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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.

INTRODUCTION

In our last blog on Master protocols, we discussed the definition of master protocol, the types and advantages of using Master Protocol in clinical trials. In today’s article, we will like to present before you the parameters that are kept in consideration while designing a master protocol for oncology drugs and biologics. During the preparation of master protocols, different parameters are kept in consideration like:

  • Specific Design Considerations
  • Biomarker Development Considerations
  • Statistical Considerations
  • Safety Considerations
  • Regulatory Considerations

SPECIFIC DESIGN CONSIDERATIONS IN MASTER PROTOCOLS

  1. Use of a single common control arm

FDA recommends the use of a single control arm with the current System Organ Class (SOC) while developing a master protocol where multiple drugs are assessed in a single disease.SOC for the target population can be changed during the conduct of the trial if there is a new drug approval or scientific evidence that makes it unethical to randomize patients based on the previous SOC. During such a situation, FDA recommends the sponsor to suspend patient enrollment until the protocol, the SAP, and the protocol informed consent document are modified to include the new SOC as control.

  1. Novel combination of two or more investigational drug

While writing a master protocol, where two or more investigational drugs are involved as a combinational product, the sponsor should summarize the following.

  • Safety of the combinational product
  • Pharmacology of the combinational product
  • Preliminary efficacy data for each investigational drug
  • Rationale for the use of the drugs as a combination product
  • Evidence of any synergistic effect (if any) of the two or more investigational drugs when given in combination.

The FDA strongly recommends that the sponsor ensure that the Recommended Phase II Dose (RP2D) for each drug having antitumor activity should be identified in all cases.

  1. Studies with drugs targeting multiple Biomarkers

Early discussion of biomarker research strategies is highly encouraged by the FDA when the sponsor plans to use one or more biomarkers to guide patient preference for trials. A defined plan for the allocation of eligible patients should be present. Patient selection studies must be analytically checked with well-defined parameters for master protocols involving drugs that target multiple biomarkers.

  1. Adding and stopping treatment arms

Before beginning the trial, the sponsor should make sure that the master protocol and its corresponding SAP identify conditions that would contribute to adaptations, such as introducing a new experimental arm or arms to the study, re-estimating the sample size based on the interim analysis results, or discontinuing the experimental arm on the rules of futility.

  1. Independent Data Monitoring Committee (IDMC)

The master protocol should provide the details of the IDMC that is involved in monitoring the efficacy results and the details of Independent Safety Assessment Committee (ISAC) that is involved in monitoring the safety results. However, the IDMC can perform both the functions of safety and efficacy. For marketing an oncology drug, if the basis of marketing application involves one or more sub studies, FDA recommends the inclusion of independent radiologic review committee to perform blinded tumor-based assessments.

BIOMARKER DEVELOPMENT CONSIDERATIONS

            Master protocols assessing biomarker-defined populations should explain the rationale behind the use of that particular biomarker.The sponsor should employ in vitro diagnostic (IVD) tests that are analytically validated, establish procedures for sample acquisition, handling, and the testing and analysis plans as early as possible. The sponsor may need to submit the IVD’s analytical validation data for FDA(CDRH or CBER) to determine whether the clinical results will be interpretable.

STATISTICAL CONSIDERATIONS

If a sponsor introduces randomization into the design of an umbrella trial, the FDA advises that a standard control arm to be used where possible.Bayesian statistical method or other methods for dropping an arm, modifying sample size, or implementing other adaptive strategies can be used in preparation of master protocols. The SAP should include details on implementation of Bayesian or other methods as described in the FDA guidance for industry Adaptive Design Clinical Trials for Drugs and Biologics and the guidance on Enrichment Strategies for Clinical Trials to Support Approval of Human Drugs and Biological Products.Statistical considerations for master protocols can be strategized in four different ways:

  1. Nonrandomized, Activity-Estimating Design
  2. Randomized Designs
  3. Master Protocols Employing Adaptive/Bayesian Design
  4. Master Protocols With Biomarker-Defined Subgroups

SAFETY CONSIDERATIONS

The sponsor should implement a structured team of ISAC or an IDMC to assess the safety as well as the efficacy of all master protocols.The constitution of this committee and the definition of its responsibilities should be well defined in the IND. A sponsor should not begin a clinical trial until the master protocol has been reviewed and approved by an IRB or IEC. The FDA encourages the use of a central IRB to promote the IRB analysis of master protocols. The sponsor is required to perform a safety review of master protocols more regularly than on an annual basis and supply the investigator with the details.If the master protocol contains proposals to include pediatric patients in the study, the FDA advises that the IRB include a pediatric oncology expert in its team who has expertise with the regulatory criteria for the enrollment of pediatric patients in clinical investigations, including parental approval and consent. The informed consent document should be submitted to the IRB for review.

ADDITIONAL REGULATORY CONSIDERATIONS

Each master protocol should be submitted as a new IND to the FDA. This is done to avoid miscommunication owing to the sophistication of master protocols that may hamper patient safety.If the sponsor is conducting a clinical trial on more than one indication for oncology drugs or biologics, the IND should then be forwarded to the Office of Hematology and Oncology Products at CDER or CBER for approval.

REFERENCE

Master Protocols: Efficient Clinical Trial Design Strategies to Expedite Development of Oncology Drugs and Biologics, Guidance for Industry, Draft Guidance.U.S. Department of Health and Human Services, Food and Drug Administration, September 2018.

With many new therapeutics approved annually, the demand for biologics has seen exponential growth in the pharmaceutical market. In the bioanalytical community, the study of large molecules is now a hot topic of discussion. The snowballing importance of peptides and proteins as therapeutic agents,combined with the colossalopportunities offered by new MS-based technology, has unlocked a new world for bioanalytical scientists.

Ligand-binding assays (LBAs) such as enzyme-linked immunosorbent assays (ELISA) or UV identification of individual peptides using high performance liquid chromatography (HPLC) are the standard methods for quantification of biologic drugs.However, these methods are typically expensive, time-consuming to develop, and havelimited selectivity and antibody cross-reactivity. This results in a lack of interference specificity and high background levels that are not appropriate for fulfilling the specifications of the biopharmaceutical industry to identify different proteins and peptides with increasing sensitivity and reproducibility.

Liquid chromatography combined with tandem mass spectrometry (LC-MS-MS) has been widely used for small molecule bioanalysis in pharmaceutical laboratories since the 1980s. As like smaller molecules, LC-MS-MS also carry advantages for biologics:

  • It is not susceptible to cross-reactivity of the antibody because LC-MS-MS involves direct assessment of the analyte’s chemical properties.

 

  • It provides excellent selectivity, being able to discern and quantify extremely homologous isoforms with precision and accuracy over a large linear dynamic range, even at low levels.

 

 

  • Due to its high analytical sensitivity and selectivity, in addition to high-throughput capability, LC-MS/MS has been considered the primary technique to measure the concentrations of the first generation and second generation antipsychotics in schizophrenia patients.

Mass spectroscopy has gained increased interest for peptide and protein analysis over LBA because:

  • LBA detects molecules based on binding affinity and 3D conformational structure but they may not be able to distinguish between a protein and its metabolites.
  • In contrast with LBA, MS-based approaches have a potential and would be able to produce more precise data on unchanged peptide/protein levels, in situations where metabolism hampers reliable LBA data.
  • MS techniques usually offer absolute concentrations of medications. This can depend on the form of an assay for LBA methods, and they may provide either absolute or free concentration of drugs.

However, LC-MS-MS-based bioanalysis for large molecule drugs poses a range of new obstacles like difficulties in sample processing and extraction measures for quantification of large molecules. The reasons include:

  • The background peptides and proteins in the biological matrices compete with the biotherapeutic molecule of interest, creating interferenceproblems and impacting accuracy.
  • The lack of significant evidence during quantification arises for being unable to catch free drugs that may circulate in serum.

Recently, many LC-MS-MS technological advancements have been made that can help solve all of these concerns. In particular, the increase of ionization efficiency and ion transmission in recent triple quadrupole instruments has greatly enhanced sensitivity, allowing biologics to be detected at picogram or sub-femtogram levels.

 

Advances in technologies inside the LC-MS-MS include improved ion collision focusing, which brings more ions to the detector, as well as upgrades to the dynamic range of the detector, to increase bioanalysis sensitivity and efficiency. Recently, there has been a growing interest in integrating LBA immunoaffinity enrichment with LC-MS-MS quantification to integrate LBAs with the sensitivity and selectivity of LC-MS-MS technologies with greater precision and wider immune capture capabilities.

Automated Column-switching LC–MS/MS, Microextraction packed sorbent (MEPS)/LC-MS/MS, and Disposable Pipette extraction (DPX)/LC-MS/MS are some of the recent techniques that have been used to quantify large molecules.

Two major methods are widely used when using LC-MS/MS based technologies for the bioanalysis of large molecules:

  1. Intact analyte LC–MS(/MS) approach

This approach is predominantly used for peptides, small proteins and oligonucleotides with a molecular weight typically below 4–8 kDa.

 

  1. LC–MS/MS approach using a digestion step

This approach is more complex and mainly used for proteins or larger peptides. This approach involves a (enzymatic) digestion step in addition to the intact analyte approach, where the protein/peptide is digested into smaller peptides.

Today, it is most common to use traditional LC-MS/MS triple quadrupole instruments for quantification for both the intact and the digested analyte approaches. According to the existing standards, 4-6-15 (four out of six QC samples should be within 15% of the nominal value) is used as an approval criterion for large molecular LC-MS/MS assays. 4-6-20 approval requirements are proposed for larger intact analytes, in particular, if a hybrid LC-MS/MS approach is used. A labeled peptide for peptide analysis or either a labeled intact protein or a labeled signature peptide can be used as an Internal Standard (IS) to establish a successful LC-MS/MS method

Several guideline documents have been issued by the ICH and FDA to help standardize large molecule bioanalysis studies. These recommendations can be found on the website of the appropriate regulatory agency. While LC-MS-MS technologies have progressed to be more appropriate for biological bioanalysis, for non-experts who need to create and measure new biologics, the variety of mass spectrometry technologies and techniques, sample preparation methods, and reagents could be overwhelming.The new advances in instrumentation and software will bring substantial changes in the consistency and efficiency of bioanalysis tests, providing more accurate and compliant results with significant patient safety consequences.

REFERENCES

  1. Suma Ramagiri, Trends in Bioanalysis Using LC–MS–MS. The Column,The Column-12-07-2015,Volume 11,Issue 22.
  2. Magnus Knutsson, Ronald Schmidt & Philip Timmerman, LC–MS/MS of large molecules in a regulated bioanalyticalenvironment – which acceptance criteria to apply? Future Science, BIOANALYSIS VOL. 5, NO. 18, https://doi.org/10.4155/bio.13.193

Will BREXIT have any impact on CROs?

Introduction

The United Kingdom comprises of England, Scotland, Wales, and Northern Ireland. It is an island nation in northwestern Europe. The exit of the United Kingdom from European Union to become a ‘third country’on February 1, 2020 is termed as Brexit. The withdrawal agreement that provided a transition period of one year came to an end on December 31, 2020.Thus, the Medicines and Healthcare Products Regulatory Agency (MHRA) has been the UK’s independent authority for medicines and medical devices since January 1, 2021. The Brexit will have both direct and indirect effect on the future of UK and EU clinical trials. The impact of Brexit on pharmaceutical companies will be seen at the levels of regulatory alignment with respect to the forthcoming implementation of the EU Clinical Trial Regulation (EU CTR).As the best universities for research in the study of clinical, pre-clinical, and medicine are present in the UK with strong regulatory and IP safety structures, the United Kingdom has become globally a major centre for the pharmaceutical industry. In addition, most generic pharmaceutical companies are registered with a UK address. The departure from the EU would thus lead to hectic structural shifts, with a huge amount of time and investment on both sides.

Impact of Brexit on Outsourcing of Clinical Trial

Till now, many pharmaceutical companies based out of Europe were outsourcing their projects to contract research organizations (CROs) and contract manufacturing organizations (CMOs) based in the UK. Post Brexit, these scenarios may change. As of now, the European Commission has given its decision that the UK authorities will have partial access to Article 57 and will also have partial access to EudraVigilance database.

Because of Brexit, CROs and CMOs located in the United Kingdom are no longer members of the EU, and this will have a dramatic impact on the European portion of the clinical trials for delivery of investigational medicinal products (IMPs).The effect of clinical trials on the supply chain post Brexit will totally disrupt the new drug development process due to major negative financial and economic effects. Brexit can influence the clinical trial and drug discovery scenario that may involve access to drugs and Investigational Medicinal Products (IMPs), results, financing and the workforce of clinical trials.

For BE studies carried out in EU, the reference product can be made to a RefMP (UK Reference product) that has been granted in the Union in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC. It is important to understand for the sponsor and the CRO that bioequivalence studies conducted with a medicinal product sourced in the UK can be used by EMA if the new MA using those BE studies have been granted before January 31, 2020.

Conclusion

United Kingdom is the 2nd destination of Indian Pharmaceutical exports after USA.  Some CROs have internal Brexit Task Force comprised of talented individuals who very well know their roles and responsibilities. CROs are preparing themselves to engage and capitalize the new regulatory process in the UK and EU so as to avoid costly delays and disruptions of clinical trials. However, many questions still remain unanswered. One of the biggest issues refers to complaints regarding the shipping of materials from the UK to the EU for clinical trials. Will the volunteers involved be at any risk? Or will international boundaries lead to delay in clinical trials and difficulty in site management? Or will there be any imposition of tariffs that could lead to disinterest among pharmaceutical sponsors in the UK in carrying out clinical research? Thus, it will be interesting to see what is in store for the CROs post BREXIT. However, because the UK and the EU account for less than 15-18 percent of total Indian pharmaceutical revenues, BREXIT is expected to have a little impact on Indian pharmaceutical firms.

References

  1. The Landscape for CROs post Brexit: An Update. Accessed at

https://dwlanguages.com/2018/02/22/cros-post-brexit/

  1. Brexit Solutions, Clinigen Clinical Supplies and Management. Accessed at

https://www.clinigencsm.com/brexit-solutions

  1. Questions and answers to Stakeholders on the implementation of the Protocol on Ireland/Northern Ireland, 11 December, 2020. European Medicine Agency (EMA/520875/2020)
  2. Future of clinical trials after Brexit.Cancer Research UK, School of International Futures (SOIF).