinical trial participation that discourages individuals from participating. As clinical trials often involve the testing of novel drugs and treatments, they may have unforeseen ADRs [64]. Pharmacovigilance, simply defined as drug safety, is responsible for the prevention of these adverse events.  Figure 5 depicts an example of the severity of side-effects associated with newly approved FDA medications. This information was provided to the FDA MedWatch program known as FAERS (FDA Adverse Event Reporting System) and exhibits patient outcomes in FAERS regulations over 9 years [39].

Patients may also view the risks to their health associated with clinical trials to be detrimental. Some clinical trials involve risky procedures or interventions that may result in complications. A clinical study for a new cancer treatment, for example, may include approaches to surgery or radiation therapy [40]. While chemotherapy destroys rapidly developing cancer cells, it can also destroy or slow the growth of healthy cells [42]. Damage to these healthy cells can cause unwanted side effects and adverse reactions in clinical trials, which is another reason why determining the root cause of such effects is difficult because it is unknown whether it was a reaction to the new treatment or it was unrelated [41]. 

Patients can find it inconvenient or undesirable to undergo frequent medical procedures, take medications on a fixed schedule, or travel to the study site or clinic regularly. Participants may also experience false hope, arriving at a trial with great hopes for an improvement or even cure for their condition but leaving disappointed when the treatment is found to be ineffective [44]. Personal health information concerning patients is shared with researchers and clinicians, which may compromise privacy and confidentiality [43]. While all of these risks exist and, understandably, may cause patients discomfort or anxiety, it is always important to remember that participants will be informed of all risks and will have the opportunity to ask questions before deciding whether or not to participate in a clinical trial.

It was also found in a review of the success rates of progressing pharmaceuticals to market over the nine years leading in 2006 that merely 9.6% of drugs that entered Phase I clinical testing achieved it to the market, with 30.7% of drugs failing after Phase II and 58.1% failing in Phase III. Due to many factors that need to be addressed, there is concern about medications being withdrawn early enough in clinical studies [28].

Phase III clinical trials often result in unsuccessful outcomes due to various factors, as is standard in the course of creating novel drugs. Safety concerns, such as the occurrence of ADRs, could lead to the discontinuation of the study to safeguard the well-being of the participants [29].  Termination of clinical trials may occur due to various reasons such as the observed efficacy of the treatment, evidence of adverse effects, or the likelihood of failing to reject the null hypothesis [54]. Brivanib, a medication intended for the management of hepatocellular carcinoma, is a case of a drug that did not receive approval from the FDA owing to its ineffectiveness. As per the FDA’s report, although showing promising anti-neoplastic efficacy during phase II clinical trials, the medication was unable to improve the overall survival rates of subjects in relation to its comparator during the phase III BRISK PS (NCT00825955) study. The study findings revealed unforeseen toxicities, wherein patients administered Brivanib displayed higher cases of low appetite, hypertension, nausea, and fatigue [53].

Clinical trials are a complicated procedure that requires thorough planning to guarantee that they are set up to provide significant results, therefore there may be preliminary concerns like design flaws [29]. Furthermore, with certain trials, such as randomized clinical trials (RCT), doctors are presented with a dilemma regarding treatment as the outcomes of RCTs do not apply to that patient [30].  Other elements including monetary and time constraints, and regulatory and recruitment issues all contribute to clinical trial failure.

How to participate in a clinical trial

The first step in enrolling in a clinical trial is to identify a trial that you are eligible for. You can check with your doctor, clinician, or a patient organization about any recruiting clinical trials that you may be eligible to participate in. Alternatively, you can search clinical trial databases online. In the Useful Links section of this article, there are links to some recruiting trials as well as more information on how to participate in a trial [71].

Once you have identified a trial, you can contact the research team to learn more about it and ask any questions you may have. It is worth noting the disadvantages mentioned in the section prior, as clinical trials are a time-consuming and restricting process. Some commonly asked questions about clinical trials are listed below.

 

    • What is the purpose of the clinical trial?

    • How long is the trial scheduled to last, and how long will I have to participate? / How much of my time is required?

    • How long will it be until the study results are known?

    • Will I be compensated?

    • What are the potential side effects of my medication?

    • How can the treatments impact my physical and emotional health?

Before taking part in a trial, it is necessary to be screened for eligibility. This is done to determine whether an applicant meets the study’s inclusion and exclusion criteria. A physical exam, diagnostic testing, and a review of an individual´s medical history can all be part of the eligibility screening process. If you are eligible to participate in a trial, you must sign an informed consent form before the start of the trial. This is done to ensure that the participant has been informed fully about the study’s objective, as well as its risks [72].

Some clinical trials may operate as a randomized controlled trial, which means you will be assigned to either the treatment or control group at random. Once enrolled, you must adhere to the study procedures, which may include making regular visits to the research site, completing questionnaires, and taking medication or receiving treatment [73].

Conclusion

Clinical trials represent a pivotal stage in the drug development spectrum, serving as a means to guarantee the optimal and safest therapeutic interventions. Although the primary objective of each of the three crucial phases in clinical trials is to determine the effectiveness and pharmacokinetic properties of pharmaceutical interventions, they also offer diverse therapeutic alternatives for patients and the general population. The drug development process plays an essential role in facilitating clinical trials by supplying drug candidates that have undergone rigorous preclinical testing for both safety and efficacy, reducing the probability of adverse effects during clinical trials and enhancing the chances of success. Additionally, the drug development process assists in identifying potential biomarkers and targets that can be benefited in clinical trials and aid in designing more efficacious clinical trials. Well-designed clinical trials can significantly contribute to the effort to enhance healthcare efficacy and advance patient care.

Useful Links

CenterWatch – This website has a comprehensive database of clinical trials, as well as information about the drug development process, regulatory issues, and other clinical research-related topics. https://www.centerwatch.com/

Clinical Connection – You can search for clinical trials on this website by medical condition, location, and other parameters. https://www.clinicalconnection.com/

ClinicalTrials.gov – The National Library of Medicine has compiled a database of clinical trials that includes information on both publicly and privately funded clinical trials from all over the world. www.clinicaltrials.gov 

National Cancer Institute Clinical Trials Search – This website gives information on currently recruiting cancer trials. https://www.cancer.gov/about-cancer/treatment/clinical-trials/search

NHS.uk – The NHS website offers advice and further information on how to participate in a clinical trial. https://www.nhs.uk/conditions/clinical-trials/#:~:text=How%20do%20I%20take%20part,in%20taking%20part%20in%20research.

ResearchMatch – Based on their medical history and interests, this service matches people with clinical studies that are currently recruiting. https://www.researchmatch.org

U.S. Food and Drug Administration – The FDA is responsible for assuring the safety and efficacy of drugs and treatments.

888-463-6332

druginfo@fda.hhs.gov

www.fda.gov

It is crucial to remember that these websites are provided solely for informative purposes and should not be used in place of professional medical advice.

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