The Success Story of an International Pharmaceutical Task Force
Project Management in Action
Late in 1 990, the Human Health Division of Solvay, S.A., an international pharmaceutical and chemical company, came up with a plan to guarantee the timely submission of a registration dossier for a drug that would be new to the U.S. market. Solvay created a multinational task force to act as the project team. This task force would coordinate the medical review and databanking of 24,624 Case Record Forms (CRFs) from European clinical marketing studies. These CRFs were written in seven different languages and were spread among various European countries. To achieve this, the team was assisted by six Contract Research Organizations (CROs) in Europe and the United States.
Speed and quality of work were crucial to the success of this project. For example, data management and analysis of the demographic and safety data were conducted and monitored according to Good Clinical Practice (GCP) guidelines. For the medical review, the U.S. Food and Drug Administration's (FDA) criteria were employed. In addition, safety tabulations and narrative text had to be produced for the safety section of a New Drug Application (NDA) for the FDA. This project was critically important to the timely submission of the NDA, which would be submitted by Solvay Pharmaceuticals, Inc. In the end, the project was successfully completed in thirteen months at a cost of approximately three million U.S. dollars.
In November of 1990, a “SWAT” team was assembled with specialists from the Dutch, German and U.S. Solvay companies. Their mission was to successfully create a crucial part of the registration dossier of the drug Fluvoxamine for U.S. registration (see sidebar). The team members were freed from all their other duties for as long as they had to work on this project.
This project team consisted of a project leader, medical director, database consultant, senior clinical research associate, and statistician. In addition, two secretaries in Holland and one in the United States were assigned to provide the required clerical support.
In the U. S., an advisory team was formed consisting of a statistician, a clinician and a regulatory specialist, all of whom had extensive experience with the type of work that had to be done for this project.
In December, a workshop was organized in the U.S. for the project team to prepare for their special task. The objective of the workshop was to define the scope of the project and also for team members to become familiar with each other.
During the workshop the following items were discussed:
- Scope of the project. More than 24,000 CRFs from European clinical marketing studies had to be reviewed, data-banked and summarized.
- Role/responsibilities of the team members and their relation to the project leader.
- Project activities and their relations, together with the most important issues/concerns (see influence diagram on following page).
- Advice and documentation received from the advisory team.
- A preliminary budget. The required budget was estimated to be approximately three million U.S. dollars, to be spent mostly in Europe.
It became clear during the workshop that two factors would be very important with respect to this special project: quality and speed.
- Quality: Because the resulting documents and tabulations would be sent to the FDA as a part of a NDA, all work had to be done based on strict Good Clinical Practice (GCP) guidelines.
- Speed: Because the New Drug Application (NDA) had to be submitted before the end of 1991, the team was allowed only one year to complete its task. Bureaucratic hurdles were reduced to a minimum to allow the team to maneuver quickly toward its goal.
Since the CRFs were distributed throughout Europe, it was decided that for six months the team would be located in Amsterdam, near one of the European marketing organizations. The U.S. members of the project team flew to Europe with their families during the Christmas holidays, so that the team could start immediately in the beginning of 1991.
THE START IN EUROPE
The first three days in Europe were used exclusively to discuss the various aspects of the project and expectations for cooperation within the team. During these three long days of meetings agreement was reached on:
- Ground rules for the team
- A planning schedule for major activities
- Procedure for selection of the right CROs
- Determination of a short list of potential CROs
- Cooperation with the European marketing organizations of Solvay
- Communications with the Solvay companies in Europe and the U.S.
- Creation of a set of Standard Operating Procedures (SOPS) based on the GCP guidelines of the Food and Drug Administration
- Weekly project team meetings to discuss the project status and to make the required decisions
- Choice of a beaver as the mascot for the project team, based on its endless zest for work
In addition, a laptop computer was bought, word processors were rented and secretaries were recruited.
The Ground Rules
Specific ground rules for cooperation within the team were agreed upon:
- Share all relevant information.
- Focus on interests, not positions.
- Stay focused.
- Disagree openly with team members.
- Discuss undiscussible issues.
- Make statements, then invite questions.
- Agree on what important words mean.
- Expect all members to identify and solve problems.
- Don't take cheap shots,
- Make decision by consensus.
THE END RESULT
Fluvoxamine is a selective serotonin re-uptake inhibitor, which is already on the market as an antidepressant in more than 34 countries. It has been developed in the United States, both in indications of depression and Obsessive Compulsive Disorder (OCD). The work of this project team was focused on the New Drug Application (NDA) for fluvoxamine in the indication of OCD. This NDA was filed by the end of 1991.
As soon as the Food and Drug Administration has approved the registration dossier, it will be launched on the U.S. market under the brand name of LUVOX™ tablets. LUVOX™ will be jointly marketed with Upjohn, which is the strategic alliance partner of Solvay Pharmaceuticals for this product in the United States, and on a worldwide basis with Solvay S.A. Human Health Division.
COLLECTION OF CRFS
The entire project team traveled to the Solvay marketing organizations in France, the U.K., Germany and Holland. All marketing studies that were finished in the clinic between 1982 and December 31, 1990, were inventoried. The corresponding original CRFS were collected through collaboration with the marketing organizations that had locally sponsored these trials. Discussed with each marketing organization were:
- Scope and importance of the project
- Cooperation with the project team
- Copying process (in total approximately 400,000 pages had to be copied)
- Shipment of the CRFs
- SOP for handling of the original CRFs
- Payments for all extra costs related to the project (hiring of extra personnel and renting of copy machines)
A clinical expert was assigned in each marketing organization. This person became the contact person in each country and played a crucial role during the first half of the project. This person would be responsible for the copying process and the shipment and storage of the huge amount of CRFs and their copies.
It appeared that more than 90 percent of the 24,624 CRFs were stored in the archives of these four marketing organizations. In a later phase of the project the project leader went to the marketing organizations in Belgium, Switzerland and Spain to collect the remaining CRFs.
SELECTION OF THE CROs
A first screening of the available European Contract Research Organizations (CROs) was done, based on a reference book containing basic information on all European CROs (The Technomark Guide). Potential candidates in France, the U. K., Germany and Holland were selected. It was decided to sign contracts with five CROs in these four countries instead of contracting the work to one multinational CRO with offices in the various countries. Through this approach, if one particular CRO would fail, only part of the work would have to be repeated. The project team developed a basic contract tailored to the special work to be done for the project. A special section specified a bonus for timely completion and a penalty for delay. This was considered extremely important taking into account the urgency of the project. The complete project team visited ten CROs to discuss:
- Scope of the total project
- Various languages used in the CRFs
- Importance of high quality
- Urgency of the work
- Regular contacts with the team
- GCP standards
Some examples of CRFs, standard sheets for databanking and a copy of the draft contract were given to the CROs. A strict time schedule had to be adhered to:
- Send a quote within one week.
- Negotiate and sign the contract in the second week.
- Medical review and databank all the safety data of the CRFS within three months after contract signing.
Solvay S.A. Human Health Division Corporate Structure
Solvay S.A., Brussels, Belgium
Solvay S.A., based in Brussels, Belgium, employs 45,600 people and is the 15th largest chemical company in the world. Solvay is active in different sectors, including alkalis, peroxygens, plastics, processing and health.
The health sector, which includes human and animal pharmaceuticals, vaccines, enzymes, bio- and pharmaceutical intermediates, is the fastest growing sector within Solvay S.A. This sector has a strong base in research and development: the funding of health research now represents more than 50 percent of Solvay S.A. expenditures on R&D.
The Human Health Division employs 5,000 people worldwide and had sales of more than one billion dollars in 1992. The core of Solvay's human health business centers on three main operating companies:
- Solvay Pharma Deutschland GmbH, in Germany (formerly Kalichemie, acquired in 1953)
- Solvay Duphar B. V., in The Netherlands (formerly Duphar, acquired in 1980)
- Solvay Pharmaceuticals, Inc., in the U.S. (formerly Reid Rowell, acquired in 1986)
All three companies are engaged in R&D, production and marketing/sales. The two European companies have subsidiaries in other countries, especially throughout Europe, as well as export activities. Plans have been implemented to allocate specific research and development areas to R&D centers of the operating companies. These centers are based in Weesp (The Netherlands) and in Hannover (Germany).
Product development is also carried out in Marietta, Georgia (U.S.), by Solvay Pharmaceuticals and in Japan through Kali-Duphar K.K. Solvay's Human Health Division ranks 48th among pharmaceutical companies worldwide.
The primary therapeutic sales areas are:
- Gastroenterology (40 percent)
- Gynecology and hormone replacement (14 percent)
- Cardiovascular system (10 percent)
- Central nervous system (14 percent)
- Others (22 percent)
Solvay Duphar, B.V., Weesp, The Netherlands
Solvay Duphar is active in the field of pharmaceutical chemistry. Duphar, a name which stands for “Dutch Pharmaceuticals” came into being in 1930 with the introduction of a evolutionary process for the production of vitamin D. The company is still the largest producer of vitamin D in the world. In addition, Solvay Duphar has developed into a multifaceted, innovative concern, with activities spread over three divisions:
- Pharmaceutical Division
- Animal Health Division
- Bio and Pharma Intermediates Division
The company has slightly more than 3,400 employees, 01 which about 2,500 work in The Netherlands. Some 90 percent of turnover is realized abroad. Outside The Netherlands, Solvay Duphar has branches and associated companies in ten countries and is represented in all major European countries.
Solvay Pharmaceuticals, Inc., Marietta, Georgia
Solvay Pharmaceuticals, Inc. has evolved over many years through the combination of several regional pharmaceutical companies active in particular therapeutic areas. Solvay Pharmaceuticals has projected 1993 sales exceeding $125,000,000. With a 375-person sales force, out of a total 1,000 employees, it is a viable member of the research-based pharmaceutical industry in the United States. Research, development, manufacturing and sales in the primary therapeutic areas of gastroenterology, women's health and mental health give the company a focus in three growing areas of pharmaceutical importance. The company is headquartered in Marietta, Georgia, and has a manufacturing facility in Baudette, Minnesota.
Solvay Pharmaceuticals maintains important business relationships with other company members of the Human Health Division. The formal business and product relationships negotiated between the companies serve to enhance the ability of the member companies to meet the needs of the various markets that they serve. Many projects involve pror-ucts and processes that require significant expertise and experience in order to fully commercialize the opportunities presented. Solvay Pharmaceuticals relies upon these resources to bring promising new drug developments to the U.S. marketplace in the most efficient manner possible.
The total number of CRFS handled by each CRO varied from about 2,500 to 10,000. The smaller CRF packages had extensive CRFS, while the larger packages included simple CRFS.
INITIATION OF THE WORK AND THE MONITORING PROCESS
After receipt of each CRO'S price quote, the definitive selection of CROS was done based on:
- Availability of qualified persons
- Experience with the required data management system
- Existing quality assurance system
- Logistical aspects
- General impression of the CRO
- Price quote
The following CROS were selected for the project:
- PAREXEL, London, England
- STATICON, Munich, Germany
- MIRAI, Amsterdam, The Netherlands
- ICTA, Dijon, France
- ITEM, Paris, France
After the selection process, contracts were signed and the marketing organizations were asked to ship the first batch of CRFS to the CROS. Each CRO was visited once every 14 days by at least one of the members of the project team and a regular telephone contact was established. During these visits the CRO'S progress was discussed, questions and problems were resolved and quality audits were performed.
A bi-weekly newsletter was issued (seven editions) to keep all five CROS informed about the progress of the project as well as to keep them aware of special issues or additional procedures related to the project. To ease communication among and with team members, at least one secretary was always available in the team's offices who knew the location of every team member at anyparticular moment. In addition, the fax machine was often used for fast communication. A workshop was organized with the clinical experts to discuss the state of affairs of the project and to exchange experiences. Regular conference calls were held with the advisory team in the U.S. to discuss special issues and to guarantee that the ongoing work in Europe would be in line with the other NDA-activities in the U.S. To further ensure consistency with the other NDA activities, an FDA-file was created to store all documents related to the project, which would allow the FDA to verify the completeness and the high quality of the project work.
THE CRO WORK IN EUROPE
The CRO work in Europe consisted of the medical review and databanking of safety and demographic data from 24,624 CRFS. The medical review was performed by medically trained professionals at each CRO and supervised by an end-responsible physician. As part of the medical review, a narrative summary report had to be written for each patient who had a serious adverse experience, who prematurely terminated from a study, or who had clinically abnormal laboratory results. The project team developed guidelines for the databanking of safety and demographic data from the studies. These guidelines included instructions on:
- Data to be captured in the safety database
- Recoding of information to fit into the safety database
- Handling of partly missing or illegible data
- Specifications of the database
- Quality Assurance rules
Before double data entry could begin, the CRF had to be prepared by checking the legibility of all data, coding of certain data items and translating of the textual data. In addition, all numeric and textual information was entered into an intermediate database that reflected the layout of the particular study CRF. The project team then developed a set of logic and edit checks and required each CRO to apply them using a computer program for each finished study database to check for inconsistencies. In addition, a computer program was used to transfer data from this intermediate database to a standard dedicated database, which was also checked. Furthermore, instructions for quality assurance were given. Approximately 135 people in five CROs worked on this project for four months, and spent about 43,000 labor-hours in the timely completion of the work.
The project had been considered a near impossible task, taking into account the time constraints and high quality requirements to be followed for a document planned to become a crucial section of an NDA.
Since quality was crucial for the success of this project, special attention was given to the quality assurance of the work. In addition to the quality assurance done by the QA units of each CRO, the project team performed its own QA audits in close cooperation with the QA units of the CROs. The project team did this extra QA work, due to the complexity of the project and the time pressure on each CRO. A QA file was created for each CRO and included the audit results from the QA unit of the CRO and the QA reports from the project team.
COMPLETION OF THE WORK IN EUROPE
During the four months that the CROs were working on the project, all the narrative summaries for serious adverse experiences were sent to the offices of the project team in Amsterdam and were stored in a fireproof cabinet, after a last QA check.
After receipt of the study databases, the database consultant checked the databases with a self-developed logic and edit check computer program to ensure their quality. The last payments to the CROs were then negotiated, taking into account any extra or unforeseen work.
In July 1991 the project team was partially disbanded. The medical director, the database consultant and the project leader moved to Marietta, Georgia, to support the continuing work in the U. S., since the database would be used for the production of safety tabulations and text in the same format as the other parts of the NDA being prepared by Solvay Pharmaceuticals, Inc. in the U.S. To ensure consistency in the NDA, one U.S. CRO was employed to do a major portion of the work for the entire NDA.
[This project] was successfully completed and resulted in a timely submission of one of the biggest NDAs ever submitted to the Division of Neuropharmacological Drug Products of the FDA.
CONTINUATION OF THE WORK IN THE U.S.
After the split-up of the project team, the team members in Europe focused on:
- Completion of the QA-file
- Collection of all the copies of the CRFs
- Translation of the blank CRFs
- Shipment of all relevant documents to the U.S.
The team members in the U.S. continued work on the individual study databases and the summaries that resulted from the medical review. Via regular continental flights, exchange of faxes and frequent phone contact, good communication between team members was maintained. Monthly progress reports were prepared on both sides of the ocean. Due to the six months of close cooperation in Europe, the work continued successfully despite the inconvenience of the team being split between two continents.
Individual study databases were combined to create one aggregate safety database and remaining inconsistencies and mistakes were discussed with the respective European CROs and resolved. In addition, the results of the summaries of the medical review were compared with the combined database. Final corrections were made and were noted in special QA log sheets to create an audit trail.
The database of more than one million safety data points was then locked and a copy was sent to a separate CRO in the U.S. This CRO had to write a portion of the computer programs and produce the corresponding safety tabulations. The other portion of the safety tabulations was programmed and produced by the database consultant from the project team. In addition, two clinical writers were added to the project team to assist the medical director in writing the text for each table.
All of these activities were completed in time so that the NDA could be submitted by the end of 1991.
CLOSING OF THE PROJECT
The project team reunited in Europe and organized a last project team meeting to evaluate the total project. In addition, an international workshop was organized in Amsterdam to present the outcome of the safety analysis to the clinical experts of the various European marketing organizations. The project team was disbanded and team members went back to their original company assignments. For everybody it was an unique experience that resulted in lasting international friendships.
An international project team worked closely together for six months in Europe and coordinated and monitored the medical review and databanking of the safety data of 24,624 CRFs compiled by five CROs in four different countries in Europe.
During the second part of the project the project team was partially disbanded and half of the team moved to support the continuing work in the U.S. In Europe, team members worked on the translations, the QA-file and the collection and storage of the CRFs, while team members in the U.S. concentrated on combining the study databases, the last QA work on the narrative summaries and the combined database, and the creation of the safety tables and text required for the NDA.
The project had been considered a near-impossible task, taking into account the time constraints and high quality requirements to be followed for a document planned to become a crucial section of an NDA. Thanks to the dedication and extraordinary efforts of this unique international project team, supported by top management of the various Solvay companies within the Human Health Division, and helped by the clinical experts of the European marketing organizations of Solvay, the task was successfully completed and resulted in a timely submission of one of the biggest NDAs ever submitted to the Division of Neuropharmacological Drug Products of the FDA.
Wagner, W., Plekkenpol, B., Gray, T. E., Vlaskamp, H., Essers, H. Review of Fluvoxamine Safety Database. DRUGS 43, Supplement 2, 1992
Wagner, W., Plekkenpol, B., Gray, T.E., Vlaskamp, H., Essers, H. Safety Database on Fluvoxamine: Analysis and Report. PHARMACOPSYCHIATRY, Supplement I, Volume 26, May 1993
Bert H.D. Plekkenpol is the director of project management and R&D administration of Solvay Pharmaceuticals, Inc., Marietta, Georgia, and moved from The Netherlands to the U.S. in 1989. He has held positions in medicinal chemistry, quality assurance, and project management in the sister company, Solvay Duphar, B.V. He earned his chemistry degrees from the Royal Dutch Chemical Academy and project management degrees from Dutch, English and U.S. institutes.
Wolfgang Wagner is corporate medical director of Solvay S.A. Human Health Division. He received his doctor of medicine degree from the University of Munich in 1975. Wolfgang has published several textbooks and international articles on clinical pharmacology and pharmaceutical ethics, and he is a member of the European Society for Philosophy of Medicine and Health Care and of the Kennedy Institute of Ethics at Georgetown University in Washington, D.C.
Hanny Vlaskamp had her education in biochemistry and started her career in the research field. In 1977 she was assigned to the Clinical Research Department of Solvay Duphar B.V From data management, via monitoring clinical trials, she became clinical trials manager, organizing the conduct of drug trials through the European subsidiaries and contract research organizations.
Hans Essers earned a master's degree in mathematics from the Technical University of Delft, The Netherlands, in 1980. He received a master of science degree in applied statistics from the University of Kent, Canterbury, U. K., in 1989. He is currently head of the Department of Clinical Statistics and Data Management at Solvay Duphar B.V., The Netherlands.
Todd E. Gray earned his bachelor's degree in mathematics from the University of Delaware in 1988. He worked for Solvay Pharmaceuticals, Inc. as a statistical programmer analyst and database consultant from 1989 to 1993 in Marietta, Georgia, and in Amsterdam, The Netherlands. He currently works as a programmer analyst in clinical data operations for Synergen in Boulder Colorado.