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Operational Excellence in Clinical Trials

Ulrike Grimm, Vifor Pharma, analyses how clinical trial processes can be improved for the better

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Clinical trials have become a challenge. Few studies are completed on schedule and within the planned budget. There are plenty of reasons for that. In the past ten years:

• The number of study procedures has increased by 57 percent translating into higher investigative site work
• The eligibility criteria have grown by 58 percent reflecting the search for always better defined patient populations
• The number of Case Report Form pages has more than doubled

Nevertheless, having said that, there is still the expectation the pharmaceutical industry executes trials according to plan bringing drugs to the market as soon as possible.

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Thus the question to be asked is: What is wrong? The answer is not simple but rather complex.

It all begins with the evaluation of development compounds. The value of the assets is higher the shorter the development period, since this guarantees longer patent protection, potentially less competition and earlier generation of sales.

The development plans therefore often reflect best case scenarios and disregard the realistic case. Now we can ask ourselves, how do we come up with realistic plans for clinical studies?

I) There are several parameters that provide guidance during the preparation phase

1. Benchmarks

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External benchmarks are available from several providers that have tracked past studies. In addition all studies conducted thus far in-house can be used to analyse the intervals between study milestones.

A combination of external and internal benchmarks to form a guide for studies in Europe and the US could look like this:

LPLV = Last Patient Last Visit

DBL = Data Base Lock

2. Recruitment period and recruitment plan

There are also benchmarks for recruitment periods per therapeutic area. However, I would caution to use high level, generic therapeutic area benchmarks for the recruitment period, because the study specific inclusion and exclusion criteria as well as the study procedure drive the recruitment period.

A detailed feasibility analysis should always be conducted to assess the recruitment period. Ideally this task is not fully outsourced to a CRO but also, or partially, done by the company’s own staff in order to have a detailed understanding of the availability of patients. The results of the feasibility analysis should be written down in a recruitment plan, where the following aspects are important to be considered:

• The availability of the required patient population at the sites;
• Implementation of referral sites;
• Competitive studies;
• Willingness of patients to participate in the study procedures;
• Advertisements;
• Patient retention;
• Risk assessment (what could go wrong?);
• Average recruitment speed of patients per months and site;
• Number of countries, proposed countries;
• Number of sites;
• Anticipated dates for the following milestones (1. First patient, First visit; 2. Last patient, First visit; 3. Last patient, Last visit; 4. Clinical study report)

3. Overall study plan

In addition to the scope, objectives, milestones and timelines, the overall study plan should include the study budget and the resource plan.

Regarding the study budget, it is usually the sum of all offers that have been received during the bidding process for the requested services. However, how many studies have been completed without any change orders? A certain amount of buffer is usually accepted by all internal stakeholders and should be added to the planned study budget.

The analysis of the resource needs is particularly important, because often major activities of the clinical study conduct are outsourced to a CRO and the need for internal resources can easily be underestimated.

It is recommended to check the internal resource needs against recently conducted studies to have a good understanding of the company-specific situation and approach.

4. CRO management

The CRO management starts with the CRO selection process. Usually a Request for Proposal is sent to several CROs and depending on the expertise, past experience in the therapeutic area, the team, and the budget a CRO will be selected. A good relationship between the study team of the sponsor and the CRO is of key importance. Therefore the bid defense meetings provide an excellent opportunity to bring together the envisioned teams of both parties.

In recent years we have seen high staff turnover at the CRO in some studies. Thus, it is advantageous to agree on replacement policies right from the beginning.

Moreover we have made good experience with agreeing on a communication plan that should detail the ways of communication and reports, and also the ways of escalation.

II) Tracking study progress during its conduct

As mentioned earlier, a risk analysis should be done during the preparation of the clinical study. Once the service providers have been selected, it is recommended to jointly work on a contingency plan.

Knowing that 20 – 30 percent of sites recruit only up to one patient, despite thorough feasibility assessments, really calls for back-up sites, may be even back-up countries early on. The triggers of activating these additional sites should be agreed with the steering committee.

Once the study has been initiated the progress will be monitored on an ongoing basis. Study dashboards allow for oversight and could look as shown below:

Dashboard of key performance indicators for clinical studies

As soon as deviations from the plan become obvious the study teams of the sponsor and the CRO should have meetings to discuss the best ways to mitigate the risks and bring the study back on track. Early communication is much better than a "wait and see" approach.

III) Lessons learned at the end of a study

Once the study report has been finalized and the TMF is ready for archiving, comes the time for lessons learned. It is worth to take the time and have a ‘lessons learned’ workshop, before the study team members will be allocated to other studies.

All parts of the study can be looked at and evaluated:

• What new benchmarks can be created from the study for timelines?
• What new benchmarks can be created for external costs and internal resource needs?
• How satisfied were we with the service providers?
• What countries are easy/difficult to work with?
• What sites would you work with again?

The outcome of these workshops should be made available on central places, e.g. on the intranet / central databases and managed by departments like clinical operations or clinical project management so that all study teams can benefit from it.

A thorough plan of all aspects of the clinical study will pay back in the end, by being prepared and able to pro-actively manage any risk and issues.

Close monitoring of the study progress will further enable the study teams to always be on top of any progress being made and to take action as soon as possible.

At the end of a study the ‘lessons learned’ workshops help to become better equipped for the planning of the next studies.

*Dr. Ulrike M. Grimm is the Head Global Project and R&D Alliance Management, Vice President of Vifor Pharma

Dr Grimm is responsible for Project and Alliance Management and joined Vifor Pharma in 2010. She has extensive leadership experience in R&D in oncology, CNS and Anemia, phase I – IV, international product launches, project & portfolio management and alliance management.

Before joining Vifor Pharma she was Vice President, Head of Global Program Management at Fresenius Biotech GmbH for three years.

Prior to this she was with Merck Serono for 10 years, in various roles of increasing responsibilities, including Global Product Leader, International Team Leader and Global Project Manager.

She is a Certified Projects Director at the highest IPMA Level A and Six Sigma Black Belt.

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Last patient last visit (LPLV)

Date when the last participant completes a clinical trial .

Although LPLV is often used synonymously with study completion, the latter may still include measurements and data collection without face-to-face involvement between a participant and an investigator.

The Clinical Trial Life Cycle and When to Share Data (Sharing Clinical Trial Data: Maximizing Benefits, Minimizing Risks, 2015) 

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Site Activation: The Key to More Efficient Clinical Trials

A new study of hundreds of thousands of clinical trial records reveals that the overall length of a trial is directly related to how long it takes to activate the study sites - and that most companies are wasting precious weeks and even months in activation. Here's how to improve your performance.

Nothing in any other industry quite compares to the pharmaceutical industry’s clinical development process.In 2007, $28 billion dollars were spent on drug development. Nowadays a single clinical trial can be capital intensive (up to $500 million), with massive geographic coverage (as many as 53 countries), long duration (five years or longer), and enroll a large number of patients (20,000- to 50,000-patient trials are no longer rare).

A median Phase III clinical trial involves about 800 patients, 50 investigator sites, and two years (700 days) from First Subject First Visit (FSFV) to Last Subject Last Visit (LSLV). Add in the costs of per-patient medical procedures, drug supplies, laboratory work, and sponsor’s personnel, and a median-sized clinical trial can cost upwards of $25 million, about $36,000 every single day.

Clearly clinical trials are extremely important to the pharmaceutical industry both as the source for clinical data and as an enormous cost center. And the patient enrollment phase of a trial is the most variable part of the process-that is, the spot where we could most reasonably expect to drive down costs. But we still lack a fundamental understanding of patient enrollment as a business process. While many companies are attempting to manage trials better, it is not surprising to see that their approaches, even those of established industry experts, lack in structure and objectivity and occasionally make things worse-for example, by making false assumptions about who has final responsibility for recruiting patients.

Because drug development operations are unusually complex, they cannot easily be handled by applying general operations management principles. There is still a need, however, to introduce quantitative methods to better describe and improve clinical trial execution. Luckily, the industry is becoming increasingly transparent, so that more and more operational data are available for analysis. I have spent the past few years building a database tracking the performance of clinical research sites (collecting 20,000 to 50,000+ site performance data every week). These data point to some strikingly clear directions for improving clinical trial operations.

Site Activation Is the Driver Patient enrollment, at its simplest, consists of three steps:

• Site selection
• Site activation
• Patient recruitment

Site selection is the process of identifying a sufficient number of and good-quality investigators to conduct the trial. This is one of the greatest challenges in clinical trial execution. You need to find someone with considerable medical skills, commitment to research, good facilities, willingness to fill in endless forms, and last but not least, access to patients who fit the patient selection standard and will agree to enroll.

It takes several steps to bring a site to the point where it is ready to recruit patients. This process is called site activation , and it consists of a variety of tasks including:

• Negotiate a financial contract
• Gain approval from Institutional Review Board (IRB) or, in Europe, Ethics Board (EB)
• Provide clinical supplies
• Obtain other documents from site (CV, financial disclosure, etc)

Though the two activities are entirely different in content, patient recruitment generally occurs simultaneously with site activation. This is partly because clinical trial teams are often not sure they have an adequate number of sites until they come very close to their enrollment target. As a result, they tend to keep activating sites until enrollment is almost complete. Inevitably, recruiting at some sites is shut down within a matter of days, creating ill will and frustration.

By analyzing the data, we can come to several conclusions: Site activation is the driver in patient enrollment Many in the industry believe that patient enrollment is the responsibility of the investigator sites, and sponsors play only a supporting role in the process. This is only part of the truth.

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Last Patient Last Visit

Last Patient Last Visit defines the date that the last subject completed the study.

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Phesi: protocol changes slow COVID-19 trial down

17-Nov-2020 - Last updated on 17-Nov-2020 at 13:47 GMT

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Sometimes one trial can start smoothly and plug along nicely, while another stalls, stutters and even stops before the finish line. Comparing two trials can provide an interesting education in what factors contribute to the success of a study, and what can drag research down.

Outsourcing-Pharma (OSP) recently spoke with Gen Li (GL) president of clinical services firm Phesi, about the company’s recent analysis of two similar COVID-19 vaccine firms, and what led to the studies’ notably different site effectiveness index (SEI) scores.

OSP: Could you please explain what factors go into the SEI metric and what a favorable/unfavorable SEI means? ​

GL: The SEI metric was developed to answer questions involved in the clinical development process that are often overlooked. For example, how should we measure site activation and what is a good site activation plan? How do we define the relationship between site activation and other variables in clinical trial planning and execution?

SEI defines utilization of enrollment capacity within a group of investigator sites allocated to one clinical trial.

The variables include first subject first visit (FSFV) and last subject first visit (LSFV) at trial level; date of site opening for enrollment and date of site closing for enrollment, targeted/actual number of patients enrolled; maximum number of investigator sites activated and opened for enrollment between FSFV and LSFV. The higher the measure the better.

OSP: Why is attaining a favorable SEI important? ​

GL: The importance of SEI is in its potential for optimizing site activation. In simple terms, improving SEI means improving the execution of a trial – it can translate to reducing enrollment cycle time and needing fewer investigator sites. This means reducing costs and reducing the time it takes a trial to be completed.

Using a SEI measure rather than just looking at historical performance, or looking at an isolated data point on the number of patients enrolled, means we can identify areas for tangible improvement in trial planning and execution.

OSP: Similarly, why might it be especially important when COVID-19 vaccines and therapies are at the center? ​

GL: There is global pressure on the search for COVID-19 vaccines and therapies, and our data show that currently there is varying success in activating investigator sites and enrolling patients. This must be tackled to accelerate development.

The difference of a few months in a global pandemic is huge. But even post COVID-19, the need for improvement will remain. Bringing innovative and life-saving medicines to patients is complicated and capital intensive. Sponsors must improve SEI through a deep understanding of real-time, dynamically refreshed data and a forensic examination of the causes of obstacles.

OSP: How can Phesi work with clients to improve things like keeping protocol amendments to a minimum, to boost that SEI number? ​

GL: Phesi has an integrated approach to assessing variables that impact clinical trial planning and implementation. We can define quantitative relationships among key variables such as investigator site performance, business processes (especially site activation), and protocol design; this means clients get actionable insights that can help them mitigate problems and manage difficult areas – like CRO selection and oversight, protocol design to minimize amendments, and developing performance benchmarks.

This improves SEI, and improves the chance of a study achieving a successful outcome. Phesi’s SEI metric allows it to carry out this comprehensive analysis of all the moving parts involved in a trial. This kind of data-driven analysis is not only important now for COVID-19 related trials, but important for all future clinical development.

OSP: What else would you like to tell us about this SEI comparison regarding the two C19 vaccine trials, or about SEI measurement/results? ​

GL: The industry knows site activation is important but tends to look at it in isolation without knowing how to meaningfully measure it. SEI provides a quantitative measure of site activation in the context of other variables. For instance, trial B in this scenario used an adaptive design. This means starting a trial from early phase then continuously advancing the trial to later stage by adjusting the design based on patient data collected.

This has the potential of being quicker, but it also increases the financial risk. The trial could fail at any point, and all the resources and money invested to date would be wasted. Moreover, if we were to measure the trial from a late stage perspective, the outputs would be poor – SEI is low and enrollment cycle time is longer.

So an adaptive design offers the possibility of allowing patients to get innovative medicines sooner, but there is financial risk. The key for sponsors, including with adaptive design, is to mitigate the risks by making use of the data available.

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