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Prioritizing Agility When Choosing a Contract Research Organization

vantagebiotrials — Sat, 23 Mar 2024 01:51:24 +0000

Prioritizing Agility When Choosing a Contract Research Organization

Publication date: September 2023 / Download PDF
Author: Josée Comeau

Introduction

Throughout the years, the field of clinical research has continued to grow in complexity and has encountered numerous challenges, and although processes have been well established, many of us have settled into a daily routine that maintains the status quo.

It’s time for us to move away from traditional practices and introduce a concept that some niche CROs, like Vantage BioTrials, have been utilizing effectively since the early days of the Covid-19 pandemic, namely using agile methodologies in running clinical trials.

There are many strategies to help with time management that are available in a PM’s toolbox, but if they were easy to implement, we as an industry wouldn’t still be struggling with it. Part of this struggle comes from the fact that humans and systems have the tendency to follow the easiest path of no resistance. For our brain, resistance is something that requires effort, and therefore it becomes relentless and demands time. A natural reaction is to ignore or postpone certain obstacles and focus on activities we are more familiar with. As a result, we end up wasting time and not meeting the expected project milestones.

Perspective

As per ClinicalTrials.gov, there is well over 64,000 recruiting studies that are “ongoing” in status. We started 2023 with approximately 437 000 registered studies as opposed to 137 000 in 2013 (which equates to a ~320% increase over a decade).¹ Have our resources grown to cover those needs? Not even close. As our workforce has been shaken by a pandemic, high turnover, new regulations and restrictive budgets for the past few years, resourcing and manpower challenges have exponentially grown as well.

To compensate, some have attempted to re-structure themselves and found more efficient ways to work but, in the last few years, for many of us, it hasn’t seemed enough to keep our head’s above water for the long haul. As we strive to achieve excellence in managing clinical trials, we need something more to accelerate our progress and conduct these studies in what we would sometimes refer to as a “smoother process” and gain efficiencies. It has become essential to bring in more experts who understand the intricacies of research and enhance process flows with agile frameworks.

Agility is Key

When it comes to effectively managing clinical trials, an agile methodology has become increasingly important in light of the challenges posed by high turnovers and low staffing. Bounded by communication breakdowns, delays in timelines, and other deviations that can negatively change the outcome of a clinical study, it’s clear that we need to find new and innovative ways to work more efficiently as we settle into a reality that brings forward long-term impacts. With the flexibility of an agile framework, we can adjust our goals and objectives in real time and keep up with the constantly evolving environment. This agility also means that we can make quick decisions based on available data and adjust our strategies accordingly. A solid risk-management plan should be prepared by the study team well in advance of the “first patient in” milestone, and continuously verified, analyzed, maintained and updated as the study progresses.

Agile management is all about being adaptable and flexible in your approach, and it can be especially useful in the context of managing and monitoring of clinical trials. As the pioneering software engineer, Barry Boehm once said, “Agile methods derive much of their agility by relying on the tacit knowledge embodied in the team, rather than writing down their knowledge in plans.” It also helps to break down large projects into smaller, more manageable tasks, so that teams can easily adjust to changes and challenges as they arise. An agile approach helps keep timelines on track and ensures that everyone remains focused on the study’s ultimate goals.

Be Empathic

Let us also switch gears for a moment and look at the current situation through the lens of clinical trial sites; in general, many sites have had to tighten their belts and over-stretch their resources in order to keep up with the demand of the sheer volume of trials being thrown at them from Sponsors, and this has led to many sites refusing to work with certain types of Sponsors or CROs, creating a further gap between the number of available sites to perform the required studies. Down the road, this can lead to entire clinical programs being cancelled due to lack of qualified sites required to perform them. To combat this negative trend, as an example, Vantage BioTrials has embedded a culture of cooperation and collaboration between our staff and the sites we manage, acting as ambassadors (not adversaries) when performing site management activities on behalf of our Sponsors. Part of that success stems from effective communication strategies between all stakeholders that results in leading through empathy in order to understand the needs of our sites and supporting them with additional training, occasional check-ins, and a supportive hand when required.

Think Outside the Box

A major lesson that the Covid-19 pandemic taught us is that with workforce shortages, sometimes we also must settle for who is available; this can create diluted knowledge but does not necessarily translate into failure. Vantage BioTrials’ experienced team can support your study by adapting to its needs with agility, analysing requirements for technology and automation, quickly adapting in order to streamline operations and ensure tasks are completed efficiently and effectively. It can lead to more accurate and consistent results and tremendous success for your projects.

Another significant challenge facing the scientific community is the environments in which we work, and the communication strategies we use.
Scientific research plays an enormous role in our daily lives, and we were lucky enough to see the power of teamwork pull together worldwide as we survived through the global pandemic. In that sense, the entire world was forced to become “agile” very quickly. It allowed us to prioritize our well-being with an adaptive and flexible work environment, but also keenly bringing to the surface other challenges already present.

Although the status of the “pandemic” officially ended a while ago, one of the most significant impacts it had on science is the way it forced us to reconsider our work environments. With so many people working remotely or taking time off due to illness, it has been challenging to keep science moving forward at its usual pace. As a result, many studies now face delayed timelines, and research data is being affected. As it is challenging to plan and prevent these issues, it is also crucial we move forward swiftly for the sake of scientific progress.

Even if remote working can bring many positive outcomes for productivity, the disruption in communications and the isolation from not being in the office are significant. Perhaps most concerning of all is the impact that mental health challenges are having on advancing research projects. The McKinsey & Company survey mentioned that more than half of Americans between the ages of 18 to 34 struggle with mental health issues, affecting their work performance when working from home. Distractions, isolation, and a lack of contact with colleagues can all contribute negatively, which is where strong communication strategies come into play.² Teams spread out across different locations or working remotely need to stay in touch and communicate effectively using tools like video conferencing, instant messaging, and other collaboration tools. By maintaining open lines of communication, teams can work together more effectively and ensure the research progresses smoothly. Maintaining proper communication can also be especially challenging for new employees who have yet to have the chance to build relationships with their coworkers and get a sense of the company culture. For them, it translates into less peer recognition and less acknowledgment of the company’s values. Their roles are often unclear due to the nature of the communications, and the distractions from home can be difficult to overcome and impacts productivity.

Final Thoughts

Keeping a team motivated and on track can be challenging, let alone transferring knowledge and work competencies with a lack of fluidity between internal groups. Clear communication is vital for the success of any scientific or business venture, and the pandemic put that to the test. It is crucial to also prioritize flexibility and agility when planning clinical trials. This means being open to changes in our approach and being willing to adapt as necessary to ensure the research stays on track. This is when risk-based management and monitoring becomes crucial as a skill and as a tool. By being prepared for unexpected events and ready to shift gears when necessary, teams can better manage the trials and ensure that they successfully reach their goals. By prioritizing open communication, breaking down larger projects into manageable tasks, and staying adaptable in the face of challenges, teams can navigate the complex world of clinical trials and ultimately achieve success.

Moreover, partnering with a strategic niche CRO like Vantage BioTrials can be a game-changer when meeting goals and objectives. Experienced CROs bring a wealth of knowledge, resources, and expertise to the table, which can help to fill any skill gaps within the team. A niche CRO can also provide valuable insights into potential roadblocks or issues that may arise, allowing sites to plan proactively and avoid any possible delays or failures.
The pandemic has shown us how capable we are of adapting to new circumstances and coming together as a team to solve problems. We must continue to prioritize clear communication, efficient workflows, and a solid commitment to our shared mission of advancing knowledge and improving people’s lives. Only then will we overcome these challenges and emerge stronger on the other side!

About Vantage BioTrials

Vantage BioTrials is a leading Canadian Contract Research Organization (CRO) with a proven track record of successfully completing & delivering clinical trial milestones on time and on budget. Since our inception in 2007, we have used innovative clinical trial management strategies for the life science industry with a focus on patient safety & advancing new therapies to market. We offer pharmaceutical, biotech & medical device companies a complete and integrated set of full-service clinical trial management solutions, based on the principles of Quality by Design and Risk-based clinical trial management.

References:

¹ https://www.clinicaltrials.gov/ct2/resources/trends

² https://www.mckinsey.com/industries/real-estate/our-insights/americans-are-embracing-flexible-work-and-they-want-more-of-it

The post Prioritizing Agility When Choosing a Contract Research Organization first appeared on Vantage Biotrials.

Criteria for Choosing a Great Contract Research Organization (CRO)

vantagebiotrials — Thu, 01 Feb 2024 01:48:26 +0000

Criteria for Choosing a Great Contract Research Organization (CRO)

Publication date: February 2024 / Download PDF Author: Viken Bartekian

Introduction

Outsourcing is often a necessity within the health care industry. Many pharmaceutical, biotechnology and medical device companies rely on outsourcing to Contract Research Organizations (CROs) as part of their strategy to advance to the next stage of clinical trials. As a matter of perspective, the CRO market size is expected to grow by USD 63.35 billion from 2023 to 2028. North America is estimated to contribute 40% to the growth of the global market during the forecast period.¹ Fueling this growth often places a burden on decision makers to make informed decisions regarding which CRO to outsource their clinical trial to. So, what makes a CRO stand apart? Simple, five important factors need to be considered: 1) Quality 2) Efficiency 3) Adaptability and Flexibility 4) Knowledge 5) Size, Culture and Values

You will notice that I have not mentioned the all-important cost factor. Understanding that for many companies, cost is an essential consideration to getting their clinical trial off the ground, we would also have to conclude that time is an important extension of cost. Just as the saying “time is money”, the clinical trial process has many moving parts, and all those parts are based on one constant factor, which is time! The lowest cost can be an influential factor to choosing a CRO. However, it’s important to understand that many CROs also use this as a bait tactic, only to generate change orders post contract win because they didn’t plan or estimate the time needed adequately.

Quality

The word quality is defined as the standard of something as measured against other things of a similar kind, or the degree of excellence of something.

To quote William A. Foster, “Quality is never an accident. It is always the result of high intention, sincere effort, intelligent direction, and skillful execution.”

We like rephrasing this quote into “Quality is an attribute we should always strive to achieve”. For this reason, quality always remains at the forefront of every clinical trial that Vantage BioTrials manages. It is embedded in our systems, procedures, and policies; in the way we train, monitor, and manage clinical trials. As experts in our field, we continuously implement risk mitigation by using Quality by Design (QbD) methodologies (to read more about QbD, refer to our previous Whitepaper entitled “Quality by Design in Clinical Research”).²

Having a quality mindset isn’t only to concentrate on results that matter. It’s to ensure that all results matter.

Efficiency

The term efficiency can be defined as the ability to achieve an end goal with little to no waste, effort, or energy. Being efficient means you can achieve your results by putting the resources you have in the best way possible. Put simply, something is efficient if nothing is wasted, and all processes are optimized. In other words, you will have mastered efficiency when you’re using the least amount of input to get the highest amount of output.

As a CRO, identifying efficiencies early on is crucial for the success of any clinical trial. But how early is too early? To give you an example, Vantage BioTrials applies Risk-based Quality Management (RBQM) strategies during the initial Request for Proposal (RFP) stage. Thoroughly reviewing a protocol and challenging a Sponsor is part of our process which helps align realistic expectations. This in turn presents an opportunity to explore changes required in order to achieve the most successful outcome for a project.

In our experience, open & transparent discussions help build a solid foundation towards maintaining an efficient long-term partnership.

Adaptability & Flexibility

Change is a constant factor in everyone’s life. Humans are often averse to change; we like a routine. Adapting to constant change is sometimes a challenge during the best of times. We can only imagine, and some of us have even lived it, changing ourselves or our environment thorough the worst of times.

As a CRO, with increased competition and a shifting regulatory landscape, we are constantly faced with significant challenges that push us to find ways to differentiate our service offering and remain competitive. As a specialized CRO, Vantage BioTrials is able to quickly pivot and apply tools and technologies that continue to conform with regulatory requirements. We remain vigilant, make quick decisions, and ensure little or no disruption to our services.

How quickly do we adapt you may ask? During the COVID-19 pandemic, we shifted from on-site monitoring to remote monitoring overnight. Even after some of our employees were poached to larger competitors, we quickly on-boarded local consultants with which we’ve formed strong relationships over the years. We went from accepting on-site Sponsor audits to remote ones by adopting a Quality Management System software. We adopted and onboarded a robust CTMS system within a month to track real time metrics of any given project.

Similarly, continuing to remain flexible is vital. Granted that in certain cases, flexibility becomes challenging. For example, a client wants your CRA to go monitor on-site across the country at the 11th hour, knowing that there are circumstances that would not allow you to do so (e.g. snow storms, ongoing airport strikes, etc.). Flexibility does not mean you jump when asked to. Flexibility is the willingness to change or compromise. Therefore, being solutions oriented is a key driver to remaining flexible. If one cannot physically go and monitor, then suggest additional remote monitoring as an option until on-site monitoring is possible again. If required, provide a valid explanation in defense of your decision. Remember that compromise swings both ways.

Financial flexibility is also important and often a driving force in the decision-making process of start-up biotechnology and medical device companies. A pricing model that Vantage BioTrials has utilized repeatedly is the fixed fee model:

Not withstanding any amendments to the study design or protocol, this pricing model guarantees a set budget for the entirety of a project. It allows the tracking of projected vs. actualized amounts on a monthly basis. The benefits of this type of model includes:

Aligning incentives
Transparent budget visibility
No unexpected fee or charges
Shared accountability on commitments
Builds trust and deepens relationships

Lastly, it is important to remain focused in providing operational excellence throughout the management of clinical trials. With our proven track record, Vantage BioTrials has managed clinical trials in various therapeutic areas from the most complex (rare disease, oncology, pediatric, respiratory, infectious disease) to simple (consumer health) and has repeatedly demonstrated its ability to adapt and achieve all clinical trial milestones.

Knowledge

Knowledge is a fundamental criterion when it comes to any business. It isn’t regarding how much you know, but also how much you can educate others with your knowledge.

With over 19 worldwide regulators (Health Canada, FDA, EMA, ANVISA, TGA, etc.) and a countless number of guidelines and standards within these governing bodies, the healthcare industry is one of the most heavily regulated. The different types of knowledge bases become even more crucial; regulatory, medical/scientific, quality standards (data, monitoring, biostatistics, risk analysis), operational best practices, budgeting, and technical. Demonstrating this knowledge base through examples of personal experiences, expertise and case studies is an important element that can strengthen the qualities of a CRO. Maintaining a sound training program/matrix ensures your organization’s ability to perform clinical trials which can in-turn instill the Sponsor’s confidence in your ability to delivery quality results.

Size, Culture and Values

The size of a CRO can be misleading when shopping for one. In fact, small size CROs such as Vantage BioTrials have proven time and again that we can manage clinical trials as good, if not better, than the larger CROs. Don’t look further than our achievement in 2021 when we announced the successful management and completion of a Phase IV observational, multicentre, postmarketing study in adult patients with a clinical diagnosis of moderate-to-severe Hidradenitis suppurativa (HS), approximately 12 months in advance.³

In the history of clinical trials, no other CRO (large or small) has ever come close to achieving this type of milestone. The result of which includes many of the factors listed above, plus, one important factor: our pharmaceutical Sponsor decided to take a chance on us, not due to cost, but because of our lean business model, which presents a more intimate, closer relationship with their team. This in turn leads to faster execution, easier conversations, and a less robotic and more genuine experience that generates trust.

Trust is the most important criteria when looking for a CRO as Sponsors need to learn to “let go” from their project and trust their CRO just as you would trust the electrician you hired to rewire your home. This is mainly the reason why having too much specialization in one domain can be counter-productive to the relationship and speed of execution. Developing trust and allowing your CRO to deliver results on their own terms also allows for mistakes to happen, for everyone to learn and grow, and for the relationship to flourish into a long-term partnership. Clinical trials are run by humans. To err is human, and mistakes will happen, it’s inevitable. Allowing your peers the space to prove their worth fosters deep appreciation for one another.

Respectively, it is the CRO’s duty to communicate properly, give regular updates, share enthusiasm, as well as to be fully transparent and accountable when there are red flags and concerns, as communication is key to the overall success of the project. The values of both companies need to be mutual and shared, and the Sponsor must fully explain the overview of the project, delegate tasks accordingly and the CRO needs to make the Sponsor comfortable by creating solid plans of action showcasing their full engagement to the project.

Having a vision explained, shared, and understood, as well as having aligned values, increases the chances of having matching company cultures and strong long-term harmonious relationships.

Final Thoughts

As competition grows, some CROs continue to over promise their capabilities and underestimate (or low ball) their costs. Sponsors are faced with challenging decisions on who to outsource to or sometimes they maintain the status quo and avoid changing CROs altogether because it’s perceptively too much of a burden. Factors other than cost need to be considered when deciding who to partner with.

As large CROs continue to remain siloed, it is important to choose a CRO that continues to offer flexibility in its service offering and fits your purpose. The same level of service should be given regardless if you’re a small biotech, medical device, or a large pharmaceutical company.

Building a strong relationship of trust will allow shared vision, values, and culture, which in turn maximizes chances of study success – always maintaining a clear Vantage Point!

About Vantage BioTrials

References:

¹ https://www.prnewswire.com/news-releases/contract-research-organization-cro-market-size-to-grow-by-usd-63-35-billion-from-2023-2028–north-america-to-account-for-40-of-market-growth—technavio-302027963

² https://vantagebiotrials.com/quality-by-design-in-clinical-research/

³ https://vantagebiotrials.com/vantage-biotrials-successfully-manages-real-world-effectiveness-of-adalimumab-in-patients-with-moderate-to-severe-hidradenitis-suppurativa-the-1-year-solace-study/ Qualities of a Best-in-Class CRO

The post Criteria for Choosing a Great Contract Research Organization (CRO) first appeared on Vantage Biotrials.

Prioritizing Agility When Choosing a Contract Research Organization

vantagebiotrials — Fri, 01 Sep 2023 01:54:53 +0000

Prioritizing Agility When Choosing a Contract Research Organization

Publication date: September 2023 / Download PDF
Author: Josée Comeau

Introduction

Perspective

As per ClinicalTrials.gov, there is well over 64,000 recruiting studies that are “ongoing” in status. We started 2023 with approximately 437 000 registered studies as opposed to 137 000 in 2013 (which equates to a ~320% increase over a decade).1 Have our resources grown to cover those needs? Not even close. As our workforce has been shaken by a pandemic, high turnover, new regulations and restrictive budgets for the past few years, resourcing and manpower challenges have exponentially grown as well.

Agility is Key

Be Empathic

Think Outside the Box

Even if remote working can bring many positive outcomes for productivity, the disruption in communications and the isolation from not being in the office are significant. Perhaps most concerning of all is the impact that mental health challenges are having on advancing research projects. The McKinsey & Company survey mentioned that more than half of Americans between the ages of 18 to 34 struggle with mental health issues, affecting their work performance when working from home. Distractions, isolation, and a lack of contact with colleagues can all contribute negatively, which is where strong communication strategies come into play.2 Teams spread out across different locations or working remotely need to stay in touch and communicate effectively using tools like video conferencing, instant messaging, and other collaboration tools. By maintaining open lines of communication, teams can work together more effectively and ensure the research progresses smoothly. Maintaining proper communication can also be especially challenging for new employees who have yet to have the chance to build relationships with their coworkers and get a sense of the company culture. For them, it translates into less peer recognition and less acknowledgment of the company’s values. Their roles are often unclear due to the nature of the communications, and the distractions from home can be difficult to overcome and impacts productivity.

Final Thoughts

About Vantage BioTrials

References:
1 https://www.clinicaltrials.gov/ct2/resources/trends
2 https://www.mckinsey.com/industries/real-estate/our-insights/americans-are-embracing-flexible-work-and-they-want-more-of-it

The post Prioritizing Agility When Choosing a Contract Research Organization first appeared on Vantage Biotrials.

Perfectly on Time: Successfully Managing Clinical Trial Deliverables

vantagebiotrials — Thu, 03 Nov 2022 03:20:06 +0000

Perfectly on Time: Successfully Managing Clinical Trial Deliverables

Publication date: November 2022 / Download PDF
Authors: Vatche Bartekian, Johanna Garcia, Sheila Ernest

Introduction

A key skill for clinical Project Managers (PM) within the life sciences industry is time management. As a PM, you are not only responsible for the project deliverables, but for every person involved as well as every task performed. Yes, it is a team effort however, in the end, the PM is the one responsible for delivering successfully on the Sponsor’s expectations, from the smallest detail to the general processes.

Manage Your Time Effectively

Resistance becomes our roadblock. If we could anticipate obstacles before they occur, we would increase the chances of avoiding problems, leading to attainable goals and solutions. So, the question becomes “How can we lower or eliminate the resistance to reaching our goals, or in other words, how can we avoid the roadblocks to delivering successful projects?” The first step is to identify them: it is important to know what issues will prevent you from successfully delivering the project whether they are intrinsic to it or not. In this White Paper, we discuss some of the roadblocks related to a typical clinical trial and some related to us, as individuals, as well as some strategies that will help you to mitigate them and better manage your time.

Roadblock #1: Lack of Project Knowledge

Each clinical study has different and unique requirements. Knowing the scope, background, and details of your project and, even more important, understanding it, is fundamental and will help you to avoid wasting time while managing the different components of the project. Something that has helped our project management team (and something that we, as a CRO, encourage them to do often) is ask lots of questions and challenge different parts of the protocol prior to study start-up or even during the proposal building stage. Here are some typical questions we ask ourselves (or the Sponsor):

“Do we have experience with this client?” Knowing your client will help you to know what to expect from them and what they expect from you. And if you do not have any experience with the client, it is important to get to know them to avoid wasting time performing activities that are not required or waiting for unnecessary answers.
“Do we have any information about the Investigational Product (IP) that could potentially become an issue for the project?” Many issues may be unexpected but being familiar with the IP is a fundamental part of the safety and well-being of the study participants. Although the ultimate responsibility for this aspect lies with the Investigator, as a PM your leadership is an essential component to supporting every member of the team including the Investigators.
“Have we (or the Sponsor) worked in the past with the sites planned for the project and how was the experience?” Using past experiences and previous information is a great way to determine the issues you might encounter. If your team has performed “lessons learned” meetings for past studies, go back into those notes and take away key determinants for future success.
“What are your study milestones (i.e. expected deliverables based on realistic timelines)?” This is a critical aspect where you should do everything possible to avoid issues. Having user-friendly electronic systems to document key information, providing adequate training, setting clear procedures, and monitoring them, is crucial to successfully managing your critical data.

Roadblock #2: Project Resources

“Do you have too many or too few people assigned to your project?” “How many Full Time Equivalents (FTEs) are required?” Having too many people involved in some of the processes might cause delays or miscommunications as well as a negative impact on your budget (i.e. too many chefs in the kitchen). Not having enough members in your team could potentially lead to activities not being performed, people being overloaded, decrease in motivation, and less performance overall. Therefore, a good analysis of the resources and assigning them properly – and at the right time – to the tasks is a fundamental part of achieving a smooth and successful project. Likewise, discussing all those questions with your team will help you not only to find the solutions but also to make sure deliverables are on target.

Roadblock #3: Lack of Planning and Organization

Planning and organization allow us to convert targets into achievements. In fact, by planning properly and organizing your daily activities, you can know what to expect and, more important, when to expect it, which is key to successful time management. However, many people struggle with these areas regardless of their role or education. Part of the issue is that most of the time we rely on our brains to remember important dates or deadlines. The problem with that is that our brains are receiving tons of information daily that needs to be processed, and we are prioritizing them automatically on a sub-conscious level, without thinking of all the consequences. This level of information sorting gets even more complicated when, let’s face it, you are assigned to several projects at once. Therefore, you usually end up missing important deadlines. The good news is that planning and organization can be cultivated and with the proper tools, you can be on top of things to avoid unnecessary stress, and get your activities performed on time. These tools help to decrease the burden of stress on your own brain and transfer the load onto helpful systems you can tap into. Some of the tools available to manage your time effectively are Gantt Charts or Work Breakdown Structures (WBS), Clinical Trial Management Systems, and team communication systems (such as Slack, Microsoft Teams, etc). By using these tools, you will be able not only to visualize the project timeline but also the dependencies and the critical paths, as well as communicate in a timely manner with key project staff. In other words, it will help you to keep your project on track.

Roadblock #4: Delegation of Tasks

As human beings, there is a limited amount of work we can perform at a given time. Therefore, delegation is another vital time management skill. As a PM you need to be able to focus on high-value activities and assign tasks to your team members while you keep them engaged and help them to build their autonomy. In fact, when delegation is done properly, it is a win-win situation for all involved. However, you need to keep in mind some factors when delegating, such as training, responsibilities, workload, personal skills, and most importantly whether the tasks should be delegated or not. Another key point when delegating is transmitting a clear message, articulating the desired outcome, and making those you delegate to accountable for their deliverables. Making sure all members are on the same page will help you to avoid misunderstandings as well as wasting time.

Roadblock #5: Lack of Structure

Having a structure and routine can be helpful at any time, in particular, if you are assigned to several projects or tasks to focus on. In fact, following your daily structure or routine will help you to get right to the tasks at a given moment rather than frittering away time to get started. This ultimately helps you to get your project on track. When you are not used to structures or routines, it might be difficult to create them or even follow them. But if you know this is something you struggle with, you can observe how your peers work; is there anyone around you who could help you to build them? Or could your manager support you and help you to improve in this aspect? Asking for help and following a model that you could eventually adapt to can be the beginning of developing a very useful skill.

Final Thoughts

At Vantage BioTrials, we are familiar with the roadblocks previously mentioned and continuously implement solutions that work within our operational structure. For example, to help our team as well as our clients to better understand the essential components of the projects, we make use of tools such as SmartSheet which allows us to update, track and access our projects’ data in real-time.

We also use project peer assignments, so our employees can benefit from learning from more senior members on how to create an effective project workflow or how to delegate effectively. On top of that, we utilize strategic planning through the use of Quality by Design (QbD) methodologies in order to identify risk factors early on and throughout the project lifespan and mitigate those risks continuously, all with the goal of successfully delivering our projects on budget and on time.

About Vantage BioTrials

Vantage BioTrials is a leading Canadian Contract Research Organization (CRO) with over 15 years of successful projects delivered on time and on budget. We use innovative clinical trial management strategies for the life science industry with a focus on patient safety & advancing new therapies to market. We offer pharmaceutical, biotech & medical device companies a complete and integrated set of full-service clinical trial management solutions, based on the principles of Quality by Design and Risk-based clinical trial management.

The post Perfectly on Time: Successfully Managing Clinical Trial Deliverables first appeared on Vantage Biotrials.

Planning a Positive Outcome for Your Clinical Trial

vantagebiotrials — Sat, 03 Sep 2022 03:27:45 +0000

Planning a Positive Outcome for Your Clinical Trial

Publication date: September 2022 / Download PDF
Author: Vatche Bartekian
Co-Authors: Johanna Garcia, Kaiser Lagman, Marina Ohouo,
Sheila Ernest

Introduction

The drug development process presents many complex steps and requires a keen set of skills, knowledge, and resources to arrive successfully at subsequent stages . Within the various phases of drug development, clinical trials, in particular, require robust, coordinated processes and systems, regardless of the size, scope, cost, or duration. With so many requirements and people involved, one might think it is almost impossible for a team to achieve good results or even the objectives of a clinical study. However, as an example outside of our own industry, there exists other processes with a high level of complexity that are performed regularly with high efficiency, low error rates and positive outcomes, such as Air Traffic Controllers. These highly specialized individuals monitor hundreds of aircraft in the sky and on the ground at any given moment. They multitask and are required to take quick decisions that could potentially impact the lives of thousands of people daily. We might therefore ask, “How are they able to complete their tasks with minimal errors?” The answer is, “By going through extensive training, adhering to strict protocols, following policies to prevent burnout, and mastering effective communication skills”, which is quite close to the requirements needed when conducting a clinical trial . Unfortunately, the current reality is that most studies don’t abide by these standards. The main reason why projects fail is due to a lack of organizational capacity and capability, hence often needing “rescue”. This ultimately costs a Sponsor huge delays and leads to inflated budgets. When it comes to providing the best possible outcome for a clinical study, part of the solution is to identify inherent risks related to the study and mitigate them throughout the entire project lifecycle.

Identify the Problem: What are your Pain Points When Conducting a Clinical Study?

The clinical research industry is highly regulated and requires working with extremely regimented protocols and SOPs, extensive and specialized training, mastery of communication skills, and effective resource management to prevent staff burnout.

Running a clinical trial can be very demanding to say the least. A large, multicenter clinical trial often involves dozens or hundreds of people whose activities are coordinated across international borders in multiple languages. There are many different points of failure that can cause minor “discomfort”, and many that can lead to significant damage or even complete disruption of your trial. These failure points can appear suddenly or can be identified early as a trend in the data. Common challenges faced by Sponsors and CROs are at the enrollment level, the lack of a comprehensive patient recruitment plan and patient retention strategy, the data quality, maintaining protocol compliance, site engagement, and even the collaborative engagement between Sponsor and CRO.

Other universal challenges faced are adequate staff resourcing, the use of multiple systems/tools that can be daunting for Study Coordinators, and tracking/reconciliation of study budgets. Historical data has shown that less than one third of studies recruit their original target number of participants within the time frame originally specified which leads to extensive project delays(1).

What’s the solution?

As a small CRO, Vantage BioTrials has learned over our many years of clinical trial management operations that both the right kind of technology and the right kind of Project Manager are essential solutions to achieving project success.

Using the right technology such as a CTMS, Site Payment System, EDC, eTMF and other digital dashboards should be one of the key elements utilized in the day-to-day operations for a clinical trial. The technology that you adopt must, at its core, make your teams’ lives easier and their work more efficient. These dashboards can take on major significance in your project and could make the difference between study failure and success! As an example, we at Vantage BioTrials have implemented Smartsheet as our CTMS in order to help us smoothly manage our projects from different Sponsors across our organization.

The second key that opens the lock to success is an experienced, qualified, and dedicated Project Manager who understands the intricacies of conducting a clinical trial and approaches it with a business management mindset, rather than just a scientific one. The following are key elements an effective Project Manager will focus on in order to deliver on study goals:

Know the Key Principles for Project Management:
• Planning
• Managing Resources
• Effective Communication
• Negotiation skills
• Leadership
• Discipline
• Quality Management

Master each Stage:
• Initiating
• Planning
• Executing
• Monitoring / Analyzing
• Closing

Every stage should be described in a well-written Project Management Plan and remember to include the right tools and technologies throughout each stage.

Project Planning: “If you fail to plan, you plan to fail”
• Set clear objectives & timelines
• Define your resources
• Make staff accountable
• Set a Communication Strategy
• Identify and mitigate Key Performance and Key Risk Indicators (KPIs and KRIs)

The Project Manager’s Secret to Success: Effective Communication Strategies

Communication is the way we exchange information to express our needs and interact with others from very early in life. However, it is known that the process is way more complex than a simple exchange. It is to convey a message that must be:
• Clear, emphasizing a specific topic or goal at a time.
• Complete, including the facts required by the audience.
• Concise, which means short and essential in limited words to the audience.
• Coherent with logic and smooth flow.
• Concrete, specific, meaningful, and based on facts that do not let space for interpretations.
• Courteous, taking the point of view of the audience and showing concern for the receiver.
• and certainly, Correct, exact, and well-timed.

In fact, these are known as the seven C’s of effective communication and they are mandatory in research as we work with many stakeholders to be able to achieve our common goal.

Another aspect to be considered when having multiple collaborators is the transmission of the information. The knowledge of the reality of the project varies depending on the level of involvement in the tasks performed. Therefore, the gap between the line staff and the executives might represent an issue when it comes to understanding the project and putting solutions in place.

Team meetings are another essential part of the project’s lifecycle, however, most of the time, meetings quickly become time-consuming and prevent the team from finding solutions to challenges presented. When a meeting is planned, it is important to focus on the objectives, to have a clear agenda with a useful format, and to invite only people directly involved with the topics. A revision of the previous discussions should be performed to avoid missing or recurrent points. It is also important to respect the time allowed for the meeting and encourage participation, as well as to provide clear indications of the actions required from the participants.

In recent years, the implementation of communication tools or software to share information has been more practical than ever. As a matter of fact, their use has become almost mandatory to disseminate information amongst project stakeholders in almost real-time, which helps to improve productivity, save time, and ultimately project costs.

Minimizing Risk to gain Fluidity in Operations

Analyzing a project’s risk categories should always be the first part of the crucial “Project planning” stage. Abraham Lincoln described it best when he was quoted as saying: “Give me 6 hours to chop down a tree, and I will spend 4 hours sharpening my axe”.

Project Planning includes setting clear objectives & timelines, defining resources, making staff accountable, identifying, and mitigating Key Performance Indicators (KPIs) and Key Risk Indicators (KRIs), and setting a communication strategy.

Once all the project planning is done and execution has started, it is time to check on the health of the project.

What if the task doesn’t happen in the set timeline? What if the resources we planned for are no longer available? Rank the impact of the effect for each risk, analyze it, and put a plan in place to mitigate it.

KPIs/KRIs are important metrics that measure the operational and financial health of the project. They proactively let you identify risks and develop specific and actionable plans, and they provide clear visibility and accountability for all stakeholders.

Why do KPIs/KRIs matter? Because if you can’t measure it, you can’t manage it. Some examples of measurable metrics are:

Time to Site Activation
Time to CDA and Clinical Study Agreement execution
Time to IRB approval per site
SEVs, SIVs scheduled and completed
Time to First Patient In
Enrollment rate (per site/per month); projected vs. actual
Screen Failure rate
Retention rate
Monitoring Visits scheduled and completed

Best Practices for Budgeting a Clinical Study

During the past years, the cost of running clinical trials is only getting higher, despite every stakeholder’s best effort to introduce efficiencies throughout the process. One of the critical aspects of running a trial is the budget forecasting. It is very important to have a thorough and detailed budget to bring the project to success.

To prevent out-of-scope costs, there are key elements to consider while preparing a project budget for a Sponsor. The following items should always be considered when building the total cost of the study:
1. Fixed and variable costs
2. Direct and indirect costs
3. Hidden costs
4. Pass-Through costs
5. Labor and materials
6. Software licenses
7. Administration fees

Based on the Sponsor protocol and depending on the type of study (Early phase, late phase or post-market), a template should be used to develop a comprehensive budget. Before sending the budget to the Sponsor it is crucial to seek the input of Subject Matter Experts and other project team members to check for budget accuracy. During the RFP process a Sponsor should take the time to answer questions from the CRO and be flexible with the RFP submission deadline, while giving the CRO as many details about their expectations to produce the most accurate budget. 10 business days is the typical turnaround time for RFPs for most CROs, assuming enough preliminary information has been provided and questions have been clarified in a timely manner.

Once the budget is sent to the Sponsor, they should:

Scrutinize the bids carefully by assuring that the CRO’s assumptions are realistic, the RFP details are accurate and that there are no outlier budgets compared to competing bids.
Avoid “assuming the worse” with the CROs and rather consider the CROs as sincere partners that are genuinely interested in the successful outcome of the trial.
Clearly communicate internal processes so that the CRO understands possible budget/ timeline ramifications.
Build-in contingencies when generating internal budgets for unexpected factors that can possibly lead to cost overruns such as unanticipated delays, recruitment challenges, changes in staffing, etc. It is important to note that a CRO cannot eliminate all budget-busting items due to unforeseen issues outside their control, and these will result in possible incremental fees.

Once the final budget is approved by all parties, a Scope Of Work (SOW) is developed and helps govern the expectations to keep everything on track. It is in the best interest of the CRO to finish the study as projected as it keeps the resource planning in check and avoids the waste of precious resource time on creating Change Orders (Cos). CROs, like Vantage BioTrials, are experts in suggesting strategies to mitigate risks and each stakeholder is responsible to implement the strategies that make the most sense in minimizing scope creep and budget overruns. The integration of technology is one solution to consider in tracking the budget and any accrual information for out-of-scopes. Having an open mindset that allows for flexibility is a must to effectively manage the cost of a project and smoothly plan for the unexpected.

Final Thoughts

In conclusion, project success is attainable, as evidenced by Vantage BioTrials’ numerous winning streaks of positive study outcomes, but you need to ensure that you have taken the time to properly consider and mitigate all risks, implement proper tools and technologies, make sure you stay organized throughout the journey, and challenge yourself on how you can improve along the way. Only then will you create new opportunities, decrease risks and obstacles, and land on your runway safe, sound, and full of a sense of achievement.

About Vantage BioTrials

References

(1) Farrell et al. Trials 2010, 11:78, http://www.trialsjournal.com/content/11/1/78

The post Planning a Positive Outcome for Your Clinical Trial first appeared on Vantage Biotrials.

CRO SELECTION: How to Find & Select the Right Partner for your Clinical Trial

vantagebiotrials — Sun, 03 Jan 2021 03:29:30 +0000

CRO SELECTION: How to Find & Select the Right Partner for your Clinical Trial

Publication date: January 2021 / Download PDF
Author: Marc Assaad

Introduction

As innovation, research and science are exponentially growing in all directions within the healthcare industry, it is only normal that the outsourcing of Clinical Research Organizations (CROs) is also rapidly growing, resulting in a spike in the numbers of such organizations available to the market. The task of finding and filtering through to the right CRO when conducting a trial is crucial to the overall viability of new drugs and medical devices attempting to obtain approval to penetrate their respective markets. In fact, in a recent webinar discussing criteria in searching for a CRO, the term “marriage” was used repeatedly as the ideal partnership where Sponsor-CRO is a relationship with the intent of being long-term, harmonious and objective-driven, and this relationship starts at the CRO selection stage.

Therefore, it is essential to understand the advantages and disadvantages of each factor determining the potential partnership with a CRO. This whitepaper will serve as a general guideline on the essential attributes a Sponsor should look for when identifying CROs as long-term partners.

Generalist or Specialist CRO?

Just like you do not need to be a nutritionist in order to be a chef, or a mechanic to be an F1 racer; in order to run a clinical trial with efficiency, accuracy and success, you definitely don’t have to be a lab scientist! However, wouldn’t it be ideal for you to find a racer for your Formula 1 team who also has good general knowledge of the inner workings of a race car?

In fact, many CROs will associate with being a Specialised CRO, with their focus in a particular therapeutic area, or a CRO with broader experiences (i.e. a Generalist) in different indications, phases or operational expertise.

A Specialized CRO may have in-house experts and the scientific data on a few therapeutic areas, however with projects repeating themselves, these CROs can slow down drastically their acquisition of knowledge and growth within the CRO industry resulting in a lack of efficiency when conducting a clinical trial.

CROs need to consistently maintain their knowledge of government regulations, site procedures, different and improved methodologies, and all other facets of the ever-changing healthcare industry. For that reason, it is optimal for CROs to specialize in the logistics and execution of conducting a clinical trial as opposed to specializing in the science that is already acquired by the client sponsoring the study. Vantage BioTrials’ business model – since its inception in 2007 – has centered around a generalized expertise of various therapeutic areas, while specializing on operational logistics such as Quality by Design (QbD) strategies, Risk-Based Approaches to Monitoring and process improvement methods to the entire clinical trial lifespan. The results of this approach have repeatedly resulted in an increase of project approvals by regulatory agencies (e.g. FDA, Health Canada, EMA, etc.), overall reduction in project timelines, and even reducing the number of trials needed to be rescued within a Sponsor’s therapeutic program.

You may visit some of Vantage BioTrials’ previous whitepapers that explain in further detail the advantages of the multitude of methods Vantage BioTrials utilizes to remain “Specialized Generalists” in our industry.

Ecosystem of Partnership

Vantage BioTrials focuses on being a specialist in the clinical trial management portion of a trial, however, there are many other important criteria needed to successfully complete the entire project. More generalized CROs tend to quickly change hats by touching on most of the complex roles. Vantage BioTrials developed a methodology to have each of these important roles specialized by creating an ecosystem of strong and trusted partners, experts in their field and sharing the same vision, values, and culture. Each partner within our ecosystem has been carefully selected and has gone through our “From Tasks to Partnership” funnel system.

In other words, as deliverables progress from task-oriented services to full-blown partnerships, the ecosystem of partners has greatly developed, trust between the partners as well as the flow is unified, while still remaining experts and specialists in their specific role within a project.

The observed results from a Sponsor’s perspective are the CRO’s ability to perform international trials by offering expert services which result in flexibility in choosing a full service or an a-la-carte one. It also gives a new perspective in terms of the capabilities that a “small CRO” with a trusted network of partners can achieve when remaining specialized in its role; in fact, the size of a CRO has very little correlation with the chances of success of a clinical trial.

Size, Culture and Values

The size of a CRO can be misleading when shopping for one. In fact, during a recent CRO Selection webinar hosted by Ed Miseta, editor at Life Science Leader, the consensus was that the size of the CRO does not reflect in any way the quality of the service received. However, a much more important factor discussed is the compatibility of the partnership as the dynamic of Sponsor-CRO is one of the most crucial criteria when looking for a CRO fitting the client’s needs.

The lean model adopted by Vantage BioTrials’ team is helpful in having more intimate, closer relationships with Sponsors. This also leads to faster execution, easier conversations, and a less robotic or more genuine experience that generates trust.

Nevertheless, it is the CRO’s duty to communicate properly, give regular updates, share enthusiasm, as well as to be fully transparent when there are red flags and concerns, as communication is key to the overall success of the project. In other words, the values of both companies need to be mutual and shared, and the Sponsor must fully explain the overview of the project, delegate tasks accordingly and the CRO needs to make the Sponsor comfortable by creating solid plans of action showcasing their full engagement to the project.

Having a vision explained, shared, and understood, as well as having aligned values, increases the chances of having matching company cultures and strong long-term harmonious relationships.

Final Thoughts

Today, in order to be successful, a CRO needs to be specialized by becoming experts in their specific role of the clinical trial, while being able to stay generalized in terms of therapeutic areas and types of trials. In addition, building strong trusted relationships with their clients and ecosystem of partners with a mutually shared vision, values, and culture maximizes the chances of success.

Ultimately, a CRO needs to position itself at the center of the clinical trial, obtaining a valuable position in the success of the clinical trial – and a clear Vantage point.

About Vantage BioTrials

Vantage BioTrials is a leading Canadian Contract Research Organization (CRO) that uses innovative clinical trial management strategies for the life science industry with a focus on patient safety & advancing new therapies to market. We offer pharmaceutical, biotech & medical device companies a complete and integrated set of full-service clinical trial management solutions.

The post CRO SELECTION: How to Find & Select the Right Partner for your Clinical Trial first appeared on Vantage Biotrials.

Study Rescue | How to get your Clinical Trial Back on Track-Study Rescue | How to get your Clinical Trial Back on Track

vantagebiotrials — Fri, 03 Aug 2018 03:29:54 +0000

Study Rescue | How to get your Clinical Trial Back on Track

Publication date: August 2018 / Download PDF
Author: Han Hsieh / Herby Delone

Introduction

It will probably come as no surprise for anyone to learn that most clinical trials do not proceed as planned since
more than 90% of them fail to meet their original timeline.1 The reason a study falls behind schedule or even fails
entirely may involve issues involving the site start-up process, patient enrollment/retention barriers, protocol compliance and complexity, data quality and integrity, resourcing issues, and overall staff qualifications and expertise. Eighty (80%) of the clinical trials conducted in the United States in 2009 were delayed by at least a month due to slow enrollment.2 Nowadays, up to 80% of clinical trials miss their patient enrollment targets, and 18% of clinical research site fail to enroll any patient whatsoever.3 A delay of one day in product launch not only postpones the public’s access to life-changing therapy but also costs the drug developer between $600,000 – $8 million in revenue.4 Each study encounters unique challenges, and therefore there is no one-size-fits-all solution to study rescue. In this white paper, Vantage BioTrials would like to share our approach to effectively rescue failing studies from disastrous consequences.

Step 1: Building a Rescue Team

In this case, size matters. Having a small rescue team facilitates effective and streamlined communications while
quickly putting in place and executing Action Plans to get a study back on track towards a successful conclusion.
We suggest that a Rescue Team comprises a Rescue Lead (a senior project manager) and only a few Assistants (perhaps one Clinical Trial Assistant and one Clinical Research Associate) with proper experience and qualifications.

Step 2: Implementing Effective Tools

The following are examples of tools we have found useful for developing strategies and Action Plans for study
rescues. We suggest you utilize an appropriate combination of these tools throughout the study rescue process.

A) Direct Site Interviews and Focused Surveys

You may gather information from the site personnel using relevant and focused questions. Contact through the
phone is preferred over email as phone interview offers a better way to establish a personal connection with the
site.

Direct Site Interviews may include questions such as:
• What do you think is the main reason that your patients are declining to participate?
• Could you describe how you pre-screen patients?
• Are you having any difficulties interacting with the Central Lab?

Focused Surveys (a.k.a. “Needs Assessment” Surveys), on the other hand, probes into the site personnel’s wish list
items that would make the trial a success within their environment. The survey may include a question such as:
• What are your current needs that you believe we can help support?

Direct Site Interviews and Focused Surveys help the Rescue Team identify critical issues in the site’s practice as well
as areas for improvement. Make sure your questions are objective and supportive, instead of accusatory, in nature.

B) SWOT Analysis

SWOT analysis is a strategic planning tool that provides a quick overview of internal (i.e., existing factors) and
external (i.e., potential elements not currently affecting or within the scope of the research project) factors relevant
to your achievement of project goals. Identify the Strengths, Weaknesses, Opportunities and Threats of the clinical
trial conduct before developing your strategies for study rescue.

C) GAP Analysis

GAP analysis involves the comparison of current performance with desired performance. GAP refers to the space
between the actual situation and the expected one. This tool helps to identify the priority issues that require
immediate attention. The level of priority is determined by the extent your intervention may bridge the GAP and
improve the performance. Whenever new information is available, promptly analyze the data and update your GAP
Report.

D) Root Cause Analysis

Root cause analysis is a problem-solving tool for identifying the highest-level cause (i.e., the root cause) of a problem
among causal factors. Perform a systematic review to identify the underlying causes of significant issues. Only
after identifying the root cause can you develop the most effective interventions for your study rescue.

Step 3: Implementing the Action Plan

It is paramount to identify Key Performance Indicators (KPIs), define the acceptable range of KPI measurements
and establish an effective way to monitor the performance metrics before starting a clinical trial. You should review
all the KPI parameters, and continue monitoring trial/site performance closely to develop and revise your Action
Plans throughout the study rescue process.

The tools we introduced to you here can not only help you analyze the problems in your clinical trial but also reveal
areas of focus for your Action Plans. Organize the proposed interventions in the Action Plan into groups and prioritize them according to potential impact, i.e., their effectiveness on the significant issues you are addressing. Communicate your ideas effectively across relevant stakeholders of the study, and hold bi-weekly or monthly Strategy Sessions with your Sponsor’s study team to discuss evolving strategies.

Last but not least, performing on-site “support visits” is often indispensable for successful study rescue. The purpose
of on-site support visits is to provide support to clinical research sites, rather than to perform monitoring
activities. Tailor your focus to the site’s needs, and have discussions revolve around critical issues such as protocol,
recruitment strategies, workflows and study resources.

In-person interactions may help motivate site personnel, and these visits provide the Rescue Team an opportunity
to understand the operational structure of a site. Include in your visit report the key points discussed as well as your
recommendations specific to each site. Send a follow-up email with detailed action plans, and let the site personnel
know you remain available to assist the site through on-site visits or teleconferences.

Study rescue is often challenging, and different studies require different approaches to addressing their unique situations. Use the tools we provided effectively for your study rescue projects. For example, you can gather as much information as possible to have an idea of fundamental problems and issues at the beginning of the study rescue. Start with a high-level overview of the study (e.g., SWOT analysis), and then proceed to analyze the issues that are failing the trial (e.g., GAP analysis & root cause analysis). Next, develop and implement interventions (Action Plan), and provide the sites with sufficient support (e.g., on-site support visits).

Continue making good use of appropriate tools, and adapt your strategies to new situations or new challenges
throughout the study rescue. Finally, always engage all stakeholders, and maintain a positive atmosphere of collaboration.

Vantage BioTrials has successfully rescued many studies entrusted by our clients. If you have a study that is missing
key deadlines or milestones, contact us to learn more about how we can help you get your study back on track.

References

1. Getz KA. Enrollment Performance: Weighing the “Facts”. Applied Clinical Trials. http://www.appliedclinicaltrialsonline.com/enrollment-performance-weighing-facts. Published May 01, 2012. Accessed August 3, 2018.
2. Tolve A. Social media: A tool for clinical trial recruitment? eyeforpharma. http://social.eyeforpharma.
com/commercial/social-media-tool-clinical-trial-recruitment. Published January 4, 2011. Accessed August 3,
2018.
3. Solving the problem of clinical research enrollment. WIRB-Copernicus Group. https://insights.wcgclinical.
com/whitepapers/solving-the-problem-of-clinical-research-enrollment. Published May 2018. Accessed August
3, 2018.
4. Hess J. Web-Based Patient Recruitment: Best Opportunity to Accelerate Clinical Trials. Cutting Edge Information.
http://www.cuttingedgeinfo.com/process/?ref=122. Accessed August 3, 2018.

About Vantage BioTrials

Vantage BioTrials is a leading Canadian Contract Research Organization (CRO) that uses innovative clinical trial
management strategies for the life science industry with a focus on patient safety & advancing new therapies to
market. We offer pharmaceutical, biotech & medical device companies a complete and integrated set of full service
clinical trial management solutions.

The post Study Rescue | How to get your Clinical Trial Back on Track-Study Rescue | How to get your Clinical Trial Back on Track first appeared on Vantage Biotrials.

How to Support & Develop Research – Naïve Clinical Sites | An Investment for the Future of Clinical Trials

vantagebiotrials — Wed, 03 Jan 2018 03:07:00 +0000

How to Support & Develop Research – Naïve Clinical Sites | An Investment for the Future of Clinical Trials

Publication date: January 2018 / Download PDF
Author: Robert Le

Introduction

Finding highly experienced and strong performing sites for a clinical trial is one of the most important steps in the drug development process, but always remains a challenging task for Sponsors and CROs. The turnover rate of Principle Investigators (PIs) in clinical research is high and keeps rising. Approximately 40% of the global pool of FDA-regulated PIs who file a Form 1572 in a given year choose not to file in the subsequent year. While lower than the other regions, the North American turnover rate is still approximately 35%(1).

This high turnover rate often means you could end up using a site which has little to no experience in clinical research for your study. Using a site new to the world of clinical research is always a risk as they require more time and resources from all involved parties to bring them up to speed with current GCP guidelines and health authority regulations for potentially no return of positive outputs or results. So is using inexperienced sites worth all the time and effort? Our short and resounding answer is “Yes”! While more time and resources are needed to train and develop these sites, we need to look at them as long term investments worth the trouble. After all, these risks can all be analyzed and mitigated at every step of the study. By taking the time and effort to invest in these sites, they are more likely to succeed. You will also be able to build a strong positive relationship with them, and will more likely be able to count on them to perform well, and perform loyally for your future studies. Sites that are well supported and have a solid relationship with the Sponsor or CRO, have better enrollment rates.

Selecting the Site

One of the reasons they are great enrollers is related to the fact that their patient populations are, for the most part, naïve to clinical trial participation. In addition, they do not have competing studies that target the same potential population. The saying “it takes a village to raise a child” applies nicely in this situation… but instead we should look at it as “it takes all stakeholders in pharma to raise good clinical research sites”.

The Protocol is the very first step where you can start mitigating the risks involved with using an inexperienced site. Each protocol is different and presents its own challenges. The best way to ease new sites into clinical research is to select them for protocols which are less complex.

Take the time to look at the various aspects of your protocol. Some key points to look at include:

Inclusion / Exclusion Criteria
Number of Study Related Procedures
Number of Subject Visits
Number of Expected Enrolled Subjects from each site

Participating in the first clinical study with complicated procedures would result in confusion, overburden, and possibly withdrawal from further participation in clinical research. Additionally, this will cause more errors and poor quality of data, with a higher possibility of violations occurring, ultimately affecting subject safety. By taking time to identify where in the protocol an inexperienced site might stumble, you reduce the chance of these sites potentially making significant errors. In essence, it’s about becoming more “site centric” in your approach. These days there’s a lot of talk about patient centricity and how to focus on the needs of the patients throughout a clinical study, and this is wonderful. However, we often forget that the needs of the sites should also be seriously considered when designing and managing a trial.

At Vantage BioTrials, we believe from our own experience that one of the best starting points for these inexperienced sites are Phase IV studies. Phase IV studies will usually have less routine activities during patient visits. The inclusion and exclusion criteria will generally be less stringent, which will help with recruitment. These factors will allow the inexperienced PIs and site staff to become accustomed to the basics of clinical research in a less demanding setting than, say, in an interventional pivotal study. This kind of environment will help set-up an opportunity for these sites to succeed. Of course, inexperienced sites can be used for interventional studies; however it is riskier due to the higher amount of time and resources a site has to dedicate to these trials. Regardless of what study phase an inexperienced site is chosen to participate in, you must be ready to work twice as hard and communicate closely with the site at each stage of the study.

If an inexperienced site has shown interest in your study, the next step is to perform a site evaluation visit (SEV). The priorities of the site evaluation for these inexperienced sites should be different when compared to one of an experienced site. The most important factors you should look for at the SEV for these new sites are how interested they are in the study and how willing they are to learn. It’s about being motivated. A site which is not willing to learn should be avoided as it is a big indicator of unnecessary push-backs and waste of time and resources further down the road.

You should go into the site evaluation expecting them to have little to no clinical research experience or infrastructure. The qualifications of the PI and site staff should be viewed differently between an experienced and inexperienced site. At an experienced site, you might look more at their previous GCP training and experience with other clinical studies. At the inexperienced site, you would focus more on how willing they are to undergo GCP training and how seriously they value training programs in general. The point is: you should not penalize an inexperienced site for their lack of experience! Another example would be site staff resources and infrastructure. At an experienced site, a lack of staff dedicated to clinical research would be a cause for concern as this would indicate the site might be unable to dedicate adequate resources and time to your study. For an inexperienced site, you should look at how they will delegate the study’s activities between their available staff. It is important to explain and emphasize how much time and resources the site needs to dedicate to the study as they will have a harder time judging how much resources they need to dedicate. If they are not sure how to delegate their staff to the study, offer them suggestions and examples on how other more experienced sites have set themselves up. As an example, suggest to the site to designate either a nurse or administrator who is in contact with patients a lot as the lead coordinator. While it is not the ideal set-up, as this staff member will have other non-clinical trial related duties, it will allow you and the site one main point of contact for communications. If the site continues to do clinical research in the future, they will develop their resources and infrastructure. Overall, a site evaluation visit should not be done to how qualified these inexperienced sites are to clinical research but to gauge how interested the sites are to participate, how willing are they to learn and to explain to them the necessary time and resources needed to perform the study. Once you have a solid foundation in place, all the infrastructure requirements for clinical research will come with time.

Study Start-up

The start-up of sites is a crucial step of any study and even more so for sites new to research. On average, the start-up phase takes 5 weeks longer for sites new to the Sponsor or CRO, which includes sites new to clinical research, than it does for sites who have established relationships with the Sponsor or CRO(2). It is important to get sites through the start-up stage as quickly and efficiently as possible, while maintaining key study deliverables and decreasing errors. Through the experience we’ve had at Vantage BioTrials, these new sites are all very excited and ready to start enrolling patients as soon as possible, sometimes even before being selected for the study. The sooner these sites are up and running, the less likely they will lose interest in the study and not meet their recruitment targets, regardless of whether they are experienced or not. Of course, it is very important to remind these inexperienced sites that they have obligations to fulfill prior to starting the study, especially if this is the very first study a site will be taking part of. This should be stated and repeated during the Site Evaluation Visit and Site Initiation Visits. If your study is planning an investigator meeting, make sure your new sites are not only invited, but motivated to attend as this will provide them one or two days of concentrated training and helpful discussions/brainstorming with more experienced sites which they can learn from.

Before the study can start, the regulatory documents must be collected. During the collection of these essential documents from the inexperienced site, it is recommended to explain exactly what documents are being collected and why they are being collected, but to also provide them an outline of the study start-up steps. Providing an explanation on the various steps in the start-up process will ensure a faster and more efficient start-up time for future studies, since a learning curve should no longer exist.

Ethics approval is one of the most time consuming as well confusing steps in the start-up phase for inexperienced sites. If it is possible, the best course of action would be to use a Central ethics committee. The start-up time and enrollment performance is better among sites who are not based in university, hospital and government clinics1. The use of a central ethics board will get your inexperienced site up and running faster, and more importantly, avoid the time consuming and confusing process of going through local ethics committees. As the Sponsor or CRO, you will also be able to take the burden off the shoulders of the site and they will have one less thing to worry about since central ethics committees are usually managed directly through you (not the site). If you have to use a local ethics board, you have to be ready to walk step by step with these inexperienced sites through the approval process and guide them on timing of submissions and general communication with local committees. More experienced sites will be able to do the submission process with minimal intervention, but with inexperienced sites, this process can be confusing to know even where to start.

For local ethics boards, it is important for both the site and you take the time to learn how the ethic boards work. If you have an experienced site in your study using the same ethics board as your inexperienced one (which can be a normal situation within the “streamlined IRB process” we have in several Canadian provinces), have the experienced site act as the primary site if possible. This will help your new sites learn about the approval process while avoiding delays and making preventable mistakes. Surveying veteran sites on their past experience and challenges faced with their local ethics board submissions could be another affective way to gain a helpful insight. Another great way to help inexperienced sites through the approval process is for you to learn from experienced sites about their experiences using the local ethics board. The experienced sites will have better insight into the inner workings of these ethics boards, what they look for and their timelines. Ask these experienced sites and as well look up on the ethics board website to learn what needs to submitted, as each ethics committee is different. While this process might be time consuming for you, you will be better positioned to help your inexperienced sites though the approval process for this study and all future studies. For the actual submission, it is recommended that you try to schedule a time to do the submission process together with the site, either remotely or in person. By doing so, the sites will be able to provide a more detailed submission to the IRB and both you and the site will learn how the IRB works. A more detailed submission will mean fewer follow-up questions from the IRB and a faster start-up time.

For site training, always recommend to the PI and site staff to attend the Investigator meeting. This not only provides these sites a chance to meet with you in person to discuss their comments and concerns with the study, but also to meet the more experienced PIs. This opportunity gives these new sites a chance to look at the study from a different perspective. The experienced sites will more likely catch details within the protocol that inexperienced sites might not notice which could potentially affect enrollment. Conversely, you would be surprised at the great level of insight and input that also comes from your inexperienced sites at investigator meetings since they might have more “real world” experience with patients than clinical setting experience of seasoned sites. If attending the IM is not possible, then an on-site training visit should be performed. If the site has to do any additional training, such as GCP training, have them do it before your site visit. This will allow them to ask questions to you in person. During this training visit, recommend to the PI to be present for as long as possible. While it might not be feasible, the more time the PI spends with you during the SIV, the more prepared for the study the site will be. In the author’s experience when performing an SIV with an inexperienced site, the PI was present for most of the SIV and that allowed them to ask questions about all aspects of the study in a more leisurely fashion. This not only allowed the site to be better prepared for the study but it allowed the author and the study team to look at the study from a new perspective. By the end of the SIV, the PI and the site should be comfortable performing the study related activities and be comfortable coming to you for questions regarding the study.

Open and Responsive Communication Throughout the Study

The most important factor to ensuring success of inexperienced sites is communication. Communicating with your sites is fundamental in every study to ensure its success. For inexperienced sites, it is even more important to be open to communicating with them at every stage of the study. These sites will usually have a lot of questions on various aspects of the study, whether it is general or study specific. It is important you emphasize to the sites you are always there to answer their questions and to help them. Recommend to them to call you prior to their first subject enrollment just to go over the summary of a subject visit. It is recommended you monitor these sites early in the study. By doing so, any mistakes can be corrected early on and will save time and effort later on in the study by decreasing the potential number of data queries or deviations. As well, if possible, allocate more monitoring visits to these sites. In the author’s experience, these sites are very receptive to monitoring visits as most realize that it is in their best interest to learn as much as possible from experienced personnel. It acts as a learning experience for the site and encourages them to do well. Do not be afraid to be thorough with these sites. For a Phase IV study the author recently worked on, one inexperienced site told the author that they welcome on-site monitoring visits, as it allows them to learn what they are doing well, what they are doing wrong and how they can improve. They were very open to feedback and very enthusiastic about improving their processes. By pointing out areas of improvement but at the same time highlighting their strengths will in turn result in a positive and successful clinical trials experience, and improve the quality of their work. By being open and responsive to the site’s questions, an inexperienced site will know they are being supported throughout the trial and will more likely participate in future trials as their confidence grows.

Clinical research is always a risky endeavor. The prospect of having to use inexperienced sites will add to this uncertainty. There are a lot of unknown factors at play which could end up affecting your trial. But these inexperienced sites are not only important for your trial, but for all clinical trials. With such a high PI turnover in clinical trials, it is essential to do as much as possible to retain as many new PIs and sites as you can. After all, we need patients to enroll in clinical studies in order to advance research, but similarly without a growing pool of sites, the advancement of breakthrough research can also slow down, or worse, stop altogether. By knowing when to select a new site and by providing close and responsive support to these sites, you will not only allow the site to have a successful clinical trial experience, but you will build a strong positive relationship with them which you can tap into for future studies. It’s time we all do our part as Sponsors and CROs and turn an unsustainable system into one that continuously produces and maintains top quality sites. And that is an investment worth taking.

Contact us at Vantage BioTrials today to learn more about how we can support your clinical programs by developing long lasting relationships with sites and speed-up the entire study process while maintaining the highest levels of quality.

About the Author

Robert Le is a Clinical Research Associate at Vantage BioTrials, Inc. He works closely with sites in successfully completing Phase I through IV studies, and has a strong passion to see that promising new therapies are delivered to patients who need them the most.

About us

Founded in 2007, Vantage BioTrials is a privately-held Contract Research Organization (CRO) that provides Phase I-IV clinical trial management services and implements Risk-Based Management through the use of Quality by Design (QbD) methodologies, all delivered to international pharmaceutical, biotechnology, generic pharmaceutical and medical device companies.

References

Gertz KA, Lamberti MJ. Global site landscape remains highly fragmented with variable performance. Tufts Center for the Study of Drug Development Impact Report. March/April 2013;15 (2)
Wilkinson M, Getz K. Tufts CSDD Study Highlights: End-to-End Site Identification Through Start-up. April 2017.

The post How to Support & Develop Research – Naïve Clinical Sites | An Investment for the Future of Clinical Trials first appeared on Vantage Biotrials.

Analysis of Highlights from Health Canada’s GCP Inspection Results in 2016

vantagebiotrials — Sat, 03 Jun 2017 03:10:13 +0000

Analysis of Highlights from Health Canada’s GCP Inspection Results in 2016

Publication date: June 2017 / Download as PDF
Author: Irina Mosesova

Introduction

At Vantage BioTrials (VBT) we pride ourselves at continuously learning and keeping up to date with the latest developments in clinical research and compliance issues that can potentially effect trial results or even patient safety. The industry is changing at an incredible rate and in an effort to continue being one of the best service providers for clinical trial management, latest regulatory findings are always on our radar in hopes that we can learn from them and continuously improve our processes and keep patient safety as a forethought rather than an afterthought. In this paper we take a closer look at the top five violations that are particularly of interest. Based on our inquiry to Health Canada, the detailed inspection reports for these non-conformities are not available to the public as they belong to the sponsors of each study, hence we will discuss how these violations fit into the historical data that is available, such as Annual Inspection Summary Reports. We will also look at how these trends have contributed and resulted in the evolution of regulatory guidelines and regulations.

According to the Government of Canada (2), eight inspections of investigative sites participating in clinical trials in 2016 resulted in non-compliant ratings. Figure 1 – Frequency vs. Summary of Observations by Health Canada GCP Inspectors in 2016 illustrates which non-conformities were the most frequent, with the top six highlighted in red below.

Table 1. Summary of Observations noted by GCP Inspectors in 2016 with their corresponding Codes.

Code	Summary of Observations
A	Medical care and/or medical decisions for the clinical trial were not under the supervision of the qualified investigator at the clinical trial site.
B	Not all individuals conducting the clinical trial had the education, training and experience to perform their respective tasks.
C	The clinical trial records had errors and/or missing information that did not allow for complete and accurate reporting, interpretation, and verification.
D	The clinical trial was not conducted according to the protocol.
E	The drug was not handled and stored in keeping with Good Manufacturing Practices.
F	The drug was sold or imported for use in a clinical trial before the clinical trial site information was submitted to Health Canada.
G	The label of the drug did not contain the required information.
H	The sponsor did not get the approval of a Research Ethics Board before the clinical trial began or before an amendment was made at the clinical trial site.
I	The sponsor did not get written informed consent for every person before they participated in the clinical trial or the amended clinical trial.
J	The sponsor did not have provisions in place to keep all clinical trial records for a period of 25 years.
K	The sponsor did not implement systems and procedures to ensure accurate and complete transcription of data.
L	The sponsor did not implement systems and procedures to ensure adequate monitoring of the clinical trial.
M	The sponsor did not implement systems and procedures to ensure adverse reactions or events were documented and reported.
N	The sponsor did not implement systems and procedures to ensure equipment was maintained and calibrated.
O	The sponsor did not implement systems and procedures to ensure that deviations from the protocol were documented and reported.
P	The sponsor did not implement systems and procedures to ensure that participants were properly consented.
Q	The sponsor did not implement systems and procedures to ensure that staff was adequately trained on Good Clinical Practices and the appropriate Food and Drug Regulations.
R	The sponsor did not implement systems and procedures to ensure the quality of the clinical trial.
S	The sponsor did not implement systems and procedures to ensure the required information was submitted to the Research Ethics Board.
T	The sponsor did not implement systems and procedures to ensure the required study information was communicated to and/or reviewed by appropriate study personnel in a timely manner.
U	The sponsor did not implement systems and procedures to ensure the study records were maintained and archived.
V	The sponsor did not implement systems and procedures to ensure the tasks were appropriately delegated to study staff.
W	The sponsor did not implement systems and procedures to train study staff.
X	The sponsor did not keep complete and accurate records for the use of the drug in a clinical trial, as required by law.
Y	The sponsor did not keep complete and accurate records to show the clinical trial was conducted in keeping with Good Clinical Practices and the Regulations.
Z	The sponsor did not keep records of all adverse events.
AA	The sponsor did not meet the requirements for information and records management.
BB	The sponsor did not notify Health Canada within 15 days of making a change to the chemistry and manufacturing information of the drug that does not affect the quality or safety of the drug.
CC	The sponsor did not notify Health Canada within 15 days of making a change to the protocol that does not alter the risk to the health of a clinical trial participant.
DD	The sponsor did not record, handle and store all information for a clinical trial to ensure the data transcribed from the original documents to case reports was accurate and complete.
EE	The sponsor did not record, handle and store all information for the delegation of tasks in the clinical trial to allow for complete and accurate reporting, interpretation, and verification.
FF	The sponsor did not implement systems and procedures to ensure the quality of the clinical trial.

C.05.012 – Records

The clinical trial records had errors and/or missing information that did not allow for complete and accurate reporting, interpretation, and verification.

The sponsor did not keep complete and accurate records to show the clinical trial was conducted in keeping with Good Clinical Practices and the Regulations.

This is quite a large category that arguably could be considered as the backbone of the regulations. If you cannot trust your records, then everything becomes questionable. This section of the Food and Drug Regulations (C.05.012) was sited 30% of the total number of observations during GCP inspections in Canada between 2014-2015 (7). The violations that fall under these categories were also seen in a 2012 report published by Health Canada that summarized the inspections between April 2004 and March 2011 (3). In that report, electronic records seem to be a recurrent non-conformity. Given the fast-paced integration of technology into clinical research, it is surprising how much confusion is still out there when it comes to the use of computerized systems and collection of e-data. Regulatory agencies have recognized the need to address and provide guidance for the use of computerized systems in clinical research, which resulted in several publications of guidelines and regulations to address these issues. For example, in 2010 the EMA published a reflection paper that heavily discussed e-TMFs (4). Another good example is the most recent updates to the ICH E6 guidelines (Revision 2) that has included a new section on validation of computerized systems (6). Furthermore, Health Canada inspectors stated in the Annual Inspection Summary Report that “As of 2014-2015, inspections have become more in-depth and now include the review of more systems (such as the establishment’s self-inspection program and validation of computerized systems).” (7).

The examples in Health Canada’s 2012 report (3) refer to the lack of validation of computerized systems and electronic forms developed in-house and used in a clinical trial. During one of the inspections they also noted the lack of procedure in place for archiving the electronic records for the required period of time. Many still fail to recognize that electronically captured data is raw data and should be treated with the same scrutiny as paper-based data, i.e. be compliant with FDA CFR 21 Part 11 or equivalent regulations. Interestingly, one of the examples of the most common observations in the annual 2014-2015 Health Canada report also lists lack of appropriate systems and procedures in place for computerized system validation but these were flagged under section C.05.010(c) instead (7).

The industry is recognizing the importance of regulated software and more software development companies are beginning to claim their products as compliant with appropriate regulations. However, caution is advisable: don’t simply take their word for it. Do your homework and (a) conduct a vigorous vendor assessment and, (b) perform a full or partial in-house software validation to ensure that the software is fit-for-use in your operational environment

C.05.010 – Sponsor’s Obligations

Good Clinical Practices – The sponsor did not implement systems and procedures to ensure adequate monitoring of the clinical trial.

As a Monitor (i.e. Clinical Research Associate) it is essential to keep in mind that we play a critical role in ensuring compliance in any particular clinical study. The following interesting example from FDA serves as a great reminder of this fact.

Last year, Dr. Cheta Nand’s site was inspected by the FDA in Richland, Washington, USA (1). This inspection resulted in a Warning Letter with six violations cited. In one of the findings, FDA inspectors noted that the repeat of one of the laboratory parameters was not performed when elevated levels were noted in the original results, as required by the protocol. Interestingly, one of the justifications that Dr. Nand offered to the FDA, which was deemed unacceptable, is that his study coordinator received “a verbal confirmation from the study monitor” that this was an acceptable course of action. In fact, this justification was used repeatedly in response to several findings. Moral of the story: what we do and say as Monitors matters and can, under some circumstances, be used to justify the violations. It is also worth noting that verbal communications are weak evidence to justify anything and the Golden Rule of clinical research “if it’s not documented, it didn’t happen” should not be taken for granted.

Given the repeated violation of the sponsor’s oversight in regard to the monitoring of the clinical trial, it’s no wonder that a significant portion of the original ICH E6 guideline was recently revised to include the discussion on Risk Based Monitoring, Monitoring Plans, and Monitoring Reports (6). This was great news to all, especially our team at Vantage BioTrials, given that we have been implementing this process since our inception ten years ago in 2007.

Good Clinical Practices – The sponsor did not implement systems and procedures to ensure the quality of the clinical trial.

The ultimate responsibility of ensuring the quality of the clinical trial falls on the sponsor but every single person involved plays an important role. It is a dynamic and continuous process. According to the FDA’s presentation – Building Quality Into Clinical Trials – An FDA Perspective (5), ”quality” means that the study needs to have the following elements: scientifically valid and ethically sound experimental design, adequate protection of subjects’ rights, safety, and welfare, qualified personnel, adequate monitoring, and current, complete, and accurate data. FDA suggests the following items to be considered for a quality study:

Adequate effort is spent in finding a qualified investigator. Solely relying on Investigator’s CV and the reputation is not sufficient. It’s important to also pay attention to the clinical site and staff, evaluating the understanding of the appropriate regulatory documents, considering skills and experiences with similar products, etc.
Adequate effort is put into writing the protocol, which might mean spending more time and effort at the start-up of the study to avoid confusion and protocol deviations in the future. Getting a proper input from the relevant parties prior to finalizing the protocol is the recommended strategy for any clinical trial.
Adequate and thorough training, with emphasis on the informed consent process.
Ensuring adequate monitoring and investigator’s compliance throughout the study.
Ensuring all third parties involved on the study also comply with the appropriate regulations.

For further examples and practical tips on Quality by Design Principles, feel free to refer to our Whitepaper entitled “Quality by Design and Risk-Based Monitoring” downloadable through our website at vantagebiotrials.com.

Good Clinical Practices – The sponsor did not implement systems and procedures to train study staff.

In the author’s ten years as an auditor, training has always been a hot subject to highlight by sponsors and regulatory agencies. Having competent and qualified staff is the foundation of any business providing a niche service, yet somehow adequate and timely training is a constant oversight and almost a guaranteed violation during site audits.

Health Canada’s annual report for 2014-2015 noted that training was amongst the top three observations (7). This was also noted in Health Canada’s report published in 2012, which included examples of deficiencies cited again in this section. Below are two examples that are particularly interesting:

“Example 1: Lack of documented evidence that the personnel, including study coordinators, involved in the conduct of the study were trained on the protocol and GCPs.”

The most common challenge noted in the author’s monitoring and auditing experience is the lack of clearly defined training file ownership. At times, even the physical location of the training file might result in confusion. For example, the training file located in the management’s office can leave an employee under the impression that it’s his or her boss’ responsibility to keep track of all training. A concise training SOP clearly defining responsibilities and ownership of the training files is a must for every operational site.

“Example 2: There was no explicit documentation to indicate that all sub-investigators and nurses to whom significant trial-related duties have been delegated had been informed of all protocol-specific requirements.”

Similar observations were noted in Health Canada’s annual report for 2014-2015 (7).

The author once had a sponsor who argued that the person who wrote the protocol had to also sign off on a “Protocol Reading Log”. This might be an example of overkill and overzealousness, but in all other cases a written attestation to understanding the protocol-specific requirements shows that study management has done their due-diligence, not to mention that an opportunity was provided (and documented) to all involved personnel to ask questions or raise concerns.

It is evident that there is a lot to consider in the process of developing and managing a compliant quality clinical trial. Health Canada noted that in response to the rapid growth of new products coming to market, “Health Canada is developing a suite of new tools to help identify risks and shift from regular inspection cycles to a more flexible risk-based approach.” (7). As a CRO, Vantage BioTrials has built its operational philosophy on remaining lean and flexible, even when implementing risk-based and “quality by design” methodologies since Day One of operations. Not only are we among the pioneers to incorporate these quality methods into our clinical management and monitoring activities, we also deliver highly experienced and qualified professionals that can support your team in every aspect of Phase I-IV drug development. But don’t take our word for it, let our awards and accomplishments speak for themselves!

About the Author

Irina Mosesova holds an advanced B.Sc. degree in Microbiology & Immunology from Dalhousie University. After spending several years at the bench of the MUHC Royal Victoria Hospital discovering novel gene mutations in the patients with deficient calcium-sensing receptor, Irina continued her career in the pre-clinical regulatory affairs field, where she spent over ten years. Last year, Irina’s focus has shifted in hopes to continue her learning journey and in effort to contribute her skills and knowledge to clinical research. She currently holds a position of a Clinical Trial Assistant at Vantage BioTrials located in Montreal, Quebec, Canada.

About us

To learn more about Vantage BioTrials, please visit us at vantagebiotrials.com and follow us on LinkedIn and Twitter.

References

FDA Warning Letter to Dr. Cheta Nand, M.D. 3/10/16. Ref. 16-HFD-45-03-01. Website: http://www.fda.gov/iceci/enforcementactions/warningletters/2016/ucm493102.htm
Clinical trial inspections, non-compliant clinical trial inspections search results. Website: http://healthycanadians.gc.ca/apps/gcp-bpc/searchResult-en.html?lang=en&sponName=&contNum=®ion=&drugName=&phase=&startDate=&rating=NC&cat=2
Summary Report of Inspections of Clinical Trials Conducted from April 2004 to March 2011. Health and Drug Products. Website: http://www.hc-sc.gc.ca/dhp-mps/compli-conform/clini-pract-prat/report-rapport/2004-2011-eng.php#a53
Reflection paper on GCP compliance in relation to trial master files (paper and/or electronic) for management, audit and inspection of clinical trials. Website: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/02/WC500138893.pdf
Building Quality Into Clinical Trials – an FDA Perspective by Jean Toth-Allen, PhD, U.S. Food and Drug Administration. Website: https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/UCM303954.pdf
Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2).ICH. Website: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf
Inspectorate Program – Annual Inspection Summary Report 2014-2015. Health and Drug Products. Website: http://www.hc-sc.gc.ca/dhp-mps/pubs/compli-conform/2014-2015-ar-ra/index-eng.php

The post Analysis of Highlights from Health Canada’s GCP Inspection Results in 2016 first appeared on Vantage Biotrials.

A Synthesis of Adaptive Designs in Clinical Trials

vantagebiotrials — Tue, 03 May 2016 03:01:57 +0000

A Synthesis of Adaptive Designs in Clinical Trials

Publication date: May 2016 / Download PDF
Author: Roy Nitulescu, Agnihotram V Ramanakumar, and Vatché Bartekian

Abstract

Since 2006, when the adaptive design working group presented their work in Washington D.C., the literature on adaptive designs has greatly expanded. Some designs have emerged as inherently better suited to exploratory-phase trials, while others are more appropriate for confirmatory phases of drug development. This article provides a high-level synthesis of available adaptive design methods and discusses their respective roles, advantages, and disadvantages. General challenges associated with the practice of adaptive trials such as concerns about operations, project management, regulatory authorities, necessary technologies, and ethics are also discussed.
Keywords. adaptive designs, flexible designs, clinical trials, exploratory, confirmatory

Introduction

In 2004, the United States Food and Drug Administration (FDA) published a report as a part of its Critical Path Initiative [5] outlining their views on issues with the medical product pipeline in the United States. According to the report, the rate at which new discoveries made in laboratories are being translated into safe and effective therapies available to patients (i.e., the product pipeline) has slowed down considerably over the past few decades despite aggregate spending on product development greatly increasing over the same period. Shortly after the FDA published its Critical Path report, the concept of adaptive designs started gaining popularity—initially, through a series of influential white papers published by a working group of statisticians practicing in the biopharmaceutical industry [7]. Adaptive designs in clinical trials have the potential to improve the efficiency with which new drugs are evaluated and subsequently brought to market. Over the past decade, the literature on adaptive designs and associated methods has greatly expanded, and regulatory agencies in some developed countries (e.g., United States and Europe) have begun issuing their own guidance on the topic as well [4, 6]. Recently, in 2013, the Tufts Center for the Study of Drug Development hosted a roundtable discussion featuring key opinion leaders, executives in the fields of clinical research, biostatistics, project management and operations, and representatives from the FDA and the European Medicines Agency. According to the report that followed the roundtable, approximately one in five clinical trials in the United States are using simple adaptive designs [19]. Moreover, the roundtable sponsors have stressed that the use of adaptive designs in exploratory-phase trials is expected to increase significantly in the near future.

According to the adaptive design working group, adaptive design clinical trials draw on accumulating data in order to decide how to alter the conduct of an ongoing study while maintaining its statistical and interpretational validity [7]. For example, some designs allow for periodic reallocation of dose or treatment regimens among enrolled subjects if initial regimens are found to be unsafe or ineffective. Other designs improve the speed and efficiency with which the highest effective and tolerable doses of a new drug can be identified. Such early-phase designs ultimately help in the planning of later-phase trials as they yield rich information regarding patient response and tolerance to wider ranges of doses and treatment courses than is possible with more traditional study designs. Furthermore, early interim data collected during the course of a later-phase trial can be used to address limitations present at the time of the trial’s design that no longer hold true once enough data is available. Modifications implemented on the basis of such interim data can potentially reduce the incidence of inconclusive or failed studies. With richer information from exploratory trials and better planned confirmatory studies, it is possible to bring safe, effective, and innovative new therapies to patients more quickly than with traditional clinical trials. Nevertheless, with all their benefits, adaptive designs also come with increased operational and methodological complexities which require rigorous multi-disciplinary planning.

Given the great and multifaceted burden of complexities that come with adaptive designs, there is a need for a high-level synthesis of all the well-established designs and methods recently developed in the literature to better inform decision-makers. In this article, the important aspects of adaptive designs are presented with the aim of helping practitioners and decision-makers in the biopharmaceutical field to come to grips with the benefits and critical challenges that adaptive designs pose. In particular, this article will outline the various types of adaptive designs, their associated adaptations, and their advantages and disadvantages. Furthermore, the article will also discuss the practical, regulatory, technological, and ethical concerns associated with the use of adaptive designs, and highlight important aspects to keep in mind when planning adaptive design clinical trials.

Choosing the right type of adaptive design

Adaptive designs are very attractive to individual researchers and industry sponsors due to their flexibility and resource-saving potential. However, there are no clear guidelines on the regulatory review requirements for these designs. This puts clinical trial designers in a difficult position in which they must select the appropriate designs and methods that will achieve their goals and satisfy regulatory authorities at the same time despite having relatively little clear-cut guidance on the matter. Although adaptive designs come with attractive benefits, researchers need to weigh these against the level of complexity and potential bias these designs will introduce into the trial. The biases due to these adaptations could be substantial depending on the types of adaptive designs that are chosen or the types of adaptations that are eventually employed within the scope of the design.

In general, the main methodological concern of regulatory agencies with regards to adaptations in clinical trials is the loss of control over Type I error rates (e.g., concluding that a drug has a certain effect when it, in fact, does not) [6]. In particular, the standard two-sided 5% error rate used in most trials cannot be guaranteed in the presence of complex scenarios of changing adaptations. Another related and important worry that has received much attention is the operational bias introduced into a study following adaptations [2]. For example, making alterations to the choice of study endpoints, patient populations, or treatment allocations based on unblinded interim results may lead to biases toward favorable study outcomes [6]. Analytical methods must be adjusted in order to yield valid estimates and inferences.

One way to avoid the difficulties in controlling Type I error rates is to consider using a Bayesian approach rather than a frequentist one. Indeed, Bayesian methodology provides a mechanism for the analysis of accumulating results during the course of a trial. This approach can be used for calculating the predicted probability distribution (i.e., posterior distribution) of future results on the basis of current results. However, it remains challenging to accurately determine the adaptive study’s operating characteristics such as sample size, randomization, or when to drop treatment arms based on interim results. Moreover, Bayesian posterior distributions are subject to other potential biases depending on the selection of available evidence (i.e., choice of prior distribution) and the choice of the likelihood model. In practice, the application of such methods, whether frequentist or Bayesian, requires the use of computationally intensive procedures and simulations based on a multifaceted set of scenarios.

Exploratory phase

Among all the available adaptive designs, some are more appropriate for early-phase trials (i.e., Phases I and IIa) and others are more appropriate for later phases of drug development (i.e., Phases IIb and III). Designs that allow for the reallocation of current subjects across treatment arms or the dropping of study arms are appropriate for exploratory trials, but they are not appropriate for confirmatory phases of drug development as they cannot offer adequate and well-controlled comparisons of treatment arms. However, such designs can yield very rich information that can help in the planning of later-phase trials. For example, by periodically reallocating subjects across treatment arms (e.g., adaptive treatment response designs) or dropping ineffective ones (e.g., “drop-the-loser” designs), it is possible to quickly identify the most promising treatments or doses among a pre-determined set. Similarly, by periodically reallocating subjects to other drug doses (e.g., adaptive dose-finding designs), it is possible to efficiently find the highest effective and tolerable dose of a drug. Table 1 depicts the pertinence of various types of adaptive designs along with their advantages and disadvantages concomitant with them in early phases of drug development.

Confirmatory phase

The role of adaptive designs in later-phase (i.e., confirmatory) trials is more complex. For example, investigators can use accumulating data to increase the likelihood of a trial being conclusive by either re-powering the study based on the analysis of interim data (e.g., sample size re-estimation) or adapting the trial from a superiority study to a non-inferiority one, if necessary (e.g., hypothesis-adaptive designs). Other study types can be used to identify subgroups of patients who may benefit more than others from the treatment under study (e.g., biomarker-adaptive designs)—particularly when the overall study sample does not show strong evidence of treatment response. Finally, some types of designs may be useful to mitigate ethical concerns associated with either continuing trials despite strong evidence regarding safety or efficacy (e.g., adaptive group sequential designs) or allocating new subjects to potentially inferior treatment arms (e.g., response-adaptive randomization)

When choosing between different appropriate adaptive designs for confirmatory trials, methodological and interpretational concerns should also be considered. Moreover, regulatory authorities are generally more cautious about permitting a large number of adaptations in the later phases of drug development. It is thus advisable to limit the number of planned adaptations in such cases. Table 2 describes various types of adaptive designs appropriate for confirmatory trials along with their advantages and disadvantages.

Challenges of adaptive designs

Adaptive designs are subject to all the challenges that are inherent in traditional group sequential studies used to terminate trials early either for superiority, safety, or futility. However, they also introduce new risks due to their ability to affect the actual conduct of a trial.

Practical and project management challenges

Similar to how many studies are terminated too early for benefit with superiority demonstrated by sequential analysis of interim data [13, 15], there is the potential for adaptive trials to make modifications too early on in the trial and thus distract the trial from reaching a valid conclusion upon completion. For example, since early results often reflect wide variations due to the play of chance rather than actual treatment effects, early interim analyses often report exaggerated effects [1, 10]. There is thus a risk of adapting a trial’s design too early.

The confidentiality of interim data is another practical concern—particularly for commercial drug development, where sponsors need to have access to some interim data to make important business decisions, but without risking to disqualify the trial from regulatory approval [7]. On the other hand, observers who do not have access to interim data can often make an inference about the general trend in the data based on the knowledge contained in the protocol and observed adaptations [7].

Another practical challenge of adaptive design clinical trials is the proper management of drug supplies. Since investigational drugs are not usually readily available for mass distribution, periodic changes in treatment randomization ratios during the course of a study can lead to unexpectedly high demand for a particular treatment. If the manufacturing process is not ready to meet these demands, the proper functioning of the study can be jeopardized.

Regulatory concerns

Health Canada’s regulatory framework does not explicitly deal with drug marketing submissions based on adaptive design clinical studies, although they have published a document in 2008 summarizing their future plans to modernize their regulatory framework [9]. In the United States, the FDA’s draft guidance has clarified their position on the matter to a certain extent, but it remains to be settled whether or not the FDA ultimately approves of the use of adaptive designs using unblinded interim analyses (other than group sequential designs) in confirmatory trials [8]. The FDA also highlighted the importance of modeling and trial simulations in understanding the operating characteristics of adaptive trials under alternate scenarios. During the trial planning phase, comprehensive trial simulation data should be submitted to the FDA along with all other relevant trial documentation. The European Medicines Agency (EMA) has also released a reflection paper on adaptive designs [4]. In general, the tone of the FDA’s guidance document is more positive than that of the EMA [8].

Since adaptive designs are still relatively novel and regulatory guidance is still lacking in many countries, few clinical trials have successfully used adaptive designs. As of the writing of this article, there are no published systematic reviews comparing the success rates of adaptive design clinical trials to fixed-design ones. Still, a report published in 2006 by the Pharmaceutical Research and Manufacturers of America (PhRMA) stated that, as of 2002, adaptive designs had been applied in 46 studies reviewed by the FDA for approval purposes [18]. A more recent article by the Tufts Center for the Study of Drug Development reported that about one in five clinical trials in the United States are using simple adaptive designs [19]. The same report also suggested that the use of adaptive designs in exploratory-phase trials is expected to increase significantly in the near future.

Technological challenges

Adaptive studies require the effective use of digital technology such as electronic data capture (EDC) systems with real-time data access. Such systems need to be designed in a way that data can be reliably collected, cleaned, monitored, and analysed in a timely fashion as to not impede the proper conduct of the adaptive trial. Beyond the data management aspects of running a study, advanced Interactive Web Response Systems (IWRS) are also needed to manage the operational complexity of adaptive designs. These systems are designed to manage and integrate the operational aspects of clinical trials such as randomization and drug supply management. Since adaptive trials are designed in a way that allows for periodic modifications to trial conduct, each stage has the potential to be considerably different from previous ones in terms of the randomization features. In particular, the recruitment, blinding process, and drug supply (i.e., packaging, distribution, storage, usage) all have to be planned before the trial starts and then modified and revalidated as per protocol. Hence, a well-designed IWRS system is needed to foresee, plan for, and then manage all possible tasks, including possible adaptations.

From a statistical stand-point, the increasingly sophisticated methods applied to plan adaptive studies and subsequently analyse the data require equally sophisticated analytical software, particularly when it comes to the simulation of multiple adaptation scenarios.

Ethical concerns

When a trial design is adapted following interim analysis, it is understood that this will have an important impact on present and future patients. For example, when early evidence appears to support one treatment regimen over another, current subjects on sub-optimal regimens may be put on more optimal ones and newly recruited subjects may be initiated on similar regimens as well. However, if the premature conclusions were false, these patients may suffer in the long-term. Therefore, there is an ever-present dilemma as to whether it is more ethical to immediately alter study conduct based on early evidence to avoid exposing patients to ineffective or toxic regimens, or to wait for more evidence to avoid reassigning subjects to worse treatment courses.

Concluding remarks

Adaptive designs offer a diverse set of research tools that can help drug developers gain insights about their investigational products (e.g., promising drugs, highest effective and tolerable dose) with high efficiency during the early phases of clinical development. Such insights can be very useful in planning later-phase trials. Furthermore, other designs can be employed to address limitations that existed at the time of trial design that are no longer present once enough interim data is available. Thus, later-phase trials can be altered in course to reduce the incidence of inconclusive or failed studies.

Methodologies for planning adaptive design clinical studies and subsequently analyzing interim and final data are continuously under development. In fact, the literature is rich with statistical methods to deal with the added statistical uncertainties arising from adaptations. However, it will take some time before these methods are extensively put to use by researchers since there is still no global agreement on what the standard tools should be.

One of the most important challenges facing academia and industry today is to train a new cohort of biostatisticians to meet the latest requirements necessary for the practice of adaptive design clinical trials and to deal with the complex analytical procedures necessary in such studies. Although most of the clinical trial operations and statistical services are conducted by a contract research organization (CRO) with substantial expertise in statistical methods, these organizations need to quickly acquire the expertise and experience in dealing with the specific statistical methods, simulation techniques, and advanced outcome analysis approaches used in adaptive design clinical studies. In order to succeed in bringing new products to patients using adaptive designs, pharmaceutical companies need to maintain strong professional relationships with their CRO partners, and in some cases may need to find new CRO partners with the most up-to-date expertise. Indeed, it is important that it be emphasized that there is a great deal of multi-disciplinary collaboration needed to successfully plan and conduct adaptive trials. Sponsors must coordinate with a team of scientists, regulatory professionals, and statisticians with the requisite expertise who understand the increased operational demands of adaptive designs. The team should also have experience in the designing and execution of all phases of clinical trials as well as a proven track record of selecting and validating available methods and synchronizing them with regulatory and scientific needs.

In conclusion, there is evidence of an increase in the implementation of adaptive designs in clinical trials. Since regulatory agencies appear to be more comfortable with adaptive designs in the exploratory phases of drug development than in the confirmatory phases (provided that suitable methods were applied and were supplemented by rigorous simulation data at the planning phase), sponsors are encouraged to adopt these designs early on in their drug development process.

References

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[4] EMEA/CHMP. Reflection paper on methodological issues in confirmatory trials with flexible design and analysis plan (draft chmp/ewp/2459/02, 23-mar-2006), 2007. Retrieved from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003616.pdf.

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