Learn what is A clinical trial protocol, why it’s important, what the protocol should include, and how to conduct a clinical trial with a CRO This article will address the following topics:
Clinical trials must strictly adhere to detailed protocols, which dictate every aspect of a trial. The clinical trial protocol documents the objectives, study design, methodology, statistical analyses, and general organization of a planned trial. It’s a critical document that helps to ensure that all data collected is robust, and also that the safety of trial participants is guaranteed.
What is a clinical trial protocol?
A clinical trial protocol is a written document that forms the backbone of the clinical trial. The protocol is finalized before any clinical trial activities commence, and must be observed and adhered to throughout the trial. A clinical trial protocol provides answers to many of the critical questions that come with a clinical trial, including:
● Why is the clinical trial being conducted?
● What are the questions that will be examined?
● How will the clinical questions be measured?
● Who can participate in the trial?
● What are the procedures that will be done during the trial?
The clinical trial provides details for physicians, study coordinators, and other staff regarding how to execute the trial. It also describes timelines for the trial, as well as ensuring data integrity and patient safety.
Before the trial commences, the protocol must be submitted for review by an ethics committee and be granted formal approval.
Why is a clinical trial protocol important?
A clinical trial simply can’t be completed without a clinical trial protocol. The protocol essentially acts as a set of quality control guidelines, put in place to protect both the participants in the trial and the integrity of data collected throughout the trial, and to ensure uniformity in the execution across all participating sites.
Specifically, a clinical trial protocol is important because:
● It ensures the safety and health of all participants in the clinical trial
● It details a strict and accurate study plan that all physicians, study investigators, coordinators, and trial staff must follow accordingly
● It ensures consistency in data collection and integrity, meaning that data from multiple different study sites can be compared or compiled
● Approval from ethics committees for the conduct of clinical trial cannot be granted without a robust clinical trial protocol
As you can see, the clinical trial protocol is crucial to the success of the trial itself.
What should a protocol for clinical trials include?
A clinical trial protocol needs to include all the information required to carry out the trial. More specifically, the protocol follows good clinical practice (GCP) guidelines or the closely related ISO 14155 guidelines for clinical trials of medical devices. GCP is an international ethical and scientific quality standard, which dictates how clinical trials should be conducted, and the roles of investigators, review boards, sponsors, monitors, and other stakeholders.
So, now that we know what a clinical trial protocol is, here is an overview of what needs to be included in a clinical trial protocol:
Purpose of the clinical trial
The clinical trial protocol must provide enough background information and rationale to outline the purpose of the trial, and justify why the trial is being conducted. The purpose of the trial will likely depend on the phase of the trial; earlier phase trials are usually to collect safety data, while later phase trials are to examine efficacy.
Trial outcomes and measures
The clinical trial protocol also needs to outline the measures that will define whether or not the trial is deemed successful. The protocol must detail measures that assess the safety and, if relevant, efficacy. Typically, a trial has one or two primary objectives and a few secondary or exploratory objectives.
Study participant criteria
Any given clinical trial has a strict set of guidelines relating to who can and cannot participate in the trial. These inclusion and exclusion criteria depend (among other things) on the disease being studied and the treatment being evaluated. For example, participants in a trial drug efficacy trial will likely need to have the condition or disease that the drug is being evaluated for. Exclusion criteria that could prevent a patient from participating in a trial may include age, medical history, or other medications that the patient is currently taking.
Study design and details
Other elements that need to be included in a protocol for a clinical trial include:
● The length of the trial and the number of participants needed
● The schedule relating to the frequency and duration of clinical visits for participants
● Suitable control measures, and whether or not some participants will be issued a placebo
To summarize, a clinical trial protocol must satisfy GCP guidelines, therefore ensuring both the integrity of the trial and the safety and well-being of trial participants.
Conducting a clinical trial with a CRO
As shown above, a clinical trial protocol needs to be extremely thorough and provide all necessary information to satisfy GCP guidelines and ethical considerations. If a clinical trial protocol is incomplete or insufficient, the trial will likely not receive ethics approval, and therefore cannot proceed. In addition, the trial objective must be carefully considered for the trial to meet the target and succeed.
Given that the clinical trial protocol is such a critical component of the trial itself, and essentially dictates how the trial will proceed, it is often necessary to enlist the services of a professional clinical research organization (CRO). A CRO works closely with the study sponsor to ensure that the clinical trial protocol contains all the necessary details for the trial to be approved.
CROs offer medical writers, clinical experts, and regulatory specialists that can assist in the clinical design and protocol development of your trial.
Clinical trials with Gsap
Gsap is a full-service CRO with years of experience in the design and execution of clinical trials. Gsap offers a team of professionals that can work with you to develop the clinical trial protocol, along with providing any other support your trial needs.
A boutique CRO providing personalized support
As a boutique CRO, Gsap ensures that you have more than an organization to develop your clinical trial protocol and manage your trial – you have a partner to assist you every step of the way.
Gsap has helped many clients create clinical trial protocols and manage the transition from pre-clinical development to clinical studies. The Gsap holistic approach to CRO services helps to ensure the success of your own clinical trial.
Contact Gsap today to discuss your upcoming clinical trial.
This article was prepared by:
Matti Hoggeg, M.Sc.
Clinical Section Manager
For more information about our CRO services visit:
In this article, we will discuss clinical trial monitoring in great detail, including what it is, what processes are involved, and why it is essential for the success of any clinical trial.
Clinical trial monitoring refers to the process of overseeing the progression of a clinical trial. Monitoring in clinical trials involves supervising consent documentation, protocol compliance and adherence, data collection and review, safety data collection and reporting, and much more.
The Importance of Clinical Trial Monitoring
The importance of clinical trial monitoring cannot be overstated. Rigorous monitoring is essential for several reasons, including: To ensure that human subjects are treated ethically and their well-being is protected
● To ensure that all data collection is consistent and accurate, particularly across multiple trial sites
● To ensure that all reported data is complete, accurate, and verifiable, with source documentation
● To ensure that the trial is carried out according to the outlined and approved study protocols and SOPs
Clinical trial monitoring is critical to ensure that accurate, reliable data is collected in an ethical manner throughout the trial process.
The Purpose of Clinical Trial Monitoring
The primary purpose of clinical trial monitoring is to scrutinize and verify the quality of the trial at every stage. Monitoring ensures that a trial is conducted according to the study protocol, with all necessary recording and reporting following the relevant standard operating procedures (SOPs), as well as regulatory requirements and Good Clinical Practices (GCPs).
The Three Types of Clinical Trial Monitoring
Clinical trial monitoring falls into three broad categories.
These include:
On-site
On-site clinical trial monitoring requires in-person assessment, carried out by clinical staff or sponsor personnel, at the trial site. On-site monitoring is the traditional form of clinical trial monitoring and was the most common form of clinical trial monitoring prior to the COVID-19 pandemic.
Remote
Remote monitoring in clinical trials has become more accepted in recent years. Unlike on-site monitoring, monitors do not visit trial sites during remote monitoring in clinical trials. Instead, data review and transfer are done using secure, specially-designed digital platforms.
Centralized
Centralized monitoring in clinical trials is the most appropriate option when there are multiple trial sites. Centralized monitoring arose due to the publication of guidelines relating to risk-based monitoring (RBM), and involves the collation of data from all trial sites to a central location for real-time evaluation.
The Services of Clinical Trial Monitoring
As mentioned, monitoring clinical trial processes involves a diverse number of services. These are some of the key elements of clinical trial monitoring:
Protocol compliance and protocol deviations
Strict adherence to study protocols and SOPs is essential in any clinical trial. The study protocol is written, reviewed, and approved prior to the commencement of the study, and any changes to the protocol, or deviations from the protocol, need to be appropriately documented throughout the trial.
Data collection and missing data
Another clinical trial monitoring service is the oversight of data collection. Clinical trial data must be accurate, complete, and verifiable from source documentation. It’s the role of a clinical trial monitor to ensure that this is the case. In addition, the collection of participant data needs to be performed according to the relevant data protection and privacy laws/guidelines.
ICF and Consent Process Review
Informed consent forms (ICFs) are a critical component of patient enrolment. Part of the process of clinical trial monitoring is to oversee patient enrolment and ensure that informed consent from each subject is appropriately obtained and documented.
Source data review (SDR) vs source data verification (SDV)
SDR and SDV are important elements of risk-based quality management. SDV refers to the process of confirming that reported analytical data accurately reflects the source data collected at the trial site, primarily on the case report form (CRF).
On the other hand, SDR refers to the review of source documents as they related to the clinical trial protocol. Compared to SDV, SDR involves a more strategic approach that focuses intently on the quality of data collection and compliance with regard to the study protocol.
IP/device compliance
An investigational product (IP) is a drug or biological product being used in a clinical trial, while an investigational medical device is typically a physical object (such as a pacemaker). Regardless of whether a trial is assessing a product or a device, compliance is integral to the trial’s success. A clinical trial monitor is responsible for ensuring compliance when it comes to how the investigational product or device is used in relation to the study protocol.
Safety data collection, review, and reporting
Safety data is one of the most important pieces of information gleaned from the study. Many trials are conducted solely to determine the safety of a potential new drug or device. During the study conduct safety data is collected and reviewed on an ongoing basis in order to ensure subject safety and safe flow of information.
Documentation review and collection
Clinical trial monitoring also involves the collection and review of the numerous documents associated with clinical trials. This process may include a review of CRFs, ICFs, and other source documentation such as hospital records and laboratory notes, and the collection of essential documents required to be part of the Trial Master File (TMF), which is the main repository of trial documentation. A critical component of document review is ensuring that all documentation is complete, legible, accurate, version controlled, and contemporaneous.
Equipment, ancillary supply, and logistics
All equipment being used in a clinical trial such as thermometers, centrifuges, etc. must be appropriately calibrated and validated, with associated documentation such as SOPs, logbooks, and training forms. Clinical trials also require a large number of ancillary supplies such as diagnostic and testing materials, and more. All equipment and materials used in or associated with clinical trials must be GCP grade, stored, and used appropriately. Coordinating this is a critical part of clinical trial monitoring.
Clinical Trial Monitoring with Gsap
Without adequate clinical trial monitoring, significant time and money may be wasted on a trial that does not meet the necessary quality standards for successful submission or review. An experienced and trusted contract research organization (CRO) can ensure that all elements of your trial run smoothly.
Gsap is a boutique CRO with vast experience across a wide range of clinical trial therapeutic areas and phases including cell therapy, gene therapy, cannabis, MD, and DH. Contact Gsap to discuss your upcoming clinical trial.
This article was prepared by:
Matti Hoggeg, M.Sc.
Clinical Section Manager
For more information about our CRO services visit:
Just like any project, a clinical trial requires stringent management and control of everything from budgets to timelines and collaborators. Clinical trial project management involves thorough oversight of the clinical study, beginning before the planning phase commences, and continuing through the data analysis and submission period.
Simply put, clinical trial project management describes the steps and processes that an organization puts in place to ensure that a trial is carried out at the highest standard. Clinical trial project management is typically carried out by a clinical research organization (CRO).
A big component of clinical research project management is ensuring the overall quality of a study; that the resulting data is reliable and robust, and that risk management and patient safety are prioritized throughout the trial. Another aspect of clinical research project management is the time management of the study, ensuring that the trial is completed according to the relevant timelines and deadlines.
The Importance of Project Management for a Clinical Trial
Without proper project management, the quality of the data generated from a clinical trial and the progression of the trial itself may not be up to the necessary standard to reach regulatory approval. With so many critical components, like managing partnerships with third-party vendors and suppliers, adhering to timelines, training all necessary staff, controlling all relevant documents, and much more, clinical trial management is essential to the completion of a successful and high-quality clinical trial.
What are the Roles of a Clinical Trial Project Manager?
A clinical trial project manager is a multi-faceted role with many different responsibilities. Some of the primary roles of a trial manager include:
Overall overview and responsibility of study conduct
While various individuals are responsible for specific aspects of a trial, like clinical data collection, quality assurance, site activation, and so on, the clinical trial project manager plays a broader role in the oversight of each of these elements. A crucial component of clinical trial management is coordinating with all specialists and individuals involved in the study to ensure a successful clinical trial.
Study planning and set up
A clinical trial begins long before the first patient sample is collected. Significant study planning and coordination must first be carried out, and extensive document preparation (including study protocols, SOPs, ICFs, and more) is undertaken prior to the commencement of the trial. Study planning plays a large role in clinical trial project management, and it is critical to work with a clinical trial manager who is able to understand the needs and objectives of the trial, in order to ensure timely progression and compliance of the study. Comprehensive planning for the study start will pay off during the study conduct and save time and budget.
Vendors selection
In a majority of cases, a clinical trial can not be executed by a single study team. Third-party vendors are often included in clinical trials to offer expertise regarding specific technologies or specialized clinical procedures associated with patient sample collection. Typically, there are multiple qualified vendors to choose from. Selecting and vetting the most appropriate vendor(s) is another role that falls under clinical research project management.
Milestones follow up
During the planning phase of a clinical trial, milestones should be established to outline various steps and stages throughout the trial. Milestones may include protocol finalization, regulatory and ethics submission deadlines, study site activation, first subject in/out, last subject in/out, completion of data review and statistical analysis, and site closeouts. The clinical trial project manager is responsible for following up on each milestone as the trial progresses, to ensure that all deadlines are met and the study progresses according to the initial study plan.
Communication and escalation
Effective communication is an essential skill that is required by all clinical trial project managers. Communication with stakeholders, within study teams, between sites, with third-party vendors, qualified personnel, and also to regulators and auditors is critical to the progression and success of the clinical trial. The project manager must also understand when to escalate any issues to the appropriate personnel. The clinical project manager is responsible for internal and external communication as well as action items follow-up, milestones etc. The Communication processes enable the Sponsor and stakeholder to be on the same page and progress the project vectors to the needed direction at each time point.
Collaboration with all parties and vendors
As well as initially selecting vendors, the project manager must maintain a collaborative relationship with vendors throughout the study. Successful clinical project management involves close communication and cooperation with all vendors and third-party players. When it comes time to submit final regulatory documentation, the project manager must coordinate with all stakeholders and vendors to ensure the appropriate materials and documents are obtained and submitted.
Timeline and budget oversight
Clinical trials are inherently expensive, and poor project management can lead to study delays, which further increase the costs associated with the trial. Clinical research project management is primarily focused on adhering to timelines and budgets, with the overarching goal being to ensure that the trial is completed according to schedule, and within the outlined budgets.
Study team management, interphases, guidance, and training
Coordinating, guiding, and managing the study team (including clinical research associates, statisticians, QA personnel, medical advisors, and site staff) is another key role of the project manager. Ensuring that appropriate personnel is fully trained according to study protocols and SOPs (and that training is comprehensively documented) is essential in clinical project management.
Project Management Plans
The project manager is responsible to ensure that each component of the study has a plan in place which is comprehensive, study-specific, current throughout the study, and updated as needed in order to cover all study aspects. The plans include a Clinical management plan (CMP) that outlines the scope and study-specific procedures, a Quality plan that ensures QC and QA procedures will be performed throughout the trial, a Data management plan (DMP) which outlines the plan for the collection and management of clinical data throughout the duration of the trial and more as needed.
Risk management
Assessing and managing risks is a significant element of clinical trial management. Risks might include IRB approval delays, issues with patient recruitment, unexpected staff turnover, unplanned protocol changes, etc. The role of the clinical project manager is to assess the probability of a given risk occurring, the impact that it would potentially have on the trial, and, of course, how to mitigate each outlined risk.
Clinical Research Project Management with Gsap
Gsap is a boutique CRO with vast experience managing a diverse range of clinical trials, including in the pharma, Medical Device, Digital Health, Diagnostics, cannabis, and gene/cell therapy fields. Gsap’s vastly experienced team can manage your project in close collaboration and partnership with all relevant parties and vendors, with respect to timelines, milestones, training materials, sites support, in-house monitoring, open action follow-up, eTMF, CMP, and internal SOPs. This approach ensures a high level of project management and quality of study conduct, leading to the success of your trial. To learn more about Gsap’s clinical trial project management services, contact Gsap here.
This article was prepared by:
Matti Hoggeg, M.Sc.
Clinical Section Manager
For more information about our CRO services visit:
Clinical trials require extensive experience, planning, and execution. With major investments, both in terms of finances and time, it’s crucial to ensure that every step is executed according to plan, from initial protocol development to data analysis. With Gsap, you can be sure that your trial will be carried out to the highest standard, and in compliance with all relevant regulatory requirements.
What are Clinical Trial Services?
Clinical trial services is a broad term that can pertain to any number of outsources services provided during the clinical trial process. Clinical trial services can include everything from the initial protocol development and study planning, to trial execution and data management, and the final data analysis and reporting.
The highly regulated nature of clinical trials, and the necessity to justify every decision made throughout the process, means that outsourcing clinical trial services can bring major benefits. A CRO (clinical research organization) can manage every aspect of the trial process and has the necessary network of suitable sites, professionals, and infrastructure.
Clinical trials are essential for the advancement of safe, effective treatments across all fields of medicine. Whenever a new treatment is developed, such as a drug, vaccine, or medical device, clinical trials must be performed to first assess safety, then efficacy. Drug dosing, contraindications, and additional crucial data can also be gleaned from clinical trials.
While in vitro and animal studies can play crucial roles in early-stage medical research, such as the identification of potential new therapeutic drug compounds, there is simply no substitution for clinical trials. Trials in human subjects, under strictly regulated and controlled conditions, are essential in the evaluation of a new drug, treatment, or medical device.
The Value of End-to-End Clinical Trial Services
End-to-end clinical trial services, or full-service clinical trial management, involves utilizing the expertise of a CRO for the entire clinical trial process. This brings invaluable consistency to your clinical trial, saves significant time in document preparation, and ensures you can work with a trusted partner who understands your goals and priorities.
Common Types of Clinical Trial Services
There are many elements of a clinical trial, all of which must come together to produce the final product. The main types of clinical trial services include:
Clinical trial design and planning
Trial design and planning is arguably the most important element of a successful clinical trial. By enlisting a CRO to assist with establishing the framework for your trial, you bring invaluable expertise from professionals who understand the objectives of your trial and can ensure your study timelines are adhered to.
In the planning and design phase alone, you can save significant time by utilizing a CRO to provide clinical trial services. A CRO can use its extensive network to coordinate everything from study timelines to site selection, ensuring your trial is set up for success from the very beginning.
Clinical trial regulatory services
The regulatory element is a key component of clinical trial services. Thorough documentation, before, during, and after the trial, is essential. Clinical trial regulatory services typically include the preparation of study protocols, which dictate every step of the clinical trial process and include the objectives.
Other necessary documentation that is usually covered in clinical trial regulatory services includes the investigator’s brochure (IB), and informed consent forms (ICFs), which provide a thorough analysis of the potential risks and benefits of clinical trial participation.
A CRO can aid in the management of multiple regulatory submissions, as well as preparing all documentation for ethics committees and other regulatory bodies, such as government agencies (MOH, FDA, etc). Outsourcing such regulatory tasks to CRO specialists results in faster trial start-up and follow-through times, which in turn can lead to significant financial savings.
Medical writings
Clinical trial study reports and associated documentation is a major component of the clinical trial process. Furthermore, there are highly specific guidelines relating to how all documentation must be written and submitted. A CRO that offers specialized medical writing services can save you significant time, and also reduces the risk of delays resulting from missing or incorrect documentation.
Clinical trial management
Overseeing a clinical trial, both in terms of the day-to-day processes and adherence to all protocols and SOPs, and the broader study progression relative to the required timelines is a monumental task. Trial management is a key clinical trial service provided by CROs, and involves everything from site selection to qualification of the study team. Budget oversight is also a critical component of clinical trial management.
Clinical trial data management
Data management for a clinical trial begins long before the trial itself. Planning what data will be collected, at which time points, and how it will be collected, stored, and interpreted, is an essential part of the clinical operation. Data management is a key clinical trial service offered by CROs, and gives you the peace of mind that all trial data is collected in line with both the clinical protocol and relevant regulatory guidelines.
Clinical trial monitoring
Clinical trial monitoring involves rigorous oversight of the study, including documentation, data collection, addressing protocol deviations, oversight of the study team, on site and remote visits, staff training, and more. Enlisting a CRO for clinical trial monitoring services helps to alleviate logistical challenges, keep trial timelines on track, and helps to ensure a smooth path to data cleaning.
Quality assurance (QA)
Another critical element of a clinical trial is quality assurance (QA). QA is responsible for the thorough, unbiased examination of all trial-related documentation. This includes the analysis of SOPs, plans, and protocols prior to the commencement of the trial, as well as all batch records and data collected during the trial.
A rigorous and experienced QA team is essential to ensure that the data collected in a clinical trial, and the manner in which it is collected, meet the necessarily stringent regulatory guidelines.
Clinical Trial Services with Gsap
Gsap is a boutique CRO that offers a wide range of clinical trial services, delivered to the highest standard. With hundreds of satisfied clients ranging from small-scale startups to large international companies, Gsap specializes in trial management across different disciplines, including MD, DH, medical cannabis research, as well as cell and gene therapy.
For end-to-end clinical trial services that can help ensure the success of your trial, contact Gsap.
This article was prepared by:
Matti Hoggeg, M.Sc.
Clinical Section Manager
For more information about our CRO services visit:
Do you work with software that manages important or even crucial processes in your organization? Are you sure that the results these programs deliver are correct and consistent?
Validation of computerized systems is required for all GXP processes. It is also a useful tool for other fields to make sure the software works well and your information is safe.
What is the conventional risk-based approach to computerized system validation?
The GAMP5 is currently the most widely used industry guidance. It advises businesses to concentrate on critical aspects of their computerized systems and use them to develop controls to reduce the risk of system failure. This is where a thorough understanding of the product and process is critical in determining the potential risks to individual safety.
Essentially, the guidance focuses on understanding the system and the process in which it is involved, allowing us to identify the critical functions that impact patient safety, product quality, and data integrity. They are commonly referred to as GxP-relevant functions. Following the implementation and verification of relevant appropriate controls to address the risks, we either redesign the system to eliminate the issues or verify the functionality to demonstrate that the risks can be managed at an acceptable level through execution IQ, OQ, and PQ testing.
What additional risks and regulations can be addressed?
A computerized system frequently plays such a critical business role that we would like it to be verified not only within GxP-relevant processes but also within other realms of critical business processes.
Specific functionality may, for example, generate a financial report to be submitted to public agencies, provide data to a Financial Consolidation System, or support other financial activities that are not necessarily regulated by the relevant regulation (SOX).
Alternatively, specific functionality is used to create, manage, or host personal information about individuals (GDPR), or to manage legal or contract data or transactions.
A system function can be critical for the business in general, like impacting the operations in a way that may lead to stopping the production, shipping, or invoicing process or even lead to legal issues.
How to approach it?
In such cases, to reduce the overall effort for commissioning the system, we will evaluate the criticality of the requirement in a manner similar to GxP evaluation, and if the function is critical for a specific business process, we will manage it as if it were a GxP critical function.
Figure 1: GAMP5 A Risk-Based Approach to Compliant GxP Computerized Systems, Appendix M3
According to GAMP5, before evaluating the Risk Class, we must first determine the Severity, which is defined as “Impact on Patient Safety, Product Quality, and Data Integrity.” If you’re implementing a system in your organization that manages other critical processes (especially ERP systems), you might want to broaden the definition of “Severity” to include additional questions, which will result in a system with reliable performance with the critical parts defined by the business.
If your company relies on systems whose failure could halt critical processes, alter the final product, or incur enormous costs, you should take extra precautions to ensure the system consistently produces the desired results and that there is objective evidence to support this claim.
The risk-based validation paradigm widely used within Pharma and Medical Device environments can be simply adapted for use in other fields.
This article was prepared by:
Vitaly Shlimovich
Engineering & validation project manager
For more information about our Validation services visit:
Creating a medical device requires you to concentrate on the process of documenting and prototyping phases. In highly regulated areas such as healthcare, a quality management system (QMS) is crucial to the development of a new product.
The question is what is the minimum QMS for the design and development stage? To answer this question, we recommend considering the following:
A medical device should be safe and effective to reduce product recalls and revisions, demonstrate compliance with all relevant regulatory standards, and be commercialized quickly.
General recommendations for QMS needed at the development stage for medical device products:
● Documentation should demonstrate consistency, reproducibility, and repeatability. Furthermore, documentation should communicate what to do, when to do it, and how to do it effectively.
●You should ‘right-size’ your QMS as you build it. In other words, the size of the QMS should reflect the size of your organization. By ‘right-sizing’ your QMS, you ensure that you build the quality procedures you need at the right time. The needs of a 5-employee company differ from one of 50 employees and from 500 employees.
●You need to make sure you consider the product realization and the lifecycle of the device. Identify all the documents that you will be required to generate as part of these processes.
●Be sure to determine who is the owner of each document, for how long it must be kept, and where it will be stored before you begin documenting anything.
●Consider the availability of documentation and an effective and efficient way of managing the documentation. Medical device companies are strong when they manage their documentation well.
We recommend using an Electronic Quality Management System (eQMS). If you choose eQMS, you need to define your documentation and record control with your eQMS.
●Developing and updating your document management strategy takes a different approach as your company becomes more established. It is advisable to break down your document management system into phases and plan each phase carefully.
The Bare minimum required QMS documents:
(1) Regulatory Strategy Document
The regulatory strategy includes product description, product intended use and indication for use, product classification, regulatory pathway per relevant markets, applicable product verification and validation tests, list of applicable standards and guidance
(2) Design and Development Control Procedure
The design and development control procedure describes the method for initiating, controlling, and documenting product design processes.
It is recommended that the procedure address the following processes:
●Processes for defining the user needs, product value proposition, and VOCs (Voice of Customer),
●Processes for defining product specification (design inputs),
●Risk Management processes in accordance with ISO 14971:2019 including failure mode analysis
●Guidelines for defining Sample size and rationale for design validation and process validation processes,
●Processes for design verification and design validation
Purchasing control procedure includes processes to facilitate supplier management, guidelines to oversee the purchase of materials, components, products, or services according to quality standards, and conformance to all specified requirements. These shall include receiving inspection processes and control of purchasing records.
(4) Document and Record Control
This is one of the most important procedures for the design and development phase. Many manufacturers are not aware of how critical it is to document the design at the very early stages of design and development. This includes a methodology for numbering and traceability of all documentation and records that are created from the very beginning of the design and development (such as design inputs, design outputs, test protocols, any test results, reports, design reviews, and any changes to the design, risk management file).
Document and record control procedure means defining a formal document control process from numbering documents and records to adding/maintaining/changing/removing documents and records.
(5) Engineering Change Orders (ECOs)
ECO is an important tool that ensures that changes that are done to a product(s) under development are identified, reviewed, validated/verified, documented, and approved before their implementation. It is highly recommended to define the ECO process for stages before design freeze (or design output review) and after design freeze. Changes before the design freeze shall include as a minimum: Details of the change, the reason for the change, and the approver of the change. All records must be kept in all phases.
(6) Quality Manual
A full quality manual is not required at the early stages of the design and development, yet a frame with the building bloc needs to be defined for the quality manual. This frame needs to include the scope of the quality management system and its exclusions, a list of the planned documented procedures for the quality management system, and a cross-reference table to later include the relationships between the QMS procedures and the regulatory requirements.
It is also advisable to include in the quality manual the company’s organizational structure, specifying the functions in the organization.
Conclusion
At the beginning of the development of a new product, it is necessary to plan for the evolution, including the minimum documentation required at this step, thinking about the right size and procedures of the QMS.
Targeted cancer therapy continues to evolve, and many new treatment combinations are being approved in addition to developmental advancements in novel checkpoint inhibitors. This article will address the lately approved antibody therapeutics (US and EU), those in regulatory review, the expanded approval of existing immunotherapies, and their associated companion diagnostics for cancer treatment. This article will address the following issues:
Between 2021 to 2022, the FDA approved six new antibody-based immunotherapies and EMA five whereas four of the five accepted were previously cleared by the FDA, Table 12,3.
Table 1: Antibody therapeutics approved in the EU or US
Starring 2021’s approval is Dostarlimab (Jemperli), anti-PD-1 Humanized IgG4, and Amivantamab (Rybrevant), a bispecific antibody targeting cancer epitopes, EGFR and MET. Both were approved in the EU (M.A. No. EU/1/21/1538/001) and US (BLA:761174/761210) to treat tumors with a high mutational burden and NSCLC with EGFR exon 20 mutations, respectively.
Companion Diagnostics and Future Artificial Intelligence (AI)-Based Approaches
The use of immune signature to predict immunotherapeutic response led to an increase in the development and approval of immunohistochemical (IHC) diagnostic assays, Table 24. Such devices allow informative decision-making to assess tumor-favoring immune responsiveness5,6. For example, the VENTANA MMR RxDx panel was approved concomitantly with Dostarlimab (mentioned above) to distinguish the patients with dMMR who will benefit from this treatment7. Additional FDA-approved companion diagnostic tests are listed below, Table 2.
Table 2:List of Approved Companion Diagnostic Devices
Important past year’s (2021) step in the immunotherapeutic approach is the expanded indication approvals for several already in-use drugs as adjuvant/neo-adjuvants therapies for the core axis PD-1/PD-L1. PD-1/PD-L1 blockade was proven to promote DFS (Disease-Free Survival) and EFS (Event-Free Survival). Atezolizumab (Tecentriq) had been cleared by the FDA as an adjuvant treatment with the companion diagnostic test VENTANA PD-L1 (SP263), mentioned above, for NSCLC (non-small-cell lung cancer) patients expressing PD-L113. Pembrolizumab (Kytruda) was approved both by EMA and FDA for the adjuvant treatment of RCC (Renal Cell Carcinoma) and neoadjuvant+adjuvant treatment for TNBC (Triple Negative Breast Cancer), respectively 14,15 . Nivolumab(Opdivo) has also been approved by the E.C. (European Commission) and the FDA for the adjuvant treatment of esophageal or GEJ (gastroesophageal junction) cancer16,17. The latter had also approved Nivolumab for adjuvant therapy of urothelial carcinoma18.
Latest Advancements in the Immunotherapy Field and 2022 Expected Approvals
From a regulatory point of view, the unexpected immune response of antibody-based biopharmaceuticals is one of the obstacles when developing biological products. Thus it is advised to navigate the strategic and regulatory decisions correctly to properly assess the safety and efficacy of such biotherapeutic 22. These assessments are usually conducted during pivotal clinical trials; as per ICH S6(R1), nonclinical immunogenicity data are not considered to be predictive of clinical safety 23. Even a greater challenge arises when designing antibody-based immunotherapy with expansion to dual targets i,e. Bispecific Antibodies (bsAbs). Such a strategy may increase immunogenicity issues which may also be related to novel complex structures. Consequently, for benefit-risk assessment, the FDA may request a comparison of the bsAb to an approved monospecific product directed against the same antigenic target(s)24.
In any circumstance, every applied BLA needs to show a clinical advantage. For example, FDA denied the approval of Retifanlimab (PD1-targeted mAb)25and Oportuzumab monatoxalso (EpCAM-targeted immunotoxin, ADC), questioning their clinical benefit. In addition, concerns were raised about the Oportuzumab monatoxalso company’s CMC (Chemistry, Manufacturing, and Controls) processes26.
Accelerated approvals are granted to many I.O. biologics; however, some are not reviewed for years. In 2021, FDA conducted an industry-wide evaluation of such drug approvals, which failed to meet post-marketing requirements 27,28. Following FDA’s call into question, several immunotherapy indications were withdrawn and removed from the US market28,29,30.
1. Cox EM, Edmund A V, Kratz E, Lockwood SH, Shankar A. Regulatory Affairs 101 : Introduction to Expedited Regulatory Pathways. 2020;2012:451-461. doi:10.1111/cts.12745
2. Www.antibodysociety.org.17Dec2021. Antibody therapeutics approved or in regulatory review in the EU or US. Antib Soc. Published online 2021. https://www.antibodysociety.org/resources/approved-antibodies/
3. Mullard A. 2021 FDA approvals. Nat Rev Drug Discov. 2022;(January). doi:10.1038/d41573-022-00001-9
4. List of Cleared or Approved Companion Diagnostic Devices (In Vitro and Imaging Tools). doi:https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools
5. Emily A. Prince, PharmD1 ; Jenine K. Sanzari, PhD1 ; Dimple Pandya, MD1 ; David Huron P; and RE. Analytical Concordance of PD-L1 Assays Utilizing Antibodies From FDA-Approved Diagnostics in Advanced Cancers : A Systematic Literature Review abstract. Published online 2022. doi:10.1200/PO.20.00412
6. Christian U. Blank, John B. Haanen AR and TN. The cancer immunogram. Science (80- ). 2016;352(6286):658-660. doi:10.1126/science.aaf2834
7. VENTANA MMR RxDx Panel – P200019. Published 2021. https://www.fda.gov/medical-devices/recently-approved-devices/ventana-mmr-rxdx-panel-p200019
8. Baxi V, Edwards R, Montalto M, Saha S. Digital pathology and artificial intelligence in translational medicine and clinical practice. Mod Pathol. 2022;35(1):23-32. doi:10.1038/s41379-021-00919-2
9. Xu Z, Wang X, Zeng S, Ren X, Yan Y, Gong Z. Applying artificial intelligence for cancer immunotherapy. Acta Pharm Sin B. 2021;11(11):3393-3405. doi:10.1016/j.apsb.2021.02.007
10. Artificial Intelligence and Machine Learning in Software as a Medical Device_Action Plan. https://www.fda.gov/medical-devices/software-medical-device-samd/artificial-intelligence-and-machine-learning-software-medical-device
11. Good Machine Learning Practice for Medical Device Development: Guiding Principles. https://www.fda.gov/medical-devices/software-medical-device-samd/good-machine-learning-practice-medical-device-development-guiding-principles
12. Roche announces the release of its newest artificial intelligence (AI) based digital pathology algorithms to aid pathologists in evaluation of breast cancer markers, Ki-67, ER ,and PR. https://diagnostics.roche.com/global/en/news-listing/2021/roche-announces-release-of-its-newest-ai-based-digital-pathology-algorithms-to-aid-pathologists-in-evaluation-breast-cancer-markers-ki67-er-pr.html
13. FDA F and DA. FDA approves atezolizumab as an adjuvant treatment for non-small cell lung cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-atezolizumab-adjuvant-treatment-non-small-cell-lung-cancer
14. FDA F and DA. FDA approves pembrolizumab for high-risk early-stage triple-negative breast cancer. Published 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer
15. EMA. Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for the extension of Kytruda as monotherapy adjuvant treatment_RCC. Published 2021. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/keytruda-6
16. Bristol Myers Squibb. Bristol Myers Squibb Receives European Commission Approval for Opdivo (nivolumab) as Adjuvant Treatment for Esophageal or Gastroesophageal Junction Cancer Patients with Residual Pathologic Disease Following Chemoradiotherapy. Published 2021. https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-Opdivo-nivolumab-as-Adjuvant-Treatment-for-Esophageal-or-Gastroesophageal-Junction-Cancer-Patients-with-Residual-Pathologic-Disease-Following
17. Bristol Myers Squibb. U.S. Food and Drug Administration Accepts for Priority Review Application for Opdivo® (nivolumab) as Adjuvant Therapy for Patients with Resected Esophageal or Gastroesophageal Junction Cancer. Published 2021. https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Accepts-for-Priority-Review-Application-for-Opdivo-nivolumab-as-Adjuvant-Therapy-for-Patients-with-Resected-Esophageal-or-Gastroesophageal-Junction-Cancer/default.aspx
18. FDA F and DA. FDA approves nivolumab for adjuvant treatment of urothelial carcinoma. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-adjuvant-treatment-urothelial-carcinoma
19. Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13(1). doi:10.1080/19420862.2020.1860476
20. Si Y, Melkonian AL, Curry KC, et al. Monoclonal antibody-based cancer therapies. Chinese J Chem Eng. 2021;30:301-307. doi:10.1016/j.cjche.2020.11.009
21. Vaddepally RK, Kharel P, Pandey R, Garje R. Review of Indications of FDA-Approved Immune Checkpoint Inhibitors per NCCN Guidelines with the Level of Evidence. :1-19.
22. Vandivort TC, Horton DB, Johnson SB. Regulatory and strategic considerations for addressing immunogenicity and related responses in biopharmaceutical development programs. J Clin Transl Sci. 2020;4(6):547-555. doi:10.1017/cts.2020.493
23. European Medicine Agency. EMA/CHMP/ICH/731268/1998 ICH guideline S6 (R1) on preclinical safety evaluation of biotechnology-derived pharmaceuticals. Comm Med Prod Hum use ICH. 2011;6(June):1-22. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-s6r1-preclinical-safety-evaluation-biotechnology-derived-pharmaceuticals-step-5_en.pdf
24. Gough J, Nettleton D. Bispecific Antibody Development Programs – Guidance for Industry_CEDER. Manag Doc Maz. 2019;(April):10.
25. Tucker N. FDA Denies Approval of Retifanlimab for Locally Advanced or Metastatic SCAC Subgroup. Published 2021. https://www.targetedonc.com/view/fda-denies-approval-of-retifanlimab-for-locally-advanced-or-metastatic-scac-subgroup
26. Biospace. FDA Slams Sesen Bio with CRL for Bladder Cancer Drug. Published 2021. https://www.biospace.com/article/fda-crushes-sesen-bio-with-crl-for-bladder-cancer-drug/
27. Astor L. FDA Cracks Down on Dangling Accelerated Approvals in 2021, Pathway Is Scrutinized. Published 2021. https://www.targetedonc.com/view/fda-cracks-down-on-dangling-accelerated-approvals-in-2021-pathway-is-scrutinized
28. FDA In Brief: FDA Oncologic Drugs Advisory Committee to Review Status of Six Indications Granted Accelerated Approval. Published online 2021. https://www.fda.gov/news-events/fda-brief/fda-brief-fda-oncologic-drugs-advisory-committee-review-status-six-indications-granted-accelerated
29. Merck withdraws Keytruda from SCLC indication amid FDA crackdown. Published 2021. https://www.clinicaltrialsarena.com/news/merck-withdraws-keytruda-for-lung-cancer-amid-fda-crackdown/
30. Nivolumab Indication in Small Cell Lung Cancer Withdrawn in U.S. Market. Published 2021. https://ascopost.com/issues/january-25-2021/nivolumab-indication-in-small-cell-lung-cancer-withdrawn-in-us-market/
This article was prepared by:
Vered Ben Hur. Ph.D
Pharma Regulation Projects Manager
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In the last decade, the cell therapy field has matured, with some notable successes, including CAR-T therapies and gene-modified cell therapies targeting specific rare diseases. There have also been some disappointments, in particular, the failure of several MSC therapies to reach efficacy endpoints in late-stage clinical trials. In parallel, however, the realization that very many beneficial effects of cell therapy can be attributed to the cells’ secretome, has gained traction. This is evident in the exponential increase in publications relating to the secretome and extracellular vesicles (EVs), as well as in the number of start-up companies engaged in the development of such cell-free cell-derived products.
Enter the new kids on the block: cell-derived, cell-free products.
These products are derived from cell culture’s secretions – the secretome – which includes: soluble proteins and peptides, cytokines, chemokines, lipids, carbohydrates, lipid bi-layer bound vesicles including micro-vesicles, extracellular-vesicles (EVs), small EVs (sometimes referred to as exosomes) and their contents, which in addition to the above, contain nucleic acids (DNA and miRNA). The composition of the secretome depends on the cell type and microenvironmental stimuli. This is a dynamic and rich soup!
In addition, to a cell’s natural secretions, companies are engineering and/or activating cells to specifically influence the secretome by, for example, enriching for secretion of a particular factor, or directing expression of a particular factor to the surface of an EV.
What are the advantages of EV’s and Secretome – cell-free cell-derived products?
Cell-free cell-derived products may offer a number of advantages over cell therapies:
In terms of manufacturing – such a product is likely to be more stable, possibly amenable to lyophilization ,and may not require cryopreservation. This represents a huge benefit in terms of process timing, testing ,and transport logistics compared to cell therapies.
In terms of safety – a cell-free product will have no persisting cells and therefore, no potential for transformation and risk of tumor formation. Similar to traditional biological products, an EV or secretome-based product is expected to have a relatively short-term effect with half-life and clearance by predictable pathways.
In terms of efficacy – a cell-free product containing multiple active components enables a broad-spectrum approach to multiple targets, amenable for a range of indications. Repeat dosing is more likely to be required, but dosing should be easier to tailor to the patient’s requirements, based on traditional PK understandings.
What are the main hurdles to be overcome when developing such a product?
One of a kind
All cell-free cell-derived products we’ve encountered at Gsap have been very different from each other in terms of the manufacturing process, product description ,and indication. As with cell therapy, each product is unique with the manufacturing process and controls developed to suit each individual product, and careful risk assessment, is a must, to accompany each step in the development.
Cell banking
Of particular importance is the use of a well-characterized, fully tested cell bank, suitable for GMP manufacture. The cell bank is subject to the same rigorous testing requirements as required for cell therapy. The use of well-characterized commercially available cell banks, manufactured according to GMP, with a well-documented history and testing certification can be of great benefit to enable efficient translation of cell-free cell-derived products into the clinic.
Manufacturing process
Similar to cell therapy, the concept that the product is the process certainly applies here. The scientific literature is replete with examples illustrating the impact of the environment, culturing conditions, cell source, cell type, donor age, media, reagents, scale-, and vessel type, amongst other things, on cell secretome content. Early implementation of appropriate process controls is, therefore, essential to develop a process for a product sensitive to so many variables. EV or secretome-based products may be less potent than cell therapy products unless the manufacturing process can successfully concentrate the main active components whilst eliminating impurities.
No benchmarks
To date, there are no approved EV or secretome-based products approved for marketing in any territory. In contrast, the main risks from cell therapy have been established, over almost two decades of clinical use. In the absence of any benchmark products and potentially more risks, it is critical to generate an understanding for the development product’s mechanism of action (MOA) in order to successfully mitigate potential risks.
Regulatory considerations
Combined regulations are expected to apply to cell-free cell-derived products such as EVs and secrotome products, both in the US and in Europe. The exact product classification may vary, based on the product composition and attributes.
Traditional biological product regulations are expected to apply with regard to nonclinical safety testing, in other words, unlike cell therapy requirements, PK and safe pharmacology evaluation may be required and GLP safety studies may be required in two species. Safety and toxicology programs should be agreed with the regulator in advance. With cell-derived products, the potential for confounding immune response should be carefully considered.
Conclusions
These are exciting times, as biotech companies explore the use of cell secretomes for therapeutic benefit. Such cell-free cell-derived products present a whole new list of challenges for the developer and regulator alike. The new products in development are complex mixtures that require sophisticated analytical methods for their characterization – proteomics, nanoparticle tracking analysis, next-generation sequencing ,and mass spectrometry are just a few of the methods that we can expect to see more of. As with cell therapy, we trust that the individual regulatory bodies will harmonize their requirements so that development is not needlessly complicated further.
This article was prepared by both:
Diana Gershtein MSc., MBA
Advanced Therapies Section Manager
Tami Horovitz, PhD
Gsap Regulatory Submissions – Content Expert
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