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Elevating Your Clinical Trial Audits with Artificial Intelligence and Centralized Monitoring 

Clinical trial audits serve as a tool to assess if a given auditee has the required qualifications and capabilities to conduct a set of tasks. Auditing assesses standards and regulations that have or will be met. Clinical trial activities may be delegated to vendors or suppliers, including Contract Research Organizations (CROs), sample processing laboratories, Contract Development and Manufacturing Organizations (CDMOs), imaging laboratories, Central Institutional Review Boards (IRBs), etc. 

In addition, audits can be used to verify the processes are followed, serving as a robust demonstration to health authority representatives that auditees are compliant and that processes impacting data integrity and patient safety have been thoroughly evaluated and vetted. Systematic audits instill confidence and assure regulatory bodies that the clinical trial sponsor maintains a vigilant oversight over every aspect of their clinical development program. 

While clinical trial audit programs can be tailored to support a sponsor’s requirements and goals, it is especially important to have a focused approach when conducting routine (data) audits (i.e., investigator site audits, Trial Master File audits, data management (vendor) audits, etc.) There are additional tools and tactics to identify data outliers that may pose a risk to their development program more efficiently. 

While attending the 2024 SCOPE summit, we listened to many sessions under the quality and monitoring and data tracks that resonate with our approach and client interactions. For example, assessing effective approaches for sponsors to review their data, identify outliers, and then remediate and act accordingly, are frequent conversations we have with industry.  

Coming out of the summit, we are even more encouraged to recommend ways to elevate clinical trial auditing practices to a more proactive approach. For example, by leveraging artificial intelligence (AI) and central monitoring (CM) generated data, sponsors (and auditors) may get a head start by reviewing AI or CM-generated information and proactively focus their data reviews in advance of their audit. We believe that if auditors are more equipped with the issues and risks in advance of the audit, they can conduct a more targeted data review and proactively identify potential non-compliances or observations. Here are our observations and recommendations. 

Leveraging Artificial Intelligence and Central Monitoring Outputs for Audit Preparation 

At SCOPE, there were numerous sessions on AI use cases across the life sciences industry, many of which focused on how to maximize the value of a company’s data. 

A common use case presented across these sessions was how to interact with the data using a more natural language where data analysis no longer needs to be done by data managers or statistical programmers. In a Chat GPT fashion, data reviewers could tell AI what data they wanted to see and how they wanted to see it. The data reviewer could then review the returned data set and drill down further without being required to write complex queries in a programmatic language.  

Leveraging AI to automate repetitive tasks was another prevalent theme during these sessions. Tasks, such as data analysis, can be accelerated with the identification of patterns and trends with machine learning, deriving actionable insights. Leveraging AI for data analysis also increases accuracy in finding outliers that were missed during human review to identify potentially missing data. 

This capability resonated with another repetitive task that is often overlooked or an afterthought until it is time for an audit – audit trail reviews. Audit trail reviews are key for a data integrity program to ensure the data is fully controlled, accurate, and complete; and until a problem has been identified, this activity does not always happen since it is generally a large data set that looks as expected. But this is a perfect use case for AI where a large data set can be analyzed by AI and outliers can be identified such as a user deleting a record with no reason documented or a user modifying a record that should not have access to that record. 

With the U.S. Food and Drug Administration’s (FDA) March 2023 draft guidance on Electronic Systems, Electronic Records, and Electronic Signatures in Clinical Investigations stating that sponsors, clinical investigators, and other regulated entities may be requested to provide all records and data needed to reconstruct a clinical investigation, including metadata and audit trails, it is clear this is a must-have.  

Utilizing CM data outputs to inform your clinical trial audits can make the selection of investigator site to audit straightforward. When preparing for an investigator site audit (ISA), the auditor may leverage CM metadata to select outliers to explore (i.e., investigator sites with high Serious Adverse Events (SAEs), protocol deviations, open action items, and data discrepancies) and zoom in on areas of risk efficiently.  

So, why not leverage AI to inform audit preparation and CM metadata to have more focused audit conduct by zooming in on the key outlier data to proactively identify and resolve areas of risk that may affect your clinical trial? The time is now. 

About Halloran’s Audit and Oversight Services 

At Halloran, we understand navigating the complexities of clinical trial audits requires precision, expertise, and a commitment to meeting the unique needs of our clients. Partnering with us will elevate your audit experience:  

Customized Audit Program Management and Execution: 
We pride ourselves on tailoring audit programs to your organization’s specific goals, objectives, and timelines   

Comprehensive Audit Support Throughout the Lifecycle:  
From inception to closure, we are your dedicated partner throughout the entire audit lifecycle. Our team doesn’t just develop programs; we stand by your side, offering unwavering support at every stage  

Client-Centric Approach:  
Your success is our priority. We craft programs aligned to your unique challenges and objectives to add the most value  

To discuss your audit strategy and approach, contact us today.

Quality Governance and Evolution of Quality Management Review 

Quality governance can be defined as an overarching framework that provides assurance of compliance with regulatory requirements, industry standards, and continuous quality improvement while enabling the risk and issue escalation process. Quality governance structures and processes provide transparency to an organization’s leadership on how well the Quality Management System (QMS) is functioning. It is through the evolution of Quality Management Review (QMR) that we can ensure continuing suitability and effectiveness by assessing an organization’s performance quality.

Today, with the rapidly changing regulatory environment and the upcoming adoption of ICH E6(R3)1, the concept of quality governance is being challenged across all organizations. It is no longer adequate to assume quality governance is a process owned by quality, but rather, it must be a responsibility retained by the entire organization. 

To take active steps in establishing effective quality governance, it is important to establish a clear pathway for issue escalation and information flow, paired with the distribution of adequate resources and support while driving the idea of continuous improvement.  

While acknowledging this can be overwhelming, here are essential considerations as you begin to build out your quality governance processes.  

Focus on Establishing a Quality Management Review (QMR) 

International Conference on Harmonisation (ICH) Q10: Guideline for Pharmaceutical Quality System states that it is essential for leadership to establish a company-wide commitment to quality.2 It is through the evolution of Quality Management Reviews that we can ensure continuing suitability and effectiveness by assessing the organization’s performance quality.  

It is a great forum to be able to evaluate the health of the QMS, review key quality metrics, discuss emerging trends, drive continuous improvements, assess resourcing, and share best practices. It is also an effective way to promote quality from top to bottom across an organization.  

The goal is to implement a culture of quality not only at an executive level, but throughout the entire organization. Proactively establishing a quality culture, where it’s recognized quality is everyone’s responsibility, will help the business to achieve and sustain compliance. A key foundation of establishing a culture of quality is by evolving a QMR, which allows organizations to take a more strategic and meaningful approach to quality and oversight by keeping everyone engaged. 

To evolve the Quality Management Review process, it is necessary to establish an organizational-wide QMR framework. A common pitfall when establishing a QMR framework is that it is only performed at higher levels of management. But when companies only have QMR at higher levels, there is no functional level transparency, and teams may have no interest because it is not apparent that quality is something for which everyone is responsible.  

A Quality Management Review needs to be a cascading framework that includes involvement up and down the organization to guarantee that quality governance fits into the organizational culture. 

QMR Can Be a Series of Reviews at Various Management Levels  

Holding a series of reviews at various management levels is an approach that allows timely and effective communication across the organization, creating an escalation process to raise appropriate quality issues to executive levels of management for review. However, if your organization is small, holding one QMR may be suitable.  

An example of the QMR hierarchy could be defined as executive level QMR, moving down to a departmental level QMR (i.e., research and development) and then to functional level QMRs (i.e., clinical, manufacturing, and regulatory). The inputs and outputs of each QMR are hierarchal with key information from the functional levels being reported up to a particular departmental level, and then again to executive levels. Quality initiatives and objectives are then disseminated from executive levels back down through the functional levels. In creating this framework, a culture of quality is promoted at all levels of the organization and incorporates all key stakeholders.

Once the QMR framework is established, the development of a quality plan is crucial to drive the process. Developing a quality plan at the executive management level allows for prioritization of key critical quality objectives for the organization. The quality objectives establish clear goals for the organization to achieve over a defined period, typically on an annual basis.  

At the executive level, the quality plan should be more strategic, focusing on overall organizational quality objectives, standardized quality metrics, identified risks, and continuous improvement initiatives. Once a quality plan is developed at the executive level, that strategic plan can then cascade down through departmental levels and then to functional levels. It is here that you will be able to take the strategic plan and adapt it to be more focused and tactical so that it is meaningful for each level of the organization. 

 Consider Differences in Priorities Across Business Areas  

For example, if a department area is Research and Development (R&D), the R&D quality plan will have different quality focuses and areas of identified risk than the next level quality plan for the functional area of Manufacturing. The department level plan will cascade down to the functional areas of the operation, with the flexibility for functional areas to further focus and establish their individual quality plans to be representative of the current objectives of that functional area.  

Functional area quality plans will differ based on their operations and risk evaluation. For example, clinical may focus on inspection readiness, risk-based auditing of sites, and protocol deviations, while regulatory may be more focused on Standard Operating Procedure (SOP) revisions for new regulatory requirements. 

Once your QMR framework and quality plans are established, you can also create standardized quality metrics for review during QMR. These actions are performed in tandem, but the quality plan should ideally highlight focus and risk areas for the year, while the standardized metrics are going to help monitor progress.  

To only incorporate performance metrics as part of a QMR without having a strategic quality plan may leave an organization in more of a reactive mode. 

Instead, strive to establish a quality plan that will drive the organization to reach a state of continuous improvement and standardized performance metrics, allowing for a measurement of that success or failure. Standardized quality metrics can include a variety of topics such as the number of regulatory inspections, audits findings, corrective and preventative actions (CAPAs), protocol deviations, serious safety issues, and training compliance. 

It is a good idea to define standardized metrics within a level specific QMR charter because that will ensure the organization states its purpose as a QMR and continues to observe and measure the same standardized metrics.  

At the functional levels, metrics will be more specific, and as outputs are rolled up throughout the QMR hierarchy, metrics begin to look broader and provide a better snapshot of the entire organization. 

So, You Have Established a QMR Framework, Quality Plans, and Standardized Metrics, Now What?

As the QMR framework matures and the organization becomes more sophisticated in using metrics, begin to establish Key Quality Indicators (KQIs) – a way to measure the overall success of an organization in meeting quality-based objectives. 

KQIs can also promote the development of Quality Tolerance Limits (QTLs) which is a level, point, or value associated with a parameter that, when deviation is detected, should trigger an evaluation to determine if there is a possible systemic issue.3 By utilizing both KQIs and QTLs, companies are able to respond proactively to potential issues at all levels in the organization and utilize the QMR hierarchy to elevate potential threats clearly and efficiently, ensuring appropriate risk-based action by the appropriate level of management. 

By building a quality governance framework, organizations are enabled to continue monitoring their QMS and focus on critical processes, championing continuous improvement. QMR allows organizations to reach their quality goals, concurrently enabling them to align with regulatory expectations. By building this QMR framework, and simultaneously promoting a culture of quality, they will begin to shift the view of the organization from being solely focused on compliance to that of more focused, quality goal setting, adopting a proactive posture and driving for continuous improvements.  

Need assistance with your Quality and Compliance program? Halloran teams provide QMS assessments, and design right-sized QMS’ to document processes, procedures, and responsibilities for achieving quality policies and objectives based on the size and operating model of their clients.  

Contact Halloran today. 

References: 

  1. International Council for Harmonisation Harmonised Guideline: Good Clinical Practice (GCP) E6(R3). May 19, 2023. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_DraftGuideline_2023_0519.pdf  
  2. International Conference on Harmonisation Harmonised Tripartite Guideline: Pharmaceutical Quality System: Q10. June 4, 2008. https://database.ich.org/sites/default/files/Q10%20Guideline.pdf  
  3. International Conference on Harmonisation Guideline Q9 (R1) on Quality Risk Management. February 3, 2023. https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use-ich-guideline-q9-r1-quality-risk-management-step-5-revision-1_en.pdf  
  4. TransCelerate Biopharma, Inc. Risk-based quality management: quality tolerance limits and risk reporting. 2017.

Preparing Now for FDA’s START Program for Rare Disease Drug Developers 

On September 29, 2023, the U.S. Food and Drug Administration (FDA) took action to help further accelerate the development of novel drug and biological products for rare diseases. The action, an announcement of an opportunity for a limited number of sponsors to participate in a pilot program (Support for Clinical Trials Advancing Rare Disease Therapeutics (START)), allows for more frequent communication with the agency to address clinical development issues as they arise. 

As intended, insight gleaned from the START pilot program seeks to illuminate how best to propel more efficient development of potentially life-saving therapies with rare disease indications, as well as to guide sponsors towards generating robust high-quality and compelling data to support their future marketing applications. 

In recognition of Rare Disease Day, here is an overview of the START pilot program, expectations to consider if you are applying into the program, and early preparation considerations. 

START Program: Mission, Benefits, and Criteria 

The Orphan Drug Designation represents an important milestone for sponsors developing products for rare diseases. The designation carries significant benefits to the sponsor including tax credits, user fee exemptions, and market exclusivity. While the benefit of an early engagement with the FDA, such as a pre-Investigational New Drug (IND) meeting or an end of Phase 1 meeting, can certainly aid in the progression from an IND to approval, challenges remain for rare disease drug sponsors. 

All product activities (clinical, nonclinical, and chemistry, manufacturing, and controls (CMC)) in these development programs are challenged by multiple factors associated with expedited rare disease development programs. For example, clinical development must balance what is typically considered appropriately designed clinical trials against the ability to recruit patients (i.e. size and location of patient population), challenges in the use of placebo, and the small but robust clinical dataset intended to show substantial evidence of safety and efficacy. Encouragingly, these challenges have been recently highlighted by top FDA officials, including FDA commissioner Robert Califf, where he notes, “We’re about to see a tsunami of therapies for rare and ultra rare disease, and I don’t think any of us think the current pathways are optimal.”  

In hopes of addressing these challenges, the FDA has launched the START program, which will be open to up to three sponsors in both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). The pilot program’s focus is to provide opportunities through the currently available meeting types for increased communication to aid in moving towards submission of a Biologics License Application (BLA) or a New Drug Application (NDA).  

For the initial pilot, the FDA has established program criteria: 

The third criterion differs for applicants of CBER and CDER: 

START applications for this initial pilot program are due to the sponsor’s IND no later than March 1, 2024, and require inclusion of the program development plan and status for CMC, nonclinical, and clinical. The sponsor should highlight the specific issues they are seeking enhanced communication with the FDA to address, and the timeline for the studies intended to provide the primary evidence to either support approval or future pre-BLA/NDA meetings. 

Selection will be based on the application criteria and factors such as potential clinical benefit, perceived benefit of enhanced communication to the proposed complications, breakthrough designation status, and the FDA has noted that for the initial pilot, significantly complicated combination products may be less likely to be selected.  

As this is the first year of applications, there is a vagueness to the selection criteria for the program, which will undoubtedly be further defined as the program develops. For instance, the program does not specifically require sponsors to have clinical data (just potential for clinical benefit); however, applications with clinical data may be able to better demonstrate their pathway to marketing application. As the START program further develops, this will be an aspect for early-stage IND programs to watch.  

As the START program is in its pilot stage, the exact implementation of ‘enhanced communication’ is still not clear. However, previous agency programs (i.e., the Emerging Technology Program) may give some insight into how this may occur. It is unclear at this stage if a specific group within the agency will be created and be responsible for these programs (i.e., the Emerging Technology Team), but the additional agency resources along with opportunities for additional and enhanced communication could address the potential pitfalls of program development.   

Early Preparation Considerations 

While much will be learned from the initial pilot program to aid potential applications for 2025, if the agency opens additional spots, sponsors should start to prepare now. The document will require significant cross-functional team input and sponsors should view the work at the level of a FDA meeting package. Addressing all aspects of development in meaningful detail will require the sponsor to plan, discuss, and agree upon reasonable development timelines prior to drafting. Sponsors should ensure their program management or regulatory teams have insight into all development plans across clinical, CMC, and nonclinical in preparation for preparing the application to ensure all challenges and discussion points are covered.  

Halloran can assist clients through these significant program management barriers to develop a successful START application, and partner on their continued rare disease program development journey through our clinical, regulatory, and program management expertise.  

Throughout the year, the START pilot program will be closely watched for aiding the selected sponsors in progressing the development programs for these rare diseases. The program will not fix all issues plaguing the development of products for rare diseases; however, the program offers the potential to alleviate many of the pitfalls sponsors encounter. The success of the pilot program will hopefully lead to increased opportunity in the 2025 application process in terms of the number of accepted applicants or expanding the eligibility criteria, and subsequently, the speed and ease at which these necessary products can be brought to market. 

The effect of the START pilot program will be closely watched for its potential success in developing programs through approval and for the trends in accepted programs.  

As you move through the early phases of clinical development, now is the time to consider and plan for the START program application as part of your regulatory strategy. Contact our team today to further the conversation. 

Small Biotech and Pharma Dilemma – Three Steps to Remain Competitive on a Budget 

While attending the annual SCOPE summit this year, listening to sessions and walking the exhibitor hall, a strong question, for me, resonated throughout the entire experience. That is, how can small biotech and pharmaceutical companies stay competitive within their realm by leveraging opportunities to advance clinical research while still navigating resource constraints?  

Let’s break this down. 

Large organizations are often backed by vast resources and deep-rooted market presence, often making it easier for them to leverage tools and technology to discover efficiencies and enhance their clinical research outcomes. Efficiency often means faster, and faster in clinical research, means money saved and potential speed-to-market. 

Over the past few years, there has been a surge in technology and services, all offering a speedy outcome. For example, Artificial Intelligence (AI) tools can support clinical research site optimization to reduce site startup timelines, clinical trial training vendors offer protocol compliance for patients and sites to reduce risk and enhance retention, and full-service decentralized clinical trial vendors offer full data management visibility, just to name a few tactics. 

But how can smaller organizations with limited resources take advantage of tools and technology (and make the right selection) with limited employees, funding, and perhaps, expertise? This question seeks to address and solve this dilemma: how to not get left behind in an environment where opportunities may not be as easily accessible for smaller organizations. 

In this article, I explore considerations for the smaller players to think like big players to remain competitive and discover efficiencies without breaking the bank and ‘keeping up with the joneses.’  

Step 1: Assess Roadblocks to Your Organizational Structure and Pipeline 

First, take a holistic view of your company’s organizational structure and pipeline, and seek to answer the following questions around what may be preventing you from getting to market more quickly. 

Step 2: Evaluate Tools and Technology Rightsized for Your Organization 

Approximately 1,000 vendors attended the SCOPE summit; the exhibitor hall was full of taglines promising faster data, improved speed to market, and patient data collection tools allowing for an easier and more efficient clinical trial experience for the entire clinical research ecosystem. Hypothetically, new CEOs of small biotech or pharmaceutical companies may believe their teams could complete a clinical trial in an unreasonably fast timeline if they utilized such tools. 

But what are the best practices when sorting through these options, particularly on a budget? First, ask the vendors the hard questions, including: 

Then, consider the resources needed to oversee the vendor, service, or product, and assess the lift on the employee(s). Fit the technology into the company based on your strategy and priorities, but do not overhaul your company for new technology just because it’s popular. Rather, prioritize the technology based on your company’s top priorities so that you right-size your selection(s). Ultimately, this is an approach for small biotech and pharmaceutical companies to stay competitive.  

Taking this critical and evaluating lens into vendor selection is essential. For example, there are more options than just the largest, more expansive Clinical Research Organization (CRO) available, and there are many vendors stating they offer similar clinical research outcomes. Since vendor selection is not a one-size-fits-all approach, if you are aligned with your strategy and priorities, that framework will successfully guide you in your evaluations and selections. 

Step 3: Decide and Execute, But Not Before Developing Your Oversight Plan 

So, you’ve decided to move forward with a tool or technology for your company. Before you purchase, the next important steps are developing an oversight plan and then executing on your decision.  

When evaluating and selecting a new technology, assessing oversight infrastructure and processes is a must. In addition to processes, you will need to establish accountability and responsibility for oversight tasks and how those processes and tasks will be documented. In addition, you will need to determine the appropriate level of oversight required. If the oversight plan hasn’t been fully developed, this is the time to do it before implementing your new technology.  

The oversight plan will outline the “who, what, and when” of bringing in a new vendor to your organization. While this plan may seem like another document, it details the communication structure between the sponsor and vendor and includes escalation pathways to follow if (and when) issues arise. The plan should outline the roles and responsibilities of individuals at both organizations, making it easier to understand peer-to-peer communication pathways. Clear timelines on deliverables should be documented, as well as the individuals held accountable.  

This plan should also include a governance structure to guide and manage the sponsor-vendor relationship, as well as processes to mitigate risks and actions in real time to prevent issues from escalating, as there will be documented mechanisms to identify risks. Upon completion of the oversight plan, teams across the organizations should feel confident in their processes, enabling a roadmap to success. 

A common clinical trial inspection finding by the U.S. Food and Drug Administration (FDA) is inadequate monitoring of clinical trials, so developing this plan is a critical foundational activity for the success of any trial.  

In summary, when faced with many opportunities and options to enhance your clinical research processes, timelines, and outcomes, if you prioritize your employees and their journey throughout your organization, you’ll often find the best roadmap to success and stay competitive within your realm. 

Passionate employees with the right skillset and mindset who believe in your company’s mission will often make as strong of an impact as the latest tool on the market. Tools, technology, and innovation are important in the clinical research space, but the key lies in the balance for small biotech and pharmaceutical companies to stay competitive and successful, especially on a budget. 

To discuss your Clinical Operations and Development approach and strategy, contact Halloran. 

Pulling the Thread on FDA’s Master Protocol Draft Guidance 

The U.S. Food and Drug Administration’s (FDA) draft guidance, Master Protocols for Drug and Biological Product Development, released on December 21, 2023, provides expanded recommendations on the design and analysis of trials conducted under a master protocol. A master protocol is a protocol designed with multiple substudies, which may have different objectives and involve coordinated efforts to evaluate one or more medical products in one or more diseases or conditions within the overall study structure. 

Previously, the FDA issued two guidance documents regarding master protocol trial design and analysis. The first guidance, issued in May 2021, addressed the COVID-19 public health emergency with specific recommendations to sponsors for developing master protocols to evaluate drugs for the treatment or prevention of the disease during the global pandemic. This draft guidance was only intended to remain in effect for the duration of the public health emergency and is set to expire in March 2024. The second guidance, issued in March 2022, focused on drugs or biologics for the treatment of cancer as a targeted strategy to expedite late-stage drug development. 

The most recent guidance expands on the FDA’s previous recommendations related to master protocols, promoting application across a broad range of therapeutic areas.  

Carefully designed master protocols allow collaborative sharing of clinical trial elements (i.e., control arms, infrastructure, and oversight), facilitating a streamlined approach to maximize data collection and accelerate drug development. A master protocol designed with multiple substudies can evaluate one or more investigational products in one or more diseases, creating an efficient approach to expedite drug approval and potentially remove barriers to patient recruitment. 

We hosted an internal workshop at Halloran, collecting responses and feedback from consultants to share with the FDA for consideration. Here is our collective review. 

Five Key Watchouts to Consider 

Halloran provided the FDA with feedback on the draft guidance; Overall, our team believes the guidance will be an excellent resource to any clinical trial sponsor considering a master protocol. However, there are five key areas in which Halloran felt the FDA needed to provide further guidance. 

Operationalizing a Master Protocol 

The guidance acknowledges the many complexities associated with operationalizing a master protocol, such as blinding across multiple studies and ensuring proper communication amongst the many stakeholders. However, we would like to see more recommendations from the FDA on what sponsors can do to avoid potential mishaps due to these complexities. Such recommendations will help sponsors to implement the proper mitigation steps early on in their development process.  

Master Protocols to be Submitted to the FDA as a New IND 

The draft guidance states each master protocol should be submitted to the FDA as a new Investigational New Drug (IND) application. The agency specifies several considerations for master protocol IND applications but does not address the master protocol IND review process.  

For example, if the agency finds the information provided in the master protocol IND application supports the initiation of all but one of the proposed clinical substudies, would the agency place that single substudy on clinical hold while allowing all other substudies to proceed with enrollment?  

Our team believes this answer is a critical point for the agency to clarify as it will likely be a strategic consideration for many sponsors intending to submit a master protocol IND. 

Complex Statistical Analyses Requirements 

Master protocols are likely to require complex statistical analyses in which comparisons are made across multiple study plans. Therefore, it is critical that master protocol sponsors consult with a statistician who is experienced in such analyses when developing their study design and statistical analysis plan. Furthermore, sponsors should get full buy-in from the FDA on their proposed study design and statistical methods prior to initiation of the study. 

Changes to the Informed Consent Form 

Changes to the informed consent form (ICF), over time, present a challenge in maintaining consistent data, particularly in platform trials where drugs are allowed to enter and leave the trial. FDA should emphasize that this process should be carefully managed to ensure comparability of subjects across substudies.  

The informed consent process should occur before a patient’s randomization and avoid substudy-specific consent. Consent that occurs after patients have been randomized to one of the substudies may result in patients with different prognostic characteristics across substudies, raising concern about the comparability of each drug group with the shared control group (comprised of control patients from different substudies). 

Criticality of Oversight 

Oversight is a critical component of a well-conducted trial utilizing a master protocol. The FDA highlights the need for the sponsor to appoint shared oversight committees (i.e., data monitoring, steering, etc.) to coordinate the successful conduct of the trial.  

Data integrity deficiencies are a critical risk to mitigate early in the master protocol trial design. Due to the extensive coordination required to successfully conduct a master protocol trial, it is essential that master protocol sponsors and individual drug sponsors establish communication plans and data management plans early on, mapping out how information will be shared in a compliant manner across the teams.  

With the FDA’s focus on data integrity, it is imperative that master protocol sponsors understand how to coordinate their data ecosystem to minimize errors, alleviate issues in oversight, and address inconsistencies in data handling, analysis, and reporting. 

The Halloran Edge  

While the implementation of a master protocol may seem complicated, there are experts available to help guide you on your way from early planning through study closure.   

During the strategic planning phase, Halloran consultants develop the roadmap for their client’s master protocol, apply relevant regulatory and compliance guidance, provide recommendations on clinical trial design considerations, conduct an early risk assessment, and provide project management support.  

The master protocol guidance highlights the need for early interactions with the FDA and Halloran’s regulatory experts, in partnership with our clinical experts, are here to help you coordinate and manage regulatory agency meetings, provide recommendations on strategy, assist with IND submissions, and provide ongoing regulatory support.  

Operationalizing master protocols can also pose distinct challenges including enrollment, randomization, informed consent management, data capture, and other electronic systems, all requiring extensive coordination with multiple key stakeholders. Halloran’s clinical team can develop the master protocol and relevant key study documents and plans due to extensive experience in Contract Research Organization (CRO) and vendor selection, management and oversight, and clinical trial and risk management activities. 

Additionally, an organizational assessment can highlight where you may have any gaps in resources, expertise, Quality Management System (QMS), software, data integrity, and documentation, and when you may be due for organizational transformation. We have the experts on hand to ensure your master protocol is inspection-ready and the applicable systems and processes are complete and robust.   

To further the discussion, contact Halloran. 

Diversity in Clinical Trials: Shifting from Challenge to Innovation Opportunity  

In the dynamic landscape of clinical research, ensuring diversity in clinical trials has emerged as a critical factor for the success for the healthcare ecosystem. Recently, I had the privilege to attend the 2024 SCOPE summit, where discussions around diversity in clinical trials sparked inspiration for future clinical trial design and shed light on its transformative power within healthcare.  

In this article, I delve into key takeaways from the summit, particularly focusing on the insightful panel discussions led by Kim Doggett, Head of Clinical Trial Diversity at BeiGene, on Brainstorming to Break Down Barriers: Real Talk about What We Can Do to Collaboratively Move the Needle on DEI and Jessica Brescher, Chief Research Officer at SGM Alliance, on Overcoming Access Barriers to Healthcare for the LGBTQIA+ Community: Bridging Gaps and Driving Change. 

These panels focused on developing strategies to enhance diversity in clinical trials, the shifting perception of diversity from a challenge to an opportunity for innovation, and the importance of inclusivity, including sexual orientation and gender identity, in data collection efforts. 

Developing Strategies to Enhance Diversity in Clinical Trials 

One of the highlights of the SCOPE summit was the exploration of strategies aimed at enhancing diversity in clinical trials. Speakers in the DE&I program track emphasized the importance of designing inclusive recruitment and retention strategies that reflect the diverse demographics of the patient populations they aim to serve. From engaging with underrepresented communities to addressing barriers to participation, the consensus was clear: a proactive approach to diversity in clinical trials is essential for generating robust and generalizable data. 

Diversity as an Opportunity for Innovation 

A recurring theme throughout the summit was the evolving perception of diversity in clinical trials. Historically, this has been viewed as an operational challenge, but now, diversity is increasingly recognized as an opportunity for innovation and advancement in healthcare research.  

By embracing diversity in clinical trial design and implementation, researchers can uncover insights that may have been overlooked. Moreover, studies presented at the conference highlighted the positive impact of diverse patient populations on the efficacy and safety of interventions, highlighting the importance of inclusivity in driving scientific progress. 

Inclusivity in Data Collection: Including Sexual Orientation and Gender Identity 

An area of particular importance was the discussion on the criticality of inclusivity, including sexual orientation and gender identity, in data collection for clinical trials. While demographic data collection is standard practice, there is often a lack of representation and understanding of LGBTQIA+ individuals.  

By incorporating questions related to sexual orientation and gender identity in trial protocols and data collection instruments, researchers can ensure the unique healthcare needs and experiences of LGBTQIA+ individuals are addressed. This not only promotes inclusivity but also enhances the validity and relevance of study findings. 

Key Learnings and Reflections 

Attending the SCOPE event provided invaluable insights into the evolving landscape of diversity in clinical trials. From the development of inclusive recruitment strategies to reframing diversity as an opportunity for innovation, the event reaffirmed the importance of prioritizing diversity and inclusivity in clinical research.  

I remain committed to applying these learnings within my research endeavors at Halloran and advocating for meaningful change that benefits all patients. 

To discuss your diversity strategies and goals for your clinical research program, contact us today. We are ready when you are. 

Five Broad Implications for FDA’s Project Optimus: The Future of Oncology Trials is Here

Oncology drug development is different from most drug development programs in other therapeutic areas, or at least, has been historically. While most drugs are evaluated in randomized dose-ranging trials prior to pursuing pivotal clinical studies, oncology drug development, by comparison, is often accelerated due to the life-threatening nature of most cancers and the inherent toxicity associated with historical anticancer therapeutics like chemotherapy or radiation therapy. Consequently, dose-ranging studies in oncology are largely focused on identifying the maximum tolerated dose (MTD) based primarily on tolerability and performed only in Phase 1 trials; additional studies intended to support a broad understanding of the impact of different doses on efficacy and toxicity are then deferred until postmarketing. The United States Food and Drug Administration (FDA) is now taking aim at revising this long-standing paradigm via Project Optimus. 

With the advent of molecular medicine, drug developers have begun to elucidate the genetic underpinnings of many cancers. This has produced targeted therapies offering marked improvements in safety and efficacy in comparison to chemotherapy. An unforeseen consequence of the success of these targeted therapies over the last decade is the exposure of patients to oncology drugs (and concomitant medications) for much longer periods of time, which increases the likelihood of long-term risks for the patients. 

As duration of therapy increases, the need to find the optimal dose becomes increasingly critical and FDA has taken notice. Project Optimus, a new initiative from the Oncology Center of Excellence (OCE) within the FDA, was launched to reform the dose optimization and dose selection paradigm in oncology drug development. The project’s mission is to educate, innovate, and collaborate with companies, academia, professional societies, regulatory authorities, and patients to establish a dosage that maximizes not only efficacy, but also safety and tolerability. The project aims for drug developers to discuss dose finding and dose optimization with FDA oncology review divisions early in their development program, well before moving to later stage pivotal trials. 

Over the past few years, we have watched FDA become increasingly vocal about the need to overhaul the current clinical development paradigm for targeted anticancer therapeutics. The industry has received regularly occurring dose optimization recommendations in early-stage feedback for various new molecular entities entering the clinic. The OCE finally released a long-awaited draft guidance in January 2023 entitled, Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases, Guidance for Industry, to help sponsors focus on defining their dosage optimization strategies earlier. An analysis presented in the 2023 Scientific Report by the Friends of Cancer Research showed that a lot still needs to be done to support premarket dose optimization since, in many cases over the past decade, the FDA has allowed for dosing issues to be a part of a sponsor’s postmarketing requirement. This has been done primarily to avoid any delays in getting drugs to fulfill unmet medical needs but begs the question of what the best time for sponsors is to initiate dosing-related questions with the FDA.  

Our continuing analysis of the dose-optimization landscape over the last years leads us to five common themes we believe will help sponsors prepare for these changes.  

Theme 1: This Practice May Be New to Oncology Trials, But It’s Not New to Industry  

The Project Optimus initiative can significantly redefine the approach to clinical development for targeted oncology products, but the need for randomized studies to evaluate multiple doses prior to pivotal trials is not a new concept. Development in other therapeutic areas have long been following this practice. Following dose-escalation, multiple (at least two) doses should be selected based on exposure and pharmacodynamic markers, as appropriate, for evaluation in a randomized study. This may result in the design of a randomized Phase 2 trial or a more flexible seamless Phase 1/2 trial with two or three doses compared to an active control. These randomized studies are critical to the further characterization of exposure-response analyses and safety assessments to inform dose selection for subsequent pivotal trials. Sponsors may learn from dose optimization success stories in other therapeutic areas, including rare disease indications.  

When looking specifically for precedent in the oncology space, one of the first companies to have directly experienced Project Optimus was Amgen. During approval of Lumakras™ for the treatment of Non-small Cell Lung Cancer with a KRAS G12C mutation, Amgen agreed with the FDA’s proposed post-marketing requirement to conduct a randomized clinical trial to compare the safety and efficacy of Lumakras™ at the approved dose of 960 mg once daily versus a lower daily dose of the drug (240mg once daily dose). Kura Oncology announced in early 2021 that it would also run a new dose-optimization trial for the acute myeloid leukemia therapy KO-539. Since the release of the draft guidance in January 2023, comments regarding dose selection and optimization have become a routine topic of conversation with the FDA during early interactions like the Pre-IND meeting.  

Theme 2: Become Your Product’s Expert to Make the Best Dosing Decisions Early On  

This theme applies to all drug developers irrespective of therapeutic area, but sponsors of oncology products should pay close attention to the preclinical activities that are intended to inform identification of an initial dose and any additional data that might facilitate efficient dose optimization in later development. Appropriately characterizing a product’s therapeutic index based on biological activity and toxicity, as derived from preclinical studies, is essential to making the right dosing decisions. 

Sponsors should also remain aware of product and/or class-specific concerns at an early stage. For example, kinase inhibitors often exhibit poor aqueous solubility. So, thoroughly characterizing potential risks related to food-effect in preclinical studies may identify a need for early evaluation of the risks and the corresponding impact on selecting the recommended Phase 2 dose (RP2D) in the clinical trial design. 

Theme 3: A Pre-IND Meeting is Not Too Early to Discuss Dose-Range Findings 

After performing preclinical work and establishing necessary data, sponsors should consider leveraging discussions with the FDA to align on a plan for dose-range findings during their pre-Investigational New Drug Application meeting (PIND). A PIND is never too early to have such discussions. As mentioned above, discussions around dose selection and optimization during the Pre-IND meeting are more routine than the exception, with the expectation these early interactions can help sponsors design appropriate studies during early development. Sponsors are highly recommended to utilize the PIND meeting to align with the FDA on the clinical design for their first-in-human (FIH) study, so their trial design appropriately accommodates efficient dose optimization. 

For example, Phase 1 trials should include adequate pharmacokinetic (PK) sampling to enable a clear determination of the PK properties of the drug and preliminary characterization of dose-exposure relationships. When feasible and appropriate, pharmacodynamic (PD) endpoints should be incorporated to determine the drug exposure that results in inhibition of the drug target.1  

In our experience with recent PIND interactions for investigational oncology products, we are routinely noticing language warning sponsors of submitting inadequately justified doses, coupled with advice toward discussing a proposed dosage optimization strategy with FDA as early as possible. There have been indications in PIND feedback that an inability to justify dosages may result in a clinical hold of the IND due to concern of insufficient characterization of safety to assess the risks of exposing a large number of patients to the IND. Sponsors should respond appropriately to this type of feedback and prospectively align with FDA on trial design in order to de-risk the subsequent IND submission. 

Theme 4:  Thoughtful Design is Paramount to Clinical Success and Patient Safety 

We are increasingly seeing recommendations that sponsors optimize their dosing regimen in advance of commencing registrational trials. The idea that randomized Phase 2 designs may be useful to provide information regarding an optimal dose(s) is becoming predominant in PIND feedback and there is recommendation to pool clinical PK, PD, efficacy, and safety data, as well as nonclinical pharmacology data, to conduct integrated dose-response and exposure-response analyses for dose optimization. 

The timing of optimal dose identification is being specified in the FDA’s feedback, but since dose escalation trials are limited in sample size and frequently do not identify an optimal dosage, the FDA is encouraging sponsors to evaluate different dosages of oncology products early in clinical development as well as to evaluate clinical data from dose-finding cohorts over a wide dosage range to characterize the dose-response relationships for activity and safety and to support the optimal dosage(s) for further clinical development. Any of these options should be discussed with the FDA as soon as possible.  

Consistent with other clinical development initiatives, the FDA is also eager to incorporate patient-reported outcomes (PROs) to guide dose optimization and selection. Although it’s unclear how actionable PROs may be in small, early-stage oncology studies, the goal appears to be better characterization of tolerability over time.  

Theme 5: This Revision Will Be Better for Patients and Industry  

While patient safety is the driving factor behind Project Optimus, FDA still recognizes the importance of accessibility for patients. FDA has signaled that randomized dose-finding studies could be designed to allow for crossover such that the trial could be continued as a single group trial including participants from the randomized study who were being treated with the selected dose.2 Such an approach may afford improved dose optimization without significantly compromising overall development timelines.  

As oncology companies continue to develop more effective therapies, patients remain on treatment for longer durations and minimization of long-term potential safety effects becomes increasingly important. Therefore, dose-finding and optimization in oncology can no longer wait until post-marketing and must be integrated into the early-stage clinical development plan. Given the heterogeneity of cancer patient populations, earlier assessments of exposure-response data may improve safety and efficacy profiles across subpopulations within one disease.  

Ultimately, this is the optimization that FDA is seeking. But this change doesn’t necessarily result in longer development timelines – a common industry concern. Something is always learned from exploring extra doses and, as stated before, reviewing preclinical data, and sharing early findings with the FDA as soon as possible can help to optimize a trial’s timelines. Alternatively, performing thorough dose optimization in earlier stages of development may help sponsors to discontinue development for drugs that are not commercially viable.  

Conclusion 

As these themes continue to emerge and the FDA further refines its vision, it will be critical for sponsors to collaborate with FDA and to remain nimble while the framework for Project Optimus comes into focus. The January 2023 guidance is full of insights and a strong step in a positive direction for patients and industry. With patients at the center of drug development, and with forward thinking and flexibility in trial design, the FDA is confident that oncology treatments will be improved and will work alongside sponsors to align on best practices.  

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If you have any questions about your oncology clinical development plan and regulatory strategy, contact Halloran.

We are ready to partner when you are. 

References: 

  1. Friends of Cancer Research. Optimizing Dosing in Oncology Drug Development: Friends of Cancer Research Annual Meeting 2021. Accessed 20 February 2024. https://friendsofcancerresearch.org/wp-content/uploads/Optimizing_Dosing_in_Oncology_Drug_Development.pdf 
  2. Shah M, Rahman A, Theoret MR, Pazdur R. The Drug-Dosing Conundrum in Oncology – When Less is More. N Engl J Med. 2021; 385:1445-1447 
  3. FDA. Optimizing the dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases, Draft Guidance for Industry. January 2023. Accessed 20 February 2024.  https://www.fda.gov/media/164555/download  
  4. Friends of Cancer Research. 2023 Scientific Report: Regulatory Advancement for Patients. Accessed 20 February 2024. https://friendsofcancerresearch.org/wp-content/uploads/Friends-Scientific-Report_2023.pdf  

Reconsidering the 3+3 Dose Escalation in Oncology Studies

Many product developers are propelled by the goal of delivering life-saving treatments as quickly and as safely as possible to patients who are left with no other options. With oncology development, the standard 3+3 dose escalation in study design in first-in-human (FIH) clinical trials is still the standard, however, we should consider alternative Phase 1 study designs to achieve the optimal recommended Phase 2 dose (RP2D) for patients before entering later stage studies.  

In recent years, we have seen the emergence of molecularly targeted agents (MTAs) and immunotherapies and a transition away from cytotoxic agents. As the oncology treatment landscape changes, it is becoming increasingly important for researchers to consider alternative study designs that determine the optimal biological dose rather than only the maximum tolerated dose (MTD).  

In March 2022, FDA released the final Guidance for Industry “Expansion Cohorts: Use in First-in-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics” which provides recommendations for leveraging expansion cohorts within FIH trials and emphasizes the importance of flexibility, safety monitoring, biomarker-driven strategies, and collaboration in the design and execution of expansion cohort studies. Expansion cohort studies can utilize both rule-based and model-based approaches, depending on the specific trial design and objectives. The guidance states these types of studies should be limited to patients with serious oncologic diseases for which there are no alternatives.  

Implementing alternative study designs to efficiently achieve a safe and optimal recommended Phase 2 dose is crucial for clinical research in 2024 and years to come. 

Rule-Based Designs 

Rule-based designs apply simple rules to allow for step-up or step-down dosing in the absence or presence of toxicities seen at each dose level. By far the most popular Phase 1 study design in oncology, the 3+3 dose escalation has been utilized in more than 95% of published Phase 1 trials in the past few decades.1 The logistical simplicity of the design together with familiarity with the escalation rules by clinicians and researchers are likely precluding exploration and implementation of novel study designs.2 Accelerated titration design (i.e., rapid intrapatient drug dose escalation) and the rolling six design (i.e., up to six patients concurrently enrolled onto a study) are extensions of the 3+3 design. 

However, continued reliance on the 3+3 dose escalation design in oncology should be questioned. Statistical simulations have shown the MTD is identified in as few as 30% of clinical trials that utilized a 3+3 design.2 Furthermore, the 3+3 design exposes an unnecessary number of patients to subtherapeutic doses. Due to the number of escalations and the number of patients required to be treated at each dose level, a large proportion of patients are treated at low doses that are potentially subtherapeutic, while few patients receive doses at or close to the RP2D.3 While this may be a suitable approach for drugs where there is limited safety data, alternative designs, such as Bayesian adaptive designs or model-based approaches, are increasingly being explored to improve efficiency and accuracy in dose finding. 

Model-Based Designs 

Model-based designs use data from each dose level to model a dose-toxicity curve and provide a confidence interval for the RP2D, once achieved.3 While these designs require biostatistics expertise and statistical modeling software, model-based designs can achieve better estimations of the target probability of a DLT at the RP2D while minimizing suboptimal dosing.2 Particularly for agents with a low expected toxicity profile, it may make sense to consider a model-based design, given that model-based designs assume a relationship between the study drug dose and the likelihood of occurrence of a DLT. Furthermore, in a model-based design, medical decisions are based on statistical inference, which reduces subjectivity in the dose escalation decision-making process.1

Traditional model-based designs, such as the continual reassessment method (CRM) and efficacy-toxicity trade-offs, were introduced decades ago, and yet are still scarcely used in practice due to a perception of being too statistically complex.4

More recently, there has been increased interest in a combination design that incorporates the simplicity of a rule-based design with the better performance of a model-based design; a model is used for decision making but allows for the decision-making rules to be pre-tabulated before the trial begins.5

Model-Assisted Designs 

One such combination design, the modified toxicity probability interval (mTPI) design, is equally as simple, transparent, and costs less to implement as the 3+3 design.1 The mTPI design requires a biostatistician to generate a decision table to be included in the protocol based on the number of planned dose levels in the study. In the decision table, the dose may be escalated, de-escalated, or eliminated based on the number of patients treated and the number of DLTs.  

‘Eliminate’ means that the current and higher doses will be eliminated from the trial to prevent treating any future patients at such doses because they are overly toxic. In a simulation of 2,000 trials comparing the operating characteristics of the 3+3 design and the mTPI design, it was concluded that compared with the 3+3 design, the mTPI design is safer, because it treats fewer patients at doses above the MTD and is more likely to identify the true MTD than the 3+3 design.1 

One of the drawbacks of the mTPI design and model-based designs, in general, is that while they can accelerate dose escalation by treating fewer patients at sub-therapeutic dose levels, the inclusion of one patient per dose level may also deprive the study team of data on interpatient pharmacokinetic (PK) variability.3 However, this limitation can easily be addressed by expanding the cohort size if additional PK data are needed. 

But a potentially superior model-assisted design is the Bayesian Optimal Interval (BOIN) method because it outperforms the mTPI with higher accuracy identifying the MTD and a lower risk of overdosing patients. 

Looking Beyond the 3+3 

The limitations of the 3+3 dose escalation in oncology study design and potential for alternative designs have been discussed for decades, with little to no increase in the number of Phase 1 studies utilizing alternate designs. In 1997, a simulation comparing the 3+3 design with three accelerated titration designs was conducted. The results showed the alternate designs were favorable for several reasons:6  

27 years later, these results have had seemingly little to no impact on clinical trial designs as the 3+3 design continues to be commonly utilized. 

Further substantiating the 1997 simulation, a recent comparison of 172 rule-based versus model-based oncology trials were conducted. The results showed rule-based designs took a median of 10 months longer than model-based designs to complete, fewer patients were treated at sub-optimal dose levels in model-based versus rule-based studies, and that despite the savings in time and minimization of suboptimal treatment, safety was preserved in the model-based design.7 

While alternative designs have remained more the exception than the rule, FDA has begun encouraging more innovative and adaptive designs in early phase studies; FDA’s recent guidance calls out a need to consider adaptive trial designs in exploratory and dose-finding studies as a way to ensure optimal dose selection while affording the opportunity to learn more about exposure, pharmacodynamics, and variability in patient response.8

In addition, FDA launched Project Optimus in 2022 – an initiative from the Oncology Center of Excellence (OCE), to reform the dose optimization and dose selection paradigm in oncology drug development. The project’s mission is to educate, innovate, and collaborate with companies, academia, professional societies, regulatory authorities, and patients to establish a dosage that maximizes not only efficacy, but also safety and tolerability. 

As new drugs are brought to the clinic, it is important to understand there is no one best escalation scheme that can be applied across all scenarios. While the 3+3 dose escalation in oncology study design still may be appropriate in some situations, clinical researchers should take into consideration the mechanism of action of their drug as well as the expected toxicity profile when considering study design and resist opting for the 3+3 design in every instance for its simplicity. 

To begin the conversation around your clinical development strategy for your oncology product, contact Halloran. We’re ready when you are.

References 

  1. Ji, Y., & Wang, S. J. (2013). Modified toxicity probability interval design: a safer and more reliable method than the 3+ 3 design for practical phase I trials. Journal of Clinical Oncology, 31(14), 1785.
  2. Hansen, A. R., Graham, D. M., Pond, G. R., & Siu, L. L. (2014). Phase 1 trial design: is 3+ 3 the best?. Cancer Control, 21(3), 200-208. 
  3. Le Tourneau, C., Lee, J. J., & Siu, L. L. (2009). Dose escalation methods in phase I cancer clinical trials. JNCI: Journal of the National Cancer Institute, 101(10), 708-720. 
  4. Wheeler, G. M., Mander, A. P., Bedding, A., Brock, K., Cornelius, V., Grieve, A. P., … & Bond, S. J. (2019). How to design a dose-finding study using the continual reassessment method. BMC medical research methodology, 19(1), 1-15. 
  5. Yan, F., Mandrekar, S. J., & Yuan, Y. (2017). Keyboard: a novel Bayesian toxicity probability interval design for phase I clinical trials. Clinical Cancer Research, 23(15), 3994-4003. 
  6. Simon, R., Rubinstein, L., Arbuck, S. G., Christian, M. C., Freidlin, B., & Collins, J. (1997). Accelerated titration designs for phase I clinical trials in oncology. Journal of the National Cancer Institute, 89(15), 1138-1147. 
  7. Brummelen, E. M. J. V., Huitema, A. D. R., Werkhoven, E. V., Beijnen, J. H., & Schellens, J. H. M. (2016). The performance of model-based versus rule-based phase I clinical trials in oncology. Journal of Pharmacokinetics and Pharmacodynamics, 43(3), 235–242. doi: 10.1007/s10928-016-9466-0. 
  8. FDA. Guidance for Industry: Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases. 2023. https://www.fda.gov/media/164555/download. Accessed 13 February 2024. 

Why The FDA Modernization Act 2.0 is The Challenge Our Industry Needs 

Shawn Roach, one of Halloran’s Regulatory Chemistry, Manufacturing, and Controls (CMC) experts, was a panelist at the Advancing Drug Development Forum (ADDF) held in Boston on December 14, 2023. Shawn and his fellow panelists discussed the regulatory implications of the FDA Modernization Act 2.0.

Passed about a year ago, the FDA Modernization Act 2.0 formally overturned the longstanding agency expectation that sponsors of regulatory submissions should include animal studies as part of their nonclinical package. Panelists weighed potential risks of conducting safety studies of a novel drug in alternative models (e.g., studies conducted in silico, using organoids, or employing Artificial Intelligence) against the known risks of studies in animal models.  

Panelists noted animal studies are time consuming and expensive, use of animals raises ethical questions, and, most importantly, safety data from animal studies is often not translatable to human subjects, contributing to the high failure rate of drugs in Phase 1 and 2 trials. 

The panel recognized clinical trial sponsors’ potential concern that there is no formal guidance yet from FDA on models and studies likely to be acceptable to regulators; however, as Shawn alerted, “pioneers in cell and gene therapies and psychedelic medicines faced this same challenge and overcame it by engaging early with the agency in the drug development process and proposing rational, well-designed safety studies.” Based on draft and final guidances on these topics, the work of these early adopters clearly shaped FDA’s thinking, thus turning this challenge into an opportunity.  

Shawn also highlighted FDA programs intended to support sponsors proposing novel responses to the challenge of using non-animal models in determining the safety of their product are available, including The Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program and the Emerging Technology Program (ETP).  

The audience also demonstrated interest in the FDA’s ETP program – a collaborative program in the Center for Drug Evaluation and Research (CDER) where drug developers can meet with the Emerging Technology Team (ETT) to discuss, identify, and resolve potential technical and regulatory issues regarding the development and implementation of a novel technology. While change is hard, especially in the risk averse biopharmaceutical industry, this seemingly small change in the law, noting the bill removes the requirement for animal studies and instead allows for the alternatives to animal studies as described above, can be seen as a great opportunity for technology development.  

The potential to build and further develop the next generation of tools used to advance safety testing in drug development is immense. Companies with promising technologies can investigate the opportunities to be had through the FDA’s ISTAND and ETP programs. There’s an open door awaiting the journey into the next chapter of drug development. All it takes is the first step.  

While acknowledging the risks, challenges, and opportunities in reducing or even eliminating animal studies in drug development, panelists agreed this change is long overdue. Or, as one panelist put it, “It’s about bloomin’ time!” 

To discuss FDA’s programs, including ISTAND and ETP, and your regulatory strategy, connect with Halloran today. We’re ready to partner with you. 

  

Clinical Trial Manager to The Rescue: The Halloran Approach 

Clinical trials are essential for bringing new treatments to patients. However, not all trials proceed smoothly, and some may require intervention to overcome challenges and find solutions. What if your trial is experiencing significant issues and you’ve just lost your Clinical Trial Manager (CTM)? You can either rush to fill the position or hire an experienced consultant to fill the immediate gap. The best-case scenario for your clinical trial management strategy may be to hire a consultant to temporarily fill the role to minimize risk, establish priorities, and address challenges until you find a full-time replacement. 

Here are the critical first steps a Clinical Trial Manager takes when tasked with taking over a project in a rescue situation. 

Initial Assessment 

Upon assuming the role of a CTM in a rescue situation, the first step involves conducting a comprehensive initial assessment of the project. This includes reviewing all available documentation:  

Team Evaluation 

The success of a clinical trial heavily depends on the collaboration and efficiency of the project team. The CTM must evaluate the current team structure, assess individual roles, and identify any gaps in expertise. Effective communication with team members is crucial to understanding their perspectives and gaining insights into the challenges they face to find opportunities for improvement.  

Stakeholder Communication 

Clear and transparent communication with all stakeholders is paramount in a rescue situation. The CTM must engage with the clinical trial sponsor, regulatory authorities, and other relevant stakeholders to provide updates on the rescue plan and address concerns. Building trust and maintaining open lines of communication contribute to a collaborative environment fostering success. 

Risk Identification and Mitigation 

Conducting a risk assessment is vital to identifying potential threats to your trial’s progress. The CTM must categorize risks based on their impact and likelihood, developing a risk mitigation plan to address challenges. Timely identification and proactive management of risks are essential for steering the trial back on course. 

Protocol Compliance and Regulatory Alignment 

A thorough review of the study protocol ensures the trial adheres to established guidelines and regulations. The CTM must identify any deviations from the protocol and work towards bringing the trial back into compliance. Regulatory alignment is crucial to ensure the trial continues to meet the ethical and legal standards set by relevant authorities. 

Data Quality and Integrity 

Ensuring the accuracy and integrity of trial data is a fundamental responsibility of the CTM. Conducting a comprehensive data quality assessment allows the manager to identify any issues affecting the reliability of the data collected. Implementing corrective measures and reinforcing data management practices contribute to the overall success of the trial. 

Timeline and Budget Reassessment 

A rescue situation often brings about delays and increased costs. The CTM must reassess the project timeline and budget, providing realistic projections for stakeholders. Transparent communication regarding any necessary adjustments is crucial for maintaining trust and support from sponsors and other financial contributors. 

In summary, the first steps of a CTM are instrumental in turning the project around and ensuring its success. Through meticulous assessment, effective team collaboration, transparent communication, risk mitigation, and regulatory compliance, the CTM plays a pivotal role in navigating challenges posed by a troubled clinical trial. The ability to adapt, strategize, and implement corrective measures defines the success of the rescue mission and contributes to the advancement of medical research. 

Ready to learn more about Halloran’s Clinical Trial Leadership and Operations services? Click here.  

If you need a temporary Clinical Trial Leader, contact Halloran today.