Understanding clinical trials in approval of novel medication into the health market

The first step in creating a new medication is to gain as much knowledge as you can about the illness or condition. Basic research offers hints about prospective treatment approaches for illnesses, including addressing their symptoms or underlying causes. Equipped with a concept, scientists endeavor to comprehend the biological targets for a prospective medication. A protein, RNA, DNA, or other molecule that is connected to the disease in any way can be considered a "drug target." Next, they search for a lead compound, which is a promising molecule with the potential to affect the target and eventually develop into a medication. Investigators carry out investigations on animal models, tissues, and cells to ascertain whether a medication can affect the target, also known as pre-clinical tests. The process of discovery and development, which starts with basic research and ends with the release of novel medications that can save or improve lives, begins with this. But before the release of the novel medication into the health market, the US FDA does not make a determination about the safety and efficacy of a pharmaceutical until several phases of clinical studies have been completed for a larger patient group.[1]

Clinical trials (CT) are a type of clinical research that specifically tests the safety and effectiveness of new or existing medical interventions according to a plan called as Protocol defining the type of patient who may enter the study, Schedule of test & procedure, drug involved, dosage of the drug, length of the study & what is the outcome of the study. CT involves cross functional team of scientist, doctors, nurses & volunteers/participants who must agree to the rules and terms outlined in the protocol. CT provides another option for validation of new intervention when the standard therapy has failed.[3]

BioPharma R&D's, the contract research organizations (CRO's) and regulated (FDA approved) hospitals who plan the CT should strictly follow the Good clinical practices GCP guideline, this became essential since in the past a number of high-profile clinical trials failed, resulting in serious harm to trial subjects. International GCP standards were created by the ICH and initially released in 1996. The GCP guidelines were first published and have subsequently undergone multiple revisions. ICH GCP E6 (R3), the latest recent revision, was released in 2021. Clinical trial conduct is now standardized globally using GCP. It is in use in more than 100 nations worldwide.

The GCP guidelines address many different subjects, such as:

a) The obligations and rights of sponsors, investigators, trial subjects, and other trial staff

b) The planning and execution of clinical trial design

c) The gathering, logging, and reporting of data from clinical trials

d) Clinical trial quality assurance and control

Clinical trials benefit from GCP since it helps to guarantee that:

a) Trial participants are safeguarded from danger.

b) Data from clinical trials are precise and trustworthy.

c) Results of clinical trials are shared in an equitable and open way.

According to the GCP criteria, clinical trials:

a) Trial participants must provide informed permission after being made aware of the advantages and disadvantages of taking part in the study.

b) Throughout the experiment, trial participants must have access to medical treatment.

c) Trial data must be gathered, carefully recorded, and comprehensively maintained.

d) Trial findings ought to be communicated as soon as possible.

e) Trial sponsors are required to possess the financial means to sustain the trial.

Every clinical study carried out in a nation under FDA regulation must adhere to GCP. In order to guarantee that clinical trials carried out in nations not subject to FDA regulation follow global standards, GCP compliance is equally crucial. All things considered, the GCP principles offer a framework for carrying out clinical trials in a way that is secure, moral, and rigorously adheres to science. Ensuring the validity of clinical trial data and safeguarding the rights and welfare of trial participants depend on GCP compliance.[4]

There are rules, known as eligibility criteria, governing who is eligible to participate in clinical trials. Age, sex, disease kind and stage, prior treatment history, and other medical problems are among the variables that determine the criterion. In addition, the FDA works to guarantee that participants in clinical studies represent a range of ages, races, ethnicities, and genders. This stage in the CT is crucial as it takes efforts with for the screening of the right participants for the study plan. There are several strategies to reduce the amount of time needed to screen potential clinical trial volunteers. Most important is to reducing the number of participants that are excluded from a clinical study and it can be achieved by carefully examining the eligibility criteria and making sure they are relevant and essential. Risk-based screening approach should be used for timely deemed ineligibility of participant as this may provide a more economical use of available resources. Other criteria's such as the screening process can be automated and made more effective with the use of electronic screening instruments also reducing duplication of work and increasing efficiency can be achieved by centralizing the screening process. The necessity for participants to visit to the clinical trial site for screening may be lessened with the use of remote screening techniques like phone calls and video conferences that is the base for the artificial intelligence (AI) intrusions in the CT. [2]

CT are conducted in four phases, each of which has a different purpose and helps researchers answer different questions.

Clinical trials begin with phase 1, which is the smallest and oldest stage. They are intended to evaluate a new medication's safety and tolerability in a small cohort of volunteers who are in good health. In a phase 1 experiment, typically 20–100 individuals are included. In a phase I trial, volunteers will be intensively observed by researchers for any unfavorable side effects. Additionally, they will research the drug's absorption, distribution, metabolism, and excretion (ADME). A crucial factor in phase 1 trials is the patient population chosen. Individuals who have specific medical disorders or comorbidities may be at a higher risk of experiencing unfavorable medication side effects. Phase 1 trials therefore usually comprise patients with mild to moderate illness or healthy volunteers. Other crucial factors in phase 1 trial's study design may have an impact on its results. The type of endpoints evaluated, the trial's duration, and the dose escalation strategy, for instance, might all have an impact on the data gathered. Also that the techniques employed to assess phase 1 trial outcomes are equally crucial. For instance, the trial's outcomes may differ depending on how adverse events are classified and reported. [3]

Figure above denotes the four clinical trial phases that is initiated after investigational new drug (IND) application is submitted. It also highlights the factors that possibly influence the study plan around the phase 1,2 &3 before finally submitting the new drug application (NDA) or a biological license application (BLA) to FDA for approval. Lastly it shows the Phase 4 is initiated after receiving FDA approval.

Phase 2 Trials usually involving 100–300 individuals with the ailment that the medicine is being designed to treat, phase 2 trials are larger than phase 1 trials. A phase 2 trial's objectives are to:

a) Evaluate the medication's safety and tolerability in more detail.

b) Analyze the medication's first effectiveness.

c) Determine the best dosage and administration schedule.

Phase 2 trials can offer insights into a drug's pharmacokinetic profile, which can help guide the planning of phase 3 trials. Biomarkers that can be utilized to determine which patients are more likely to respond to a specific medication or device can be found through phase 2 trials. Patients reported outcomes (PROs) are metrics used to assess how a condition or course of therapy affects a patient's quality of life. PRO data, which can be used to evaluate the patient-centered benefits of a novel medication or device, can be gathered through phase 2 trials. Overall the results of phase 2 trials are used to decide whether a drug or device should be moved forward into phase 3 trials. Phase 2 clinical trials are influenced by a number of factors such as drug characteristics, disease mortality, goals of the trial & regulatory US FDA requirements. Careful consideration of these factors is essential for designing and conducting a phase 2 trial that is successful and informative. [3]

The largest and most demanding stage of clinical trials is phase 3. Their goal is to assess the novel medication against a placebo or the accepted standard of therapy. A phase 3 trial often involves hundreds or thousands of participants.

A phase 3 trial's objectives are to:

a) Verify the medication's effectiveness.

b) Determine the drug's negative effects and long-term safety.

c) When comparing the medication to a placebo or the standard of treatment

Factors influencing the phase 3 trails are similar to the phase 2 trials along with the resources available to the trial sponsor, such as funding, staff, and facilities that can also influence the design and conduct of the trial. Hence a trial sponsor with limited resources may need to choose a phase 3 trial design that is less complex and less expensive. A medication with a unique mechanism of action may have a higher chance of success in a phase 3 trial than one with a mechanism of action comparable to that of alreadyapproved medications, according to criteria that are significant in these trials. Furthermore, an illness with a high unmet medical need is more likely to draw a sizable participant pool for a phase 3 trial, enhancing the trial's ability to identify a meaningful difference between the new medication or technology and the accepted standard of care. A new medication or gadget may need to demonstrate its superiority over the standard of care in order to be deemed successful if it is already very effective. Based on the CT data sharing facts, a long-term, large-sample trial has a higher probability of finding a slight but clinically significant difference between the new medication or gadget and the accepted standard of therapy. Most valuable is a rigorous and transparent data analysis which is essential for interpreting the results of a phase 3 trial fairly. [3]

Post-marketing surveillance trials are another name for phase 4 trials. They are carried out to track a medication's long-term safety and effectiveness in a broader patient group after the FDA has approved it. New uses for the medication may also be investigated in phase 4 trials. [3] Phase 4 trials can be carried out in a number of methods, such as:

a) Studies that gather information on patients who are using a medication or technology in a typical clinical setting are known as observational studies. E.g. COVID-19 vaccine effectiveness. [5]

b) Comparative studies: In a comparative study, a novel medication or equipment is compared against a placebo or to other medications or gadgets. E.g. A study of five centrally acting drugs on the pharmacological treatment of obesity. [6]

c) Interventional studies: In interventional studies, patients are assigned at random to receive either another treatment or the new medication or technology. E.g. interventional oncology-moving from efficacy to outcomes. [7]

In conclusion, CTs are a crucial step in the creation of new drugs or medical devices and conducting trails as per GCP guidelines & a transparent documenting of all the four phases in the CTs are important as the new medications are released into the general population, they aid in ensuring that they are secure and efficient.

References:

1. Research & Development Clinical Trials, PhRMA Updated May 2022. 31st October 2023 URL: https://phrma.org/en/policy-issues/Research-and-Development-Policy-Framework/Clinical-Trials 

2. Basics About Clinical Trials, US Food & Drug Administration content current as of 05/08/2023. 31st October 2023 URL: https://www.fda.gov/patients/clinical-trials-what-patients-needknow/basics-about-clinical-trials

3. What Are Clinical Trials and Studies? National institute of Health, Content reviewed: March 22, 2023. 31st October 2023 URL: https://www.nia.nih.gov/health/what-are-clinical-trials-and-studies

4. INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE (ICH) ICH HARMONISED GUIDELINE INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R2) Current Step 4 version dated 9 November 2016

5. Interim results from comparison of immune responses elicited by an inactivated and a vectored SARS-CoV-2 vaccine in seronegative and seropositive participants in India Mangaiarkarasi Asokan et.al. medRxiv 2023.01.03.22284082; doi: https://doi.org/10.1101/2023.01.03.22284082

6. Suplicy, H., Boguszewski, C., dos Santos, C. et al. A comparative study of five centrally acting drugs on the pharmacological treatment of obesity. Int J Obes 38, 1097–1103 (2014). https://doi.org/10.1038/ijo.2013.225

7. Franklin JM, Gebski V, Poston GJ, Sharma RA. Clinical trials of interventional oncology-moving from efficacy to outcomes. Nat Rev Clin Oncol. 2015 Feb;12(2):93-104. doi: 10.1038/nrclinonc.2014.199. Epub 2014 Dec 9. PMID: 25488395.

About the Author:

Shruti Talashi

Ms. Shruti  Talashi  boasts a dual mastery of lab research and writing. Her doctoral study outcome as M.Phil in biomedical science while studying breast cancer and an extraordinary masters degrees dissertation work on exploring role of Gal-lectin in cancer metastasis fuels her extensive research interests. She has gained few publication in journals. Bridging the science-public gap is her passion, aided by expertise in diverse techniques. From oncology to antibiotic/drugs production, she's led and managed complex projects, even clinical trials. Now, as a freelance Content Coordinator for Sinoexpo Pharmasource.com, her industry knowledge shines through valuable insights on cutting-edge topics like GMP, QbD, and biofoundry.