The following Web sites are focused on oncology trials for the professional and/or potential participant. Please note that many pharmaceutical companies currently running trials offer access to them through their own Web sites. In addition, many cancer patient advocacy groups and organizations may have listings for oncology clinical trials on their home pages on the Web.—

American Cancer Society/EmergingMed Clinical Trials Matching Service

www.cancer.org/docroot/ETO/content/ETO_6_1X_Clinical_Trials_Matching_Service.asp

This free Clinical Trial Matching and Referral Service is made available to American Cancer Society visitors through a collaboration with EmergingMed. By filling out one questionnaire, patients learn whether they match any trials in the system. The EmergingMed database contains more than 3000 clinical trials for treatment, prevention, and early detection of cancer. 

www.centerwatch.com/cgi-bin/cl.pl?p=patient/studies/cat29.html&h=bcfhd.txt&f=bcfft.txt

This site accesses a database of industry sponsored clinical trials for Breast Cancer. Trials are listed according to U.S. states. Each listing provides information about center names, drug names, and the type of study. Names of international research sites conducting breast cancer clinical trials are also provided. 

www.patient.cancerconsultants.com/trials.aspx

This popular site is managed by the oncology research center  CancerConsultants.com Inc. and provides numerous resources, including a drug and cancer dictionary, a section for newly diagnosed cancer patients, a free newsletter (SURVIVE), coverage of major medical meetings, and access to clinical trials searchable by cancer type and U.S. location. 

A resource-rich Web site offering cancer-related information for professionals and patients. Features include coverage of over 20 cancer types, access to medical reference texts, live and archived webcasts, continuing education accreditation, multimedia clips, a dose calculator for physicians, online medical journals, a clinical trials search engine, practice guidelines, and disease-specific moderated message boards. Free registration is required to access portions of the Web site. 

A free information service sponsored by Cancer Research UK that provides information on cancer treatments and research along with a search engine that allows users to search clinical trials by type of cancer, trial name, or drug. 

TrialCheck is a search tool developed by the Coalition of Cancer Cooperative Groups to assist patients in finding cancer clinical trials. After answering nine simple questions, patients receive a list of cancer trials for which they may be eligible. TrialCheck allows patients to search for cancer clinical trials according to location so that they can find trials close to home. Patients may be updated via email whenever a new cancer clinical trial has been added to their search results. 

Focusing on cancer trials, the site compares patient profile questionnaires to a list of recruitment trials to find a successful match. All profiles are confidential. 

European Organisation for Research and Treatment of Cancer (EORTC)

On this well-designed and easy to navigate Web site, visitors will find a link to the EORTC protocols database, which contains EORTC protocols (classified according to the name of the group undertaking the protocol) as well as protocols from other organizations. The database may be searched by protocol number, group, tumor site, treatment, or drug. 

This search site, run by the NIH, allows users to find trials by stage/subtype of cancer and type of trial (e.g., prevention, diagnostic, or genetic). It also takes travel into consideration, allowing a distance search by zip code and the option to choose trials from 20 to 500 miles away. 

OncoLink/EmergingMed Cancer Clinical  Trials Matching Service

www.oncolink.upenn.edu/treatment/matching.cfm

EmergingMed's free Cancer Clinical Trial Matching & Referral Service is made available to OncoLink visitors through a collaboration between the University of Pennsylvania Cancer Center and 

. Patients fill out a simple questionnaire and the Trial Matching & Referral Service provides them with matching information about trials taking place at the University of Pennsylvania. 

This is not a clinical trials database, but by giving the company name and drug name, visitors can easily find company Web sites to obtain additional information, including information on cancer clinical trials in progress. 

www.cancer.gov/cancertopics/pdq/cancerdatabase

The National Cancer Institute maintains their PDQ cancer database on this site. This comprehensive resource contains peer-reviewed summaries (updated monthly by six editorial boards) on cancer treatment, screening, prevention, genetics, supportive care, and complementary and alternative medicine. It also features a registry of approximately 2,000 open and 13,000 closed cancer clinical trials from around the world and directories of physicians and other professionals who provide genetics services and cancer care. 

RTOG is a cancer cooperative research group that focuses on radiation therapy. All of the RTOG trials are in the NCI's PDQ database; however, what sets RTOG's offering apart is that they make the entire protocol document for every RTOG trial free to everyone. The protocol document is the complete technical plan for the trial, and includes all the treatment details, a history of the treatment, and references to medical literature. 

www.411cancer.com/ctrials/CTCSearchSteps.jsp?ClinicID=1&Group=domain

			 411cancer.com  offers visitors a database of industry sponsored cancer trials. A simple three-step process will identify available trials and their locations. The site also offers general information about different types of cancer and cancer management, and has a section on cancer news as well as a provider directory. 

Based in Birmingham, Alabama, this nonprofit organization is dedicated to giving clinical research patients the ability to participate in far-off trials via philanthropic flights. 

Trials Central provides easy, free, and confidential access to listings of clinical trials. Users can search by condition (e.g., cancer diabetes, or HIV) and by type of organization (e.g., hospital, nonprofit, or government). There are also links to other health care information Web sites, including medical dictionaries and published articles. 

Articles

Resources

Selected oncology Web sites to assist readers in becoming more informed about cancer and available clinical trials in this therapeutic area.

Internet Resources

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., 

 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.

  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.

  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.

  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.

Phase II trials mitigate Phase III MTT risks

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.

  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. 

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.

  Their findings strongly support the trend toward more robust trial designs in earlier stages for MTTs. 

Additional challenges in conducting MTT trials

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.

  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.

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.

  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.

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.

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. 

 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.  

 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: 

1. J. Whittaker, "Targeted Therapeutics," 

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," 

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," 

Feature Article

The need for new trial designs will require flexibility with regard to cost drivers.

Oncology Clinical Development: Retooling for MTTs

Medical imaging in oncology trials is already well documented. Techniques such as computed tomography (CT), magnetic resonance imaging (MRI), and conventional radiography can provide insights into drug safety and efficacy faster than traditional clinical endpoints. Adopting an imaging strategy, however, introduces challenges, particularly around the potential variability of imaging data collected in multicenter trials and the interpretation of that data. Centralized independent review of imaging data can reduce the variability and bias inherent in these types of trials. 

Ensuring consistency and lack of bias in clinical trials is a critical issue for sponsors and regulatory authorities such as the FDA. This is particularly relevant when medical imaging is utilized for the evaluation of surrogate endpoints in multicenter trials, a practice increasingly adopted in the management of oncology trials. Image acquisition protocols can vary across sites, and each center may interpret data somewhat differently according to local practice. Radiological assessment of images is often subjective, resulting in high interobserver variability among radiologists viewing the same images. In a study involving 50, 60, or 100 sites, significant variability and inconsistency with interpretation is inevitable. While there remains a requirement for on-site evaluation by the local oncologist and radiologist when making a diagnosis or providing patient care, a central review allows an auditable, rigorous, and uniform process of evaluation.  This provides greater consistency across sites, patients, and timepoints, achieving higher confidence levels in data generated. 

Trials involving medical imaging and the associated need for independent review require a significant operational and technological infrastructure, considerable expertise and foresight, as well as the ability to coordinate such undertakings. The process should include: 					

Standardization of imaging and image management at the sites

Image collection at a central location and management of the blinding process

Developing and documenting the independent review criteria and independent reviewer roles and responsibilities

Coordinating the overall logistics of independent review.

The format of the independent review and the makeup of the panel of experts is dependent on many factors, including disease indication and study phase. For registration studies, the independent review process may require a double read by two independent radiologists, unassociated with the study sites or sponsor. A third radiologist acts as adjudicator to resolve differences of interpretation between the two readers. There may also be a requirement for a separate review of clinical and laboratory data by an independent oncologist. 

The process must demonstrate that no bias was introduced during the administration of the independent review. Highly qualified therapeutic experts with no vested interest in the outcome of the study should serve as independent reviewers. When designing an independent review process for an imaging trial, certain factors should be considered, such as the implications of different types of indications within oncology, suitability of assessment criteria, regulatory preferences, lesion selection rules, the appropriate modality for the image used to document disease response, and proper blinding of the reviewer. The study team must also decide how the study objectives and endpoints impact the type of independent review recommended, by addressing questions such as: Is it appropriate to implement a modification to a published response criterion? Is it appropriate to use more than one reviewer? What specific interpretations should the reviewers make so that the necessary data is collected to derive all study endpoints? 

When applying independent review to oncology trials, the study team must take into account the type of cancer and the characteristics of lesions inherent to that type of cancer, the type and schedule of images for assessing disease, and the clinical data that the independent reviewers should consider to make an accurate, unbiased assessment (see Table 1). 

Table 1. An overview of oncology indications and assessments from an independent review perspective 			

 Rules for what constitutes a measurable lesion at baseline or a new lesion, how lesions that become confluent or split will be handled, and how nonmeasurable lesions such as pleural effusions and ascites will be assessed must be defined prospectively. In lung cancer, mediastinal nodes can be clustered, limiting a reviewer's ability to accurately measure these lesions, while atelectasis and pleural fluid can blur margins of a tumor. Likewise, head and neck cancers can produce lesions in the neck that are often matted and small, also limiting an accurate measurement of these lesions. Conversely, colorectal cancer produces tumors that are ideal for measurement since they are typically large and round. 

A finite number of lesions can be selected as measurable based on their size, location, shape, and relationship to other lesions. All remaining lesions should also be accounted for and followed qualitatively. The radiologist follows both lesion types throughout the review process; however, the types of assessments that can be made are dependent on the nature of the lesion and whether the reviewer is making a qualitative or quantitative assessment. Further complexity arises when skin lesions are involved, which are common in melanoma and breast cancer trials. These may be assessed and even measured by an independent oncologist, who will then take both the assessments made by the radiologist as well as his/her own assessment of skin lesions into account along with the clinical data history of the case. 

 Since a radiologist reviews cases with little or no clinical data available on the subject, an oncologist may be employed to review the results of the radiology assessment, as well as clinical data on the subject, for a more comprehensive independent review that mimics the clinical environment, without the inherent bias. For some oncology trials the clinical data may have a significant impact on the overall assessment of the case. The oncologist may assess clinically detected lesions, performance status, the results of pathology or cytology reports, tumor markers, as well as any abnormal laboratory results taken at the investigative site. Ovarian cancer trials will often require that the tumor marker, CA-125, return to normal in order for a response to be considered a complete response. In lymphoma and leukemia trials, clinical data such as organ size and bone marrow biopsy results may be required to make a truly accurate response assessment. 

Case Study-Independent Review of Bone Lesions			

 Missing or incomplete images can dramatically impact study outcomes by resulting in unconfirmed responses as well as multiple assessments of "unknown" and in some cases progressive disease called earlier than actually present. The review of an image that is not part of the required imaging outlined in the study protocol can change the outcome of an assessment. This impacts study endpoints, such as overall response assessments, and affects time-driven endpoints derived from imaging review, such as time to progression, progression-free survival, and time to response. For example, breast cancer may infiltrate the skin, lung, liver, and bone. As a result, imaging for breast cancer may require bone scans and skin lesion photographs in addition to CT or MRI. If any of these modalities were present at screening but then missing at follow-up timepoints, the reviewer may not be able to make a clear assessment for the case, resulting in a call of "unknown." Conversely, a lesion seen on an image at a follow-up timepoint that was not imaged at baseline may result in a call of progressive disease. Hence, ensuring clear assessment rules for all modalities and the implications of missing imaging are key to a successful independent review. 

 Prospectively defining the process for independent review early on in the study start-up process is of utmost importance in oncology trials. The Independent Review Charter (IRC) is the cornerstone of the independent review process and allows the sponsor and imaging CRO to not only define the process up front, but also present a document to the regulatory authorities for review and agreement. The IRC is particularly important in pivotal trials for registration where the primary endpoint or important secondary endpoints are based on imaging data. 

The IRC is a document that the imaging core lab and sponsor develop together, which: 					

Describes the role and responsibilities of the imaging contract research organization

Outlines the process for the independent review of imaging and clinical data to ensure consistency and objectivity of the independent reviewers

Serves as good business practice for the sponsor in order to understand and be critical of the independent review process.

A primary challenge in developing a solid independent review process is to anticipate unforeseen problems that may arise during the independent review. Hence, writing a successful IRC requires a fine balance between describing the process comprehensively and providing as much detail as possible, while also allowing flexibility for problems that may not be foreseen. 

Process control and independent review play an important and ever increasing role in the clinical development of oncology therapeutics. A review of the imaging and clinical data by independent experts skilled in the therapeutic area is critical to reducing variability and bias, thus giving the data greater validity. Throughout the process, careful thought must be given to the collection, processing, reporting, and export of data for final statistical analysis and integration into the full submission. 

Independent review in oncology trials is influenced not only by sponsor requirements and the phase of the study, but also by the complexity of the review process, which is impacted by the type of cancer. The assessment criteria, type and number of reviewers, and methodology of the review process are affected by the clinical particulars indicative of the disease. Anticipating the unexpected is a critical aspect of independent review in oncology clinical trials. Prospectively defining the process as comprehensively as possible, while keeping in mind that other unanticipated scenarios may arise, is key to a successful independent review in oncology clinical trials. Furthermore, by allowing the process to be reviewed and approved by regulatory authorities, the sponsor can further ensure the validity of the independent review.  

Gaurav Sawhney,* Barbara Chandler, Kelie Williams

, MD, are with Perceptive Informatics, Inc., 200 West Street, Waltham, MA 02451, (866) 289-4464, email: 

*To whom all correspondence should be sent.

1. B.D. Cheson, S.J. Horning, B. Coiffier et al., "IWC: Report of an International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas," 

2. M.E. Juweid, G.A. Wiseman, J.M. Vose et al., "Response Assessment of Aggressive Non-Hodgkin's Lymphoma by Integrated International Workshop Criteria and Fluorine-18-Fluorodeoxyglucose Positron Emission Tomography," 

3. B.D. Cheson, J.M. Bennett, M. Grever et al., "National Cancer Institute-sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia: Revised Guidelines for Diagnosis and Treatment," 

4. P. Therasse, S.G. Arbuck, E.A. Eisenhauer et al., "New Guidelines to Evaluate the Response to Treatment in Solid Tumors," 

WHO Handbook for Reporting Results of Cancer Treatment

, Offset Publication No. 48 (Geneva, Switzerland, 1979). 

Independent experts help reduce variability and bias in trials that use medical imaging.

The Role of Independent Review in Oncology Trials

April 1 is usually a day to expect the unexpected. However, on April 1, 2005, the U.S. Food and Drug Administration (FDA) released the "Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics."

  The document describes the agency's "current thinking" while providing "recommendations to sponsors on endpoints for cancer clinical trials submitted to the FDA." 

The following article explores the impact this guidance is having on the clinical research industry and the increasingly important role that imaging has in the assessment of cancer tumors. 

As part of its Critical Path Initiative (

), FDA has joined the U.S. National Cancer Institute (NCI), the pharmaceutical industry, and academia in a number of activities that will facilitate the use of medical imaging during product development and the development of new imaging agents. These efforts are focused on finding new surrogate markers and validating new endpoints for clinical trials. 

Endpoints based on tumor assessment include disease-free survival, objective response rate, time to progression, and progression-free survival. In the FDA's recent guidance document, two tumor assessment endpoints emerge as clear favorites: objective response rate (ORR) and progression-free survival (PFS). These are both based on radiological endpoints. 

ORR, as the name suggests, is determined by an observable and measurable response to treatment (i.e., tumor shrinkage) over a predefined period of time. Its biggest advantage as an endpoint, in the FDA's view, is that it is directly attributable to drug effect and can be assessed in single-arm studies. 

				 PFS is also cited as a desirable endpoint because "it reflects tumor growth (a phenomenon likely to be on the causal pathway for cancer-associated morbidity and death), can be assessed prior to demonstration of a survival benefit, and is not subject to the potential confounding impact of subsequent therapy." Today, ORR is the endpoint most often used to support cancer drug approvals, but the FDA is clear that PFS is also a "preferred endpoint." 			

Endpoints based on tumor assessment (ORR, PFS) are typically based on medical imaging evaluations of the size of the tumor. In practice, this means Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and more recently Positron Emission Tomography (PET) imaging are used  over the course of a clinical trial to view and measure changes in tumor size or function. 

Although a variety of assessment tools and measurement criteria exist, the FDA itself does not have standard regulatory criteria for defining tumor progression. Instead, the agency relies on sponsors to "carefully define tumor progression in the protocol" using established criteria such as the World Health Organization criteria, the newer RECIST (Response Evaluation Criteria in Solid Tumors) guidelines for solid tumors, the International Workshop Criteria for Lymphoma, and emerging standards for PET. 

The adoption and use of imaging to support efficacy endpoints is well established. However, acceptance of medical imaging-based trial endpoints requires data to be rigorously acquired, collected, analyzed, and delivered. Medical images must be treated as source documents, and their interpretation must be standardized and objective. Because tumor assessment is so critical, the FDA has expressed its concern for reliability, especially given "the potential for uncertainty or bias in tumor assessments." To reduce bias, the FDA has made some specific recommendations: 

"When the primary study endpoint for drug approval is based on tumor measurements (e.g., progression-free survival or ORR) it is recommended that tumor endpoint assessments generally be verified by central reviewers blinded to study treatment." 

			 This is accomplished through the use of an Independent Endpoints Review Committee (IRC), which provides "a mechanism to minimize bias in interpretation of the radiologic findings and independent adjudication of endpoints." 			

In order to clearly understand the imaging components of the study, the FDA recommends that an independent review charter be submitted before the study begins, outlining the IRC design and detailing key points such as image handling, endpoint interpretation, and review discrepancy resolution.  The charter must be aligned with the study protocol and the statistical plan, all of which may be required to support a Special Protocol Assessment (SPA). 

Recent approvals of oncology drugs such as Sutent, Erbitux, Gleevec, and others have highlighted the use of imaging to support accelerated approval. The FDA guidance document is evidence of an increasingly rigorous approach to documentation in oncology trials. For sponsors, this approach presents  increased complexity given the need to integrate imaging into the mainstream clinical trial functions. Key to the success of the imaging-based endpoints are the participating radiology departments. Inclusion of the radiology department in the development of the investigational site is essential in optimizing performance. Radiology will need to acquire data consistent with a protocol and submit the image data for central analysis. Adding the radiology department to the sponsors' budgets and including them in activities such as investigator meetings, monitoring visits, and study communication will go a long way toward improving the chances of success. 

Further integration with data management and biostatistics activities can improve the speed and accuracy of the blinded reads. The use of electronic case report forms during the blinded reads affords the reader the use of logic tools and auto calculations in their interpretation of the criteria. Integration of the imaging and clinical databases can streamline the statistical analysis and ensure high-quality data supporting the endpoint. 

The FDA guidance also strongly advises that the images be available for submission to the agency for review if and when necessary. Often this is accomplished through interactive databases that combine the clinical information, results of the blinded reads, and the images themselves. This allows the reviewer and the sponsor to search for specific cases, to look for specific outcomes such as all complete responders, and to consider what the readers saw and how they made their decisions. Additional tools and methods are currently available to execute the use and management of this data in an efficient and auditable manner. 

The FDA and the pharmaceutical industry have adopted medical imaging to support the latest endpoints in cancer oriented clinical trials. The arrival of the April 2005 guidance not only reinforces the FDA's full adoption of medical imaging to support cancer endpoints, it also clearly points to the importance of skillful management of the imaging aspect of cancer oriented trials in responding to more rigorous expectations of documentation and methodology.  

 PhD, is the CEO and co-founder of Beacon Bioscience, 4259 W. Swamp Road, Suite 410, Doylestown, PA 18901-1033.

1. Food and Drug Administration, Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics, 

The 2005 guidance reinforces adoption of medical imaging for cancer endpoints.

Supplements-05-02-2006

Internet Resources

Oncology Clinical Development: Retooling for MTTs

The Role of Independent Review in Oncology Trials

FDA Guidance Document Focuses on Cancer Trial Endpoints