Abstract
This is the first attempt to implement project management principles in bioequivalence clinical studies (BESs) in Bulgaria for the period 1998 – 2005. The data from more than 30 clinical trials, 22 of which BES has been summarized with the aim to optimize trial conduct, harmonize activities and lower expenditures.
As a result of the changes in Bulgaria there lately has been an increased demand for BES. The number of BES/year can be limited by technical and financial capacity, of both Sponsors and trial centers, but also by fluctuating regulatory requirements/practice, as well as by inadequate organization and management practice. The authors focus their efforts on understanding the separate steps of the process, trying to prove its relative importance in terms of time and resources. The ‘responsibilities’ for the timely flow of the trial process are defined as related to contract research organization (CRO), to Sponsor and to regulatory authorities, while those related to CRO cover responsibilities concerning trial preparation, clinical part conduct, drug sample analysis and reporting.
Once the CRO related part of the process, including investigators and analysis plus statistics and reporting, is under control, it becomes easier to evaluate the role and responsibilities of the rest of the stakeholders – Sponsors and regulatory authorities.
The results help sponsor and CRO management to predict the ‘narrow’ parts of the clinical trial management process and concentrate their efforts on overcoming the typical problems, thus saving time and resources - both human and financial. It becomes also possible to plan the trial duration more precisely and fix more accurately the date for final filing of the application for approval by regulatory authorities.
Introduction
There is a serious amount of efforts in the pharmaceutical industry supporting the process of drug development with the tools of the project management (PM). At the same time not so much attention is paid to a part of the process – the clinical trials, which are an important step and thus can represent a critical phase of the management of the drug development.
As a type of clinical trial (CT), the bioequivalence study (BES) bears all specific characteristics of a regular clinical trial, while being much less complicated to organize and manage. By all means, though, it is quite healthy to handle the BES as a project, which makes the management at least more structured and well defined. On the other hand we are fully confidential that the leading role in the PM of CTs should stay with the organizers – in our case a Clinical Research Organization (CRO).
Is Clinical Trial a Project?
General views
Clinical trials characteristics
Although this has not been explicitly defined, we can come to the conclusion that every clinical trial is a project. It fully complies with the project definition of the Project Management Institute in A Guide to the Project Management Body of Knowledge (PMBOK® Guide)(2004, p. 5)
No doubt that a clinical trial is a temporary endeavour, as it has a definite beginning and a definite end. No matter whether it will continue for several months or 10-15 years, the duration is always finite. Although some may argue that the project teams in clinical trials usually outlive the project this is not exactly so as it might be viable for a part of the team but almost never for the whole team.
The deliverable of any clinical trial is unique. We believe that the trial's deliverable can be defined as result. It is true that the deliverables from a clinical trial create the “capability to perform a service” (PMI, 2004, p. 5), which might be related to the health care or the manufacturing of pharmaceuticals, but the results are, in our understanding, the most typical deliverable a clinical trial creates. The results from the controlled clinical trials form the basis of the evidence based medicine, which is the trend in the modern medicine for the last two decades.
No doubt as well that a clinical trial is always characterized by its progressive elaboration and a well-prepared clinical trial protocol (CTP) is an example of a step of development.
Bioequivalence studies (BESs)
The BESs have some specifics, which are further supporting our view that clinical trials are definitely projects. They always have one objective – to prove the equivalence between the bioavailability of a generic product and its original; its actual clinical part can rarely last more than 17-20 days; the analytical part is in general not more than 2 months and in this sense the duration of the BES (or the project) from the beginning to its end in most cases should not be longer than 1 year. The deliverables are definitely defined as results – bioequivalent, Yes or No. And finally the results can be achieved only following the line of the progressive elaboration – step after step.
But are pharmaceutical companies, which are sponsoring these events, happy with the duration and the price they pay to achieve results? In the highly competitive drugs development environment they would like to get the results as soon as possible, better tomorrow. So, when they hear of one year duration, they are ready to jump to the next CRO where they might be promised a much shorter duration of the trial. How can a pharmaceutical company be sure that the duration negotiated for contract is realistic and at the same time completely optimized so that it get is real value and pays real money?
Analysis
Historical records
While trying to answer these questions we have started to analyze a bunch of 9 BESs done for the period 1998-2001. We have tried to follow the standards and knowledge concerning PM of the PMI available on their web site www.pmi.org, and the theoretical and practical ideas from different publications on the subject o PM related to CT. (Birnie, 2003; Castellani, P., Dubini, A., Lietti, F. Mangrella, M., Rossi, C., \Stabilini, M. C., Luigi Visani, L.., 2004; de Balicourt, C., Marreaud, S., Placchi, M., Vandael, B., Lacombe, D. 2004; Odeleye, 2001; Stark, 2001; Verzuh, 1999). Unfortunately the latter could not provide a lot of useful information but at least we found out that there are other people who also try to implement PM principles in CTs. And another important group of documents we had to adhere to was the international regulation for clinical trials published on the web site of the International Conference for Harmonization (www.ich.org).
Another important issue to consider was that the environment we live and work in lacks project management culture and we had to dress our analysis and recommendations in a popular for that is easy to swallow. On the other hand we treated these circumstances as an advantage as there were no “white elephants” with life-long experience in project management. Not that we wanted to become white elephants ourselves, but rather most of our efforts could be placed to deal with illiterate in the sense of project management managers, which is much easier than fighting highly educated and experienced literates.
Our analysis has shown that a BES includes the following steps once an invitation from a Sponsor to a CRO for placing an offer is received:
- Preparation of an offer to bid for a BES
- Contract negotiation
- Study documentation development
- Ethical Committee application
- Regulatory application and approval
- Clinical part
- Analysis of blood samples
- Statistical analysis
- Final report preparation and delivery
- Post-study activities
- Study close-down
The duration of these steps for the first bunch of studies analyzed is shown on Table 1.
The average duration of each step is given on Exhibit 1.
Exhibit 1 – Average duration of each step (days) of a bunch of analysed BESs
Having achieved these initial results we had two options – either to stress our efforts and pay more attention to those steps that look most time consuming (3, 5, 6 and 7) or start from a scratch following the PM rules and definitions and see what the effect of implementing them will be after several years or several studies. We choose the second approach and instead of trying to shrink the long steps (which was what the Sponsors would like to see), we put the horse in front of the carriage and so the journey began. We think time has shown the choice we had made was the right one.
Phasing a project
As already mentioned, we have started by defining the steps a project would have to go through. The analysis done later has shown that these steps are the phases of a BES as each one has a certain sets of deliverables that have to be either approved or presented so that the study can enter the next phase (PMI, 2004, p. 22). The deliverables of each phase are presented on Exhibit 2.
Exhibit 2 – Clinical trial phases and deliverables
For the reasons of detailed costing and budgeting and allocation of resources we have further subdivided the phases into sub phases, which is subject to a separate paper.
Stakeholders analysis
Our detailed analysis has shown that the stake holders can and do play a substantial role in a BES. This analysis is also subject to a separate paper, but it is worth noting that once we have settled the problems with identifying the needs and found ways to approaching these stakeholders, who were affected by the project (BES), we have succeeded to substantially change the duration of some of the phases. We would also fully agree with those saying that identifying stakeholders can be difficult sometimes – it always is in a turmoil environment and the most difficult to identify always have a negative impact on the BES.
It is also worth noting that for a BES the customer and the Sponsor are usually one and the same institution; the Project Manager should be an employee of the CRO; the Project Management Team (PMT) should include the Principle Investigator and the Chief Analyst, in other words the PMT should not include more than 3 members.
Organizational structure
The BES as any kind of clinical trial, is never a project run within a single organization. It includes not less than three organizations when managed by a CRO – the Sponsor, the CRO and the Clinic (in case the analyst and the statistician are part of the CRO not as employees but per contractual basis. It is worth having dedicated groups (teams) for each BES (project) in any of these three organizations and this is almost ever the case with the Sponsor, but never with a small CRO of functional type like in our case. The quality implication of these specific characteristics is very important and need special separate analysis.
Standard Operating Procedures
In order to secure quality and consistency in our work we have prepared Standard Operating Procedures (SOPs) for every phase or sub phase identified. The SOPs are subject to annual validation following assessment. When prepared for the first time they should include, amongst the rest of the basic documents, the results from the PM approach analysis.
Clinical Trial as a Project
Project's initiation
Surprisingly enough our analysis has shown that the duration of time spent for trial's initiation and planning in our case was quite short. Knowing by theory the importance of these parts of a project we were not very happy with our finding, and what is more, the analysis has shown that the extended duration of the next phases and especially the low profit rate are most of the the result of improper initiation and bad planning.
Developing the project's charter is important for BESs, but due to the low level of complexity of the project and the similarity between projects (studies), once created it needs only validation and/or refining if found necessary. Initially this has lead to a slight increase of the duration of Phases I and II, but later the days spent have come back to a reasonable figure – about 1-2 days. The same, more or less, can be said for the process of developing the preliminary project scope statement.
The planning phase has been probably the one most seriously affected by our efforts. The project management plan prepared once is easy to use as a template for future projects. Two of the inputs here have to be paid serious attention – the environmental factors and the organizational assets. Scope planning and definition, although looking similar between projects (studies), can bear some substantial differences and this is something that always has to be taken into account. A very important part of the job, with positive effect on the managers and the other stakeholders is the Work Brake-down Structure. It is also very important for the CRO to define very precisely the activities and to estimate the corresponding resources and duration. The activities sequencing is something that looks natural for clinical trials, but sometimes can create problems if not precisely followed by putting more trust into intuition and practical experience than theory. I would not discuss all items under Plan Process Group (PMI, 2004, p. 46), which are all important but would rather mention these, which we found extremely important – cost estimating, risk identification, risk response planning. We would like to explicitly note that all the rest are not less important.
The specific issue for a clinical trial is that all these elements (excluding the cost-related issues) become part of the clinical trial protocol (CTP). This is definitely the most important document for the project from any perspective. It also covers directly all Phases from VI through XI and indirectly Phases IV and V. It is very important, in this sense, to include the Project Management Team as early in the project cycle as possible, make the protocol the first and the most important deliverable of this team and communicate the drafts to as many of the stakeholders as possible (from those who can have an access to such document). The widely (reasonably, of course)communicated clinical trial protocol makes running the rest of the project a simple routine work to do.
The CTPis used afterwards during the execution of the project, forms the basis for monitoring and quality control and gives helps defined a project as finished. We also call the CTP a “trial management plan” and treat it as the item, which needs most of our time and efforts. What we should never forget is that this plan is a part, even the most substantial, of the project management plan.
The result of this understanding we have developed is the substantial increase of the duration of our Phase III, especially for the projects between 2001and 2003. We have also to mention that due to similarity between BESs, once created the CTP can be implemented for further projects, but it still needs a lot of efforts for validation, editing to include any technical and/or regulatory changes, communication within the team and with the stakeholders, and most of all, of course, implementation. The effect of our efforts in this direction can be seen on the charts reflecting the trend in the duration of Phase III for all projects under complete analysis.
Execution
The execution of a BES includes Phase III, excluding the CTP and Phases IV through X. The analysis of the execution has shown the following:
- a) the time for execution is fixed in its Phase VI by the CTP and its Phase VII by the amount of blood samples to be tested and the analytical equipment used;
- b) Phase III in its execution part includes the preparation of all documents but the CTP and is mainly dependent on the efforts and the organization at the CRO plus the communication patterns within the Project Team and the Project Management team. These activities shape the success of Phases IV and V;
- c) Phases IV and V depend on Phase III, but are also subject to obstacles, which cannot be controlled (regulatory and legislation changes) or can be controlled to a certain extent by paying reasonable attention to the issues related to stakeholders (see above). These phases can be best defined in terms of duration with the existence of proper approved and implemented legislation;
- d) Although fixed by CTP in its clinical part, Phase VI can be prolonged by bad planning of its start or positioning in the calendar (i.e. coincidence with holidays), which is always a result of lack of communication within teams, CTP and PMP badly communicated, etc.). However once started it is fixed in time and any exclusion is major violation of the CTP and can lead to unsuccessful clinical trial;
- e) Phase VII also can be prolonged due to the same reasons mentioned for Phase VI, but also by bad laboratory organization, failure in laboratory equipment and problems with lab staff. The time for sample analysis can be shortened by the implementation of new equipment. In any case it is more or less fixed once optimized in the sense of organization and equipment. Phase VIII is nearly constant in our analysis but we intend to intervene there and see for the future whether the time for statistical analysis can be reduced.
- f) Phases IX and X are totally dependent on proper organization and management within CRO and through proper planning. Thus we have achieved good results here.
- g) For all phases – the start can be a problem when badly planned and managed.
Close-down
The process of closing down a BES depends on proper planning and management. Once a standard operation procedure is approved the duration of this step becomes nearly fixed, as a deviation in any direction will represent a deviation of the procedures. There isn't much to be done here but follow the rules.
Results
The average duration of the phases is graphically presented on Exhibit 3.
Exhibit 3 – Average duration of each phase (days) for BESs following analysis
We have compared the duration before and after the analysis and the results are graphically presented on Exhibit 4. The trends in the different phases are shown on Exhibit 5 (a through h)
Exhibit 4 – Comparison of steps/phases average duration (days) before and after the analysis
Here is a summary of our findings:
- - Our theoretical views have been more or less proved by practice;
- - There are always outliers, but their existence has to be minimized as they have an impact on the average performance. Most often the outliers are the result of bad stakeholders management
- - Certain phases totally depend on their sub-phases and changing the performance of the stakeholders is difficult. The results achieved reflect only the performance of the CRO;
- - The complex approach is to be preferred in performance improvement via project management approach; yet if stakeholders are difficult to manage it is worth putting efforts in improving at least the performance of the CRO.
Exhibit 5 (a through h) – Dynamics in different phases (days)
Conclusions
Our efforts to implement project management principles in running and management of a clinical trial, and more precisely BES, from CRO perspective might look like inventing the hot water for some experts from developed countries, but are revolutionary for this area in our country. Although we were unable to find specific literature on the subject, the amount of training courses with similar subject has given us the confidence that such an animal like project management in clinical trials does exist. The fact that we have succeeded to improve our performance has given us more than just satisfaction and has shown that it had been worth the efforts.
Here are our conclusions:
- A project management implementer in the clinical trials area should have not less than 2 “bibles” – PMBoK and GCP/ICH rules and regulations, the latter being of greater importance.
- Any CRO, which would like to improve its performance, should invest in project management.
- The SOPs of any CRO should be prepared following a PM analysis of its activities.
- Once implemented, the PM results should be continuously validated to reflect any changes in legislation, theory and practice that might be of importance.
- The project records are of ultimate importance, as they provide most of the data needed for project performance analysis looking for improvement.
- Much more efforts are needed to make PM approach popular with most of the stakeholders and especially the Sponsor.
- And last but not least – the project management approach can help the CRO provide higher quality services at a lower, competitive price, while maintaining and even increasing the profit rate.
