PANEL DISCUSSION I—BARRIERS TO TRANSLATING RESEARCH INTO REDUCTIONS IN THE BURDEN OF CANCER
INTRODUCTION—DR. MARK CLANTON
Background
Dr. Clanton is currently the Deputy Director for Cancer Care and Delivery Systems at the National Cancer Institute (NCI), with responsibility to increase the impact of the Institute on the quality and cost and reimbursement of cancer care, as well as to provide leadership in the national effort to reduce cancer health disparities. Prior to joining NCI, Dr. Clanton was President-Elect of the American Cancer Society (ACS). In 2003, he served on the National Cancer Institute External Work Group for Cancer Progress Report 2004 and the Harvard School of Public Health Leadership Council. Dr. Clanton completed his medical training at Tulane University Medical School and the Texas Children’s Hospital in Houston.
Key Points
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NCI and the U.S. Food and Drug Administration (FDA) have developed a relationship with the goal of aiding the FDA approval process by electronically sharing information about NCI clinical trials of new drugs. Likewise, the Centers for Medicare and Medicaid Services (CMS) and NCI work together to develop quicker clinical trials and payment processes regarding off-label uses of drugs. The goal is to have all three agencies—NCI, CMS, and FDA—working together to acquire information about what works and what makes sense, as well as how to ensure that decision makers receive that information.
MR. CLIFTON LEAF
Background
Clifton Leaf is the Executive Editor of FORTUNE magazine, where he helps oversee the magazine’s editorial coverage and staff in addition to directing FORTUNE’s Wall Street and investing coverage. Mr. Leaf has written nearly a dozen articles for the magazine, including his provocative analysis on the War on Cancer: “Why We’re Losing the War on Cancer (and How to Win It).” Prior to joining the staff of FORTUNE, Mr. Leaf was Executive Editor of SmartMoney, where his writing shared a nomination for the National Magazine Award. Mr. Leaf has also written for The New York Times and many other national publications and held editorial positions at fitness magazine and Harper’s BAZAAR. Mr. Leaf received his Master of Fine Arts degree in Writing from Sarah Lawrence College.
Key Points
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Three-quarters of the cancer drugs approved by the FDA between January 1990 and November 2002 do no more to keep people alive than the standard treatments in use. In half of the cases, the primary basis for approval was a partial tumor-response rate. However, in 90 percent of cancer deaths, the process of metastasis, rather than the initial tumor, is the cause of death. Many of the cancer drugs approved by the FDA do not combat metastases, though they may improve quality of life or increase time to progression of the disease.
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During the same 1990–2002 period, English-language newspapers reported “cancer breakthroughs” in 691 separate articles. The perception is that progress is being made in the fight against cancer, but the drugs being developed do not actually fight cancer in a way that leads to higher survival rates. The cancer community’s overuse of medical jargon also contributes to this misperception.
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Misleading statistics also obscure how many people are developing and dying of cancer. The age-adjusted death rates the cancer community relies upon to measure progress over time do not measure the actual change in death toll. Because the American population has been aging as it grows, the cancer rate has increased. Age-adjusted death rates do not reflect the aging population; there are actually more people dying of cancer than the age-adjusted rates show.
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The annual cost of cancer treatment will exceed $94 billion in 2014. Americans will spend $800 billion on cancer treatment in the next decade.
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The cancer community has become so focused on specialization that it is difficult for researchers to communicate across specialties. Using plain language instead of scientific jargon would enhance the solicitation of feedback from researchers in other specialties. Likewise, this would provide a richer basis for applied and collaborative research.
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The lay press is culpable as well and has misguided the public in its search for and presentation of early medical breakthroughs.
DR. SCOTT GOTTLIEB
Background
Dr. Scott Gottlieb is a physician and Senior Advisor for Medical Technology to Mark McClellan, Administrator of the Centers for Medicare and Medicaid Services (CMS). Prior to joining CMS, Dr. Gottlieb was Director of Medical Policy Development at the U.S. Food and Drug Administration (FDA). He has served on the editorial staff of the Journal of the American Medical Association and the British Medical Journal and writes frequently on topics of health care, politics, and culture for The New York Times, T h e Wall Street Journal, USA Today, the Los Angeles Times, and other publications. Dr. Gottlieb is a graduate of the Mount Sinai School of Medicine.
Key Points
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CMS recognizes the important role off-label use of cancer drugs plays in personalizing cancer treatment, giving doctors the ability to tailor regimens to specific tumor types and individual patients. More and more treatments now being used represent those highly personalized regimens. CMS is looking for ways to encourage the development of better information around the general use of cancer drugs and in the off-label setting in particular.
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CMS is not looking for ways to stop paying for off-label use of cancer drugs; recent media reports to the contrary are inaccurate. CMS is required by law to pay for all on-label use of cancer drugs as well as all uses that are specified in certain compendia of drug treatments, including off-label uses. Legislation does not require CMS to pay for off-label uses not listed in the compendia. Traditionally, CMS has let local carriers make local decisions about payment for such unlisted uses. This has led to much disparity across the country: some carriers will pay for all uses of a new cancer drug, and some will pay only for what is provided by the law. It is reasonable to expect a CMS policy of coverage for all labeled uses, off-label uses listed in compendia, and some unlisted off-label uses for which information can be collected.
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CMS needs to move away from the paradigm of global reimbursement decision making for new drugs and toward a paradigm of local decision making, empowering local hospitals, local regions, individual doctors, and patients. There is opportunity under the new Medicare law to contribute to the development of better information that can help guide such decisions. The new law provides funding for comparative-effectiveness studies of new treatments; funding for oral replacement therapies; new authority and resources for participation in development of clinical trials, clinical studies, and, in particular, practical clinical studies; and establishment of the Council on Technology and Innovation, which gives CMS new authority and resources to specifically target new technologies and develop guidelines to speed the reimbursement process for new drugs.
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There are real opportunities in the FDA-CMS relationship, but there are also challenges. One of the opportunities is in allowing CMS access to data earlier in the FDA clinical trials process so that when an approval decision is made, CMS will be ready to make a reimbursement decision quickly, and reimbursement will not become an obstacle to obtaining access to the drug. One challenge, however, lies in the same process. Drug developers may be concerned that the FDA reviewer will perceive the exchange of information between FDA and CMS as pushing the approval process. Another challenge is that clinical trials should not be designed based on future reimbursement considerations. Adding mandates for new information requirements to the FDA approval process for the sole purpose of guaranteeing reimbursement would invariably delay access to the drug.
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Recently, CMS changed its payment for infused cancer drugs to more accurately reflect the true price of those drugs in the marketplace, which is significantly less than CMS has historically paid. Clinicians had used the excess payment to cover the cost of administering the drugs. CMS is now attempting to pay a true price for the drugs themselves and a true price that reflects the cost of administration. CMS has been talking closely with the American Society of Clinical Oncology (ASCO) and others in the cancer clinical community to reach a resolution that all stakeholders can accept.
DR. MICHAEL R. GREVER
Background
Dr. Grever is the Associate Dean for Medical Services at The Ohio State University Medical Center, Chairman of the Department of Internal Medicine, and the Charles A. Doan Chairman of Medicine. He is also a Professor of Medicine and Program Co-Leader for Experimental Therapeutics at Ohio State’s James Comprehensive Cancer Center. From 1994 to 1999, Dr. Grever was Director of the Hematologic Malignancies Division and Professor of Oncology at Johns Hopkins University School of Medicine. Dr. Grever received his M.D. from the University of Pittsburgh.
Key Points
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The majority of drugs in current use has been discovered through the empiric screening approach, and many are derivatives of natural products, such as the bark of the yew tree (Taxol), or from “broths” of bacterial cultures, among others.
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No fatal disease has been successfully addressed without using a combination of strategies to circumvent diverse mechanisms of resistance. Underestimating the importance of new agents for fatal disease treatment would drastically alter the potential for improving survival. The only way to increase the number of complete remissions and see improvement in survival is to use combination strategies.
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In the early 1990s, Dr. Anthony Fauci mandated that the drug development process for patients with fatal diseases be expedited. While the initial intention was to help patients with HIV, many benefits have been shared by the cancer patient population.
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First trials in man are critically important, and no hint of activity should be underestimated. Ninety-five percent of all the drugs introduced into humans at NCI are introduced very safely.
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The Government must remain committed to the drug development process. NCI has been a stalwart supporter of cancer drug development—as well as anti-HIV therapies—which would not be possible were it accountable to investors as are others in the industry.
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One challenge in drug development is the lack of communication between the scientific and physician communities. Forming teams is one way to shorten the preclinical drug development program. In the university setting, having adequate mentorship for new physician-scientists is important. Also, NIH K23 grants allow a physician-scientist who wants to be a clinical investigator to partner with a basic scientist as a mentor. R21 grants for translational research also provide funding for basic scientists, thus aiding the scientist who is not in a university setting, where most rewards, such as tenure and promotion, exist.
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Another challenge in this process is the lack of time available to simultaneously mentor researchers, serve patients, provide education, and target clinical research. There are also increasing restrictions regarding appropriate hours for trainees in hospitals. Junior faculty are burdened with long hours and still do not have enough time to do everything.
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The greatest obstacle to drug development and delivery is the disease process itself. The greatest opportunities, though, lie in people keeping faith and exercising patience. Important treatments would be lost if patience in the development process were lost. Persistence is critically important.
DR. HOMER PEARCE
Background
Dr. Homer Pearce is a Distinguished Research Fellow in Cancer Research at Lilly Research Laboratories, Eli Lilly and Company. Previously, Dr. Pearce was Vice President of Cancer Research and Clinical Investigation at Lilly. He is a member of the American Association for Cancer Research, American Chemical Society, American Association for the Advancement of Science, and C-Change. Dr. Pearce received his Ph.D. in Organic Chemistry from Harvard University.
Key Points
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During the last 25 years, there has been a revolution in the knowledge of cancer as a disease process that is beginning to be understood on both a genetic and biochemical level. This new understanding is creating new opportunities for the cancer drug industry to discover medicines and other disease interventions that will be far more effective than past attempts to treat patients.
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Cancer will soon overtake heart disease as the leading cause of death in the United States. One of the reasons that advanced cancer is so hard to treat is that a metastatic tumor has undergone a complex and heterogeneous process of transformation. The clinical manifestation of this advanced disease may be too complex to cure or even treat effectively; intervening in the early stages of the disease process—before the tumor becomes hopelessly complex and spreads—may provide the best opportunity to reduce cancer deaths.
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It is not clear that early pharmaceutical intervention in the disease process—also known as chemoprevention—will ever become a real option for individuals at risk of developing cancer. To bring a new chemoprevention drug to physicians and their patients, there are a number of substantial impediments to overcome. First, there are developmental challenges. Even with treatment study commitments, the true risk/benefit ratio of chemoprevention drugs is hard to demonstrate. Second, the time required to develop a cancer chemoprevention drug quickly erodes available patent life that enables the private sector to fund these high-risk research and development investments. The U.S. system of intellectual property protection significantly discourages clinical trials research in the development of chemoprevention alternatives. Also, it is important to have a methodology to identify patients who are at risk. Therapies must be delivered in a way that is sensitive to the molecular structure of the disease, using different treatment regimens.
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As technology evolves, the medical community will have access to malignancy biomarkers, which will help doctors take preventive measures. Other technologies will also be needed.
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There will also need to be significant public education at the national level; this is an effort with which the press can help. Once cancer is understood as a disease process rather than as a diagnosis at a point in time, participation in prevention efforts—even lifestyle modifications—would be much more likely.
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A partnership needs to be formed among industry, regulators, Congress, patient advocates, and other key stakeholders—like the NCI—with the goal of reforming the process by which prevention drugs are brought before the FDA and reviewed. This means a new system for approving prevention indications that actively encourages prevention research. There is yet to be meaningful change in the current system; the Panel could play a role in encouraging change.
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The greatest current opportunity for information about cancer and cancer drugs to be communicated to patients lies in the public education system. It would be very easy to begin reframing public school education to include information about cancer as a disease process.
MS. LISA ZIMMERMAN
Background
Lisa Zimmerman is Director of Quality Assurance and Regulatory Compliance at Duke Clinical Research Institute (DCRI). Ms. Zimmerman’s main areas of focus have been regulation and compliance. In her tenure at DCRI, she has developed a Quality Assurance and Regulatory Affairs department and has spearheaded a number of initiatives consistent with that academic mission. Ms. Zimmerman has also been involved with The New Jersey Governor’s Conference on Effective Partnering in Cancer Research, Health Insurance Portability and Accessibility Act (HIPAA) privacy laws and how they shape the future of research, and a host of other projects in different subject areas.
Key Points
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There has been a significant increase in spending on biomedical research in the past 10 years, but output of new products has declined since 1997. Fifty percent of applications fail in the Phase III stage of clinical trials; according to a 2003 FDA report, cancer drugs have more late-stage Phase III study failures than most other therapies. These failures drive up the price of successfully bringing a new drug to market, currently estimated at about $802 million.
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The cancer research process is essentially broken. The system is reactive rather than proactive; it is time to change the system to a proactive one. Major barriers to change include the inability to share information between and among scientists and researchers; lack of training available to researchers who design and conduct clinical research; lack of education available to mentors who are responsible for educating others; lack of support systems at the university level; and lack of support systems at NCI for those navigating the regulatory pathways.
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Steps toward overcoming systemic challenges include allowing the FDA to share information about cancer trials and why they fail; managing and effectively using the volumes of available information about disease and the regulatory pathway, as well as local and Federal regulations that impact research; and creating common goals, frameworks, and avenues of communication. Only then can drugs begin to be sped to market at reduced costs.
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Those in academia works very hard to receive NIH grants, build relationships, and work on current “hot buttons,” but they are not educated about regulatory processes. Here again, communication and education would benefit the system.
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Coordination of academic grants and industry funding is very difficult. Each institution has its own set of regulations and processes. The institutional review board (IRB) process is also difficult to maneuver, as each IRB has its own process for approval. A meeting of IRB members to discuss how to make tough decisions is strongly encouraged.
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These problems persist when academic centers work with community centers to run clinical trials. Many community centers are not educated about trial and regulatory processes. Because of cost concerns, DCRI has decided that the regulatory group will operate on a volunteer basis to assist investigators.
MR. WILLIAM BRO
Background
Mr. Bro is Chief Executive Officer (CEO) of the Kidney Cancer Association, which serves 60,000 constituents in the United States and 90 other countries. He is a past Chair of the Association, having succeeded the organization’s founder, Eugene P. Schonfeld, and has served as its CEO since 2002.
Mr. Bro is a retired corporate executive with a 35-year background in broadcast station management, ownership, consulting, and Web site development. Mr. Bro is also a 14-year kidney cancer survivor.
Key Points
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In 1989, when Mr. Bro was diagnosed with renal cell carcinoma, there was no FDA-approved treatment and virtually no option other than surgery to treat the disease. The Kidney Cancer Association was founded by a few strongly committed kidney cancer patients with the goal of improving treatment for their disease. The Association has since been influential in the FDA decision to fast-track interleukin-2 for approval and has formed durable relationships with NCI researchers, industry, and influential politicians.
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Sometimes, discussions are so focused on current trends that the considerable effort that has already been expended becomes lost in the clutter. The substantial work of the various progress review groups (PRGs) should be acknowledged with an eye toward encouraging implementation of their recommendations. In August 2002, the Kidney/Bladder Cancers Progress Review Group submitted a report to the Director and the Advisory Committee to the Director of NCI, which accepted the Director’s charge to develop a national plan for the next 5 years of kidney and bladder cancer research. If implemented, the 13 priority recommendations identified by the PRG will stimulate multidisciplinary research that can significantly advance progress, ultimately leading to discoveries that will reduce the burden of these diseases.
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The lack of participation in clinical trials needs to be addressed. With accrual rates in the range of 2 to 3 percent, it is very likely that many useful clinical trials will fail to accrue sufficient numbers to hit their targets; the public may never recognize the benefits of these novel agents. By the time an agent reaches the clinical trial stage, better mechanisms need to be in place to educate the public so that participation is improved. One step would be to improve public school education about cancer, cancer research, and why understanding cancer is important.
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The fact that there are now 160 kidney cancer clinical trials listed in the clinicaltrials.gov database indicates that there is considerable interest in kidney cancer. Patient advocate organizations have done a good job of raising awareness for “small” cancers in recent years. However, there still has been little progress toward finding a cure; there still is only one FDA-approved drug for the treatment of this disease. In order for a cure to be deployed, there must be sufficient interest by industry in finding a cure.
DR. GARY GORDON
Background
Dr. Gary Gordon is currently the Divisional Vice President for Global Oncology Development at Abbott Laboratories. Prior to joining Abbott, Dr. Gordon was Chief Scientific Officer and Vice President of Clinical Affairs at Ovation Pharmaceuticals. His professional memberships include the American Association for Cancer Research (AACR) and the American Society of Clinical Oncology (ASCO). Dr. Gordon received his Ph.D. in Pharmacology and Experimental Therapeutics from the Johns Hopkins University School of Medicine.
Key Points
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Remarks at this meeting are centered on three basic areas: communication and interaction within the oncology community, including the FDA, NCI, academia, and the Cooperative Groups; information availability, especially as it relates to the FDA and clinical trials; and prevention.
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How laboratory advances are applied in the prevention setting is particularly important and needs more attention. The cardiovascular community has made huge strides in prevention; the oncology community is considerably behind. There are ways of identifying people at risk for cancer, but new knowledge needs to be appropriately applied. For example, oral leukoplakia is a precursor lesion to various types of head and neck cancers and is relatively easy to identify in a physical examination. The problem up to now has been identifying the type of oral leukoplakia that represents highest risk for becoming cancer. It appears that there are certain molecular characteristics that allow doctors to identify higher-risk leukoplakia; pursuing research on this lesion could be helpful in prevention program development.
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Another problem for oncology prevention is that cancer is classified anatomically. If the FDA were to abandon anatomic classification and move to molecular classification, it would aid in developing measurements in a reproducible and reliable way. Assay development might also follow.
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The biggest issue currently being faced is the inability to communicate with FDA early in the drug development process. Drug developers need to be able to communicate with the FDA without the, perhaps, irrational fear that asking questions will somehow provoke a regulatory response that creates an even bigger burden. The ability to discuss clinical trial implementation processes, particularly around data collection and quality assurance, would be very helpful. If information-sharing processes can be developed, it would be possible to reduce the $800 million-to-$1 billion drug development costs.
