Whatever the source of the new agent (academia, industry, NCI, or other), if the clinical development of the agent is to take place under an NCI-held Investigational New Drug (IND) application, the NCI Drug Development Group (DDG) will be responsible for oversight and for pre-clinical and clinical decision-making at the key "go - no go" decision points. The DDG thus prioritizes use of NCI resources supporting pre-clinical development by DTP and clinical development by the Cancer Therapy Evaluation Program (CTEP), except that the Biological Resources Branch Oversight Committee (BRB-OC) governs acquisition and production of biologics approved by DDG, as described above.
The DDG is advisory to the Director, DCTD, who usually accepts its recommendations. In exceptional cases, the Director may approve the development of agents whose priority rating from the DDG is low, if the Director considers the scientific or societal impact to be substantial. In other cases, the Director may elect not to proceed with agents afforded high priority by the DDG, if competing priorities, scientific judgment, or other considerations do not support DCTD involvement.
DEVELOPMENT STAGES
| Stage | Activities | Governance |
| I (Small Molecules) | Screening | DTP Access and Information Group (AIG) |
| I (Biologicals) | Pilot Production and process development in addition to above | BRB-OC after DDG* or RAID approval (IRP may purchase) |
| IB (Small Molecules) | Pre-Clinical. Non-GMP Synthesis drug, pre-formulation, PK/PD, efficacy, schedule, molecular target clarification, pre-range finding toxicology. | DTP Biological Evaluation Committee (BEC) or RAID |
| IIA | Range-finding toxicology, GMP synthesis, formulation | DDG (without external review) or RAID (IRP may purchase) with BRB-OC for Biologicals |
| *IIB | IND-directed toxicology, clinical lot manufacture. | DDG or RAID (IRP may purchase) with BRB-OC for Biologicals |
| *III | Clinical trials. Phase I with progress to Phase II | DDG without external review for molecules externally reviewed at IIB DDG with external review for molecules new to system |
*DTP originated molecules present with external review at IIB; CTEP originated molecules present with external review at III.
GENERAL CRITERIA FOR NCI INTEREST AND EXPANDED ACTIVITIES AT EACH STAGE
The following are general criteria that determine the degree of interest of NCI staff in a screening or development candidate. Note, however, that compounds at all stages of development are considered on an individual basis, and additional criteria may apply.
Stage I
- What we are looking for:
- Compounds with novel structures or libraries with unique scaffolds from academia, small biotechs and large pharmaceutical companies.
- Compounds reasonably postulated or demonstrated to have novel cancer-relevant targets.
- Compounds from NCI-supported grantees in direct support of grant specific aims.
- What happens at this stage:
- Evaluation in anti-proliferative screens (3 cell line assay, 60 cell line assay Evaluation in a molecular target-directed assay, particular to each compound
Stage IB
- What we are looking for:
- The effect of the compound on the target is demonstrated in vitro;
- Empiric screening results demonstrate potency, "differential" activity; COMPARE "negative" or a novel chemotype with activity in a novel target assay.
- What happens at this stage:
- Assurance of supply of compound by practical synthesis or extraction.
- Pharmacology studies to demonstrate ability to achieve concentrations in vivo that are concordant with an effect on the target.
- Mechanism of action studies in vitro/in vivo
- In vivo studies to demonstrate the compound effect on the target.
- Pre-range finding toxicology studies
- Solubility/stability studies.
Stage IIA
- What we are looking for:
- Pharmacokinetic/dynamic studies show that the effect of the compound on the target is confirmed in tumored animals;
- The compound availability is assured;
- The compound has a favorable solubility/stability profile;
- The compound is pharmaceutically tractable;
- Intellectual property issues are clear;
- There is an interest by CTEP in the compound and the target.
- What happens at this stage:
- Range-finding toxicology studies.
- Development of a suitable clinical formulation.
Stage IIB
-What we are looking for:
- The compound has acceptable range-finding toxicology results and a suitable clinical formulation, with IIA criteria satisfied.
-What happens at this stage:
- IND-directed toxicology on a schedule expected to yield activity and which shows no irreversible toxicity at a dose level likely to produce grade III-IV toxicity in humans.
Stage III
-What we are looking for
- The compound has acceptable (IND-directed) toxicity profile
-What happens at this stage:
- IND filing by CTEP for NCI-sponsored clinical trials.
THE DDG PROCESS
Application process
Initial presentation of an agent to the DDG requires an identified CTEP or DTP staff member to act as liaison. The NCI Liaison coordinates with the originator the preparation of an application with the following sections (up to 5 single spaced pages):
Abstract: 300 words or less.
Background: a summary of the field that clarifies the scientific and medical context from which the opportunity emerges.
Hypothesis or Pressing Opportunity: a clear statement of the hypothesis or important public health related opportunity that entry of the relevant molecule into the clinic will test.
Specific Request: a clear statement of the tasks and support specifically being requested to allow a test of the hypothesis in the clinic.
Justification: why the project under consideration represents a particularly innovative or promising approach to cancer treatment.
Uniqueness: a discussion of related or similar molecules already under development by NCI or known to be in development under industrial sponsorship, and why the NCI should undertake development in light of this.
Additional Support: a clear statement by the applicant of all current or anticipated support for the development of the agent. This includes, where relevant, a summary of the status of past, planned, or ongoing negotiations with companies related to licensure or future development of the product.
Intellectual Property: information regarding any patents issued or pending with respect to the product.
Anticipated Costs: these should be broken out by task, and include ancillary tasks such as conduct of specialized bioassays on samples collected and shipped during a clinical trial; cost of fermentation, scale up, vialing, and distribution of clinical grade material.
Appendix: background preprints or reprints (maximum of five; not included in the page limitation).
The application including appendix is due at the time of the pre-DDG meeting of NCI staff.
Accepted applications from the pre-DDG are distributed to members of the DDG staff. Presentation at the IIA level occurs without external review. Presentation at the IIB (NCI-originated) or III (external drug company collaborations) level will have two expert external reviewers selected from the NCI reviewer pool of peer reviewed grant awardees. In addition to this usual source of reviewers, knowledgeable ad hoc reviewers from other sources (e.g., NIGMS for structural biology, NIAID for AIDS related matters) can be called upon for particular items. The usual conflict of interest recusals will be in effect, and a specific statement that there is no conflict of interest with the particular matter will be obtained, with a signed confidentiality agreement. Reviewers are ad hoc and are not permanent members of the DDG. Note that a particular compound or construct will normally have one presentation with external reviewers by the DDG. Molecules presented at IIB for NCI-sponsored toxicology and bulk manufacturing which meet criteria will proceed to DDG III development upon completion of IND-toxicology without external review.
The DDG Meeting
At the time of the DDG Meeting, the identified staff liaison in conjunction with the originating party present, in about 20 minutes, the nature of the opportunity and what specific resources are being requested. DDG Members and reviewers (if involved; attendance by teleconference), are provided the opportunity to ask questions. Note that a member of the DDG may also serve as a liaison for a compound under discussion. Reviewers may elect to remain anonymous and to convey written questions and requests for clarification of data up to 48 hours prior to the meeting. Following the question period, representatives of the originating party will leave. The NCI Staff liaison may remain for the subsequent discussion.
At the discretion of the Co Chairs, a DCTD staff member may be appointed as a "Reader" for a particular matter under consideration. The Reader may or may not be the staff liaison with the originating party. The Reader will be expected to present a detailed critique of the proposal, including special reference to concurrent or similar opportunities under evaluation by NCI or extramural organizations.
Reviewers are then asked to assign priority scores to the proposal, after which NCI staff will then actually vote their own preferred priority scores (Outstanding=1.0, Excellent=1.5, Very Good=2.0, Good=3.0, Fair=4.0, Acceptable=5.0). These priority scores will be assigned and weighted as described below to arrive at a total priority score.
- Strength of the proposal's credentials (40% weight): how does the total package to that point (e.g., activity in predictive in vivo models, existence of suitable expression vectors or production vehicles, availability of reagents, etc.) support the likely value of the item under consideration as an important clinical trials candidate.
- Novelty (30% weight): the extent to which this discovery will enable clinical testing of new approaches to cancer that have not been adequately explored.
- Costs and Benefits (20% weight): appropriateness of the anticipated costs (as estimated by NCI Staff) in light of the possible payoffs.
- Need for NCI Involvement (10% weight): the extent to which this discovery is not likely to be explored without NCI assistance.
External reviewers submit a paragraph-length critique of the proposed effort after a brief summary of the requested resources. No specific scores should be assigned on the critique sheets. Note that because the extramural reviewers do NOT actually vote on the proposed items, they or their institution remain qualified to apply to participate in clinical trial activities related to the agent(s). They do remain bound by confidentiality to the contents of the Review meeting. This provision is designed to solicit extramural expert advice while assuring the possibility of access of reviewers' institutions to compounds and constructs originating from this process.
Results will be forwarded to the Director, DCTD. Agents with priority rankings of >2.5 will ordinarily not go further in development immediately, and the NCI staff proponent and the originating organization will be offered the opportunity to address concerns in the written reviews.
The public will be informed via the DTP Web Site of what "open" compounds are accepted for DDG development. Information regarding "Discreet" compounds, unacceptable compounds, and priority scores for all compounds will not be disclosed.
More details:
- DDG meetings are closed to all but interested DCTD staff.
- The agenda of DDG meetings are determined at a "pre DDG" meeting to be held four to six weeks prior to the DDG meeting.
- The standard NIH Conflict of Interest policies are in effect.
- Extramural Reviewers are compensated as per a study section
- Molecules intended solely for a prevention application will NOT be considered here but will be referred to staff members of the Division of Cancer Prevention.
- The NCI staff liaison can assist the originating party by editing or adding NCI-generated data to the application
- Verbatim recording of the proceedings does NOT occur. Rather, a summary of Action Items proposed for each compound, vote for approval or disapproval, priority scores, and written reviewer comments accompany the application itself as the record of the matter.
- A quorum (defined as a simple majority) of the DDG membership is necessary for a meeting to occur. Designated proxy substitutes for the appointed members may vote in place of the permanent member.
MEMBERSHIP OF THE DRUG DEVELOPMENT GROUP (DDG)
Associate Director, DTP (Co-chair)
Associate Director, CTEP (Co-chair)
Associate Director, CIP
Chief, DSCB, DTP
Chief, NPB, DTP
Chief, TPB, DTP
Chief, PRB, DTP
Chief, BRB, DTP
Chief, BTB, DTP
Chief, RAB, CTEP
Chief, IDB, CTEP
Associate Chief for Chemotherapy, IDB, CTEP
Associate Chief for Biologics, IDB, CTEP
Associate Chief for Signaling Pathways, IDB, CTEP
Associate Chief for Pediatrics, CIB, CTEP
Special Assistant, Office of DCTD Director
Deputy Director, DCTD
Director, MTP, CCR
Clinical Director, NCI
Contact Information
Office of the Associate Director
6130 Executive Blvd.
Room 8017
Rockville, MD 20852
| Telephone: | 301-496-8720 |
| Fax: | 301-402-0831 |
| E-mail: | ncidtpddginfo@mail.nih.gov |