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The need for new trial designs will require flexibility with regard to cost drivers.
With the advent of molecularly targeted therapies (MTTs), the face of oncology clinical trial design is rapidly changing from the traditional approach seen for cytotoxic chemotherapeutics. This change is recognized throughout the industry, as evidenced by the plethora of meetings to discuss trial design and endpoints, position papers released by FDA (e.g., JCO 21(7) 1404–1411 in 2003), and the very recent press release "New Federal Health Initiative to Improve Cancer Therapy" from FDA, NCI, and CMS announcing the Oncology Biomarker Qualification Initiative (OBQI). As a result, creative and adaptive trial designs are becoming "the new norm" to accommodate novel endpoint collections, adaptive go/no-go decisions on flexible schedules, and MTTs' mechanism of action.
Many of these MTT trials are being conducted by small and midsized pharma and biotech companies, often backed by venture capitalists (VC) funding. These companies outsource almost all trial work to CROs, and they need to tightly manage that outsourcing and their development dollars. They place their financial "bets" on only the most promising drug candidates and must arrive at go/no-go or proof of principle as soon as possible.
All of this requires that companies are agile with decision making and with the finances to support those decisions, often rapidly reallocating spending where it is best utilized. However, it is not clear that standard outsourcing, contracting, risk management, and project planning activities within these companies, or the CROs that serve them, have kept pace with these changes and the need for more flexibility/adaptability.
In the oncology therapeutic arena, diseases have been categorized historically by organ pathology, even though the resultant disease categories are often heterogeneous. Today, we are moving toward a genetic or metabolic pathway-based taxonomy of disease.1 It is becoming more common to see agents that are MTTs, that are directed against specific cellular mechanisms (e.g., angiogenesis, signaling pathways supporting tumor cells), and that have little impact on healthy cells. MTTs therefore are theoretically more precise therapeutics than cytotoxic agents that generally target any rapidly dividing cell.
Phase II testing, the primary indicator of antitumor efficacy, is arguably the biggest challenge in modern oncology drug development.2 Historically, agents were prioritized for Phase III trials based on their ability to induce objective tumor regression. This paradigm may not be appropriate for MTTs, which are often cytostatic rather than cytotoxic and so may not induce significant tumor regression on a traditional response time scale. Recent examples include Avastin® (bevacizumab) and Erbitux® (cetuximab). Both had limited single-agent activity when measured by traditional Response Evaluation Criteria in Solid Tumors (RECIST). A lower level of response may be considered acceptable for agents with a mild toxicity profile and administration over a prolonged period of time.
For MTTs, modest but durable tumor regression (or prolonged disease stability) are more appropriate measurements of success. Accordingly, new trial designs are necessary to determine whether or not an effect is distinguishable from no treatment or placebo. Two such trial designs are the randomized discontinuation trial design and the randomized, placebo-controlled, dose-ranging study with cross-over at progression.
Sorafenib (BAY 43-9006) was recently evaluated in a randomized discontinuation designed Phase II multicenter trial across a variety of solid tumors. Patients were sorted according to their initial response after 12 weeks of therapy. Those patients with at least a 25% tumor shrinkage continued to receive the drug. Those patients with stable disease, which was defined as tumor shrinkage or growth less than 25%, were randomized to receive drug or placebo.
The interim results presented at ASCO 2004 showed a significant benefit for patients with renal cell carcinoma. Further, the results justified the Phase III trial in 800 renal cancer patients. Of note is that Sorafenib was originally intended for use in patients with colorectal cancer; the design of this study allowed for inclusion regardless of the organ pathology.1 In development of MTTs, it is the biology of the tumor and not the pathology, age or hormone status that determines the outcome/benefits of therapy.
Phase II trial designs for MTTs are necessarily larger than traditional open label, single-arm Phase II studies of cytotoxic agents. Because the single-agent effect of an MTT is moderate at best, the trial designs must distinguish disease stability due to drug effect from intrinsic growth patterns. The larger studies are needed to ensure robust answers, upon which Phase III studies are built.2
Roberts, Lynch, and Chabner conducted a systematic review of the characteristics of Phase III trials in 2003 to formalize the criteria that sponsors use to make the go/no-go decision. Their findings demonstrated that Phase III trials are the most time-consuming, scrutinized, and expensive aspect of the drug development process.3 These trials hold the most risk from the sponsor's perspective, due to the resources they consume: A positive result will likely support a marketing approval while a negative result could kill the drug.
CROs Retooling for Better Service
Of the 280 oncology agents brought into clinical trials from 1975 to 1994, only 10% received FDA approval. This is the second lowest approval rate of any therapeutic drug class (CNS has the lowest), and the later the failure occurs during development, the higher the cost. Roberts et al. suggest that a greater investment in Phase I and II trials may be required to reduce risk in Phase III, as they found that few sponsors identified subgroup populations likely to respond to MTTs by the end of Phase II.3 Their findings strongly support the trend toward more robust trial designs in earlier stages for MTTs.
Competition for cancer patients to participate in clinical trials has increased significantly across nearly every tumor type. In their analysis of Phase III trials, Roberts et al. identified several factors that stimulated the demand for Phase III trials, which in turn impacts the competition for patients.3 One very obvious factor is the incredible growth in the number of anticancer agents in development. IMS Lifecycle data from March 2002 estimated that there were 1345 antineoplastic drugs in development: 801 in preclinical development, 205 in Phase I, 250 in Phase II, and 76 in Phase III. According to the Pharmaceutical Research and Manufacturers Association (PhRMA), the number of anticancer agents in the pipeline increased 87% from 1995 to 2001.3
Another factor is more specific to MTTs, which have modest activity in Phase II trials. It has become increasingly common for sponsors to abbreviate Phase II and initiate early Phase III trials. Roberts et al. found that 30% of the 71 active Phase III trials tested an approved regimen with or without an MTT in the second or third line setting, and 20% used a design that tested the MTT alone versus observation in minimal residual disease states.3 Ratain and Eckhardt argue that patients are a precious resource and it is incumbent upon industry and investigators to reduce the risk of Phase III trials by initiating Phase III only when substantive proof of activity is shown. This will, in theory, lead to greater incentive to develop more oncology drugs and reduce costs.2
Roberts et al. extrapolated available data and determined that the direct cost of each industry sponsored Phase III trial can exceed $10 to $20 million. As time has a direct impact on the cost of a trial, the authors have seen an increase in the number of sites per study in an effort to shorten the enrollment period. Despite this increase, the clinical phase of development time has more than doubled since the 1960s.3
The cost drivers for any trial include the number of patients, the number of sites, and the length of time to conduct the trial. The new trial designs for MTTs have increased all three components of trial conduct, and additionally have added a level of complexity in an effort to confirm their underlying proof of mechanism for targeted therapy. This is in an era of increased competition for all resources. The 2006 Outlook report by the Tufts Center for the Study of Drug Development found that small to midsize companies now manage the majority of projects in active clinical trials. These companies must reach go/no-go decisions as soon as possible on their compounds to tightly manage their funds. They are also among the highest users of contract research service providers. Thus, CROs must be more innovative in meeting the clinical development demands of today's agents to better serve their sponsors.
Rolling budget forecasts and flexible contracting. For most small to midsize firms, closely managing their costs over the longer period of clinical development that MTTs may require will be key to their economic health, if not survival. It will also support any fundraising efforts required along the way. A full program budget (Phase II and III trials included) should be developed with rolling quarterly forecasts that can account for the impact of each major decision or contingency plan in the program. It is not necessary that the same CRO conduct both Phase II and III programs, but it does require that the sponsor and CRO(s) work closely to keep the financial forecast aligned to trial activities and decisions.
The contract should contain work orders for each trial. Each work order should be parceled by stage of the trial, with the study start-up phase and early enrollment being unitized. Once target enrollment is reached, any patients enrolled thereafter are costed on a per-patient basis. This allows the sponsor to terminate the contract as dictated by trial activity and the CRO to cover sunk costs.
Additionally, each work order or unit of the work order should be "right priced" (i.e., priced for the level of expertise of the team member required by that stage of the trial). Billing rates for core team members in a Phase II designed to aid in selecting patient population, endpoints, and key markers for the Phase III trial would be higher than for the "halo" team or the core team members of the Phase III, which necessarily has a higher degree of focus on logistics.
Teaming. While all trials in an MTT drug development program require experience, the early stages of the Phase II trial demand considerable expertise as well. These studies will need an attention to detail and early trends to allow for course corrections as soon as possible. Keeping in mind that Phase II trials for MTTs tend to be larger, missed trends/issues are amplified if not caught early as more patients are enrolled. The core team at this stage of the trial should be very experienced with a high degree of expertise in the therapeutic arena to better differentiate disease progress and site issues from study-related issues as early in the study as possible.
As in any study, no matter the trial design, there will be high enrolling sites. It will be critical to keep the data flow on par with enrollment to enable earlier, more grounded decisions. Two mechanisms make this possible: intelligent monitoring (discussed later) and the "halo" team. Halo teams are clinical research associates (CRAs) and data managers with less therapeutic expertise who are employed on the study to support the function of the core team. At high enrolling sites, halo CRAs are used in conjunction with core CRA team members to complete lower level activities, such as reviewing regulatory binders, assessing drug inventory status, and copying. They are integral to the study, but have a billing rate of approximately 25% to 30% less than core team members.
Within the data management group, the same concept applies. Halo data managers, those with less therapeutic expertise, are assigned volume tasks such as looking at screen fails in order to keep up cleaning and auditing, while the core team members are focused on identifying trends and managing database activities. In this manner, teams can lock visits on a rolling monthly basis along with patients who have terminated, so that at the study's end only the last patient visit is outstanding to database lock. This is more straightforward in electronic data capture and intelligent monitoring trials, but the same idea applies.
As the trial progresses to later stages, and in Phase III trials, logistics become a greater issue. At this stage, most of the complex development decisions for the MTT have been made and incorporated into the program. Now, the team of CRAs can incorporate a much larger proportion of original halo team members and experienced CRAs (both in the function and in the therapeutic arena), but without the requirement of being therapeutic experts. The same holds for the data management team. Thus, proportionately, the cost for the Phase III team is lower per patient than for the Phase II team. The CRA and data management teams will have core therapeutic leads who will act as the therapeutic resource and mentors to the rest of the team. The size of the study dictates how many of these higher level positions are required.
This structure provides the appropriate level of therapeutic expertise and functional experience adjusted to the stage of the study so that it is possible to "right price" each stage.
Intelligent monitoring (iMonitoring) and EDC—Access to data. As mentioned previously, rapid access to actionable data allows earlier decisions to be made about all aspects of the trial conduct—from protocol changes to early termination—and also allows additional site training to be identified and implemented as needed, in a time frame that can positively impact the quality of the data. iMonitoring is a process to increase the quality of the data and improve the quality and efficiency of monitoring while decreasing project costs. It is designed to provide early access to actionable data.
The current practice of conducting interim monitoring visits involves the CRA scheduling on-site visits at a predetermined interval (e.g., every six to eight weeks) in order to verify case report form (CRF) data against source documentation, in addition to monitor site management, regulatory document management, and test article accountability. Scheduling site visits at a predetermined interval does not take into account variations in patient enrollment and completed patient visits. Rather, the CRA may be reviewing CRFs for as few as one patient or as many as 10+ patients at each visit.
CRAs spend a majority of their time focused on CRF completion issues rather than on data integrity and clinical review. Some time after the monitoring visit, the retrieved CRF data are cleaned and data queries are generated and sent to the site staff for resolution. The CRA has not reviewed the queries but may be asked by site staff to interpret. The resolved queries may require changes to the previously monitored CRFs. At the next visit, the CRA not only must verify newly completed CRFs but resolved queries as well—overall, a very inefficient process.
The strategy of iMonitoring changes the order of the traditional data monitoring process, but does not eliminate any steps or review stages. It is simply using the data and technology already in use to optimize the data source verification process. Site visits are scheduled based on a predetermined number of completed and "cleaned" patient visits. This allows the CRAs to review completed CRFs and queries, support staff in resolving the queries, and more importantly to have enough clean CRFs for review at the next on-site monitoring visit. The main quality improvement over the traditional process is that CRAs are reviewing "clean" data against source documents. CRAs maintain ongoing contact with the site staff to provide feedback from their in-house clinical review of the data and to provide feedback and training on queries, study issues, enrollment issues, and any other site management issues. The end result is an optimized monitoring process that produces higher quality data more efficiently.
iMonitoring is most effective when implemented in conjunction with EDC, as this ensures data are available electronically almost immediately after the patient visit. Immediate availability expedites the computerized aspects of data clean up, and allows the CRA to review the data in-house and focus on protocol and other issues on an ongoing basis.
Therapeutic expertise in the investigator databases—Access to patients. Despite all the technology, the primary key to a successful study is enrollment.
With the advent of targeted, less-toxic oncology drugs, treatment of metastatic cancer patients is no longer the exclusive domain of medical oncologists. Other organ specialists will become more involved in clinical development. Any one protocol may encompass a variety of clinical specialists entering patients with various tumor types in the study. As a result, the number of potential sites/investigators for oncology trials will be expanding. This requires that investigator contact management programs keep pace with this development.
Access to investigators is the first step. But subsequent access to patients is the next. Some therapies are so targeted that because of the complexity of the treatment, only one center, or a selected few, can conduct the trial. However, that center will certainly not have sufficient patients to produce a reasonable accrual rate. Thus, creative patient recruitment strategies (e.g., advertising, patient Web sites, Internet recruitment) will become crucial.
A third layer of complexity after finding the right investigators and patients is the demands on the center/hospital infrastructure and logistics. Many MTTs need both the screening for proof of mechanism of the study drug as well as the validation of a biomarker that demonstrates the proof of mechanism. Functional imaging and tumor tissue sampling are becoming standard. A CRO must be sure of each site's abilities, as poor selection at the beginning can cause costly mistakes later on.
Connie Wierman is executive director of INC Oncology, a division of INC Research, Inc., 4700 Falls of Neuse Road, Suite 400, Raleigh, NC 27609, (512) 439-4210, email: firstname.lastname@example.org
1. J. Whittaker, "Targeted Therapeutics," EPC, 94–98 (winter 2005).
2. M.J. Ratain and S.G. Eckhardt, "Phase II Studies of Modern Drugs Directed Against New Targets: If You Are Fazed, Too, Then Resist RECIST," J Clin Oncol, 22, 4442–4445 (2005).
3. T.G. Roberts Jr., T.J. Lynch Jr., B.A. Chabner, "The Phase III Trial in the Era of Targeted Therapy: Unraveling the 'Go or No Go' Decision," J Clin Oncol, 21, 3683–3695 (2003).