Clinical Safety

A. Definitions of Clinical Trials:

Clinical trials (CT) are research studies performed to discover new treatments that are safer and more effective for the prevention, detection, or treatment of diseases. In this blog, I have interchangeably used clinical trials and clinical studies.

1. Phase I Trials: For the first time, a small group of people, healthy volunteers (20–80) is tested with an experimental drug or treatment to assess its safety and identify any side effects.

2. Phase II Trials: The experimental drug or treatment is given to a larger group of individuals (100–300) to verify its effectiveness and further assess its safety.

3. Phase III Trials: Large groups of participants, the general population (1,000–3,000) receive the experimental drug or treatment to confirm its efficacy, monitor side effects, compare it to standard treatments, and gather information for the safe use of the experimental drug or treatment.

4. Phase IV Trials: Post-FDA/HA approval and public availability of a drug, researchers continue to monitor its safety, collecting additional information on the drug or treatment's risks, benefits, and best use.

Various other types of definitions are expected to be known and concept understood e.g. interventional studies, observational studies, PASS (Post-authorization safety study), Randomized trials etc.

B. PV-related elements for Clinical 

 1. Design of study: 

The safety team is involved from the beginning of the study i.e. study concept or proof of concept along with other departments such as clinical, medical affairs, marketing, and regulatory. 

Which population needs exclusion based on the data available in terms of risks or data unavailable where we cannot specify or characterize the non-reversible or non-treatable risks i.e. teratogenicity, mutagenicity, etc. Which population will be included based on maximum data generation to understand the benefit-risk profile of drug with minimal patient safety concerns and a cost-effective model. The safety team is also involved in the study milestones i.e. interim report, final study report, etc.

2. Clinical study protocol safety review: Clinical study protocols are the document that will describe the title, aim, methods, monitoring of patients, guidance for investigators for conduct of trials, and primary and secondary outcomes for the study. This document needs to be reviewed by the pharmacovigilance/safety team. The sections in the protocol about the study concept in itself e.g. is this the correct population for the study outcomes, are there any restrictions due to safety reasons, which SAE will be expected. Instructions for the investigators on identification, treatment, and prevention of known SAE associated during the study conduct will be reviewed by the safety team.

 3. Informed consent form (ICF): This is a document that is signed by the clinical trial participants and describes the risks associated with being in the CT. This document is prepared by the clinical team; however, it is reviewed by the pharmacovigilance/safety team. This document is designed in a very simple form so that layperson/common man/nonscientific person should understand. Each adverse event added in the ICF should be simplified and the usage of signs and symptoms is preferred to diagnosis as patients/participants will be able to identify them easily. The safety team has to ensure the adverse events are addressed appropriately as per the current safety profile of the drug. 

4. Clinical study report submission: The interim study report and final study report are major milestones where the safety team will also review the study report in terms of the presentation of adverse events and the conclusion on the safety of the product. 

5. MA application based on study and safety involvement: 

The marketing authorization dossier requirements are complex and varied across regulatory agencies. One critical and consistent requirement is the presentation of data and its analysis with a conclusion on the positive benefit and safety of the product. The clinical data from the study has to be reviewed by safety and its analysis based on the seriousness, severity, reversibility, and treatability of the adverse events described and then categorized and characterized into risks.

6. Scientific elements 

While preparing, conducting, and concluding clinical trials there are key scientific principles that are expected from a safety team to be aware of.

1. Pregnancy prevention:

Classification of the investigational drug if it fits the profile of teratogen or genotoxic if yes, then how will the study team ensure pregnancy is prevented. The contraception methods and duration of contraception must be described. if pregnancy occurs how it will be addressed. Usually, this means termination from the study if they choose to continue it. If the product is not teratogen or genotoxic, pregnancy can be allowed and subject can still be in trials but this will depend on study indication and if benefits outweighs risk to remain in study. Regardless of pregnant subject staying or discontinuing from study, she will be follow up to document the outcome of pregnancy . 

2. Hepatic, renal and cardiac monitoring:

Pragmatic monitoring of hepatic, renal and cardiac values instead of stringent baseline values has become acceptable. As liver diseases become common due to other diseases leading to liver dysfunction, patients recruited in clinical trials have already dysfunctional liver profiles at baseline. Even for kidney function tests choosing the right lab parameter to monitor i.e. instead of low GFR, sustained lower decline in GFR is more noteworthy to monitor in patients with kidney diseases. Cardiac functions are also important to be monitored as with more and more populations having some preexisitng cardiac dysfunction, excluding them is not the best outcome. So the organ toxicity identification and treatment has to be based on a baseline that considers this preexisting medical history and dysfunction. The duration of monitoring liver, renal, or cardiac enzymes, mechanism of action of the drug, study indication, and other risk factors should be considered when the safety team reviews and includes the about identification, monitoring, and treatment of liver dysfunction. Parameters and their clinical relevance for monitoring like AST, ALT, AST: ALT ratio, Serum bilirubin, GFR, Troponin, ECG Ultrasound are chosen in a way that makes the most efficient results when it comes to early identification and treatment for patients.

 

References:

1. FDA Website

2. Stanford Clinical trials

3. Treem, W.R., Palmer, M., Lonjon-Domanec, I. et al. Consensus Guidelines: Best Practices for Detection, Assessment and Management of Suspected Acute Drug-Induced Liver Injury During Clinical Trials in Adults with Chronic Viral Hepatitis and Adults with Cirrhosis Secondary to Hepatitis B, C and Nonalcoholic Steatohepatitis. Drug Saf 44, 133–165 (2021). https://doi.org/10.1007/s40264-020-01014-2

4. International consensus definitions of clinical trial outcomes for kidney failure: 2020Adeera Levin ,Rajiv Agarwal,William G. Herrington,Charu Malik, Vlado PerkovicInternational Society of Nephrology’s 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials

 Written by:

Dr.Shraddha Bhange.

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