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Improving the Quality of Cancer Clinical Trials: Workshop Summary REGULATORY ISSUES With its regulations aimed at ensuring safety and efficacy of therapeutics, the FDA controls not only the entry of drugs and diagnostics into the market, but affects the design of the clinical trials of these medical products. Consequently, FDA regulations have the potential to stimulate or hamper the implementation of biomarkers and other innovations aimed at improving the quality of cancer clinical trials. The third session of the second day explored current regulations and how they affect cancer clinical trials. Regulatory Barriers to Innovation The first speaker was former FDA cancer drug regulator Dr. Susan Jerian of OncoRD, Inc. Dr. Jerian discussed the interplay of current laws, regulations, and policies that inadvertently deter innovative clinical trial designs and foster what is expedient for business instead of providing the public with clinical trials that answer important questions. The first regulation she discussed was accelerated approval, which was codified in 1992, and is intended to expedite marketing of drugs for patients suffering from serious or life-threatening illnesses when the new drugs provide meaningful therapeutic advantage over existing treatment.15 The acceleration is enabled by using surrogate endpoints for efficacy, such as response rate or time to progression. The regulations also allow for accelerated approval based on restricted use of a new treatment when “a drug, effective for the treatment of a disease can be used safely only if distribution or use is modified or restricted”; this has rarely, if ever been applied in the oncology setting. The accelerated approval regulation stipulates that product approvals will be withdrawn if confirmatory studies fail to show clinical benefits, or if the drug sponsor fails to conduct the confirmatory study. But such product withdrawals have not occurred within oncology, most likely because “it is untenable and difficult to think of withdrawing a product when there may be patients who are benefiting,” Dr. Jerian said. Accelerated approval has benefited many cancer patients, Dr. Jerian noted. But it has also fostered new cancer treatments being predominantly tested in advanced, refractory cancer patients because the testing and approval process with such patients via the accelerated approval pathway 15 Final Rule: New Drug, Antibiotic, and Biological Drug Product Regulations; Accelerated Approval, 57 FR 58942 (December 11, 1992).
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Improving the Quality of Cancer Clinical Trials: Workshop Summary occurs faster than it would for drugs tested in patients with early-stage cancers. “We have inadvertently incentivized sponsors to do their more rigorous studies in the end stages of disease because the sponsors see this as a quick path to market,” Dr. Jerian said. “The public wants cancer prevention and cures, but more often gets end-stage care.” Furthering this trend is the increasing use of compendia to support reimbursement of off-label use of cancer drugs. This was facilitated by congressional legislation passed in the early 1990s that made it acceptable for Medicare to reimburse for some off-label use of products if that use is supported by clinical research that appears in peer-reviewed medical literature, or if it is listed in one of two compendia; either the American Hospital Formulary Service Drug Information or the U.S. Pharmacopoeia DrugPoints.16 For the former, physicians are responsible for acquiring the supporting medical literature, but this can be challenging in a busy practice, Dr. Jerian said. Pharmaceutical companies may not routinely disseminate publications of off label use, but FDAMA regulation17 and a landmark case in 199818 made it easier for them to provide such publications when physicians query the companies for additional information. As for using the compendia route to support off-label uses, there is a lack of transparency and third-party oversight on the requirements for listing a drug for an off-label use in these compendia, Dr. Jerian pointed out. The use of compendia by CMS and other insurers to evaluate the appropriateness of off-label uses of drugs requires clinical and scientific expertise that often is lacking by third-party payers, she added. The compendia set a different and less rigorous standard for safety and effectiveness of drugs than that of the FDA. Dr. Jerian noted that CMS convened the Medicare Payment Advisory Commission (MedPAC), which developed the criteria for a desirable compendium. But none of the compendia that they reviewed met all of their criteria. “So what we have now is a nontransparent system that we can’t really access, and the ability to influence the system. The physicians who are busy in their practices are really stuck in the middle,” Dr. Jerian said. Although 16 See http://www.ashp.org and http://www.micromedex.com/products/drugpoints/. 17 Food and Drug Administration Modernization Act, 21 U.S.C. §§ 351 et seq. (1997) amended by 21 U.S.C. § 401 (1998). 18 Washington Legal Foundation v. Friedman, 13 F. Supp. 2d 51, (D.D.C. 1998), aff’d mem., 36 F. Supp. 2d 16 (1999), aff’d mem. 36 F. Supp. 2d 418 (1999), aff’d mem. sub nom. Washington Legal Foundation v. Henney, 56 F. Supp. 2d 81 (1999).
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Improving the Quality of Cancer Clinical Trials: Workshop Summary regulations supporting reimbursement of off-label use of cancer treatments have improved overall cancer care in the United States, she said, they also pose logistical challenges for conducting rigorous cancer clinical trials. Early-stage cancer patients are being enrolled in studies for compendial listings rather than in more rigorous scientific studies intended for full-market approval of drugs. Accelerated approval and enhanced use of off-label drugs via the compendia route has “created a disincentive to companies to conduct rigorous registration studies in less refractory or earlier stage patients. Conduct of these studies is hampered by competition for patients, many of whom enroll in ‘compendial’ studies,” Dr. Jerian said. Another FDA process that can be problematic for the adoption of biomarkers in clinical trials, according to Jerian, is the special protocol assessment (SPA), developed in 1997.19 On request, the FDA will evaluate within 45 days certain protocols and issues relating to the protocols to assess whether they are adequate to meet scientific and regulatory requirements. The SPA process led to improvement of clinical study designs for trials intended to support efficacy claims, and improved the likelihood of success for such regulatory approval. But Dr. Jerian’s experience with the SPA is that the more innovative or complex the study design is, and the more it employs the use of complex elements such as biomarkers or adaptive trial designs, the more difficult it is for the trial to successfully complete the SPA agreement process within one 45-day review cycle. It might take as long as a year for the sponsor to reach agreement with the FDA under the SPA process because they must go through multiple cycles; the 45-day review clock is reset each time a protocol change is made. Consequently, to have their trials up and running quicker, sponsors often avoid these innovations in their study designs, Dr. Jerian said. With sponsors much less inclined to submit novel trial designs, the promise of personalized medicine becomes more challenging, she noted. “The SPA process is not user friendly for complex study designs that the Critical Path wants to see more of,” Dr. Jerian said. The final regulation Dr. Jerian discussed was the 2005 FDA ruling on 19 PDUFA Reauthorization Performance Goals and Procedures, an enclosure to a letter from Donna E. Shalala, the Secretary of Health and Human Services, to Senator James M. Jeffords (November 12, 1997) (on file at http://www.fda.gov/CBER/genadmin/pdufago111297.htm). See also, Center for Biologics Evaluation and Research, Guidance for Industry: Special Protocol Assessment (May 17, 2002) (on file at http://www.fda.gov/cder/guidance/3764fnl.htm).
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Improving the Quality of Cancer Clinical Trials: Workshop Summary the definition of a combination product.20 This ruling states that in cases where a diagnostic is used to select patients for treatment with a therapeutic, the diagnostic and therapeutic together are considered a combination product. For example, if trastuzumab (Herceptin) were approved by the FDA today, it would be considered a combination product only with the IHC test for HER-2, the HercepTest. This regulatory link between a therapeutic and biomarker test can lead to an undesirable business outcome between the therapeutic’s sponsor and the device’s sponsor, she said. Screening using a biomarker can result in many ineligible patients, which can extend enrollment time lines. The combination product ruling also makes it more difficult to introduce scientific advances by not allowing for flexibility as the science advances. The understanding of how best to employ biomarkers is rarely present at the onset of clinical trials, Dr. Jerian noted; complex molecular pathways take time to delineate and thus need a flexible regulatory system. Dr. Jerian proposed ways to improve the regulatory environment to foster more innovative and rigorous, high-quality cancer clinical trials. She suggested “cleaning up” the compendial process so it is more transparent and congruent with FDA standards. Scientific and medical expertise should be required and documented for those individuals who provided input for product monographs in compendia and for those individuals making reimbursement decisions. She also stressed the need to improve the depth and quality of data review. These changes should reduce the number of non-rigorous “frivolous” clinical studies done to gain compendial listings for off-label uses of drugs. Dr. Jerian also suggested that the FDA could consider using the “restricted use” pathway for accelerated approval of products whose use would be restricted based on an in vitro diagnostic assay or other testing procedure. The restricted use pathway allows for accelerated approval by restricting the use of a drug to certain facilities or physicians with special training or experience, or is conditioned on the performance of specified medical procedures, which could be biomarker tests. Accelerated approval could be granted to a drug if the use of that drug was restricted to those patients predicted to respond to it via biomarker tests. “I think as oncologists, if we saw compelling efficacy data in a biomarker-selected group of patients, that would be more meaningful to us than a 10 percent response 20 Final Rule: Definition of Primary Mode of Action of a Combination Product, 70 FR 49848 (August 25, 2005).
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Improving the Quality of Cancer Clinical Trials: Workshop Summary rate in end-stage disease, and I propose that this rises to the same level of importance,” Dr. Jerian said. “This is one way to give an incentive to a commercial sponsor to do a biomarker-based study. It also is a way to try to get the most exciting scientific advances to patients earlier in their state of disease and really answer the important questions that we want to answer.” Finally, Dr. Jerian proposed a number of revisions to the SPA process, including hiring, training, and retaining more reviewers who are expert in complex trial design issues, and making it easier to modify study protocols without extending the FDA review process. “There are clear changes that a sponsor can make to a protocol that are easily addressed and can be reviewed efficiently within a reasonable amount of time. To have to restart the 45-day review clock for that type of situation adds to the regulatory burden,” she said. There already exist examples of frequent communication used in other regulatory interactions between sponsors and the FDA. Those same principles of frequent and open communication could be applied to the SPA process, but it would require an increase in the number of review staff at the FDA. The FDA currently does not have the capacity to provide this level of communication for the SPA process. Implementation of increased communication and allowing for protocol revisions during the 45-day review process would likely result in an increase in the submission of novel trials designs, an improvement in the quality of clinical trials and an improvement in clinical development timelines. A strong and well-staffed FDA is good for product development, Dr. Jerian said. In the discussion following the presentations, Dr. George Mills suggested the initial 45-day review for SPA be followed 2 weeks later by a teleconference to address any needed adjustments to the SPA. After that, an annotated follow-up review should be completed and submitted to the agency in a timely manner, Dr. Mills said. Dr. Jerian said she thought this was a good suggestion, but noted that it would depend on staffing at the FDA to carry it out. Patient Advocacy Perspective The next speaker, Ellen Stovall, a cancer survivor and President and Chief Executive Officer of the National Coalition for Cancer Survivorship (NCCS), gave a patient advocate’s perspective on regulations and what is needed to improve the quality and patient participation in cancer clinical trials. Ms. Stovall began her presentation by noting the diversity of patient
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Improving the Quality of Cancer Clinical Trials: Workshop Summary advocate perspectives and pointing out that views about patient participation in clinical research are not universal. But studies and anecdotal experience suggest that clinical trial design is not a major barrier for patients participating in clinical trials. “Few cancer patients would say ‘if it weren’t for the design of the trial, I would have definitely wanted to participate,’” she said. One survey of 1,000 adults noted the primary reasons that patients do not participate in clinical trials were unavailability of an appropriate trial, not meeting eligibility criteria, and reluctance of their physicians to even raise the issue of a clinical trial with them (Comis et al., 2003). Another study confirmed these main reasons for lack of participation and added other reasons, such as unwillingness to be randomized as to whether they receive an innovative treatment, time constraints, excessive distance from a treatment center, insurance denial, and distrust of the medical establishment (Metz et al., 2005). Ms. Stovall noted that people with life-threatening diseases such as cancer are less likely to be concerned about the safety of new drugs than patients who take drugs for other conditions. “No medical intervention is entirely free from risk, and pharmaceutical innovation may be deterred if decision makers focus too much on risk avoidance,” she said. But Ms. Stovall added that NCCS, while advocating for maximum access to new therapies for people with cancer, also believes that access should be based on sound and reliable medical evidence. This is in contrast with other advocacy groups, such as the Abigail Alliance, which, along with the Washington Legal Foundation, has raised a lawsuit against the FDA that claims individual access to unapproved therapies by those who can pay for them is a constitutional right. The regulatory and financing issues that Ms. Stovall identified as most pressing in the cancer patient advocate community include the recent revisions to CMS requirements for coverage of routine patient care costs within clinical trials, the FDA’s ability to follow up on supplemental labeling issues once a drug has been approved under the accelerated approval process, the status of the FDA’s issuance of its final guidance on expanded access programs, and proper oversight that ensures adherence to FDA policies in the review of new cancer indications by the Oncologic Drugs Advisory Committee. “Some new drugs have gone to groups to review that don’t have the complement of oncology reviewers on them that we would like to see, nor people who understand how these drugs are actually going to be used in clinical practice,” Ms. Stovall said. She also proposed creating incentives that reward individual physicians for engaging in clinical research. “People
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Improving the Quality of Cancer Clinical Trials: Workshop Summary value what they get paid to do and we need to put the rewards in place” to promote more physician participation in clinical trials, she said. Ms. Stovall suggested that patient advocates work with the FDA and clinical trial sponsors to design drug development programs and clinical trials, noting that such cooperation would facilitate greater patient accruals to clinical trials and lead to expanded access to innovative cancer treatments. After Genentech developed a working relationship with the National Breast Cancer Coalition, she said, patient accrual for their clinical trial of Herceptin rapidly jumped from 16 to 40 women a month. “Articulate, educated advocates who understand the science and can come to the table can really transform the way clinical trials accrue, the way they are designed, and the way they are monitored. There is a fourth wheel to the bus at times—it is not just academia, government, and industry, but patients. We are the end user,” she concluded. Dr. Janet Woodcock concurred that “it has been the patient groups that have driven many of the major policy changes that have been made over the past two decades.” Regulation of In Vitro Diagnostics Following Ms. Stovall’s talk, Dr. Steve Gutman of the FDA gave a presentation on the regulation of in vitro diagnostics, otherwise known as lab tests. The FDA has been regulating these tests since 1976, when the Medical Device Amendments gave the agency the mandate to conduct premarket reviews of in vitro diagnostics, and to monitor good manufacturing practices and postmarket reporting of adverse events. For such premarket reviews, tests considered high risk are reviewed primarily via two pathways. The premarket approval application pathway is the most rigorous because it often requires clinical studies and is reserved for diagnostics that pose the most risk to patients. Those diagnostics considered less risky are reviewed via the premarket notification, or 510k pathway, which involves showing that the test is similar to tests already on the market and performs adequately. For both pathways, the FDA uses the same core science or standards to evaluate tests. The evaluation process is well established and transparent, and “although it is rapidly evolving, we have a very rich base on which to ground our evaluation of new diagnostics—there is rich literature and numerous standards,” Dr. Gutman said (Box 3). Dr. Gutman did note, however, that for innovative biomarker tests where there is not an intuitive relationship between the analytical and clinical signal, the agency might require the sponsor to conduct a feasibil-
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Improving the Quality of Cancer Clinical Trials: Workshop Summary BOX 3 Model for Evaluation of Diagnostics Literature Standards Clinical and Laboratory Standards Institute (CLSI) International Organization for Standardization (ISO) Standards and Reporting of Diagnostic Accuracy (STARD) Guidances FDA template SOURCE: Gutman presentation (October 5, 2007). ity study that specifies a model for a subsequent clinical study. This model would indicate the intended use and targeted performance of the test, what the test population and type of test sites will be, and what the cut-offs are for the test parameters. This feasibility study “works out all the bugs” for the subsequent validation clinical study, Dr. Gutman said. In that study, sponsors have to demonstrate that “whatever signal is generated stands the test of time with independent validation of the data and demonstrates that the hypothesis works and is linked to the claim,” Dr. Gutman said. For that demonstration, the clinical sensitivity and specificity of the test usually are required. Dr. Gutman noted that the agency tends to shy away from reviewing predictive values of positive and negative tests because these values vary according to the prevalence of the condition in the population being studied. He added that the FDA is “very concerned with the endpoint against which the new diagnostic is being measured, whether that is a drug effect or the presence of disease, or the risk of future disease, and the weaker the endpoint then the more semantically interested we become in cautionary labeling.” The “bad news,” as Dr. Gutman put it, is that for cutting-edge science with clinical implications, such as biomarker tests, there is a lack of material and method standards, complex bioinformatics for the agency to wade through, and a lack of gold standards. “Often as we look at a new diagnostic, we will look for a silver or bronze standard. Sometimes we will settle for
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Improving the Quality of Cancer Clinical Trials: Workshop Summary a lead standard, but we do look for a yardstick of truth,” Dr. Gutman said. As is true for other diagnostics, the agency will continue to be on guard for biases in sampling, selection, verification, and spectrum. The agency will pay close attention to the impact of missing datasets because the impact of even small sets of missing data can sometimes be magnified, he noted. The “good news,” according to Dr. Gutman, is that the agency has interest in and understanding of adaptive designs and Bayesian statistics, and will let sponsors take regulatory shortcuts by using cautionary labeling and by initially narrowing their claims to bring a test quickly to market, with expanded claims dependent on the collection of future data after the product is on the market. The Critical Path plan for modernizing the agency is “alive and well” and being executed on many fronts within the FDA’s diagnostics arena, Dr. Gutman stressed. The agency also has a flexible regulatory toolbox, he added, including a process for expedited reviews, de novo classifications, niche submissions, and preinvestigation device exemptions (pre-IDEs). Expedited reviews enable cutting-edge new products with real public health impact to move to the head of the queue of products to be reviewed at the FDA. Products with a modest amount of data may undergo a niche submission, which is reviewed within 30 days. The de novo classification enables the agency to down-classify new devices or tests that are not similar to those already on the market, but not likely to pose much risk. The pre-IDE is a free service of the FDA in which it they will review a sponsor’s protocol within 60 days. “It is sort of the antithesis of a pop quiz because, when we get the protocol, we tell you all the questions we are going to ask when the study comes in, and you get to sort of negotiate. We will argue and talk and learn so that there is a decrease in uncertainty when the product actually hits the decks in my shop,” Dr. Gutman said. This results in more well-developed submissions to the FDA that the agency can review more quickly. Once a test is approved based on its performance in small studies, there is still uncertainty whether it will perform similarly in the hundreds or thousands of labs that will use it on millions of patients. “My center is undergoing a transformation in which it is deliberately looking at what kinds of mechanisms it has for tracking real-world use of products, and we have a variety of programs looking at active surveillance, better integration of signals,” Dr. Gutman said. In the discussion following the presentations, a conferee pointed out the variability in the accuracy of HER-2/neu testing and noted “it is not only the test that matters, but how it is performed in the laboratories and how CLIA [the Clinical Laboratory Improvement
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Improving the Quality of Cancer Clinical Trials: Workshop Summary Amendments] regulates the performance of laboratory testing,” he said. Dr. Gutman agreed and also stressed the importance of standardizing the preanalytical phase of testing, that is, the process for procuring and handling the sample being tested. Dr. Woodcock added that “we can develop the best drugs and diagnostics in the world, but if the health-care system is going to be error prone, we still are not going to be delivering quality care to the patients.” Dr. Gutman concluded his talk by saying, “FDA has a dual mission across the board—we are trying to promote public health by getting new diagnostic devices out more quickly, and we are trying to protect public health by keeping bad ones off the market. There is a clear tension which we try to address by applying good science, by asking the right questions.” Regulatory Issues in Improving Cancer Clinical Trials In the final talk of the session, Dr. Woodcock of the FDA gave her regulator’s perspective on what is needed to improve cancer clinical trials. The need for such improvement is indicated by the average success rate of only 5 percent for oncology drugs, from first in human to registration (Kola, 2004). Dr. Woodcock pointed out that most experts in drug development agree that better evaluation of candidates earlier in the process will increase the success rate and decrease the amount of residual uncertainty about the performance of a product. This requires changing the traditional cancer trial process, which is more empiric than mechanistic. Dr. Woodcock gave suggestions for improving every phase of cancer clinical studies. Although she recognized the value of Phase 0 trials for revealing proof of mechanism in people early in the testing phase of drug development, they require personnel and approaches that are not traditional and thus less likely to be adopted. “It’s going to take a lot to change traditional drug development because there is a tremendous amount of inertia,” she said. Phase I is typically a dose tolerance study where there is a dose escalation to maximal tolerated dose, “and often very little else is learned except how much people can take and that is not very informative from a scientific perspective,” she said. More information could be gained by using “biomarkers, pharmacokinetic analyses, and other scientific lenses into the performance of the product as early as possible,” she said. But, like other speakers, Dr. Woodcock stressed the need for proper validation of biomarkers. As for Phase II trials, Dr. Woodcock advocated using adaptive trial
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Improving the Quality of Cancer Clinical Trials: Workshop Summary designs. These designs are especially suited to finding the optimum dose, which is the main goal of Phase II trials. “Better dose finding means studying more dose strata and rapidly trying to converge on appropriate doses, and nothing would be better than using adaptive designs to do that. They are tailor-made for this,” she said, adding that there is nothing controversial in their use for this purpose. Dr. Woodcock also proposed mathematically modeling the relationships among dose, toxicity, and effectiveness, using Phase II data. “This is extremely labor intensive, but it is extremely informative. It turns what is basically an observational descriptive exercise of Phase I and II into something that is quantitative and understandable,” she said. She hopes to reinstitute a highly popular FDA pilot program that did such modeling for drug sponsors. Dr. Woodcock encouraged the use of composite endpoints in Phase III trials, noting that this is not a novel concept; the use of several outcome measures in one composite is accepted for many other conditions, such as arthritis and cardiovascular disease. The validity of the composite needs to be established, but this need not entail conducting large numbers of validation trials, and instead could be done by gathering expert agreement on how best to combine already individually validated outcome measures. Dr. Woodcock also discussed the paired development of investigational drugs and diagnostics. Such development does not bypass the need to do a normal safety workup of the drug, or the need to establish analytical validity of the diagnostic, but rather means that the same trial(s) can determine the clinical utility of both the drug and the diagnostic. The most controversial aspect of this codevelopment pathway, according to Dr. Woodcock, is the need to demonstrate that the test contributes some information of value. “The test needs to actually discriminate two populations and you need to measure that at some level—to understand the predictive value of a negative test,” she said. As for combining several investigational drugs in a single development program, Dr. Woodcock explained that this is not traditionally done, but may be needed for the innovative targeted cancer drugs that must be combined to be most effective. In addition to commercial concerns, such as the ability of the drug sponsors to work together, a combination treatment trial has to show that each agent makes a contribution to the clinical effect, and has to measure the toxicity of each agent individually, as well as in combination. “We want to be sure that we are not adding one of the agents that adds no benefit and adds significant toxicity to the regimen,” Dr. Woodcock said. “Smart” Phase I trials that measure pharmacokinetics
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Improving the Quality of Cancer Clinical Trials: Workshop Summary can indicate individual toxicities, she noted, and a factorial design can demonstrate the individual effectiveness of each agent being studied in combination. In the discussion following the presentations, one conferee asked for more specific guidance from the FDA on how to study early in development two combined investigational agents, such as how many patients the combination needs to be tested in for the various phases of clinical testing. “The sad aspect is that it is just much easier to add [a new investigational drug] onto standard chemotherapy because we know that toxicity profile,” he said. Dr. Woodcock responded, “This is an action item for the FDA to take home and think about because this is coming.” Dr. Woodcock pointed out that many surrogate endpoints are used now in oncology trials, including the Response Evaluation Criteria in Solid Tumors (RECIST), but these surrogates do not always correlate with “something a patient values such as prolonged survival or progression-free survival,” she said. Such surrogates need to be refined, and the use of functional imaging might provide such refinements without requiring complex endeavors, Dr. Woodcock noted. “For the purposes of drug development, it is often better just to have a reliable response measure. It doesn’t have to be a surrogate,” she said, but instead could be the use of FDG PET, for example, to reveal whether a drug is having an effect on tumor metabolism. “It won’t be a surrogate endpoint, but it will tell you that it looks good or bad, which can be an extremely helpful type of measure to have in the Phase I stage of clinical testing. In many cases we need a good predictor of ultimate success more than we need a surrogate endpoint,” Dr. Woodcock said. She added, however, that the field of cancer drug development would benefit from rigorous identification of some candidate surrogate markers and an assessment of what is needed to qualify them. Qualification could be carried out by a consortium of interested parties, such as the Biomarker Consortium. “There are some low-hanging fruits—markers that could be developed [relatively easily] and used as surrogate endpoints in the future,” Dr. Woodcock said. Surrogate endpoints for prevention trials are especially needed because the time frame for outcomes is so long, yet “that is where we have the greatest risk if we are wrong and exposing large numbers of people to an ineffective or maybe harmful intervention,” she said. Dr. Woodcock’s final suggestion for improving the quality of cancer clinical trials is to standardize all aspects of trial design and execution because the mechanics of trial conduct and execution across all disease areas are extremely suboptimal, she said. “Quality of cancer trials also includes