1. SIGNIFICANCE OF PEER REVIEW OF CLINICAL STUDY PROTOCOL

Clinical Research Protocol is the single most crucial document describing the study design, objectives, methodology, scientific background of the molecule, the rationale of the study, guidelines to be followed, statistical consideration, and safety precautions for ethical conduction of the study. Hence, peer review of the protocol plays a significant role in order to capture all the necessary information considering the risk involved with the investigational medicinal products.

We have reviewed the protocol of one anticoagulant drug, Rivaroxaban, on behalf of our client during the draft stage of the protocol. Based on the relevant literature (OGD recommendation, Public Assessment Report, and articles), we found that clotting parameters (e.g. PT, APTT) are being affected by Rivaroxaban. During protocol review, we observed that clotting tests (APTT and PT) were only mentioned on the day of screening.

Hence, considering the safety of subjects, we suggested performing clotting tests on the check-in day of each period and at the time of check-out of the last period. In addition, we have also strongly suggested performing a creatinine clearance (CrCl) test, as a low level of CrCl results in an increased plasma level of Rivaroxaban leads to an increase in bleeding risk, on the day of Period 01 check-in and on the end of the study.

A peer-review process is a filter to ensure all relevant information and required procedures are captured comprehensively, and also to avoid any methodological errors, gaps in knowledge, and other improvements through constructive feedback.

We at Zenovel have extensive experience in designing the study protocol based on the molecule profile, route of administration, therapeutic indications, and the risks involved with the molecule.

Design your complex trial with Zenovel.

2. SIGNIFICANCE OF POSTURE IN PHARMACOKINETIC CLINICAL STUDY

Posture is crucial in a clinical study as it influences physiological characteristics. These characteristics interact with critical factors determining the pharmacokinetics of drugs (dissolution, absorption, distribution, metabolism, excretion). Posture affects blood flow which may substantially affect the absorption of drugs with a high first-pass metabolism. In addition, posture also has a prominent effect on gastric emptying.

One of the clients conducted a bioequivalence study for a highly variable molecule; however, the study resulted in a poor concentration profile and did not match bioequivalence criteria. To investigate the root cause, the Sponsor has appointed Zenovel. We have initiated an investigation in order to identify possible root causes in the study. During the investigation, it was identified that one of the factors was Posture Restriction, among other factors.

As per protocol, the time duration of posture restriction was only 02 hours, and blood samples were not collected at the bedside during these first two hours. As a way forward, we suggested keeping uniform sitting posture restriction for at least 04 hours, and all blood samples, till the time of posture restriction, to be collected at the bedside.

During the repeat study, we monitored the complete compliance along with posture restrictions. The study conducted with all suggested points and thorough monitoring resulted in favourable results.

In clinical pharmacokinetics studies, precise and appropriate posture is conducive to reducing inter-subject and intra-subject variability, especially for the highly variable drug. Hence, posture restrictions should be standardized to minimize the variability of all PK study factors and improve the outcome of bioequivalence studies.

3. Adverse Event Assessment

In BA-BE research, many a time investigators use subjective language to describe the symptoms of an Adverse event or a Side Effect. Frequent use of subjective judgement in the AE severity assessment as well as in the AE reporting is commonly observed.

Individual assessment is unlikely to help determine attribution for common AEs.

The assessment of an adverse event and its severity should be based on an Investigator’s clinical judgement and such Clinical Judgement should be based on standardized and consistent classifications.

Proper scientific terminology should be used to assess and report AEs.

The Common Terminology Criteria for Adverse Events (CTCAE) is one of the tools that offer a standardized language to report adverse events by assigning uniform terminology for symptoms and a grading system to assess AE severity.

CTCAE gives a set of terminology which can easily be understood. CTCAE is also useful to grade symptoms or adverse events which in a way makes it possible to quantify symptoms and analyze improvement or deterioration of symptoms.

Quantifying information not only helps in the determination of the efficacy and toxicities related to specific treatments but also in the comparison of safety profiles across different interventions and different studies.

Uniform reporting of AEs, also promotes consistency within a given grade across all AEs.

At Zenovel we are highly concerned about the safety of trial participants.

4. Significance of Centralized Cross-Participation Verification In Clinical Research

Fair subject recruitment is now more important than ever with the advent of numerous new CROs and study centres while having the same pool of volunteers. Therefore, it is required to have integrated, Centralized, robust, zero error, countrywide Human Volunteers Eligibility and Cross Participation Tracking to be followed.

It is mandatory to block those subjects who have participated in the study in order to avoid any possible chances of excessive blood loss and to complete the washout of the drug. This will make volunteers wait for a stipulated time between two such participations.

So, if the same volunteer applies at any other CRO will be tested on this platform and if his/her re-participation is not satisfying the participation criteria, he/she will be disallowed from participating.

Such a system would be a bulwark against any attempt to re-participate in the study sooner than specified due to some financial or other benefits. Frequent participation can create health hazards for the volunteers.

A severe drug cross reaction may not only be harmful to the subjects and make the relationship between drug and adverse event analysis difficult but also affect the study outcome. Thus, there should be a common platform to check the cross participation of volunteers.

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