publication date: Jan. 13, 2017
NCI develops a “formulary” to make it easier for cancer centers to test drug combinations
By Paul Goldberg
Academic investigators encounter a regulatory maze and lengthy delays when they attempt to test cancer drugs. Obtaining the compounds for testing combination therapies is especially challenging.
A formulary that tames the bureaucratic procedures to allow investigators at NCI-designated cancer centers to get the drugs—and clearance—faster.
With a simplified tech transfer agreement, six industry partners and 15 compounds (but no dedicated research funds), NCI challenges investigators to think creatively.
“It has been a considerable problem over many years to bring drugs together into combination treatments for agents that are derived from a variety of different companies,” said James Doroshow, NCI deputy director for clinical and translational research and director of the Division of Cancer Treatment and Diagnosis.
Working under the general rubric of the National Cancer Moonshot Initiative, NCI has put together a public-private partnership, starting with six participating companies and 15 investigational agents. Pharma companies sign a uniform technology transfer agreement dubbed CRADA Lite by one insider, CRADA being the acronym for the Cooperative Research and Development Agreement. The formulary was announced Jan. 11.
Under the formulary’s rules, drug companies have a right to allow—or nix—an investigator’s access to their agents. However, under shortened review deadlines, they have 60 days to respond.
As the administrator of the formulary, NCI acts as a clearing house, getting the compounds to investigators. The drugs are provided at no cost.
NCI doesn’t fund the research and doesn’t hold the Investigational New Drug license from FDA. Under a standard CRADA, the institute holds the IND.
“This process, we hope, will facilitate the ability of investigators at our NCI-designated cancer centers to use novel drugs in combination, which we think will be very useful in trying to address the new ability—through next generation sequencing—to find mutational aberration that actually, to be best treated, require combinations of treatments,” Doroshow said at a press call rolling out the formulary.
CRADA agreements and instructions for companies are posted here, and instructions for investigators are posted here.
The companies that have provided the initial fifteen compounds are:
Compounds available through the NCI formulary – Source: NCI
ALK inhibitor, tyrosine kinase inhibitor
PD-L1 blocking monoclonal antibody
Anti-angiogenesis inhibitor, monoclonal antibody
Xcovery Holding Company LLC
ALK, TrkA, TrkC, ROS, EphA2, c-MET
anti-CTLA-4 monoclonal anibody
Tyrosine kinase inhibitor
NTRK-1, NTRK-2, NTRK-3 fusion proteins; TrkA/B/C proteins
Eli Lilly and Company
PD-1 blocking monoclonal antibody
anti-CD20 monoclonal antibody
anti-HER2 monoclonal antibody
Eli Lilly and Company
Checkpoint kinase 1 inhibitor
anti-HER2 monoclonal antibody
BRAF mutant v600 inhibitor
BRAF V600 mutant, CRAF, ARAF, wild-type BRAF, SRMS, ACK1, MAP4K5, FGR
“This program is an opportunity to remain close to the academic community and access the best ideas through more accessible, streamlined research models as we continue the never-ending fight against cancer,” Christopher Slapak, vice president of early phase clinical research, and Distinguished Lilly Scholar at Lilly, said to The Cancer Letter. “Lilly’s participation in the National Cancer Institute’s formulary is an opportunity to work with the top cancer centers looking for novel, innovative ideas to help advance our pipeline molecules. The data generated will answer important questions from research that Lilly would not necessarily be able sponsor itself.”
Investigators wouldn’t receive money specifically for studies done under the formulary. However, their institution may receive funds under any one of NCI’s existing grants.
They can also approach the pharmaceutical sponsors for funding or technologic support which may or may not be needed, depending on the research. An example could be support for a vendor that already has methods, needed to support future regulatory submissions by the industry collaborator, to conduct pharmacology or biomarker testing.
NCI would be fine with having companies pose research questions for potential studies, with the institute essentially acting as a matchmaker.
“It is an interesting and important opportunity that should diminish the challenges of access to new agents for investigator-initiated studies and encourage more flexibility for combination drug trials that have been difficult when they combine agents from multiple suppliers,” said Stanton Gerson, president of the Association of American Cancer Institutes and director of Case Comprehensive Cancer Center and Case Western Reserve University and Seidman Cancer Center at the University Hospitals Cleveland Medical Center. “It does not provide support other than drug access, but this is an important first step.”
Since the institute already has the infrastructure for distributing drugs and collecting data, the cost of the program in fiscal 2017 will be under $1 million, NCI officials said. Spending on the program would increase if investigators use it.
Research could lead to new indications
For companies, investigator-initiated trials could produce scientific leads that may translate into new indications.
The regulatory schema for getting new indications for some compounds through FDA approval appears to favor drug combinations.
Consider cancer immunotherapies that rely on the PD-1 protein and its ligands, PD-L1 and PD-L2. In what looks like a race to the market, the industry is experimenting with 20 of these drugs. A recent analysis by The Cancer Letter found 803 registered clinical trials of these agents, suggesting an unprecedented push. These studies had slots for 166,736 patients (The Cancer Letter, Oct. 7, 2016).
How does the agency plan to process the expected flood of applications for these similar drugs?
“We anticipate combinations of drugs in this field will be the future,” said Gideon Blumenthal, lead medical officer at the Office of Hematology and Oncology Products, FDA Center for Drug Evaluation and Research (The Cancer Letter, Nov. 11, 2016).
“After all, in second-line lung cancer in an ‘unselected’ patient population, only about 20 percent of patients respond to PD-1/PD-L1 inhibitors.
“Even in PD-L1 high-expressing lung cancer, about 40 percent of patients respond. There is a huge unmet need for addressing those patients who do not benefit from these drugs, as well as those patients who do respond initially but eventually develop resistance.
“This is where data sharing and improved collaboration is critical. The community as a whole needs to be shrewd in trial designs in terms of figuring out which patients are likely to respond to monotherapy, which are unlikely to respond, and figuring out which combinations to prioritize and move forward and which combinations should fail quickly.”
FDA is not involved in the formulary.
Doroshow said several companies are finalizing their participation in the formulary.
“We are launching today, because our initial goal was to start with at least five companies with at least ten drugs,” Doroshow said on the press call. “We have agreements with six companies for 15 drugs, and it’s our expectation that over the relatively near term we will have several more companies and many more agents, and that that will continue to grow over the course of time that it takes to conduct these negotiations. That being said, in the relatively near future, the range of compounds that are available will be substantially larger.”
Takeda Pharmaceuticals is one of the companies preparing to take part in the formulary.
“Building on research with single agents or treatments that combine agents from multiple industry collaborators, the formulary will encourage speed, flexibility, and innovation, including expanded experience with new technologies, biomarkers, and therapeutic platforms designed to introduce personalized approaches to benefit patient care,” said Howard Fingert, senior medical director at Takeda Pharmaceuticals.
“Through these new collaborations between academics and industry sponsors, the formulary should also enable shared learnings that promise to advance R&D productivity and quality, including experience with data standards, bioinformatics, evaluation of biospecimens & biorepositories, and data-sharing.”
Idea grew out of NCI-MATCH
The task of putting together combination therapies has been daunting for years.
“Let’s just say that there are two drugs, one from Company A and one from Company B,” Doroshow said on a media call announcing the formulary. “The issue—especially for trials that are not under the auspices of the NCI—involved having formal negotiations with each of those separate companies, and then developing a way to convince both of them that the compounds should be combined, and that they should separately and together be able to share any rights that are developed from the clinical trial itself.
“That does involve significant negotiations with each company and then with the institution that wishes to carry out that trial, and then one has to negotiate whether or not the two companies would allow their compounds to be used together.”
A standard CRADA often took a year to negotiate. After said CRADA became active, review of a letter of intent could take a year, without necessarily resulting in a nod.
“One of the things that we have negotiated with our agreements that are now in place is the commitment on the part of the companies to do a relatively rapid review—up or down—of the clinical trials ideas,” Doroshow said. “That’s something that can happen, apparently. It often doesn’t happen. The notion that the companies will commit over a relatively short period of time to either providing agents or not providing agents is something that has ever happened before. It’s not something that even with our other CRADA arrangement, with other trials that are, in fact, supported by NCI grants, we do not have that built-in negotiated rapid review as part of those agreements, and sometimes that takes longer than we would like. And so we are hoping this whole process will be substantially faster.”
The magic number for formulary review is 60 days.
“The companies will have a full review and approval process for the proposals that are coming in,” said Sherry Ansher, associate chief of the Regulatory Affairs Branch of the Cancer Therapy Evaluation Program. “One of the difference between this and the [standard CRADA] program is that NCI will not be doing a scientific or clinical review of the proposal.
“It would be left to the pharmaceutical collaborator, and the 60-day window is that we are asking them to make this determination as to whether they want to provide agents for the study within 60 days of receiving that proposal. And then if they approve it, the investigator would move to writing a full protocol for the trial.”
The idea for the formulary grew out of the NCI-MATCH trial, Doroshow said.
“This has been an issue for some years, but we didn’t think that it might actually be possible to do this until my colleagues started a prolonged and very successful process of negotiating the drugs that became part of the formulary, if you will, for the NCI-MATCH trial, a trial that is trying to associate a particular molecular abnormality with an investigational agent,” Doroshow said.
“Many companies were engaged with us in trying to develop, under one IND, this large umbrella phase II trial. The success of negotiating all of those different arrangements for the provision of drugs for that trial made it possible to think that something of the nature of this formulary to be used for many trials that would be investigator-initiated might be possible.”
How it works:
An NCI Formulary CRADA is executed between the NCI and pharmaceutical company collaborator to afford accessibility to the agent(s).
CTEP acts as a “facilitator” of submitted proposals from NCI-Designated Cancer Center investigators. Investigators submit Letter of Intent (LOI) proposals for the NCI Formulary agent(s) to CTEP, and CTEP provides the pharmaceutical company collaborator with the proposals for review. CTEP will not provide scientific review of the Formulary LOI proposals. All scientific discussion is conducted between the pharmaceutical company collaborator and investigator.
Pharmaceutical company collaborators are responsible for providing scientific review of the proposals and clinical trial, agent for the clinical trial, and a letter of cross-reference to their IND/DMF. A time limit of 60 days on the LOI review process will ensure that requests are processed in a reasonable time frame.
Should a proposal be approved by the pharmaceutical company collaborator, the NCI will use its established clinical trial infrastructure to facilitate trial conduct.
The study will be conducted under investigator-sponsored INDs by the requesting investigator/Cancer Center.
NCI will transfer agents to the clinical trial sites via a clinical Material Transfer Agreement (MTA) executed between the NCI and the clinical trial site under which rights and responsibilities of the recipient investigator will be described.
All serious adverse events will be submitted to the pharmaceutical company collaborators via CTEP’s Serious Adverse Event Reporting System (CTEP AERS).
Clinical trial data will be submitted via CTEP’s Clinical Data Reporting System, which will be made available to pharmaceutical company collaborators.
Intellectual Property will be handled under the terms of the CTEP IP Option to pharmaceutical company collaborator, with rights flowing down under the clinical MTA.
Pharmaceutical company collaborators will have access to all data generated under the study and have the rights to review publications consistent with the current mechanism used in CTEP agreements.
Neither NCI nor pharmaceutical company collaborators are required to provide per patient funding for the studies or any other study costs. Trial sites participating in this program are required to have the ability to support the full costs of the trial and demonstrate the source of this funding prior to protocol approval. However, if pharmaceutical company collaborator desires to provide funding for selected aspects of the study, they may provide funds directly to the investigators or could use the NCI CRADA mechanism to convey funding.
Transfer of agent for preclinical work in support of clinical trials will also be facilitated under the NCI Formulary. It is anticipated by NCI that any agent provided for clinical trials would be made available for preclinical studies as well, as this may be critical to the rationale and design of the clinical trial. Agents may also be available for preclinical studies only.