Clinical Research (Phase IIb-IIIa)
Case Studies |
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TIMI 14 Trial
The TIMI 14 drug combination therapy interrupts a heart attack in progress by breaking up the clump of platelets and proteins that have shut off blood flow to a region of the heart.
Like most drug trials, the TIMI 14 trial has not been without its challenges, and in fact, it required many innovative, flexible solutions to complex issues. The final result is success in terms of realized goals in trial design and end points, cooperative communication and discovery in pure science. The TIMI 14 trial became a laboratory for learning on everyone's part. Here's the story:
Sponsors spawn a novel antithrombolytic. Eli Lilly Inc. and Centocor, inconjunction with the TIMI Group, took on the project of bringing the drug to market. The trial was named TIMI 14 because it was the 14th major study in the area of Thrombolysis in Myocardial Infarction (TIMI) conducted by the TIMI Study Chairman's Office.
A Complex Global Trial
Covance, a contract research organization, was approached in 1996 to assist with a Phase II dose finding study, initially enrolling 450 patients with myocardial infarction in eight countries throughout Europe and North America. The TIMI 14 trial was divided into four arms to test the effects of tPA (alteplase) alone; in combination with abciximab; in combination with streptokinase and abciximab; and compared to abciximab alone. The dose combinations within these arms, and the total number of arms active at a time, were to change throughout the study in response to preliminary safety/efficacy results. The study was later extended to include the active comparator from rPA (retevase) in a two-armed trial, in which dose groups of rPA alone, and in conjunction with abciximab, we reexamined.
Initial Challenges
Given so many players in the trial — two sponsor companies and an academic research center, as well as a central angiographic laboratory, an independent endpoint review committee, two packaging and distribution facilities, and other groups in Europe — establishing excellent communication at the outset was of paramount importance. The study was global in every sense of the word, from investigator sites to packaging plants and consulting research groups scattered throughout Europe and North America. Coordination and communication were key.
The communication issue was addressed by forming an Operations Committee, a group comprising representatives from each key entity who teleconferenced weekly to keep apprised of the study progress. "With operations all over the globe," says Kevin Vernarec, Project Director at Covance working on TIMI 14, "we needed everyone regularly communicating to reach our goals. This team effort fostered very good two-way communication. It became an extremely cooperative and goal-oriented group, with individuals willing to change philosophies and remain flexible. This made it much easier for us to offer and implement solutions."
Another difficult challenge was preparing for immediate drug-specific dosing instructions for each of the randomized patient cohorts. A flexible, proactive solution was required to accommodate this requirement. To be ready for the most probable dosing scenarios, over 50 different dose combinations, referred to as a "series" format, were planned. A series consisted of all dosing instructions for each of the various treatment arms that would run simultaneously. As one series (i.e., dose and treatment arm combination) would near completion, the next most likely series was readied for use.
Preparing the investigative sites for dose changes globally, while minimizing drug wastage as the changes were implemented by the sponsors, posed another challenge to the management team. To facilitate this intricate study design, Covance designed flexible study drug kits, with an exterior pocket to hold the specific dosing instructions for the various treatment groups. Kits were prepackaged to contain drug supplies for one of the four possible treatment arms. With this design, dosing instructions could be changed simply by switching the exterior dosing envelope, allowing flexibility in changing medication regimens and combinations of agents. Of the 50 combinations, 15 ultimately were chosen for testing throughout the course of the study.
To further reduce drug wastage (in this case the drug was in short supply and had limited shelf life), the trial team drew on two invaluable tools — the interactive voice response system (IVRS) and a 48-hour fax CRF (case report form). Dipali Nanavati, Senior CRA working on the project at Covance, explains: "The IVRS was set up with resupply trigger points at each site, which were predetermined by the clinical group, in conjunction with the TIMI Study Chairman's Office.
"In order to maintain drug supply at the site level, the Covance clinical team worked closely with the IVRS group to assure that drug supplies were adequately available at the site level throughout the trial. That way the bulk of the study drug inventory was maintained at the respective packaging facilities, not at the investigative sites, ensuring that the higher enrolling sites never ran out of study medication. In addition, the IVRS maintained the expiration date of each study drug kit component, allowing kit assignment to occur in the order of their expiration dates." Beyond that, the IVRS provided the Covance team with real-time enrollment information. Says Mr Vernarec, "We were ready to end the trial in March '99 and the sponsors were worried about over enrollment, should numerous new patients suddenly come in on the last day. So we kept a 24-hour watch on the IVRS and the minute the last patient was entered, we closed the trial."
The CRF was designed to capture critical patient information and be faxed to Covance by the investigative site within 72 hours of patient randomization. The information was valuable to the sponsors in several ways. With these forms, the sponsors had access to data within 72 hours of patient enrollment - almost real time. This was a crucial element in monitoring safety on this program, since the patient population has a potential for bleeding events. Also, the fax forms provided preliminary primary efficacy data that allowed the sponsors to make the best decisions quickly regarding subsequent drug combinations and dosing levels to investigate for the trial. Furthermore, the fax forms confirmed what patients actually received, keeping randomization errors to a minimum and allowing excellent control of the project.
Switching Midstream
Adding to the complexity of an already complex trial, about three-quarters of the way through, the comparator drug was changed. Now, there were actually two trials. Within a short period of time, the protocol was amended, new study drug kits were packaged, CRFs were redesigned, the IVRS was modified, and additional investigative sites were recruited to participate in the next phase of the trial. A decision was made to maintain two separate clinical databases for analysis of dose determination, efficacy and safety of the comparator drugs. For regulatory purposes — analysis and regulatory submission and to address the change in comparator drugs in the trial — it was treated as one study.
With this change in place, the trial was taking on new dimensions in patient enrollment. What once was a study involving 450 patients was now one of the largest Phase II angiographic trials ever, with 1188 patients enrolled in 90 investigative sites — a 2.5-fold increase in patient population.
A New Model Created
Thanks to the cooperative communication among the multiple participants and the flexibility and dedication of all the major players, the TIMI trial took on an energy of its own, yielding valuable medical knowledge far beyond what they originally set out to do. "It was a learning experience for all, and we feel everything we did improved customer satisfaction," says Mr Vernarec.
This trial is a great example of successful partnership, team effort and dedication, allowing parties with varying agendas to achieve goals of benefit to all.
In grateful acknowledgement of Eli Lilly and Company's assistance in developing this article. |
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