July 25, 1994
There are a number of problems with how AIDS malignancy research is carried out, including the basic funding mechanisms, the clinical trials systems and the overall lack of support from those who know AIDS and those who know oncology.
Let's look at AIDS-Kaposi's sarcoma (KS) research as a microcosm for AIDS-related malignancy research. There are only a dozen or so researchers doing work on the pathogenesis of KS. There are two sites on the west coast: Steve Miles and O. Martinez-Maza at UCLA; and Parkash Gill, Shuji Nakamura, and Syed Zaki Salahuddin at USC. On the East coast there are Alvin Friedman-Kien and Yao Huang at NYU; and Bob Gallo's NCI funded Laboratory of Tumor Cell Biology (LTCB), which includes top researchers such as Barbara Ensoli and Yanto Lunardi-Iskandar. Except for some other researchers, including Judah Folkman (Harvard), Philip Browning (Vanderbilt), Theodore Maione (Repligen Corp.), and Jonathan Vogel (NCI), that's about it.
To investigate the problems with funding this research, we need to back up and look at 1) the basic funding mechanisms for AIDS related malignancies within the NIH (RFAs, RFPs, RO1s, RO3s, UO1, etc); and 2) who is reviewing these grants (i.e., one of the seven AIDS study sections of the NIH's Division of Research Grants (DRG) or special review committees from selected NIH institutes); and 3) if there are qualified oncologists and immunologist on these committee or elsewhere who can actually judge the scientific relevance of these applications?
Unsolicited RO1s that deal with AIDS-related malignancies -- or AIDS in general -- go to the one of the seven AIDS study sections in the DRG. These seven AIDS study sections are: 1/A) Immunology; 2/B) Epidemiology; 3/C) Molecular Virology; 4/D) Pre-clinical Drug development; 5/E) HIV/OI clinical trials; 6/F) Behavior Research; 7/G) Neurology. It is up to Marcel Pons, Ph.D., to decide which of the seven study sections will review the grant applications. Pons must also decide which NIH institute will have the jurisdiction (and must come up with the funds) for the specific application. Pons also happens to be the Scientific Review Administrator (SRA) for study section 3/C. The SRA of the study section must designate primary and secondary reviewers for each grant application, assess conflicts of interest, ensure the grant application was filled out properly and decide if outside AD HOC experts (there is a long list of them) will be needed. to review a specific application. Members can be borrowed from certain study sections if he/she has some expertise that will be helpful for another section's review.
Pons believes that he is qualified to decide which study section a grant application should go to. He also said that it makes his job easier if the PI writes a cover letter and asks that his/her grant go to study section X and for what reason. Pons, however, says that only 20% of the PIs specifically ask to be reviewed by a certain study section.
Pons said that he usually places an AIDS-related malignancy grant in either Immunology (1/A), Molecular Virology (3/C) or sometimes in OIs/clinical trials (5/E). According to Pons, these three sections have oncologists, immunologists, and virologists who are up to date on the problems in the pathogenesis, histogenesis and clinical research of KS and other AIDS-related malignancies.
When asked if he felt there was a need for an eighth study section set up specifically to review AIDS-related malignancy grants, Pons said, "NO." He felt that it would be too difficult to get oncologist who not only knew AIDS malignancies, but also virology, immunology and basic chemistry. He also said that there was no need because there were not that many AIDS-malignancy grants that came into the DRG anyway.
A well known Midwest oncologist who sits on one of the study sections says that there is no need for a separate study section. He says that there will be separate ad hoc AIDS-malignancy study section set up for the late summer to look at on the etiology of AIDS-related malignancies. Here, he is obviously talking about a special study section/review committee for Ken Cremer's recent NCI RFA on the etiology of AIDS malignancies. This RFA grant review has nothing to do with the DRG except for the initial data entry. After that, it will go back to the NCI where they will set up their own special review committee. I was asking Dr. Midwest whether an eighth study section needed to be developed for reviewing unsolicited RO1s, R29s and applications in response to program announcements.
In fact, when asked about his study section, he felt that there were about two truly qualified experts who understood AIDS-related malignancy grants. When I asked about the lack of oncologists in his and other study sections, he told me that there were "several immunologists on our committee who were more familiar with cytokines and interleukins [and their role in the pathogenesis of KS and lymphoma] than most oncologists."
He also felt that while AIDS malignancy grants fared just as well as other HIV grants in his study section, he said that if an expert in crystallography of RT submitted a grant it would be looked at favorably and probably score well "as opposed to something in KS where nobody has done a lot in any extramural NIH lab. It's [the grants we get] all people coming into the field developing studies of KS based on previous experiences." He is basically saying that work done at any extramural NIH Lab (which basically means all other labs outside Gallo's LTCB) has not come up with anything new. Has he not read studies or seen abstracts in the past five years from the USC, UCLA and NYU labs?
And yes, these labs, as well as other researchers might be doing work based on previous work, but don't we need some confirmatory studies and real answers (instead of guesses) about the pathogenesis and histogenesis of KS? Gallo, Yarchoan, Miles, Gill, etc. all say they don't know the complete answer and their pathogenesis models often differ. Funding some of these basic science studies in KS, and even some clinical trials may help solve some of these ambiguities.
Dr. Midwest did make one relevant point and that was: "the issue is not the study section [their expertise], if there is money." What he meant by that was the fact that the NCI (where most of the KS and Lymphoma grants go) has a payline for RO1s at the 15th percentile and a payline for R29s at the 27th percentile. That means that if the grant in question does not fall within that percentile by ranking, it won't be funded.
Another study section member from AIDS & Related Research Study Section (ARRS) 1/A (Immunology) believes that grants applications for AIDS-related malignancies are evaluated fairly. As an immunologist, he did admit that there were only a few oncologists or practicing clinicians who might be familiar with the many aspects of AIDS-related malignancies and actually treat patients. He also said that a grant's fate is often in the hands of the study section member who is picked as the primary reviewer. If the primary reviewer does not comprehend all aspects of the grant or understand its scientific merit, then the grant application is in jeopardy.
As one of the top AIDS immunologists in the world, he contends that being on a study section is a long-term commitment for which most people have no time. Thus, some of the best AIDS researchers and clinicians won't ever become study section members.
When asked why many of the KS grants (from 1990-92) involving the study of angiogenesis which went to his study section were turned down and critiqued so poorly, he said that these grants in question involved cytokines (IL-6, IL-1, TNF, etc.) and that there wasn't the degree of understanding of cytokines back then as there is now.
Even if a grant is turned down at the DRG level because of a poor score or it did not make the payline, there are still ways this grant might be funded. There are exceptions to the general rules for grant funding. But are they for real? There is something called "Special Pay." Roy Wu, a grants officer at the NCI's Cancer Therapy Evaluation Program (CTEP) said that if some of the grants that first come to the NCI (after being sent over from Marcel Pons at the DRG) don't make that 15th percentile, then the NCI program director can ask that the grant be funded "Special Pay." The program director can pick out grants of high priority and submit them to the director of their division (there are 4 scientific Divisions and 1 Division of Extramural Activities within the NCI) where he/she will prioritize and defend them in the executive committee and at National Cancer Advisory Board.
There are also "Shannon Grants," named after James Shannon, Director of the NIH from 1955 to 1968. Shannon grants turn into R55s from RO1s and R29s that did not make the payline. Each NIH institute can pick a small number of RO1s and R29s that did not make the payline that they find worthwhile and interesting and submit them to the Office of the Director (OD) of the NIH where they are reviewed. The OD will prioritize the requests from the different institutes. The Big question is: How many AIDS malignancy grants that did not make the payline get funded either through NCI's "exception to the payline" or through "Shannon grants?"
A separate granting mechanism is the PO1 (program project grant). These are integrated, multi-component grants with a minimum of three projects. They are supposed to involve both basic and clinical science. The PI who applies for these grants would need a clinic and labs. Dr. Wu said that he likes these, but very few PIs are submitting PO1s. Some researchers, however, who believe that PO1s are even harder to get funded than RO1s.
There are also UO1s that the NCI issued. U01s are cooperative agreements The ACTG, for example, is a UO1. An institute solicits the U01 and the grantee works with the institute staff in implementing these grants. The most current example of a U01 is the Tissue Bank U01 from Ellen Feigal at Cancer Therapy Evaluation Program (CTEP). Unlike contracts, the institute does not dictate projects to the cooperative agreement awardee.
Wu also said that there is an unwritten agreement between the DRG and the NCI that involves multi-institutional clinical trial grant applications. These multi institutional grants are sent straight to the NCI where they will convene a separate review committee. For example, if a PI from Dana Farber writes a clinical trial protocol that involves University of California at San Francisco and Memorial Sloan-Kettering Cancer Center, this grant will be solely reviewed by a committee assembled by the NCI.
Wu also remarked that he did not think the DRG AIDS study sections fully understand AIDS malignancy grants. He contends, "I have been saying that these grants don't do well in the DRG for the past eight years. I have been bucking the system. I am thought of as a trouble maker over at the DRG."
Harold Varmus, the NIH Director, has recently commissioned an NIH-wide review panel called the Clinical Research Study Group (CRSG) to review the DRG's granting trends. The CRSG has been assembled from intramural and extramural NIH clinicians and researchers. The CRSG is mainly analyzing and comparing scoring on clinical grants vs. basic science grants and they are finding that clinical grants don't do well. They have found that the basic science grants usually receiving better scores.
Jeanne Ketley, Chief of the Clinical Science Review section at the DRG is acting as the Executive Secretary for the CRSG. Ketley reported to me that this group has met three times. Her minutes from the first meeting of the CRSG state:
The CRSG was formed because increased competition for NIH research funds has led to a degree of anxiety and concern in the scientific community of the grant review process, And, [there have been] many requests for new DRG study sections.
It is important to remember here that the CRSG is not solely focussing on AIDS, but all unsolicited, extramural clinical research grants funded by the NIH. The fact that Varmus et al. set up the CRSG and believe that all is not well at the DRG does give those who have been complaining about the funding mechanism of AIDS-malignancy research something to go on. It seems as though AIDS activists and AIDS oncologists are not the only ones unhappy with the DRG study sections. However, our claim is that there is a lack of understanding in both the basic and clinical science of KS and AIDS-lymphoma.
The rejected basic and clinical science KS grants that I have reviewed (either deemed not worthy of further consideration or their scores were too high to put them within the pay line) have all been quite interesting for a number of reason: 1) many of them dealt with the various cytokines and growth factors that we believe are involved in the pathogenesis of KS; and 2) the questions that the grants posed (some in 1991, '92 and '93) still have not been answered -- and probably won't be answered.
Below is a synopsis of six grants ("pink sheets") that were not funded from three of the leading KS researchers. This information is from their DRG "pink sheets" with paraphrased critiques from the study sections.
Grants #1 and #2 were studies of IL-6's role in the pathogenesis of KS. Grant #1 also involved in vitro experiments on four compounds that may downregulate the production of IL-6.
Grant #3 was to study the in vitro and in vivo effects of all-trans retinoic acid.
Grant #4 was for funding to establish of a center (an AIDS Malignancy Network) for the treatment of patients with KS which would also conduct clinical trials on novel anti-KS agents and serve as a tissue bank.
Grant #5 was to conduct a phase I/II clinical trial of liposomal encapsulated doxorubicin (LED) on patients with KS.
Grant #6 was to analyze the mechanism of fibroblast growth factor (FGF) 3 gene activation in KS and to develop antisense, monoclonal antibodies and angiogenesis agents to determine their inhibitory KS effects in vitro and in vivo.
The critiques and comments were unfortunately misguided for all of these grants. The generalized critiques/comments were:
There is still general confusion as to who is "specifically qualified" to treat patients with AIDS-related malignancies. Should oncologists be the only ones allowed to treat KS or should infectious disease doctors and primary care physicians attempt to treat their patients with KS?
Nobody knows if KS is a "true" malignancy (clonal proliferation) or if it is a dysregulation of angiogenesis in HIV + individuals. Even the semantics of this question can be damaging. This centers around the term "true" malignancy (meaning cancer/meaning life threatening/meaning bad). If physicians want to say that KS is not a "true" malignancy, this leads to a sense of ambivalence concerning treatment and comments such as, "Well if it's not a true malignancy it can't be that bad and therefore why would there be why should there be the need to treat it?"
Would an oncologist with no understanding of AIDS be able to adequately care for an individual with KS? Isn't it important that a treating oncologist be well versed in important aspects of the other complications of his/her patient's HIV disease?
Why are there so few oncologists who have a basic understanding AIDS? And why are so few AIDS oncologists capable of doing basic and clinical research.
It seems to be a sad truth that the ACTG Oncology Committee has very few friends in the hierarchy of the ACTG and also within the general oncology world. The ACTG Oncology committee has and continues to be heavily invested in the treatments for patients with HIV-related malignancies. These oncologists specialize in AIDS unlike the vast majority of their fellow oncologists. Hence, they don't fit in with the traditional oncology groups. There is little interest in the study of AIDS-related malignancies in the general oncology research community, and the oncology/cancer conferences devote little time or effort to AIDS-related malignancies. Thus, these ACTG AIDS oncologists and others like them have chosen to live and work in the world of AIDS. But why are they the black sheep within the AIDS research community?
The ACTG is made up primarily of infectious disease doctors who have been used to having it easy for many years. As one NCI oncologist noted:
Those ID docs lived their lives with a "find a bug, find a pill" mentality. They have never worked in a field such as cancer or leukemia where advances and successes are slow in coming and sometimes don't come at all. They look down on oncologists because we don't have a myriad of great success stories. But, now they are baffled because HIV has finally stumped them. Things are no longer so easy. There is no quick fix.
The Oncology Committee has had to battle with the Executive Committee to get concept sheets approved. In March of 1990, the Executive Committee attempted to cancel all four of the Oncology Committee's high priority trials.8 Susan Krown (the Chair), Alexandra Levine (the co-Chair), and Ronald Mitsuyasu (the past Chair) of Oncology Committee had to fight like hell to save 3 of their 4 trials.9
More recently the Executive Committee has chided the Oncology Committee for slow and low accrual to its various studies. Are these members of the Executive Committee not aware of the overall problem in accruing for all ACTG trials and for their own lack of support for Oncology trials? that fundamentally goes back to them? Many of the members of the Executive Committee are the head PIs at some of the largest ACTUs in the country. Michael Lederman (Case Western), Peter Frame (University of Cincinnati), Michael Saag (University of Alabama), Henry Balfour (University of Minnesota), and Ruy Soeiro (Albert Einstein) have not entered one patient on an ACTG Oncology protocol nor have they registered for any oncology trial at their site. Their ACTUs don't have oncologists to conduct these trials and there obviously is no committed money to hire one. They surely must realize the fact that a lack of committed funds for oncology trials makes it impossible to court a qualified AIDS oncologist. Having trained AIDS oncologists10 at only a limited number of sites around the country will result in even the most compelling oncology trial to be slow in its accrual.
It is also the unfortunate truth that the Oncology Committee has been stuck with doing uninteresting -- yet nuts-and-bolts -- trials with old cytotoxic chemotherapy drugs and only moderately effective antiviral agents. Why is that? Because we don't have better treatments yet, and we need to know how to use the mediocre ones we do have.
In the late 1980s and early 1990s we already had identified the common chemotherapy drugs active against KS. But questions had to be answered such as:
There was also IFN-alpha to consider with the same list of questions. Additionally, KS patients (as well as all AIDS patients) were inundated with the concept that antiviral therapy was crucial for their survival. Whatever one thinks of AZT, ddI, or ddC, we must realize that there are thousands of KS patients on these drugs. This led to further questions such as: 1) Is combining antiviral therapy with cytotoxic agents and IFN-alpha beneficial or harmful? 2) Will the synergy we see with some of these combinations in vitro result in enhanced clinical benefit? 3) What doses of both drugs can be used safely in combination? Are there overlapping toxicities? Can we administer IFN-alpha and AZT even knowing that they are both myelosuppressive? How extreme is peripheral neuropathy with vincristine and ddI or ddC?
Suffice it to say, the Oncology Committee has answered a great many of these questions, but there are still a number of questions that have not been -- and need to be -- fully answered in KS therapy, such as:
Over the last few years, however, things have changed. We have learned more about the pathogenesis of KS in the past 2 1/2 years than we have during the entire epidemic previously. Basic science research into the pathogenesis of KS has suggested possible etiologic mechanisms for KS and why KS develops in some HIV+ people and not in others. These findings have suggested several new agents which might be effective in controlling KS and even inducing regression of existing lesions. There is now the possibility that some cytokine inhibitors (soluble receptors of IL-1 and TNF, IL-4) and angiogenesis inhibitors (Tecogalan, PF4, TNP 470) might have activity either alone or in combination. Some of these agents down regulate IL-6 and TNF in vitro, but how they will work in humans has yet to be evaluated. Only time will tell.
The group needs time and resources. Time is needed to run to run phase I through phase III clinical trials. An effective clinical trials network is needed to run these trials. If the ACTG does not survive or the Oncology Committee is discarded, who's is going to run these trials?
Various other studies also require an "AIDS" clinical trials network. A natural history study is needed to establish the natural history of KS and lymphoma in AIDS. We also need a cancer surveillance study that would tell us how, when, how many and why some HIV+ patients develop KS, lymphoma, or other neoplasias. The ACTG is the perfect place to do these studies. The Oncology Committee with the assistance and resources of the NCI has such the follow up study planned with CS252. CS252 will investigate the cancer consequences of HIV infection and its treatments, including the incidence, spectrum of disease and risk factors of cancer development in HIV. Such a study is crucial in light of the fact that over 25% of HIV+ patients in large antiviral trials (ACTG 019, ACTG 196, and Concorde) developed an AIDS-related malignancy as their AIDS defining endpoint. In fact, 23% of the deaths in ACTG 196 were cancer related.
The NCI also plays a complicated role in this dilemma. Their intramural staff which includes effective and dedicated individuals such as: Sam Broder and Judy Karp; Bob Gallo and his Lab; Bob Yarchoan and Hiraoki Mitsuya; Ellen Feigal, Jim Pluda, and Roy Wu at CTEP have made important contributions to AIDS and AIDS-related malignancies. Gallo's laboratory has been in the forefront of the KS pathogenesis research. Various divisions at the NCI have worked hard at putting out broad based RFAs on AIDS-related malignancies. Intramurally, the NCI has -- and continues to -- conducted well designed small phase I/II trials for KS and lymphoma.
At the urging of TAG (and prominent KS researchers), the NCI has also consented to organize and fund a KS Workshop in April 1995. This workshop -- which is overdue and badly needed -- will assemble the leading KS researchers and clinicians for presentations of current data, discussions on the pathogenesis, epidemiology, natural history, and therapy of KS.
Extramurally, the NCI has dropped the ball by not creating official AIDS committees within their many cooperative groups (Southwest Oncology Group, Cancer & Acute Leukemia Group B, Gynecological Oncology Group, Radiation Therapy Oncology Group, etc.). With the exception of Eastern Cooperative Oncology Group (ECOG), no other cooperative group has an official committee to review possible AIDS malignancy protocols or expedite a protocol through with the appropriate staff. While there are a few qualified AIDS oncologists floating around in these cooperative group, their is no unified structure. Interestingly enough, it is Jamie von Roenn, current Chair of the ACTG Oncology Committee, who is also the Chair of ECOGs newly formed AIDS committee. Von Roenn has the experience in AIDS, KS, lymphoma and knows what it takes (who to work with or have as consultants) to run an AIDS malignancy trial. She either needs to be cloned or serve as a role model for other cooperative groups.
This lack of a cohesive AIDS effort within the cooperative groups is a fundamental problem for the NCI. The cooperative groups -- for all of their years of existence during the AIDS epidemic -- have never worked together by signing onto and completing an AIDS malignancy study. Individually, some of these group have done several AIDS lymphoma trials. Funding for these trials, however, mostly came from the AIDS Lymphoma Network. It is only now that these cooperative groups will jointly start a CNS lymphoma trial. This trial which will test combination cytotoxic agents followed by radiation is the cooperative group's first trial solely dedicated to the treatment of an AIDS malignancy. That's a milestone. Another milestone involving this trial is the NCI and the ACTG working together by both signing onto this protocol, which will help with broad based patient accrual and hopefully will lead to a sharing of resources. This is the right step, but it comes far too late.
The NCI once believed that they alone could and should conduct phase I through III AIDS malignancy clinical trials without the ACTG. During 1992, there were a number of meetings between intramural and extramural staff of the NCI and the ACTG Oncology Committee with other NIAID staffers. Many of these meetings (AIDS-Lymphoma Network, NCI-NIAID Meeting on AIDS malignancies, Task Force on AIDS Malignancies, and the NCI Strategy Meeting on AIDS Malignancies) brought both institutes together to share knowledge, discuss the pooling of resources, and basically discuss the current state of AIDS-KS and lymphoma. Unbeknownst to ACTG Oncology Committee members, the NCI considered themselves as the ones who should "lead the effort in the fight against AIDS-related malignancies."
Much of this might have been due to the existence of the NCI's AIDS Lymphoma Network which ultimately involved many of the best researchers and clinicians from the ACTG and elsewhere. Publically, the NCI was mentioning that they should be the ones to conduct future AIDS-lymphoma trials. Their master plan was to subsume all of the activities of the ACTG Oncology Committee. This however, was not publicized.
The ACTG Executive Committee was outraged when they learned of this possible coup. The outrage was that both DAIDS and the NCI colluded in this without a word to the Executive Committee or the Oncology Committee.
Three things resulted from this controversial aborted coup:
In the end, it simply looked as a rude and aggressive plan on the part of the NCI. However, what is most perplexing is the question that was never really addressed: Did the NCI actually think that they could suddenly assume all AIDS malignancy trials in their ill prepared and AIDS-inexperienced cooperative clinical trials networks? If their cooperative groups were already on board and had a number of experienced AIDS oncologists to activate AIDS-KS and lymphoma protocols, then the coup would not have seemed so pointless. But to disband the present system, albeit somewhat flawed, without a better, functioning system to take its place is asinine and detrimental to people with AIDS.
Do AIDS-KS patients need to be involved in an aids clinical trials network? Are there resources they can get that they won't get elsewhere?
Yes! And for many reasons. Knowing that patients with AIDS have a 30% or greater chance of developing an AIDS-related malignancy later on in their illness (usually when their CD4s drop below 100) means that KS and lymphoma are not going to be their first OIs. They will often be under the care of a primary care physician or an infectious disease doctor who might be associated with an ACTU. While on an AIDS clinical trial (say an ACTG study), they might develop an AIDS-related malignancy and could easily be funneled into an existing oncology protocol. Having this patient in an ACTU that offers oncology trials ensures the patient better access to needed drugs, helps with accrual to important studies, and beefs up the trial network's data bank.
Setting aside the debate as to whether KS is a "true" malignancy, these patients have HIV -- a complex immunodeficiency virus we still don't fully understand. To insure proper care of these HIV infected patients on AIDS malignancy studies, there will often be the need for consultation from specialists in HIV infection and OIs these patients have and will develop. With the knowledge regarding pathogenesis factors (the role of cytokines, etc.), we now have on AIDS-related malignancies, it has become more apparent that AIDS oncologists must interact with AIDS immunologists in the development of certain protocols.
There is also the need for a comprehensive AIDS research agenda in this world of limited funding. The OAR must insure that various NIH Institutes work together with the ACTG to pool resources, to share data, to share patients and to better distribute funding. With the upcoming recompetition and resultant reorganization, the NIAID's ACTG will no longer be able to exist in a vacuum. It will be virtually impossible with only a $68 million RFA. The NCI and the National Heart Lung and Blood Institute (NHLBI) both have nascent AIDS malignancy efforts. In the future, all three institutes (plus others) must evaluate their efforts to ensure that they are not duplicating certain functions. The NCI and the NHLBI should assess their budgets to determine if giving supplemental funding to the NIAID's ACTG Oncology Committee might be more opportune than commissioning RFAs that might not answer relevant questions. If the NCI and NHLBI choose not to, then the OAR should reduce portions of their budgets and allocate the funds to NIAID's ACTG AIDS-related malignancy efforts.
For example, the NCI's $700,000+ RFA CA-93-10, Clinical Trials in AIDS Malignancies, distibuted approximately $70,000 each to 11 grantees to conduct pilot or small phase I and II clinical trials of novel therapies. However, giving $700,000 to the ACTG as supplemental funding for Oncology studies would have been more opportune and cost efficient. In fact, certain ACTUs would be able to hire oncologists at major sites that should be registering for oncology trials but aren't because there is no oncologist on staff nor funding to hire one.
This $700,000 distibuted widely for "novel" trials in AIDS malignancies is an excellent idea, but it makes more sense to give the money to the one and only existing AIDS clinical trials network that conducts AIDS-related malignancy trials which is incredibly underfunded. While the ACTG Oncology Committee is currently conducting "novel" phase I/II trials of biological modifiers and angiogenesis inhibitors, they are also still attempting to answer old questions that are essential to establishing the basic standards of care. Clinical trials must first determine how best to utilize existing therapies before we go monkeying around with a myriad of experimental compounds. Thus, having supplemental funding would help answer questions, provide more trial sites for patients over a wider geographic area of the country, and in turn, help with the sluggish accrual of most oncology trials.