NCI'S CANCER THERAPY EVALUATION
PROGRAM: A COMMITMENT TO TREATMENT TRIALS
Jeffrey S. Abrams, MD, Anthony Murgo, MD, Michaele C. Christian, MD
Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland, USA
1. INTRODUCTION
As the lead federal agency for cancer research, the National Cancer
Institute supports a broad array of interventional clinical trials, using
medical, surgical andlor radiation therapies to treat, prevent and control
symptoms of cancer.' The trials are coordinated or conducted by different
Divisions/Programs within the NCI, including the Division of Cancer
Treatment and Diagnosis (DCTD), the Division of Cancer Prevention, the
Cancer Centers Program, the Specialized Programs of Research Excellence
(SPORES) and the Center for Cancer Research. This chapter will focus on
the cancer treatment trials sponsored by the Cancer Therapy Evaluation
Program (CTEP) located in the DCTD, the largest program sponsoring
cancer treatment trials at NCI. CTEP is organized into distinct branches
(Figure 1) that work closely together, in many ways similar to the
functioning of a large pharmaceutical firm, with the important difference that
the primary stakeholders are the American public. Because development of
effective therapies in the public interest is CTEP's prime mission, achieving
this goal requires multiple collaborations with pharmaceutical firms, public
and private academic institutions and physicians in oncology practices in the
U.S. and abroad. This myriad of public-private partnerships has made CTEP one of the largest sponsors of oncology trials in the world.
Development of new therapies traditionally occurs through a logical sequence of trials, moving from the first trials in humans (phase 1) to disease-specific efficacy trials (phase 2), and finally, to definitive trials comparing the new therapy to a standard control (phase 3). CTEP is organized to support and evaluate all phases of these trials. Staff in the Regulatory Affairs Branch submit and manage the investigational new drug (applications), termed INDs, and coordinate interactions with the Food and Drug Administration (FDA). As an example, their efforts have resulted in contractual language acceptable to different companies, thereby allowing two or more targeted, investigational agents to be co-developed in a single trial (Figure 2). The Pharmaceutical Management Branch monitors distribution and dispensation of investigational agents, and forecasts drug supply needs. Quality assurance for CTEP-sponsored trials is managed by the Clinical Trials Monitoring Branch, and its staff oversees an extensive on- site auditing program. Medical and statistical input into the planning and evaluation of new trials is supplied by the Investigational Drug Branch, the Clinical Investigations Branch, and the Biometrics Research Branch. This multidisciplinary structure allows CTEP to provide broad expertise and experience regarding the conduct and evaluation of clinical trials.
With its primary focus being the accumulation of useful knowledge to treat cancer, CTEP-sponsored trials are not exclusively directed towards drug approvals. The goal is not to find a niche for the agent, but rather to find an effective treatment for the disease. Thus, a hallmark of CTEP- sponsored trials is the inclusion of translational science and other correlative studies. Knowledge gained in this way is shared with all investigators whether or not it is supportive of the agents in the actual study. Review of these scientific efforts is accomplished by including experts from other NCI programs (quality of life, prevention, imaging, biomarkers, and preclinical models) in the CTEP review processes. Non-NCI reviewers provide valuable input in the solicitation process for new agents in the phase 1-2 program and disease experts and patient advocates serve as reviewers for concepts for phase 3 trials.
In view of its broad scope and interactive components, the CTEP review process is complex. The schema in Figure 3 provides an explanation of both the NCI-supported studies that are subject to review and the types of reviews conducted for each. Full review involves contributions from the entire CTEP program, and includes relevant internal and external non-CTEP reviewers.
Development strategy reviews andlor safety reviews are limited to select CTEP reviewers whose recommendations are usually non-binding, whereas
"file only" studies are listed in CTEP's Protocol and Information Office
database for reference but the studies are not reviewed formally. Why audit?
Clinical trials have played pivotal roles in the care of cancer patients.
Randomized comparisons of therapies have defined the optimal treatment strategy; early-phase investigations involving novel agents have stimulated and advanced cancer care; and multi-institutional trial participation has propagated promising new treatments to many patients. As scientists and care providers, clinical trialists must assure and protect the integrity of clinical trials. A quality assurance audit is a formal process by which the quality and completeness of the reported trial data are independently appraised in relation to the raw clinical data and the actual conduct of the trial. Detecting both systematic errors as well as deliberate falsifications of data is important for ensuring that trial outcomes are valid. Indeed, quality control represents both an ethical obligation to the human subjects who voluntarily participate in the clinical trials, as well as a scientific obligation to the trial investigators who contribute to the collective results of the trial.
The NCI has defined several goals for the quality assurance program of cooperative groups.2
Auditing aims to prevent problems, by fostering the development of a responsible research team. Investigators who understand the importance of faithful adherence to the trial protocol will likely recruit and train support staff who are careful and honest in data collection and reporting.3 Building such a research team guards against noncompliance with the protocol or the regulatory requirements.
The audit program aims to detect problems through periodic monitors and checks. Random errors and systemic errors may result in data that are missing, incorrect or variable beyond expected ranges. These errors may be detected by statistical methods. Auditing, as defined above, is a process where reported data are checked against the original medical records or source documents, constitutes a more detailed and rigorous method of error detection.'
The third goal of the audit process is to ensure timely and effective correction of detected errors. Indeed, deficiencies identified in an audit require responses from enrolling institutions within a pre-defined time frame.
Finally, the quality assurance audit has been increasingly recognized as a
valuable educational opportunity. Through on-site visits, the audit staff not
only evaluates the trial support structure at individual institutions, but also
compares and shares sound research practices from other member
institutions. Additionally, as identified deficiencies are communicated and
plans for corrective action are developed, the investigators and the institution
have the opportunity to learn and improve their research practices in the
future.
CTEP'S EARLY PHASE DRUG DEVELOPMENT PROGRAM
CTEP's early phase investigational drug development program is managed primarily by the Investigational Drug Branch (IDB). IDB directs the clinical development of a large number of investigational new drugs and biologics and makes them available for trials conducted by a vast, national network of investigators and Cooperative Clinical Trials Groups (hereafter referred to as the "Cooperative Groups").
IDB is staffed by physicians, all of whom have extensive experience in medical and pediatric oncology and in the development and conduct of cancer clinical trials. During pre-clinical testing, IDB works in close collaboration with scientists in the NCI's Developmental Therapeutics Program (DTP), providing medical input into the assessment and prioritization of agents considered for future or further pre-clinical development. Through each phase of clinical development, IDB works jointly with disease experts in CIB and in the extramural community to establish cancer treatment strategies that are grounded in the latest available knowledge of tumor targets and novel therapeutics.
CTEP's early drug development program involves a large number and variety of agents and the sponsorship of about 150 active INDs for drugs and biologics. These agents come from a variety of sources (Figure 4). Most are obtained through collaborations with biotechnology and pharmaceutical companies. NCI-CTEP has approximately 80 collaborative research and development agreements with over 60 different companies. The purpose of these agreements is to provide a regulatory and legal foundation for the exchange of funds, materials and information between NCI, industry, and academia, while addressing issues such as human safety, good clinical practice guidelines, data sharing, and intellectual property. The three agreement types - Collaborative Research and Development Agreements (CRADAs), Clinical Trials Agreements (CTAs) and Clinical Supply Agreements (CSAs) - are utilized, respectively, according to whether the research plan for an agent is broad (multiple phase 1-2 trial), targeted (just a few focused trials) or only involves distribution of the investigational agent for a multicenter trial. Some of the agents are "home grown" at the NCI.
Others come from scientists at universities or other academic or research
institutions, often produced with the support of NCI grants or NCI-funding
agreements, such as RAID (Rapid Access to Intervention Development). The
RAID program is designed to accelerate the transition to the clinic of novel
anticancer therapeutic interventions, either synthetic, natural product, or
biologic, arising in the academic community. Information about RAID can
be obtained on the NCI DTP ~ e b s i t e . ~
Before NCI can file an IND or expend significant resources on the development of an agent, approval must be obtained from NCI's multi- disciplinary Drug Development Group (DDG).~ The DDG is advisory to the NCI-DCTD Director, with membership that includes senior staff from DTP and CTEP and other relevant NCI programs. DDG meetings are confidential since proprietary information is reviewed (Figure 5). For each application discussed, there are usually two ad hoc external reviewers who are selected based on their expertise with the particular drug, target or indication. Agents can enter the DDG review process in various stages of preclinical (DDG 1-11) or clinical (DDG 111) development. Upon completion of the review, the DDG assigns priority scores (ranked 1-5; Outstanding=l.O, Excellent=1.5, Very Good=2.0, Good=3.0, Fair=4.0, Acceptable=5.0) which are weighted as follows: Strength of Proposal's Credentials (40%); Novelty (30%); Cost and Benefits (20%); Need for NCI Involvement (10%). A score of 2.5 or less is usually required for approval.
For agents considered for DDG 111, CTEP commences clinical development upon DDG approval. In addition to involvement of industry collaborators, CTEP seeks input from extramural scientists in establishing drug development plans. The usual next step is the solicitation process whereby CTEP solicits for proposals to conduct clinical trials. These solicitations, which provide background information on the agent and the types of studies sought, are distributed to cancer centers, principal investigators of cooperative agreements (termed UOls), contract holders (termed NOls), SPORES and Cooperative Groups. Letters of Intent (LOIs) to conduct clinical trials are usually due within about 45 days from the solicitation date. Templates for preparation of the LOIs are provided on the CTEP ~ e b s i t e . ~ The LOIs are reviewed and prioritized by CTEP and selections are usually made within 4-6 weeks. CTEP also accepts unsolicited LOI's, recognizing the value of investigator initiated proposals. Priority scores are assigned for each proposal based on a variety of characteristics (Figure 6). The rating system is similar to that described for the DDG review and scores lower than 2.5 are usually successful. Even some very good proposals may not be approved if they are duplicative with ongoing studies or with other proposals with better priority scores. To improve a particular study's overall quality and accrual potential, CTEP may request that investigators with similar proposals collaborate and conduct the study as a multicenter trial to take advantage of the merits of both proposals. The approximate number of LOIs received and approved in 2004 is shown in Figure 7.
Investigators with approved LOI's are asked to submit protocols within
30-60 days. To assist in the preparation of the protocols and to standardize
across all CTEP-sponsored studies, CTEP provides protocol templates
specific for the phase of study. These protocol templates are available for down-loading from the CTEP ~ e b s i t e . ~ In addition, investigators with approved LOI's are provided with clinical brochures and often with agent- specific protocol templates to lessen the time and burden of document preparation.
There are a variety of ways to obtain funding to support the research costs of clinical trials. In addition to funding the Cooperative Groups, CTEP also provides funding for clinical trials through several other mechanisms, including about 16 UOI cooperative agreements to conduct early phase trials, with a focus on phase 1. In addition to support to conduct clinical trials, the U01 funds pharmacokinetic studies. CTEP also funds 7-8 NO1 contracts to support the costs of conducting phase 2 trials with investigational agents.
These contracts involve more than 18 cancer centers within the US and Canada. Unlike grants, these contracts provide funding on a fee for service basis. Patient accrual to UOl-funded studies is shown in Figure 8. The accrual to NO1-funded studies has steadily increased since the inception of the current structure in 2001 (Figure 9).
Support for the laboratory correlatives must be obtained from other sources such as ROl or R21 grants. Recognizing these research grants are often difficult to coordinate with the start date of a trial without requiring significant delays, CTEP provides support for these early correlative studies in these critical early development trials through its Translational Research Initiative (TRI). TRI is a contract mechanism to provide supplemental funding for correlatives studies that are part of an NCI-sponsored, early drug development trial. Only correlative studies that are considered to be relevant to the further development of the investigational agent are eligible for TRI support. Information about TRI funding can be obtained on the CTEP
~ e b s i t e . ~
In addition to clinical trials, CTEP manages programs for
"compassionate" and expanded use. If a CTEP-sponsored investigational agent has been found to have reproducible clinical efficacy, such as objective responses in the setting of a phase 2 trial, CTEP may provide the agent for "compassionate" use under its Special Exception program. These are single-patient protocols for individuals with the appropriate cancer type who have no other treatment options and are not eligible for an appropriate clinical trial. On average, about 8-12 investigational agents are available under this mechanism. Other CTEP-sponsored expanded access programs include Group CJTreatment IND and Treatment Referral Center (TRC) protocols. Further information about these programs can be found on the CTEP ~ e b s i t e . ~
Investigators conducting CTEP sponsored clinical trials are required to
follow certain requirements for data reporting. To manage and monitor the
enormous amount of data from approximately 1000 active protocols, CTEP
has in place several electronic submission systems. Many of the protocols involve investigational agents and, as such, must be monitored very closely.
Investigators are required to submit serious adverse events through the Adverse Event Expedited Reporting System (AdEERS) according to timelines stipulated in the CTEP Guidelines for Adverse Event Reporting
~ e ~ u i r e m e n t s . ~ Investigators are also required to utilize CTEP electronic systems for routine reporting of data.7 Data from Phase 1 trials are to be submitted via the Clinical Trials Monitoring System (CTMS) every two weeks whereas Phase 2 data are to be submitted quarterly using the Clinical Data Update System (CDUS). Compliance with data submission requirements is essential to allow CTEP to fulfill its regulatory responsibilities to the Food and Drug Administration (FDA) as an IND sponsor and its obligations to pharmaceutical company collaborators.
LATER PHASE CLINICAL TRIALS
Controlled, randomized phase 3 trials represent the gold standard in oncology and are required by the FDA for final approval of most new anti- cancer agents. To accomplish such trials, CTEP has sponsored a Cooperative Group program for the past 50 years that performs phase 3 trials utilizing new medical, surgical and radiation therapies, either alone or in combination. Multi-modality and specialty Groups (Figure 10) provide a unique, highly qualified, standing apparatus that permits the rapid testing of new agents andlor surgical and radiation techniques, and their integration into standard treatment. Cooperative Group trials have accounted for over 60% of plenary session presentations at the American Society of Clinical Oncology (ASCO) in the past 5 years, and these trials have often set the standard of care for the treatment of cancer patients world-wide.
The Groups are funded via cooperative agreements, a funding mechanism
used when a collaborative relationship between extramural investigators and
NCI staff is thought to be optimal to achieve the research goals. CTEP staff
in the Clinical Investigations Branch (CIB), primarily physicians and nurses
specializing in oncology, coordinate the overall Group research effort by
emphasizing opportunities for collaboration, and by helping to integrate
expertise in imaging, diagnostic, and correlative sciences from other NCI
programs into Group trials. Because of their broad access to and knowledge
of diverse research portfolios, CTEP staff can assist the Groups in
identifying important research opportunities and questions. They also
provide leadership in formulating a consensus review for all Group phase 3
trial concepts that go through the NCI review process. Investigators submit
concepts for review utilizing the Concept Review ~ e m ~ l a t e ~ . Evaluation of concepts focuses on the scientific underpinnings of the clinical question, and spares investigators the time and effort required to prepare a protocol until a commitment to fund the trial is assured. Because approval of a concept implies that a large and costly study will be performed, effective concept evaluation requires that the investigators provide a strong preclinical/clinical rationale as well as the study design with treatment regimens, toxicities, and statistical plan in sufficient detail to allow an in-depth review. In addition to these factors, concepts are evaluated for the overall impact of the scientific question and its feasibility relative to the planned sample size. The scoring system is based upon a 5-point scale, similar to LOIS. Concepts scoring less than 2.5 are usually successful.
Over the past 5 years, CTEP has reviewed 219 concepts and has approved 154. Based upon these studies, enrollment into Group trials has consistently averaged approximately 20,000 patients annually for phase 3 studies with approximately 140 phase 3 studies open at any single time (Figure 11). Further details regarding the Cooperative Group research agenda are reviewed in Chapter 5.
Once a concept is approved, CTEP and Cooperative Group staff now
work rapidly in tandem to develop the final protocol. Utilizing this new
approach, several recent trials have gone from concept approval to approved
protocol in under 100 days. This is a major improvement compared to the 9-
18 month development periods that were required previously. To further
facilitate joint protocol assembly, a new, web-based protocol
authoringheview tool called Docu-Mart has been developed that permits on-
line editing by multiple authors/reviewers. This new approach, due to be
implemented in selected Groups in late 2005, should further speed protocol
development since it avoids the sequential, paper-based processes used
previously. To address an additional, oft-cited, barrier to clinical trials,
CTEP has worked with the Cooperative Groups to build standardized case
report forms for all diseases in which phase 3 trials occur. The approach is
based upon a standard vocabulary, housed on-line by NCI in the Cancer Data
Standards Repository (c~DsR)'. Data collection items with their respective
valid values are stored on the website along with template case report forms
for each disease. Utilization of common definitions and similar case report
forms is a major benefit since it lowers staff training costs for intergroup
trials by reducing confusion and inconsistencies, facilitating standardized
data collection and rendering data sharing more feasible.
CANCER TRIALS SUPPORT UNIT (CTSU)
In an attempt to improve the rate of accrual to phase 3 trials, and to leverage advances in technology and communications, NCI created the Cancer Trials Support Unit. Its primary goals are to centralize regulatory support for Cooperative Group trials, previously maintained separately by the eight adult Cooperative Groups, and to establish a national network of physicians who can participate in NCI sponsored phase 3 adult cancer treatment trials, without regard for their individual Group affiliation.
The CTSU has increased physician and patient access to Phase 3 adult cancer treatment trials, the majority of which are led by the Cooperative Groups. Cooperative Group members are able to enroll eligible patients for any trial on the CTSU menu that is not available through their own Cooperative Group. For example, if a SWOG member is interested in a study on the CTSU menu that is being conducted by GOG, the SWOG member can open the study at their site through the CTSU.
This system appears to have broad appeal, as the number of accruals through the CTSU has steadily increased (Figure 12). During the past twelve months, the cumulative accrual through the CTSU since its inception in 1999 has nearly doubled, from 5000 to almost 10,000 patients.
Additionally, using the CTSU as a readily available mechanism for collaboration, many more Group-led studies have been "endorsed" by other Groups such that most phase 3 studies are now Intergroup efforts both in terms of scientific leadership and accrual.
The steady increase in accruals is, in part, a function of the large variety of studies available on the CTSU menu (Figure 13). Initially, the CTSU protocol menu included protocols from 5 disease areas - gastrointestinal, genitourinary, lung, breast, and adult leukemia; however, the CTSU has expanded to include other diseases such as melanoma, head & neck, multiple myeloma, and some rare cancers. There are currently 58 trials on the CTSU menu, with 28 more in development. In addition to Group-led studies, the menu now also contains phase 3 trials led by International study groups, CCOP research bases, and some phase 2 studies in uncommon cancers. It is anticipated that eventually all phase 3 CTEP-sponsored studies will be available through the CTSU.
A unique aspect of the CTSU is its extensive use of the Internet. It has
both a public web site9 and a limited access, password protected members'
web site1'. All CTSU members have access to protocols, protocol-specific
forms (e.g., case report forms, materials ordering forms) and patient
educational materials on the members' web site. Protocol-specific materials
that are provided on-line include the following: completed IRB submission
applications, audit worksheets, protocol-specific time and events schedules,
and pocket-sized protocol cards that outline protocol-specific eligibility requirements and treatment plans.
To assure that investigators would not be overly burdened by the requirements of participating in clinical trials led by different organizations, the CTSU consolidated regulatory processes (site and investigator credentialing, specific protocol requirements and IRB approvals). All adult Cooperative Group regulatory submissions, with the exception of some of the major phase 3 prevention trials, are now submitted to a single CTSU regulatory office. The CTSU and the Adult Cooperative Groups have collaborated to develop a web-based Regulatory Support System (RSS), capable of housing all Adult Cooperative Groups' regulatory documents in centralized repository. This consolidation has streamlined the regulatory process for investigators at local sites who can now submit their credentials once each year including a 1572 form for investigational drugs and a supplemental group membership form that are made available to all relevant Groups via RSS.
Cooperative Group trials supported by the CTSU are steadily migrating to electronic data capture from local sites, rather than the traditional paper- or fax- based approaches that have predominated previously. The CTSU is helping to standardize web-based data entry by utilizing an Oracle toolset that is potentially scalable across the country. Currently, a large pilot effort is underway to utilize this electronic data capture tool. Lessons learned during this pilot experience should enable NCI to rapidly move towards offering a national system for electronic data capture on multi-center studies.
A single electronic data capture system will streamline training of research personnel and should further facilitate cross-group enrollments.
TOWARDS THE FUTURE
CTEP's commitment to the development of new drugs and better multi-
modality treatments is evidenced by a solid track record of past
accomplishments (Figure 14) and by novel approaches that address new
challenges. The ability to combine multiple targeted agents early in their
development, the inclusion of correlative science endpoints in the majority
of phase 2 and 3 trials, and the integration of functional imaging approaches
in early trials exemplify some of these innovations. In the phase 3 arena, the
CTSU has proven to be a useful addition to NCI's longstanding Cooperative
Group system. As the CTSU matures, cost savings should be realized as
redundant activities conducted by individual Groups are eliminated. These
efficiencies should permit Groups to focus their resources on study design
and analysis thereby speeding the processes of protocol development and
reporting. The CTSU's accomplishments - a unified menu of Group trials linked to a national system of qualified investigators managed in a consolidated regulatory database - indicates that the Cooperative Group system is evolving to meet new challenges. The formation of the CTSU has positioned NCI's Cooperative Groups to be more nimble partners for pharmaceutical companies seeking assistance with new drug development and to be more capable of addressing the most compelling cancer treatment research questions in a rapid and reliable manner.
The future evolution of NCI's approach to clinical trials has recently been charted. In June 2005, the NCI Clinical Trials Working Group (CTWG) presented their report to NCI's National Cancer Advisory ~ o a r d " . Commissioned by NCI's Director to review all of NC17s clinical trials programs, the Working Group's report called for important changes in the development, prioritization, review and conduct of treatment, imaging, cancer control and prevention trials. It noted that even greater consolidation of standards across trials, with increased utilization of common data elements, uniform templates for protocols and legal contracts was essential.
Consistent reporting tools were required so that a common database with trial information from all NCI-sponsored trials could be made available to the research community. Such a database was felt essential if treatment strategies were to be optimized and unnecessary redundancy was to be reduced.
Ultimately, the Working Group's vision calls for a more tightly integrated matrix of NCI-sponsored trials that, when realized, could more effectively synergize their efforts in moving anti-cancer strategies from early phase studies to definitive trials. The SPORE and Cancer Centers Program, CTEP, the Division of Cancer Prevention, the Cancer Imaging Program and NCI's intramural program have all committed to participating in this new framework for clinical trials. The plan also requires the extramural community to work closely with NCI staff to prioritize utilization of the Institute's finite, clinical trials resources. Towards this aim, tools for better communication and collaboration will be critical for success, and this effort is ongoing through NCI's Center for Bioinformatics, the leader of the CaBIG (Cancer Bioinformatics Grid) initiative12.
CONCLUSION
In summary, the NCI's commitment to clinical trials remains strong.
Collaborative by design and evolving with the times, the infra-structure is
ready to confront the challenges posed by exciting, new, molecularly-based
discoveries. NCI recognizes, however, that clinical trials could not be carried
CANCER THERAPY EVALUATION PROGRAM (CTEP) CANCER THERAPY EVALUATION PROGRAM (CTEP)
Protocol and Information Office Protocol and Information Office
Clinical Clinical Investigations Investigations
Branch Branch
Regulatory Regulatory Affairs Affairs Branch Branch
Investigational Investigational Drug Branch Drug Branch
Pharmaceutical Pharmaceutical Management Management
Branch Branch
Clinical Clinical Trials Trials Monitoring Monitoring Branch Branch Office of the Director, DCTD
Office of the Director, DCTD
Biometric Research Branch
Biometric Research Branch
Figure 2. Investigational Drug Combinations Supported by CTEP
EGFR Inhibitor Combinations:
Gefitinib +CCI-779 + mTor inhibitor Gefitinib +Bay43-9006 + raf inhibitor
Erlotinib +bevacizumab + angiogenesis inhibitor Erlotinib +cetuximab +bevacizumab + angiogenesis inhibitor Cetuximab +bevacizumab + chemo + angiogenesis inhibitor Erlotinib +R 1 15776 + farneslytransferase inhibitor EKB-569 + CCI-779 + mTor inhibitor
Raf Kinase Inhibitors
Bay43 -9006 +bevacizumab + angiogenesis inhibitor Bay43-9006 +R115776 + farneslytransferase inhibitor
mTor inhibitors
CCI-779 + bevacizumab + angiogenesis inhibitor CCI-779 + erlotinib + EGFR inhibitor CCI-779 + imatinib + kinase inhibitor
Trials conducted in multiple tumor types: renal, melanoma, glioblastoma, lung, ovary, pancreas, head & neck, colon, breast
Multiple companies involved: Sanofi, OSI, Novartis, AZ, Millennium,
JJRD, Supergen, Genta Celgene, Fujisawa
Cooperative Group
Expected Accrual
No Submission
Required
Full Review
> 100 < 100
Phase 1
Safety Review NO
Phase 2
No Treatment
File Only
Developmental Strategy R21 type
detailed Peer Review of
Protocol
NO
Safety Review
(Examples:
Industry sponsored Cancer Center Trials, investigator Initiated, charitable-funded trials, Trials with investigator IND’s, etc..)
NIH Type Peer Review
of Protocol CTEP Funded
Consortium or International Collaboration
Treatment
YES
NO YES
YES
Figure 5. Drug Development Group (DDG)
DDG approval needed to expend NCI resources on development, IND filing, and sponsorship of clinical trials
DDG is advisory to the Director, DCTD Preclinical
- DDG I (Screening)
- DDG 1B (Non-GMP drug synthesis, PWPD, efficacy, schedule, molecular target clarification, pre-range finding toxicology)
- DDG IIA (Range-finding toxicology, GMP synthesis, formulation)
- DDG IIB (IND-directed toxicology, clinical lot manufacture) Clinical
- DDG I11 (Clinical Trials, phase 1-3)
DDG meetings closed to all but interested DCTD staff; =: every 6-8 weeks
Membership
- Representatives from NCI DTP & CTEP
- External ad hoc reviewers (2) Priority Scores
- Strength of proposals credentials (40%)
- Novelty (30%)
- Cost and benefits (20%)
- Need for NCI involvement (10%)
Figure 6. Letter of Intent (LOI) CTEP Review
Priority Scoring of Clinical and Laboratory Components:
Strength of scientific rationale
Consistency with CTEP development plan
Ability to accrue and complete study in timely manner Appropriateness of patient population
Adequacy of study design
Quality and relevance of laboratory correlatives
559 557
812 880 742
849
0 100 200 300 400 500 600 700 800 900
Accrual
1998 1999 2000 2001 2002 2003 2004 Year
U01 Annual Accrual
611
784
992
0 200 400 600 800 1000
Accrual
2001 2002 2003 2004
Year
N01Accrual
19,918 19,338
23,318 25,014
19,315
39 29 25
34 27
140 135
142 155
169
0 5,000 10,000 15,000 20,000 25,000 30,000
2000 2001 2002 2003 2004
Fiscal Year
Accrual
0 20 40 60 80 100 120 140 160 180
Number of Studies
