Partnering with Industry

Several speakers, including Doroshow and Abrams of the NCI, reported that significant progress has been made in facilitating NCTN-industry collaborations. Doroshow pointed out that the NCI has harmonized all its guidelines for programs engaged in the conduct of clinical trials, so that the appropriate incentives are in place for collaboration among investigators in different programs. In addition, the NCI, in collaboration with the CEO Roundtable on Cancer, developed START clauses for company and academic collaborations to speed clinical trial negotiations (NCI and CEO Roundtable on Cancer, 2008).

The NCI has also revised its IP option on all CTEP CRADAs relating to drug development. The IP option clarifies the rights to diagnostics or other IP that might result from studying biomarkers and tissues in the trial. “If a diagnostic is discovered in one of our trials, the company that provided the drug and is our collaborator does not have the first right to that diagnostic. The investigator retains that right. On the other hand, there is no blocking of the IP so that the company would have to pay royalties every time its drug was used if a regulatory authority said the drug had to be used with that companion diagnostic,” Abrams explained.

Instead, each collaborator receives a non-exclusive, royalty-free, worldwide license for research purposes only, and a non-exclusive, royalty-free worldwide license to disclose and promote inventions as necessary or as required by a regulatory authority to be used with a drug. For alternate uses or dosing schedules for agents being tested in a clinical trial, companies are granted a non-exclusive, royalty-free, worldwide license for commercial purposes. But companies can still negotiate a co-exclusive or exclusive license for such IP.

The NCI also established IP terms for investigational multi-agent combination trials, which are becoming increasingly common in cancer research. For such studies, each collaborator receives a non-exclusive, royalty-free, worldwide license for all purposes, including commercial purposes of any combination IP. Companies can still negotiate a co-exclusive or exclusive license for a collaborator’s IP pertaining to the agent. To help stem trial startup delays due to IP issues, the NCI set a new absolute deadline of 6 months for CRADA negotiations with industry sponsors.

Edward Benz, director of the Harvard Cancer Center at the Harvard School of Medicine and president of the Dana-Farber Cancer Institute, said that he appreciates the value of this new approach, and noted that

the usual way we’ve set up these intellectual property agreements is based on the bet that you’re going to get My Fair Lady instead of the play that never makes it to Broadway. Everybody protects jealously that potential big hit, but getting upfront research support in return for licensing terms that are friendlier to the pharmaceutical partner is actually a better deal. The value of the research support and the chance you have to make an impact with present-day support in exchange for a discount down the road in the IP arrangement, we think, is a much wiser way to approach it, and it’s been part of allowing us to have better relationships with the pharmaceutical industry.

Abrams added that collaboration with industry is more likely “now that we have done a number of things to make sure the data quality for the NCTN system is quite high and comparable to what’s achieved when industry does a study on their own. Our new IT data management system is really state-of-the-art for collecting quality data and is critical to being able to go to the FDA and support the needs of our company collaborators.”

The Web-based IT system also facilitates contracts with research agencies because “it doesn’t really matter which group is leading the trial anymore,” Abrams said. He added that “it will probably allow us to meet all the new FDA requirements that are upcoming for secure electronic data capture and transfer, and will enable our different cooperative groups to collaborate on additional scientific projects much more easily and make the data available to other people outside the groups more easily.” The IT system also facilitates the systematic and all-inclusive reporting of adverse events from Grade 1 to Grade 5, which is necessary for the drug registration trials of industry sponsors.

New aggressive timelines for getting clinical trials under way are also encouraging more industry partners to participate, Abrams pointed out. “Our industry colleagues have told us that ‘time is money.’ We can’t sit around waiting a very long time for NCI studies to get up and running.”

Genentech has had several productive clinical trial collaborations with NCTN, Horning noted, and she offered several lessons learned from those collaborations. For example, one clinical trial collaboration between the NCTN and Genentech, a study of paclitaxel with or without bevacizumab in metastatic breast cancer, fell short of FDA data quality standards The same study raised FDA concerns about investigator bias, which was addressed retrospectively through a radiological independent review facility (IRF). Further research by the FDA and independent groups indicated that although reader discordance at the patient level was common, there was no evidence of systematic investigator bias for the progression-free survival (PFS) endpoint (Amit et al., 2011; FDA, 2012a). In addition, these studies found the potential for IRF bias through informative censoring. These results led the FDA to propose that when PFS is used as an endpoint for clinical trials on agents for solid tumors, a random audit by an IRF could avoid some of the missing data issues and mitigate informative censoring, while reducing the cost and burden of more complete IRF reviews.

According to Horning, this example serves to illustrate that industry and NCTN partners must prospectively clarify regulatory requirements to satisfy global regulatory authorities when they collaborate on clinical trials, because most drugs are registered and marketed globally. There also should be prospective agreement between a clinical trials group and an industry sponsor of a registration trial regarding data collection and curation; safety reporting and access to records; and communications, publications, and presentations; all of which should ensure that data are of high quality, reported in a timely fashion, “fit for purpose,” and compliant with regulatory requirements, Horning said. (A more extensive discussion of this trial design issue is described below in the “Regulatory Issues” section.)

Ultimately, the data collected must be adequate to reliably assess whether an investigational agent has a good risk/benefit ratio when added to or used in place of a known standard of care, Horning noted. Safety assessments need to include enough data to assess whether there are subsets of patients for whom the risk/benefit ratio is different, she added, and critical safety data must be integrated with efficacy data.

Horning observed that because of lessons learned from previous industry-NCTN collaborations, NCTN trials with registration potential have become more “industry-like” in terms of data standards, costs, and timelines, characteristics that have increased the likelihood of regulatory approval.

Changes in how NCTN studies with registration potential are conducted include

• ensuring that safety data have onset and resolution dates;
• providing more complete safety data rather than just targeted adverse event data;
• using an internally consistent database with symmetrical data collection on both arms;
• documenting why physicians or patients stop therapy;
• having procedures in place to minimize missing forms and fields; and
• reconciling expedited adverse event reports with the clinical adverse event database.

“The data management improvements address key industry considerations for quality, timeliness, and cost,” Horning said. She also appreciated the NCI’s revised IP stipulations in the CRADAs, which recognize the value to industry of annotated specimens and what they can reveal in the current era, in which predictive diagnostics have become more essential to drug development and therapeutic approval.

In addition, Horning applauded the shortened timeline the NCTN has recently instituted between concept submission and trial activation. However, she noted that there is still room for improvement in the relatively long time the NCTN takes to prioritize which trials get the final green light to go forward—a delay due to numerous discussions among investigators, groups, and NCI steering committees. In contrast, Horning said, this process is much more streamlined in Europe, where such decisions are often made at a single meeting, without as much deliberation among the various parties involved.

Global Collaborations

Horning also stressed the need for the NCTN to collaborate with global partners and satisfy global regulatory bodies. A prespecified plan for selective data collection must be agreed upon not only by the FDA but also by other relevant global health authorities, and more effort should be made to harmonize international requirements for global registration trials, Horning said. “Trials are now done globally for global registration,” she added.

Debasish Roychowdhury, senior vice president of global oncology at Sanofi, suggested that the NCTN should consider not just European collaborators but also those in other countries, such as China.

This may require ensuring that the patient populations in clinical studies represent the diverse ethnic populations that will eventually use the new drug should it be approved for the international market. However, Rachel Sherman, program specialist at the Center for Drug Evaluation and Research (CDER) Office of Medical Policy at the FDA, noted that the FDA accepts trials with no patients from the United States and has approved drugs based on such studies, but sponsors must show that those studies are applicable to the U.S. standard of medical care.

Richard Pazdur, director of CDER’s Office of Oncology and Hematology Drugs at the FDA, also stressed the international scope of drug testing and marketing. “All of the trials that come to the FDA at the present time are international trials. For the NCTN to be relevant for the next decade or so, they are going to have to address the issue of how they play into not just the national cancer trial system, but the international cancer trial system, especially as we take a look at rarer and rarer subsets of diseases. The pharmaceutical firms have already realized this and are doing trials internationally,” he said.

Capdeville described the RATIFY² trial, an innovative, global phase III trial that Novartis is conducting in collaboration with CALGB (Cancer and Leukemia Group B; now part of the Alliance for Clinical Trials in Oncology). RATIFY is testing a multitarget kinase inhibitor called midostaurin, which preclinical studies showed is especially effective at inhibiting the FLT3 tyrosine kinase. Mutations in this kinase are associated with poor survival in acute myeloid leukemia (AML).

After midostaurin had shown clinical activity in wild-type and FLT3-mutated AML in phase I and II trials, Novartis wanted to launch a phase III trial to test the drug in AML patients with activating FLT3 mutations. According to Capdeville, they decided to collaborate with CALGB for this trial because the group had done previous studies documenting the prognostic significance for mutated FLT3 in AML and had the scientific expertise to run the trial. It was advantageous for CALGB to collaborate with Novartis, he noted, because the rareness of the FLT3 mutation in AML would require a large, global multisite study to acquire enough patients. “This was beyond what CALGB could deliver in itself, so there was this potential synergy with the global operational infrastructure of Novartis that could bring together multiple cooperative groups and centers,” Capdeville said.

RATIFY is a simple randomized phase III study. CALGB was responsible for writing the protocol for the trial, with input from 12 other participating cooperative groups (in the United States and internationally). CALGB owns the database and is responsible for reviews by a Data and Safety Monitoring Board on a regular basis. CALGB has sponsored the trial in North America and Novartis has sponsored the trial outside North America. CALGB and the other cooperative groups share accountability for FLT3 testing. A joint clinical trial team oversees day-to-day operations. If the study is successful, Novartis will submit its findings for regulatory review.

The main challenge in the trial has been to detect the FLT3 mutation in tumor samples before patients receive chemotherapy, given the clinical urgency of the diagnosis, Capdeville noted. That testing is completed within 3 days of sampling at 1 of the 10 central labs in each of the main cooperative groups. There is a common protocol for consistency and periodic cross-validation of the test sample among laboratories.

After meetings with the FDA, trial leaders decided that a companion diagnostic would be developed at a later stage in drug development, with a bridging study aimed at showing concordance between the clinical trial assay and the companion diagnostic version of the assay. This required patients to consent to their samples being used not only for the phase III clinical trial, but also for the later bridging study, as well as central storage of all tumor samples.

The study is ongoing, but Capdeville listed several lessons that have already been learned from the collaboration:

• Keep the data flow as simple as possible.
• Foster open and transparent collaboration between industry and the cooperative groups, “which takes some time so the two understand each other well and expectations are well aligned,” Capdeville said.
• Be open to using a slightly different process than normal. “We can’t just use the Novartis SOP [standard operating procedure] or only the cooperative group SOP, so there has to be dialogue on this,” Capdeville pointed out.
• Preserve the independence of scientific and academic oversight on the study while balancing industry’s needs.
• Involve a range of disciplines, including technical as well as scientific expertise.

Partnering with Cancer Centers

Benz reported that the Dana-Farber Cancer Institute recently reorganized its oncology research program to better enable clinical translation. Prior to the reorganization, which began in 2002, most of the cancer research resources were devoted to disease programs and centers that were anatomically focused. These centers were the sites of Dana-Farber’s clinical trial activity, except for phase I studies, which stemmed from the institute’s Early Drug Development Center. Although the centers were multi-disciplinary, including surgery, radiation, oncology, nursing, pharmacology, and medical oncology, “they were becoming somewhat siloed around their particular cancers that they were interested in,” said Benz.

Recognizing that this setup was slowing the pace of clinical translation, Dana-Farber made a number of changes. One change was to recognize that the ultimate end product “wasn’t papers published in Nature or other academic metrics, but the goal would be to bring things into clinical practice,” Benz said. The restructuring aimed to implement project management principles that would translate discoveries into clinical benefit while preserving the culture of independent discovery. Dana-Farber faculty identified 12 areas ripe for translation, such as genomics, vaccines, and systems biology, and created “integrative research centers” around each, Benz reported.

Although some of these integrative research centers, such as the Center for Cancer Genome Discovery and the Center for Functional Cancer Epigenetics, focus on research pursuits grouped according to the primary method or technology being employed for discovery, Benz stressed that they are not traditional core facilities. Instead, they provide both a technology platform and an intellectual hub, and membership in each crosses departmental boundaries.

The centers are girded by business rules and accountability. The faculty leader of each center is charged with developing a business plan that explicitly includes milestones and deliverables over 5 years. The financial plan requires the center to be self-sufficient within the same time frame. “Whether it is mouse modeling, lead molecule development, or other projects, the expectation is that the work will move something closer to a clinical application,” Benz said.

To incentivize faculty to lead the centers, Dana-Farber created opportunities for responsibility and career advancement, and provided seed funding to start center activities. “We created a place in the institution where scientists with this kind of background and orientation had a home and could make a contribution with professional upward mobility,” Benz stressed. “We realized that we had capabilities that were scattered across various labs and needed to be organized into programs,” he said. For example, a Cancer Chemical Biology program was started with three recruited faculty who had synthesized materials in their own laboratories. These newly discovered agents were about to enter or were already in clinical trials.

One of the centers, the Belfer Institute for Cancer Sciences, aims to bridge the gap between academia and industry. Researchers at the Belfer Institute have expertise in preclinical models, including genetically engineered mice, primary tumor xenografts, and short-term tissue cultures. They are also well versed in biomarkers and clinical biomarker assays and have access to clinical specimens through academic collaborations with a broad network of investigators. The Belfer Institute has been partnering with large pharmaceutical firms such as Merck and Sanofi to identify and validate new drug targets and delineate a clinical path for drugs in clinical trials. “The Belfer creates an interface where faculty or any kind of external partner can bring a target molecule and get the studies done that they need to do to decide if it should end up in an early-phase clinical trial,” Benz said.

Dana-Farber has a more traditional and longstanding partnership with Novartis that enables Dana-Farber researchers to receive 2-year research grants from Novartis on topics of interest to the company. The researchers have the freedom to publish their findings. “A lot of oncology drugs in Novartis’s pipeline have moved through that pipeline a little faster thanks to these partnerships,” Benz said.

Benz summarized what Dana-Farber has learned from its restructuring and its industry partnerships in terms of what it takes to move things more quickly from bench to bedside. “You need a great group of investigators, and they have to be a mix of basic, clinical, and translational scientists who want to collaborate and interact in this more team- or goal-oriented scientific application,” Benz said. He stressed that these investigators have to be situated in a place where there is expertise and understanding of what the clinical problems are. “They can’t be purely clinical centers, but must also have many of the features of a strong academic partner,” he said. Another necessary ingredient is technical expertise, and “a broad interface that allows multiple points of entry, exit, and reentry for this process of partnering and translation outside of the immediate sphere,” Benz noted.

Partnering with Foundations

There are also many potential benefits for the NCTN in partnering with disease-specific foundations, as well as with more general foundations, Benz pointed out. Margaret Anderson, executive director of FasterCures, agreed, noting that venture medical philanthropy is a growing area. Venture philanthropy not only funds novel, high-risk research that bridges disciplines, institutions, and ideas, but also taps strong scientific expertise to guide its efforts, she said. “Venture medical philanthropy groups tear down some of the collaboration barriers due to the silos that exist in medical research,” Anderson added. Disease foundations also tend to have a great deal of oversight in whether the funds they provide are being well spent. “The hallmark of all these groups is if they are going to put a dollar down on the table for any activity, they’re going to monitor that money and look at how it is being spent and what the outcome is,” she said.

Some medical philanthropy organizations run entire trials themselves at various institutions, or support clinical centers that do so. For example, she said, the Multiple Myeloma Research Consortium has 16 member institutions and has initiated 30 trials, which launched 60 percent more quickly and enrolled patients 10 percent more quickly than industry trials. Eight of these drug studies are in their final stages. Venture medical philanthropies can also bankroll industry endeavors that prompt pharmaceutical firms to develop treatments for a specific disease they are not already inclined to explore on their own, Anderson added. She highlighted the recent approval of Kalydeco, the first drug to target the cause of cystic fibrosis—the protein product of a faulty gene (CFF, 2012; FDA, 2012e). This drug resulted from a longstanding collaboration between the Cystic Fibrosis Foundation and industry, in which the foundation provided much of the seed capital needed to launch the clinical development of the drug.

Anderson stressed that one should consider not only financial capital but also human capital when evaluating whether collaborations furthered by venture medical philanthropy will be productive and valuable. If patients trust advocacy organizations and foundations, they will be more willing to participate in the research they sponsor; these organizations “are really changing the game of clinical trial recruitment,” Anderson said. She noted that the Michael J. Fox Foundation for Parkinson’s Disease has its own “trial finder,” which had 14,000 patient volunteers and 200 clinical trials in its database within 10 months of being launched in April 2012. “It’s absolutely critical that you have clinical trial matching like this because oftentimes patients are not going to be finding out about these trials from physicians,” Anderson said. She added that the clinical center associated with the Translational Genomics Institute has 60 percent of patients participating in clinical trials, compared with the national average of 3 percent.

“Venture medical philanthropy is fixing the leaks in the clinical trial pipeline that are diverting the stream of patients from such trials,” Anderson concluded. Improving the efficiency of trials will encourage broader participation by both physicians and patients.

In addition, many disease foundations have longstanding relationships with FDA staff, which “really paves the way for things to go more quickly. They do regulatory de-risking,” Anderson said. “They lay the groundwork for determining and answering the questions the FDA needs answered to start looking at approvals in this space.”

Anderson ended her presentation by stressing that “now’s the time to start to look at efficiencies and ways to potentially leapfrog things forward and think about how we can change this, because the bottom line is that if we’re not patients already, we’re going to be.”

An Example of Collaboration in Cardiovascular Research

David Sabatine, associate professor of medicine at Harvard Medical School and associate physician of cardiovascular medicine at Brigham and Women’s Hospital, described the TIMI Study Group, which he chairs. The TIMI Study Group,³ which was named for its first trials on thrombolysis in myocardial infarction, is an academic research organization based at Harvard’s Brigham and Women’s Hospital dedicated to advancing the knowledge and care of patients with cardiovascular disease and its risk factors. Since 1984, TIMI has conducted 65 clinical trials at more than 4,000 sites across 6 continents. More than 8,000 investigators have participated in TIMI trials, which have enrolled more than 300,000 patients to date. Most TIMI trials are sponsored by industry and enroll between 15,000 and 25,000 patients per trial.

Sabatine explained how the TIMI Study Group operates and how it collaborates with industry in conducting clinical trials. He noted that pharmaceutical companies choose to work with TIMI because it offers experienced and skilled research scientists, clinical trialists, and project managers. “These trials are so big, they are like a jumbo jet—they’re very hard to steer so you need a lot of expertise to fly them,” Sabatine said.

Another advantage of TIMI’s infrastructure, Sabatine noted, is that “it brings all the necessary parts together under one roof. The principal investigator works very closely with the project director, who works on a daily basis to ensure all aspects of the trial are integrated. So, if we wanted to have a high rate of adjudication of events, for example, someone can take care of that by walking down the hall and talking to one of his or her colleagues.” The TIMI Study Group also offers core services that include a safety desk; trial hotline; biomarker, genetics, and electrocardiography core laboratories; a clinical events committee; and a quality-assessment team.

Monitoring of the trials is typically done by contract research organizations hired by industry sponsors, but the monitors are trained by the TIMI Study Group on the disease state and the study protocol. “We sort of take charge of them, but they aren’t on our payroll,” Sabatine said.

TIMI physicians include

• clinicians on the staff at Brigham and Women’s Hospital;
• global principal investigators for trials who come from the faculty at Harvard Medical School and dedicate between 75 and 80 percent of their time to research; and
• clinical trialists (TIMI investigators), who are highly experienced in the design of clinical trials and work daily with the senior project director on trial implementation.

The TIMI Study Group also focuses on ensuring adequate training and communication for participating sites, according to Sabatine, and has a trial hotline, staffed 24/7, that responds to all medical and operational inquiries.

TIMI project managers generally have more than 10 years of experience in running megatrials with more than 10,000 patients. “There’s a special skillset for running such large trials and our project managers have the experience that is required and that even industry may lack,” Sabatine noted. TIMI staff also apply their expertise to develop an appropriate trial design that includes the right patient population, drug dose, and endpoints. This effort is aided by the TIMI Working Group’s online databases of electronic patient records collected during its trials. Researchers can tap that database to refine inclusion and exclusion criteria for their trials. “We work very closely with the sponsor beforehand, using our databases to give information on what might be the right enrichment factors for the trial,” Sabatine said.

As Figure 2 illustrates, each TIMI trial has a joint management team with members from both industry and TIMI, including key physicians, study chairs, and sponsor representatives, who meet biweekly.

FIGURE 2

TIMI trial organization. NOTE: CEC = Clinical Events Committee; Dir Ops = Director of Operations; EC = executive committee; EXEC CMTE = executive committee; IDMC = Independent Data Monitoring Committee; IXRS = interactive voice recognition/website system; (more...)

In addition, a joint working group focused on operational issues meets weekly. Often, there is also joint management of the blood samples collected in the trial. The samples are typically split between TIMI and the sponsor, according to Sabatine.

Open and frequent communications between sponsors and TIMI gird the success of its collaborations with industry, he noted. “We have very frank conversations at the beginning of any potential marriage with our sponsors that set the boundaries and reinforce respect for and trust in the area of expertise each group will have,” Sabatine stressed. He added that during a trial, there are ongoing discussions with industry sponsors about all aspects of the study, including protocol design and the statistical analysis plan. “We maintain a dialogue with our sponsors throughout the half a decade that we work together,” Sabatine said.

Regarding legal agreements for the TIMI-industry collaborative trials, Sabatine noted that because of the long track record TIMI has with a number of companies, “we don’t need to reinvent the wheel but just specify the scope of work for a particular project.” He added that Harvard has strict rules that give TIMI some ownership of the data and the ability to publish results.

TIMI relies on industry support. Most TIMI trials are funded by industry, Sabatine said, “and it’s my job to keep the trials coming” to ensure financial support of TIMI’s infrastructure.

In response to a question about what motivates clinicians to participate in TIMI trials, Sabatine noted that participating study sites are not dedicated solely to TIMI trials: “There’s no pledge of allegiance to TIMI, but they do tend to work with us frequently because we spend a lot of time designing trials that are high-quality and high-profile.” The findings of many of the studies are published in prestigious scientific journals. Meaningful physician-to-physician contact also motivates doctors to participate in the research, Sabatine added. “If there’s a question from the site, they can talk to the TIMI investigator who’s spending 75 to 80 percent of his or her time on the trial,” he said.

Participating physicians are rewarded by the scientific success of the trial, according to Sabatine, and are also given financial compensation for their time. Sponsors determine how much participating physicians are paid per patient enrolled in the trial. “We advocate for the highest, most reasonable amount, but the sponsor ultimately determines the dollar value and that ends up being constant for all the sites,” Sabatine said.