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.
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
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:
FPFV = First Patient First Visit
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;
- 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.