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Introduction

Cancer is a deadly disease leading to the death of many individuals across the globe. Biotech and Pharmaceutical researchers are carrying out extensive studies to develop drugs to treat cancer. However, the current medications used in cancer treatment have many loopholes. They are toxic, lack specificity, and have short half-lives. The difficulty in administering complex oncology molecules, along with the above hurdles, has led to side effects, noncompliance, and patient inconvenience of many current treatments for cancer. Liposomes are Nano-sized drug delivery systems that have shown to be quite effective in improving the selectivity of cancer chemotherapeutic agents.

However, clinical trial experts face many challenges when designing a Bioequivalence (BE) study for generic oncology drugs. It includes selecting the study population, selecting the individual dose for patients, selecting the required study design (cross-over vs. steady-state design), processing samples at investigator sites due to sampling uncertainty, high patient dropout rates, and stringent regulatory guidelines. A bioequivalence study is generally conducted in healthy volunteers if the drug has shown a safety profile in a healthy population and is not a narrow therapeutic index drug. However, the same is not ethically and medically acceptable in most anticancer drugs because of cytotoxicity in a healthy population. Moreover, the regulatory requirements also vary from region to region.

How to design a study for a generic oncology product on liposome injection involving cancer patients?

Study overview

Veeda Clinical research completed an open-label, randomized, two-treatment, two-period, two-sequence, single-dose, multicentric, fasting, cross-over bioequivalence study of Doxorubicin Hydrochloride Liposome Injection 2 mg/mL in ovarian cancer patients for an Indian based Sponsor Company towards submission to USFDA. The study was completed within the stipulated timeframe with meticulous project management. In both periods, the subjects received a 50mg/m2 Single dose (intravenous infusion) of  Doxorubicin Hydrochloride Liposome Injection 2 mg/mL (either test or reference product) , according to the randomization schedule created before the trial, on the first day of the chemotherapy cycle. The wash out period was at least 28 days between each consecutive dosing period. Each cycle began with the collection of serial blood samples, a total of 25 blood samples were collected with the last blood sample collected at 360.00 hours in each period. Blood samples starting from 72.00 hours till 360.00 hours were collected on an ambulatory basis in each period to determine free and liposomal encapsulated doxorubicin plasma concentrations for PK analysis.

Subjects inclusion and exclusion criteria

The study involved female patients between the age of 18-65 years who had ovarian cancer (confirmed through cytological and histopathological tests) and who were already receiving or scheduled to start therapy with the reference listed drug (RLD) or the reference standard product. The four major inclusion criteria in this study were:

  • Subjects with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Subject with Left Ventricular Ejection Fraction ≥ 50%
  • Subjects with a life expectancy of at least three months determined by checking liver, kidney, and bone marrow function.
  • Subjects who had recovered from minor (at least one week) and major (at least four weeks) surgery.

Women who were pregnant, or lactating, or planning for a family were excluded from the study. A total of 18 parameters were judged under exclusion criteria. Some of the major exclusion criteria were:

  • Impaired cardiac function with the occurrence of unstable angina/arrhythmia/ myocardial infarction/ Qtc prolongation/ coronary artery bypass graft surgery/ heart failure/ symptomatic peripheral vascular disease within the last six months
  • Known history of brain metastasis.
  • Pre-existing motor or sensory neurotoxicity of a severity ≥ grade 2 according to NCI criteria
  • Positive test result for hepatitis and HIV

Reporting and handling of adverse events

The investigators reported six serious adverse events (SAE) during the entire study. Fever with diarrhea was reported in two subjects. Another two subjects were observed with Nausea, Vomiting, and weakness. Fever due to hospitalization and Non-neutropenic fever with acute gastroenteritis were also found in one subject each. At the time of writing this article, all SAEs have been resolved after constant follow-up with the patient.

During the study, hypersensitivity reaction due to Doxorubicin Hydrochloride Liposome Injection was avoided by administering Prophylactic Antiemetic and Dexamethasone Injection 8mg.

Conclusion

The study was successful as the test product showed bioequivalence with the reference product. The pharmacokinetic parameters like Cmax, AUC0-t, and AUC0-∞ were within the range of 80.00 to 125.00%. Veeda Clinical research provided end to end services in identifying and selecting the clinical trial sites, prepare and submit regulatory documents like protocol, ICF, CRF, and Clinical Study Report to drug regulatory authority on behalf of the sponsor company. Trained and experienced nurses and investigators regularly monitored the oncology patients who participated in the study. The study was completed successfully with less patient dropouts, abiding by the principles of Good Clinical Practice. Finally, the product was approved by USFDA. Experienced personnel including Principal and Clinical investigators team at different sites, the project management team, CRAs, phlebotomists, nurses, medical writing team, and the bioanalytical team of Veeda Clinical Research is responsible for successfully completing this clinical trial.

Hi, I am Mansi Shah, a clinical research nurse with over 9 years of experience. I started my practice in 2013 at Sterling Hospital after completing my GNM nursing course. I have been working with Veeda since 2015. As a clinical research associate, my day mainly constitutes of assisting in research activities and ensuring volunteer safety, protection, and that volunteers are well supported throughout the research study

Even though every research is unique and every day is varied, I’m a seasoned Senior Research Associate and my duty is to be right alongside the research participants in the journey, from the day of admission to their dosing and till the time they get discharged. However, the most important task of a clinical research nurse involves determining consent of suitable volunteers, who consent to proceed with the study. I have to ensure that the volunteer understands what the research seeks to accomplish and the protocols associated with it. After educating the volunteers, I have to check her/his eligibility through OVIS and double-check it through routine screenings like blood and urine tests.

A usual day starts with a doctor assigning me my duty as per the study slots. I go to my designated location and mind the volunteers and check their vitals. I hope and work to minimize the risk of adverse events during the research, but the risk is always there. Identifying adverse events at the earliest possible time requires disciplined training and an in-depth understanding, thereby minimizing risk to research participants. With the nature of conducting novel research, the risk of adverse events is always there and the way we counteract it by having ICU wards with doctors and nurses on standby so that we can treat any complication with haste. Volunteer Safety is of the utmost importance to me and to Veeda and we take all the necessary measures, in terms of personnel skills and our infrastructure, to ensure the same. 

Besides taking care of research participants, documenting and recording information during clinical trials is the most important responsibility that a research nurse has. And we at Veeda ensure the Quality and reproducibility of data by taking meticulous approach and following highest level of integrity.

I am extremely passionate about my job as, I feel, I am a part of something that is larger than us & larger than my role. I wanted to be a part of it, as I get to be a part of the research that aims to test an experimental practice onto willing volunteers and see it becoming a part of standard practice, therefore, saving many lives to come in the future. 

A day in the life of a CRA

Hi, I am Gangichatti Laxman Kumar & I work as Clinical Research Associate with Veeda and this is how a day in my life looks like

Although I’m based out of Hyderabad, I might be visiting a site that’s in a completely different part of the country by the time you’ll read it. This blog is supposed to walk you through a typical day in the life of a CRA.

A Clinical Research Associate plays a crucial role within the pharmaceutical businesses. A CRA is responsible for pre study qualification visits, reviewing the study progress, checking the quality & accuracy of data collection, compliance of patients to trial visits, and will ensure good clinical practices are maintained throughout the trial

After successfully completing Pharma-D, I started working as a Safety Associate to the regulatory bodies, after that I switched to clinical research operations and started working as a CRA in Oncology, NeurologyEndocrinology, Cardiology and General Medicine. I have also worked in the department of BA/BE trials where I experienced a multi-functioning team and finally moved to Veeda Clinical Research where I got the opportunity to work in BA/BE studies as well as Late Phase Trials in the field of Oncology.

Being a CRA, I have to spend a significant amount of time traveling to and fro to all the research sites that I have been assigned with which are spread throughout the country, I visit 4 to 5 sites in a day.The very fact that I have to be constantly on the move, which happens to be a part of my job, adds a travel aspect into the mix that always remains fresh.

I believe Social interaction plays an important role in learning and with this role I get to interact with a lot of people,from site coordinators to doctors to project managers, which has proven to be quite effective in my cognitive learning.

My standard operating day comprises of monitoring and supervising data files as a part of source data verification process to ensure that the site is entering data accurately and in a timely manner.The safety of a patient is of the utmost importance at Veeda and I, along with my staff, regularly assess patient notes to ensure safe undertaking of procedures as per the protocol.

Every role comes with its own set of challenges and the role of a CRA is no different. Veeda offers workplace flexibility, which helps me deal with challenges calmly & efficiently. Being a CRA, I practice a fast-paced lifestyle but for me, the sense of accomplishment I get from tackling all those challenges is what makes me choose this line of profession every time.