Drug Development on Rails: Part Two

Developing an integrated project plan requires the involvement of experts from each of the functional domains. It is always good to set benchmarks from industry best practices within those domains. Best practices identified from wide experience in numerous clinical trials were incorporated in the New Chemical Entity (NCE) template described in Part One of this article (ACT, August 2006). Naturally, some task times will vary widely by product and indication, but a starting framework is a useful baseline from which to then later modify using more specific assumptions. Even with the variation from product to product, a standard best practices timeline can help set general expectations even before the detailed aspects of the preclinical or clinical development plan are known. Particularly in the clinical area, many tasks are fairly standard from one study to the next (e.g., four months to initiate a trial).

Discovery and project initiation

Discovery research is by nature the most creative aspect of the process and is best managed with modest schedule constraints and maximum flexibility. The project template allows one year for Discovery activities. Following Discovery, the first detailed part of the project plan template is the Initiation Phase. Before a project can transition from research to development, it must be critically evaluated in the Initiation Phase for overall feasibility from the technical, financial, marketing, and resource perspectives. Once the project is approved to advance into the development domains [Nonclinical; Chemical, Manufacturing, and Controls (CMC); and Clinical], the work on manufacturing and formulating the Investigational Product (IP) may begin. Figure 1 shows a breakout of the Discovery pharmacology and proof of concept section of the template, and an overview of the steps for the project Initiation Phase.

Chemistry, manufacturing, and controls

The CMC effort requires several years to produce IP at Good Manufacturing Practice (cGMP) standards, but early Nonclinical safety testing may be conducted using non-cGMP product that is usually produced within 12 months. Another 12 months are allowed for manufacturing to reach pilot scale process. The toxicology and early Phase I clinical studies require cGMP investigational product from pilot scale batches. CMC is often plagued with long lead times that can compromise development schedules and delay critical Nonclinical and Clinical milestones if there is inadequate advanced planning. As a result, it takes a dedicated effort to assure that manufacturing responds to development initiatives in a timely fashion. Getting into the queue for manufacturing the various batches of IP (laboratory scale, pilot scale, and production scale) can create months of delays if not addressed early. In addition, the manufacture of pilot and production scale batches involves extensive validation and quality control procedures that add significantly to the overall time requirements. An overview of the CMC section of the template is illustrated in Figure 2.

Figure 1. The template´s pharmacology and proof of concept section, and initiation phase steps.

Nonclinical

Once CMC has initiated its plan and there is confidence that the IP can be manufactured at the required scale and on time, more specific details from the Nonclinical and Clinical plans supplant the automatic defaults in the project plan template. The safety studies in the Nonclinical module of the template are planned for completion in a few months and assume the use of unformulated, laboratory scale IP. Toxicology studies begin only after preliminarily formulated cGMP IP is available.

Figure 2. Overview of the CMC section of the template.

CMC commonly is on the critical path for early Nonclinical studies, particularly toxicology studies. Once cGMP investigational product is available, most of the toxicology studies are finished within two years. Toxicology studies that are not required for Phase I and/or are very expensive (e.g., definitive carcinogenicity studies) are delayed in the template until they logically fit into the project plan timeline. In Figure 3, the major studies and elements of the Nonclinical template module are detailed.

Figure 3. Major elements of the Nonclinical template module.

Clinical

Subject enrollment in the clinical program is initiated 30 calendar days after IND filing. (All other days described below are work days per MS Project^® .) Human dosing at an investigational site begins when the following predecessor steps are completed: 1) protocols are written and approved; 2) the IND is accepted; and 3) IP is available at the site (requires completion of essential regulatory documents).

Clinical studies usually follow the same basic operational tasks, no matter what product is being studied, and the template was designed with that assumption. Start-up tasks are generally similar between studies, although timelines expand with the number of sites involved. In practice, a single-site Phase I study could be scheduled and initiated with a single phone call, while a large global trial involving 300 sites would require more time. A complicated protocol or one in which investigative sites are not readily available might also require substantially more time. There are, of course, many other design variations other than the number of sites that might occur and affect study start-up timelines. For template consistency the Study Start-up module allows two variations in duration of time required to identify and select investigative sites: 1) a Phase I and pharmacokinetic-type trial is set at 23 days; and 2) a longer Phase II and III timeline is set for 52 days. An example of the Study Start-up module in a Phase I trial is shown in Figure 4.

Figure 4. Example of the Study Start-Up module in a Phase I trial.

In the Study Conduct module, two enrollment rates and three "on-study" durations were allowed for subject enrollment and treatment defaults. This keeps the template for the Study Conduct module standardized and reusable, but modifiable when more specific study information becomes available.

• Phase I and pharmacokinetic-like studies allow for enrollment over 20 days from "First Subject In" (FSI) and "Last Subject In" (LSI) and one day on-study.

• Most other studies (Phase II and Phase III) use a 60-day enrollment window for FSI to LSI and 60 days on-study.

• Safety studies are usually longer term and the module provides for 60 days for FSI to LSI and 260 days on-study.

A breakdown of the Study Conduct module for Phase II and III studies is illustrated in Figure 5.

Figure 5. The Phase II and III Study Conduct module is standardized, yet it can also be customized.

The template defaults to a Phase I program duration of approximately 12 months assuming that most trials will be conducted in parallel. It allows for some pauses and delays to modify trial designs based on information learned as the development process proceeds. The basic Phase I program has a test of concept protocol and four other protocols required for single-and multiple-dose tolerance studies and pharmacokinetic evaluations.

The template assumes a Phase II program duration of approximately two years. A typical Phase II program involves 20 or more studies to test for safety, biodistribution, and drug interactions and to demonstrate initial efficacy and dose response. Many Phase II studies can be conducted in parallel and resemble pharmacokinetic-type trials rather than longer and larger efficacy trials. A high-level overview of a broad Phase I, II, and III clinical plan in the template is shown in Figure 6.

Figure 6. High-level overview of a Phase I–III Clinical Plan. The End of Phase II FDA Meeting is critical.

A critical regulatory deliverable in the middle of the clinical program is the "End of Phase II Meeting" with the FDA. Usual discussions with the FDA focus on information obtained in the first two Phase II studies in the template: the pilot efficacy study and the first dose response study. These two studies deliver the bulk of information necessary to plan the major components of the Phase III protocols and prepare for the End of Phase II meeting. Completing the End of Phase II meeting milestone triggers the start of Phase III planning and completion of operational work steps while the rest of the Phase II studies continue.

Phase III is usually the longest clinical phase due to the size and duration of the trials. The template allots three years for this clinical phase, which includes two well-controlled trials and a long-term safety study. Final compilation of the CTD submission begins immediately following completion of the long-term safety study in Phase III.

Figure 7 highlights some of the typical durations for major components of the plan and lists key predecessors that may need to occur prior to beginning that task or activity.

Figure 7. Typical plan component durations and the predecessors necessary prior to beginning tasks.

Regulatory

Since all R&D activity is ultimately designed to meet the obligations of regulatory authorities, every project plan task in the template feeds into one of the five primary Regulatory deliverables: 1) the pre-IND meeting; 2) the IND submission; 3) the End of Phase II Meeting; 4) the pre-NDA/CTD Meeting; and 5) the NDA/CTD submission. Using MS Project^® , the operational tasks embedded in the template and required by the Regulatory domain are made dependent upon completion of upstream tasks by the other functions. The schedule is kept coherent through a regulatory backbone composed of IND and NDA requirements. The backbone extends through the postsubmission time frame and includes recurring requirements such as IND Annual Reports and CTD Safety and Periodic Updates. The content outline for the CTD is shown in Figure 8.

Figure 8. The template´s regulatory deliverables outline helps keep the project on track.

Accelerating project progress

Any size company may achieve project acceleration through utilization of a plan. Large pharmaceutical companies with multibillion dollar R&D budgets are often envied for the financial resources they can apply to a particular problem or hurdle, but ultimately they have little advantage over any size company conducting a well-managed project. Smaller teams are often as effective as large ones in tackling complicated projects. Small teams communicate quickly, make changes more easily, and adapt to changing information readily—leading to faster progress overall. The detail of an NCE template can be used to great advantage by the project team during implementation of specific operational drug development strategies, including project acceleration through outsourcing and establishment of fast-cycle performance.

Project planning and outsourcing

Outsourcing is an acceleration tactic that especially benefits smaller companies. A detailed and fully integrated project plan (or evolving plan in a completed template) is a key to outsourcing any project activity effectively and communicating clear expectations to outsourcing partners. Outsourcing may be strategic or tactical. Strategic outsourcing implies that outsourcing decisions are made for the entire R&D portfolio to assure that priority projects receive appropriate internal and/or external resources. Tactical outsourcing is transacted by the project team or functional department. It usually involves only certain elements of the operational activity, which is delegated to specific outsourcing partners. These partners perform narrower functions and have developed an expert niche, such as nonclinical studies, specialized manufacturing, designing pharmacokinetic protocols, recruiting and prequalifying clinical study sites, data collection and analysis, auditing/QA or medical writing.

An evolving project plan embedded in a complete and detailed template assists the project team, or functional departments appropriately delegate blocks of project activities to appropriate outsourcing partners and still manage those activities successfully. In the template, the tasks have standardized names, which facilitate communication inside and outside the outsourcing company. The template alerts the project team to minute detail where the partner must perform per timeline to stay off the critical path, where the partner and company need to communicate and interact, and where achievement of milestones allows comparisons of the partner and the company's own internal performance against recognized industry benchmarks.

Project planning and fast-cycle performance

Another strategy to accelerate projects that requires a very detailed, complete, and integrated project template is fast-cycle performance. Fast-Cycle Teams (FCTs) are usually implemented to surmount normal company processes that would otherwise delay a critical project. FCTs work outside the traditional company hierarchy and are empowered to make project decisions that will move the project forward.² In the "tiger team" variant of FCTs, team members typically come from the highest ranks in the company: vice presidents and directors. They take sabbaticals from their R&D functional responsibilities for the duration of the project and streamline Standard Operating Procedures (SOPs) to maintain project quality and increase project speed; tiger teams are not required to operate within the company's traditional network of functional management. Getting the job done is the goal, and normal corporate constraints that help keep less experienced employees on the right track are relaxed when using tiger teams. The techniques these teams use to compress timelines are:

Immediate decision making. There is no waiting for senior management attention that can often take 30 days or more to occur in typical corporate environments.

Start with firm draft of the final labeling. Everything works more efficiently if the project team starts with the end labeling in mind. Protocols are designed to address the desired label, data is analyzed to prove the defined labeling targets, and reports are written to support the draft labeling. Everyone from Marketing to Research & Development have the same goals for the product.

No rework. Work is done once because all the normal checkpoints, Clinical Quality Assurance (CQA), and Regulatory are involved in process during the origination, conduct, and completion of the operational activity. As team participants, the departmental Quality Control (QC), CQA, and Regulatory assure in-process quality and compliance. When the final work product or document emerges, sign-offs happen immediately.

Team members retain accountability throughout the entire process. There is no multiple level of management sign-off, since the functional representatives on the project team are the departmental vice presidents and directors. If someone is accountable for writing a report and sends it to another team member, their accountability does not end once the next responsible person has received the report (i.e., "throwing it over the wall"). The writer remains accountable and is expected to follow-up and set the time for getting return feedback and completion of the activity. While responsibility can be delegated, accountability cannot.

Parallel activity and advance work. Many activities are undertaken in parallel rather than waiting for serial results and everything that can be done in advance is done as early as possible. Advanced planning and prework are the keys to speed. Prework is completed and ready for integration when the final pieces become available. For instance, report shells can be written very early, practically at the same time the protocol is written.

Constant management and participation. Management by the tiger team functional representatives (i.e., leads) is conducted through daily short briefing meetings with other team members to identify problems or bottlenecks and develop immediate solutions.

Highly visual project management tools. The project team operates from a war room that contains graphic depiction of the plan and progress. All submission documents are posted on walls with color coded status from origination through publishing status and final submission.

This fast-cycle approach can cut normal development times by 25%–50%. A detailed project plan (in template format) is of particular benefit to FCTs since the whole project is already laid out before them. They can predict the next steps, know immediately where other work product dovetails with their tasks, and make decisions quickly with full knowledge of the priority and timing required of them. Less consultation is required so decisions are made quickly and confidently, resulting in accelerated development.

Summary

Full transparency of the NCE project plan (critical milestones and functional interdependencies) from Discovery to NDA submission is the primary advantage of using a NCE template. From the beginning of the development process, the template visually creates the entire project plan for full examination by project team members and senior management. The template shows activities of all functional domains and how the activities integrate, and provides a focus on achieving the product labeling targets. The plan provides a solid visual reference that enables the project manager to keep the project team and senior management attuned to the project status. As project assumptions change or milestones are reached, the project plan template can be easily modified.

The fully integrated, 12-year project plan template developed in MS Project for use with NCEs provides a common scheduling platform with standardized modules. The modules are clearly documented, and have plainly delineated key predecessors/trigger events. Event lead times derived from industry best practices are integrated into the template to benefit resource planning and scheduling. Departmental QC organizations, CQA, and Regulatory compliance all benefit from a composite plan, as found in the NCE template. Working from the template, a project team can identify wasted time and poorly matched tasks. By reducing the inefficiency of a project, costs are reduced and the return on investment is enhanced.

Outsourcing is simplified with a project template. Partner and internal performance is monitored using industry- accepted benchmarks. Attempting to integrate multiple independent plans from various departments or outsourcing partners without an acceptable template is very difficult. Starting with a complete plan in a template format eliminates future complications. A project template provides a highly visible roadmap for fast-cycle performance, and FCTs are able to make quick, accurate decisions and accelerate project development.

Drug development projects can be compared to a freight train with five different engines and engineers. The idea is to keep everyone on track and to arrive safely at the destination at the appointed time, or earlier if possible. Good project management and a fully integrated, detailed project plan from a template can keep all that energy focused and pounding on down the rails. All aboard!

Timothy A. Wurst,* MBA, is president of Eriban Research, 3101 Broadway, Suite 630, Kansas City, Missouri 64111, (816) 753-5329, email: timwurst@eribanresearch.com www.eribanresearch.com. Brock G. Guernsey, PharmD, is executive director, clinical pharmacology, at Quintiles Inc., F3-3428, 10245 Hickman Mills Drive, Kansas City, MO 64137, www.quintiles.com, and is a member of the Applied Clinical Trials Editorial Advisory Board.

References

1. W.S. Humphrey, Managing Technical People: Innovation, Teamwork, and the Software Process (Addison-Wesley, Boston, 1997, page 42).

2. C. Meyer, Fast Cycle Time: How to Align Purpose, Strategy, and Structure for Speed (The Free Press, New York, 1993).

3. G. Pinchot and E. Pinchot, The Intelligent Organization (Berrett-Koehler Publishers, Inc., San Francisco, 1994).

4. P.A. Roussel, K.N. Saad, T.J. Erickson, Third Generation R&D, Managing the Link to Corporate Strategy (Harvard Business School Press, Boston, 1991).

*To whom all correspondence should be addressed.