Background: The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD), as an investigational new drug sponsor, may provide early access to investigational agents for treatment use. Until recently, the NCI had 3 protocol mechanisms for distributing investigational agents through the Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program of the NCI’s DCTD. The first mechanism is the Group C protocol, the second mechanism is the TRC protocol, and the third, and most common, mechanism is the Special Exception protocol.
Objectives: The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011.
Methods: Capital Technology Information Services performed PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception.
Results: More than 60% of requests were either referred or approved between 2000 and 2011. The peak number of requests was 1664 between 2000 and 2011 and occurred in 2003. The peak was mostly a result of Special Exception requests; however, more than 400 TRC requests and 20 Group C requests were approved that year. The total number of requests dropped precipitously after 2003, and since 2008 have totaled fewer than 50 annually. All Group C and TRC protocols were completed by March 2006. The lowest number of treatment use requests occurred in 2011.
Conclusion: Providing agents through the Special Exception mechanism is one way that promising investigational new drug agents can get to patients with life-threatening illnesses. In general, the PMB’s TRC is a useful drug information resource for sites conducting clinical research in oncology, and it provides a valuable service to the oncology community.
Although medical oncology has furthered effective cancer treatment for many decades, finding effective treatment for patients with advanced cancer is challenging. Millions of dollars support publicly funded cancer research every year, and patients expect that the latest cancer research will bring us one step closer to discovering a cure.
Instances often exist when patients have exhausted all standard therapies, and they are ineligible for any active research studies. The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD) has a long history of providing early access to investigational agents for patients with cancer for treatment or for nonresearch use. DCTD, as an investigational new drug (IND) sponsor for dozens of agents, may approve early access to investigational agents that (1) show evidence of therapeutic activity in a specific cancer diagnosis and (2) have reasonably acceptable risks of toxicity. Treatment use is frequently referred to as “compassionate use,” “expanded access,” “treatment IND,” or “single-patient IND,” and is regulated under 21 Code of Federal Regulations Part 312, subpart I.1,2
The NCI’s Treatment Referral Center (TRC), a service provided by the Pharmaceutical Management Branch (PMB) within the Cancer Therapy Evaluation Program DCTD, distributes investigational agents through multiple protocol mechanisms. Although the following mechanisms differ somewhat, all of them require adverse event reporting as a basic requirement of IND sponsorship.
One such mechanism was the Group C designation established in 1976 by the NCI, with US Food and Drug Administration (FDA) approval. The agents that were considered worthy of altering the standard of care, but were not yet available commercially, were handled through this program.1,3 Since 1975, the NCI has approved or distributed 21 agents under the Group C protocol mechanism.3,4 The Group C protocol mechanism is no longer active, and the last protocol was closed to accrual in 2005. Historically, Group C–designated agents:
- Had reproducible efficacy in specific tumor types
- Were considered likely to change standard of care practice
- Could safely be administered by a properly trained healthcare provider
- Did not require a specialized supportive care facility for treatment
- Were likely to have a New Drug Application (NDA) or a Biologics License Application (BLA) approval in the near future.
- Have highly promising activity in high-priority tumor types
- Have limited availability that necessitates an equitable distribution system
- Have participation generally limited to NCI-designated cancer centers
- May have an NDA or a BLA submitted, but time to approval and marketing may be delayed.
The most common treatment protocol, the Special Exception protocol, is approved on a case-by-case basis and is written for individual patients.3,4 Special Exception agents:
- Vary from patient to patient
- Have therapeutic activity in a specific cancer diagnosis
- Must have a justification provided by the requesting investigator
- Must have a well-established and acceptable safety profile.
The Cancer Therapy Evaluation Program has received thousands of treatment use requests from mostly domestic investigators, but also some from international investigators. The submitted requests are reviewed and are assigned a disposition within the Cancer Therapy Evaluation Program. Since 1994, 1 or more pharmacists within the PMB served as the point of contact for treatment use requests and as a general resource for the oncology research community. The pharmacist reviews the request and asks for additional information if needed. The pharmacist evaluates active studies that may be suitable based on the patient’s history. If the patient is eligible for 1 or more ongoing studies, the investigator is referred to the appropriate studies. If the patient is not eligible for any active studies and the request is justified, then the pharmacist collaborates with Cancer Therapy Evaluation Program senior investigators to assess eligibility for one of the treatment use mechanisms. If suitable, the Cancer Therapy Evaluation Program requests approval from the pharmaceutical collaborator. Once all parties have approved the request, the documentation is authorized, and arrangements are made to send the agent to the investigator so the patient can start treatment as soon as possible.
The purpose of this article is to describe and report on the activities of the TRC at the PMB since 2000 through the end of 2011. It is an update to an article published in 2000 by 4 pharmacists at the Cancer Therapy Evaluation Program.3 Our database query begins in January 2000. The Shalabi and colleagues report ended with a total of 1015 requests for 1999.3
Capital Technology Information Services performed the PMB data mining for all treatment protocols from January 1, 2000, to December 31, 2011. Requests to PMB were sorted in spreadsheet format by disposition, either as referred, approved, or denied, and were counted by type, either as Group C, TRC, or Special Exception; requests that were not categorized as such were not counted for the analysis, but counted instead as “other.” Request disposition was only prospectively recorded in the PMB database after 2002, when the database became fully functional. Gaps in data from requests before 2002 were completed from internal annual reports that were manually collated at the end of each respective year. All discrepancies were reconciled between paper reports and the PMB database.
The results of the database query by request disposition from January 1, 2000, to December 31, 2011, are displayed by year in Figure 1. The total numbers of annual requests by type are displayed in Figure 2. The peak request total for this time period occurred in 2003, with 1664 requests. The peak was mostly a result of Special Exception requests; however, more than 400 TRC and 20 Group C requests were approved that year—more than any other single year in the analysis.
The total number of requests dropped precipitously after 2003, and since 2008 they have totaled fewer than 50 annually. Both bevacizumab and 5-azacitidine were FDA approved in 2004, accounting for 350 TRC protocol requests and 708 Special Exception protocol requests in 2003, respectively. All other Group C and TRC protocols were completed by March 2006 (Table 2). The lowest number of requests through the TRC occurred in 2011.
With the exception of 2011, the PMB either referred or approved more than two thirds of the requests annually between 2000 and 2011. Requests that were counted as “other” came from either the public or healthcare professionals outside of the NCI. Most inquiries involved agent availability and available clinical trials for specific diseases at the NCI. Table 3 provides examples of these inquiries from 2000 to 2011.
The PMB’s TRC has seen a significant change in the total number of treatment use requests over the past decade. With a peak of 1664 requests in 2003, the PMB currently only receives a few dozen requests for a variety of agents in clinical development. The days of enrolling hundreds of patients into an NCI-sponsored treatment use protocol are in the past, because the requests through the TRC to provide early access to cancer therapies has diminished.
Of note, the number of FDA-approved oncology agents increased annually, and there is certainly no shortage in the number of practice-changing therapies that emerge from clinical research. Why then the decrease in requests? Two phenomena are likely responsible for this change—a reduced NDA approval time and a smaller number of investigational agents that are either manufactured by the NCI or for which the NCI is the sole source.
Before the Prescription Drug User Fee Act (PDUFA) of 1992, the median time from first NDA submission to FDA approval for new molecular entities and significant biologic agents was 2.7 years between 1985 and 1989.5 Since 1992, the approval times gradually decreased, and the most recent 5-year increment (2005-2009) demonstrated a median approval time of 1.2 years.5 Antineoplastic agents in particular have a median approval time of 0.5 years for the same period, and have generally seen reduced times in overall drug development (IND filing to FDA approval) since 1980. This is despite more than a 4-fold increase in the number of antineoplastic agents that have been approved since 1980—11 from 1980 to 1989, 38 from 1990 to 1999, and 47 from 2000 to 2009.5
Based on the timing of the TRC and Group C protocols as shown in Table 2, all of these protocols were closed to accrual approximately the same time as the NDAs were approved. The TRC and Group C protocols successfully bridged the gap between positive clinical trial results and NDA approval, without interfering with marketing approval. Many patients benefited from practice-changing therapies that would not have been otherwise accessible to them.
Early drug development was the mainstay of the NCI’s Cancer Chemotherapy National Service Center, a congressionally mandated initiative that was started in 1955. Its mission was to screen and evaluate novel compounds for the treatment of cancer. By 1976, it was consolidated within the Developmental Therapeutics Program (DTP).6 Over the years, the DTP collected hundreds of thousands of compounds, some of which reached clinical development.6
The NCI was responsible for developing a number of agents with unique mechanisms of action, often with minimal industry collaboration.7 The NCI’s Frederick facility manufactured agents, and, in a few instances, the NCI was the only source of drug available for clinical research. Although most of the agents that were developed at the NCI were not responsible for the bulk of the treatment requests, 5-azacitidine, developed at the NCI was provided to thousands of patients via the Group C and Special Exception protocols. Table 4 lists agents developed by the NCI that the PMB received Special Exception requests between 2000 and 2011. One of the agents listed in Table 4, chimeric 14.18, has been requested for treatment use from the PMB in the past year for pediatric patients with neuroblastoma. These requests accounted for more than 20% of requests in 2011.
In the past 25 years, pharmaceutical companies have stepped up investment in anticancer drug development, resulting in more industry-directed development.8 It is not unheard of for the pharmaceutical company to have a pending NDA approval for the agent of interest, while simultaneously developing it with the NCI, in less prevalent malignancies. As a result of increased industry focus on cancer drug development, the DCTD holds fewer active INDs. For example, the DCTD held INDs for 200 agents in 1997 compared with approximately 90 agents today.7 As pharmaceutical industry drug development plans become more comprehensive, companies evaluate the need for their own early access programs, and this, along with the ability to prescribe commercially available agents off label, have led to a diminished need for NCI treatment use protocols.
The PMB TRC pharmacist serves as a drug information resource for the cancer community inside and outside of the NCI. Not only is this pharmacist the point of contact for PMB-directed drug information questions, but also for relevant inquiries that come through the Cancer Information Service, the NCI’s community hotline. The types of questions have varied over the years, but they mostly pertain to agent or clinical trial availability.
Although the activities of the TRC at the PMB have decreased over the past several years, the infrastructure at the DCTD is available to meet the demand for larger-scale, expanded-use protocols if necessary. The current trends in the pharmaceutical industry obviate a lot of the need at the present time, but future circumstances may change that as early drug development enters new frontiers.
The DCTD is the IND sponsor for more than 90 investigational agents, a number of which have unique mechanisms of action. As an IND sponsor, the DCTD has the privilege and the responsibility to further develop these agents, especially those that demonstrate positive clinical trial results. Providing agents through the Special Exception mechanism is one way that effective agents get to patients with life-threatening illnesses who may benefit from these agents. The PMB reviews requests serves as the liaison with the pharmaceutical collaborator and coordinates with other Cancer Therapy Evaluation Program branches and the requesting investigator. In general, the PMB’s TRC is a useful drug information resource for sites that are conducting clinical research in oncology, and it provides a valuable service to the oncology community.
Clinical pharmacists at sites have a role in the Special Exception process. They can help identify patients who are neither suitable for standard care treatment nor eligible for active clinical trials. As drug therapies grow more complex, clinical pharmacists can assist investigators who are navigating the details and determine the best options for a patient. In addition, pharmacists can be instrumental in preparing the Special Exception protocol for submission, obtaining Institutional Review Board approval, securing drug supply, monitoring toxicities, and ensuring patient follow-up.
Special Exception requests for DCTD-held IND agents are directed to the PMB at the Cancer Therapy Evaluation Program. See http://ctep.cancer.gov/branches/pmb/referral_center.htm for current contact information.
The authors would like to thank Patricia R. Schettino, RPh, MS, for her writing assistance.
Author Disclosure Statement
Dr Johnson reported no conflicts of interest. Mr Boron has a stock benefit at MedImmune/AstraZeneca through his spouse’s employment.
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