IN SUPPORT OF RIGHT TO TRY LEGISLATION
In a great editorial piece in the Wall Street Journal on 27 November , Darcy Olsen author of " The Right to Try", out this month from Harper/ Collins, makes the case for support of right to try legislation now passed by 24 states. This legislation simply says that terminally ill patients have a right to try a promising new drug, even if it is not approved by the FDA , as long as it has passed basic safety tests. I liked the editorial  because we had a working version of right to try in operation, approved by the FDA and the Pharmeceutical industry and  operated by the NCI all the way back in 1976. It was called the Group C program. It was a rough slug fest to get it operational, as the FDA never liked it. But the NCI director has the use of the bully pulpit to defend its programs and cancer patients and I used it.  The FDA never liked being out it bright sunshine so they approved it as part of a master plan submitted by NCI for cancer drug development. But it was never codified by the FDA so they took the first opportunity to drop it in  1987 shortly before my departure as NCI Director  in favor of the treatment IND program . The latter was developed to cover drugs for AIDS patients and has never worked for cancer patients who have been denied free access to promising cancer drugs by the FDA ever since. This is all described in detail in my book "The Death of Cancer ", written with Elizabeth DeVita -Raeburn, in a chapter called " The Francis Kelsey syndrome" also out this month from Ferrar Strauss Giroux.
In the Group C program all cancer drugs in development and supported in any way by the NCI were put into three groups A, B and C. A and B were for drugs in early testing called  phase I and II trials. If a drug showed promise in a minimum of two trials in groups A and B the NCI could move it into group C. Once in group C a drug was available for cancer patients who were not in a clinical trial for compassionate use. The determination of the potential benefit for  cancer patients was made by the patient's doctor at the bedside. He or she only had to be registered at the FDA which required filling out a one page form 1573 only once. The only paper requirements was that the physician needed to report any adverse event to the NCI which in turn reported them to the FDA. Notice that all the important decisions were made by active cancer doctors. The decision to go into group C by NCI doctors; the decision to use the drug, by the patient's Oncologist. The FDA claims, as Olsen points out, that patients can still access drugs through their compassionate use program which is pure and utter nonsense because the paper burden on a doctor is oppressive and unworkable. And there are other notable difference between the present compassionate use program and NCI's group C program. The determination of whether a drug should be made available at all is made by the FDA not the NCI and the determination of whether the drug should be used in an individual patient is made by an FDA bureaucrat thousands of miles away not the patient's doctor who is actually at the bedside. And another factor was added to the authority of the FDA. They had to determine that giving out the drug would not be harmful to NCI's clinical trials program. There is no other way to determine this except to  ask the person running the trials in question who invariably protect their turf by saying it would be. This is a straw man used to suppress access to drugs by cancer patients by organizations that should know better including the NCI . I ran the Clincal trials program in the period from 1976 until 1987 and there was no evidence  that making drugs available to patients, many of whom weren't  even candidates for clinical trials, had any negative effect on NCIs trials. The Pharmeceutical industry by the way liked the program and willingly supplied drugs to NCI at no cost . They felt it was good exposure for their programs.
The right to try legislation differs in some ways from the group C program. In right to try a drug has to have completed phase I testing for safety. This is not unreasonable but in some circumstances drugs already show great promise in Phase I trials. The most recent example is the agent brentuximab vedotin , the hottest new treatment for advanced Hodgkin's disease , which was already producing complete remissions in heavily pretreated patients in its phase I trial which was published in the prestigious New England journal of Medicine. The oldest example is the drug vincristine which is part of almost all curative programs for childhood leukemia which was clearly active in the earliest of clinical trials. And drug companies are able to recover the cost of drugs in right to try legislation.
Two more points.  The FDA is panicking over loss of control as a consequence of right to try legislation and is promising to speed up their compassionate use program which is really a tacit admission of the failure of he program . Nothing promising has been forthcoming and none is likely.
 The final point is that the NCI which  should be on the bully pulpit urging passage of the legislation has been silent. So have organizations who purport to be the voice of cancer patients like ASCO ( The American Society of Clincal Oncology ) and even the AACR ( American Association for Cancer Research) and the American Cancer Society all in defense of the integrity of clinical trials based on zero evidence. We need an NCI director who will rise to the occasion and  take the lead again and speak up for cancer patients everywhere.

Getting to the meat of the issue.

I must say I don't blame the public for being annoyed at the announcement  that eating red meat or bacon can increase your risk of getting cancer. Some articles even say you can put these foods in the same category as tobacco. And some medical sites on Facebook are having a field day scaring the public with the new information.
These data come from epidemiological studies that are notoriously difficult to carry out because they rely on people's memory of what they ate or drank years ago. And while some studies do show an association between these foods and cancer it is with one cancer, colon cancer, not all cancers. And to lump  bacon and red meat in with tobacco is misleading and in fact ludicrous and perhaps harmful. If you make a bar graph of different lifestyle factors plotted against the risk of getting cancer the smoking bar would not only be the highest bar it would go through the the roof while the rest would stay on your table !
 If you smoke and eat a lot of red meat and bacon quit smoking and your risk of getting a whole bunch of cancer will decrease dramatically. If instead you stop eating red meat and bacon but keep  smoking you will see very little decrease in your risk of dying of cancer.
This is called the relative risk. While from a public health perspective it is useful to encourage people to eat a healthy diet the advice needs to be put in perspective. People enjoy eating. And if you expect them to respond to advice you need to temper the advice to take enjoyment and relative risk into account.
Here's another  example of why you need to temper your advice. In the early 1980s I was at an international cancer congress in Seattle Washington when an article was published in the New England Journal of Medicine, a prestigious medical journal, by Brian McMann and equally prestigious epidemiologist, showing that drinking a lot of coffee increased the risk of getting pancreas cancer.  The press ran with it and a real panic set in. I was director of the National Cancer Institute then and the Reagan White House called me and asked me what my position was. I said I thought the conclusion was flawed. They asked if I would hold a press conference and say so. It so happens I was asked to go on a morning TV show and talk about it. I walked out on the set with a mug of coffee in my hand. That made the point. No subsequent study ever confirmed the association of coffee with pancreas cancer.  I used to joke with my staff that any  study reporting an association of a lifestyle factor and cancer should be kept in a vault until a second study on the same subject became available to confirm or deny it. That won't happen of course but instead those of us in the medical profession who need to interpret these kinds of results for the public should proceed with more caution.

The FDA Feigns Activism

On March 6^th I picked up the most recent edition of “The Cancer Letter,” a trade newsletter read by many oncologists, and saw a picture of Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, beaming out at me.  

Pazdur’s smiling face was accompanied by the announcement that, on March 4^th, the FDA had rapidly approved Bristol Myers Squib's drug, Opdivo (nivolumab), citing “a dramatic increase in survival in second-line squamous non-small cell lung cancer.”   

“The Cancer Letter” characterized the approval as activism by the FDA, saying that it was an example of the “extraordinary activist stance” the FDA can take when it sees an advantage in overall survival. They went so far as to say that the FDA, had “sprung into action” when they received the clinical trial data, moving toward approval before the results of the study were even clear to the sponsoring drug company.  

It would have been amusing if it wasn’t so sad.

PD-I inhibitors are a new breed of therapy that inhibit cancer cells’ ability to evade its host’s immune system. Every lung cancer specialist in the country has known that PD-1 inhibitors such as Opdivo are the most important advance in the treatment of advanced non-small cell lung cancer to come along in 40 years. For the last two years, in fact, most oncologists have been seeing data on the effectiveness of these drugs presented at national meetings and widely discussed among investigators.

Some might say defend the FDA by saying that the food and drug laws require that the FDA determine that a new drug is both safe and effective before it is approved for general use. True, in a general sense. But in this case, we know that the two PD-1 inhibitors now in advanced clinical testing, Opdivo (nivolumab) and Keytruda (pembrolizumab) are safe. In fact, the FDA said so itself when they approved both drugs for patients with advanced melanoma. (Though, as usual, they tied doctors’ hands—allowing them to be used only in patients who had failed other therapies and listing all the prior treatments the patients had to have failed before their doctors were allowed to use them).

What are the odds that these drugs, which were deemed safe enough for some patients with advanced cancer, would have proven to be unsafe in patients with advanced lung cancer? The answer: between slim and none. In fact, the data show that they are even effective in patients with poor performance status, i.e. patients who are frail and bedridden, making them ideal for older and unstable lung cancer patients, especially those who have smoked.

But the real irony of the FDA seeing themselves as activists is the failure to approve the drugs for all subtypes of all non-small cell lung cancer, given that the data show them to be universally effective. Only 25% of advanced lung cancer patients have the squamous cell subtype for which the FDA has approved Opdivo. That means the majority of patients are excluded from this advance.

All lung cancer specialists already know the PD-1 inhibitors are far better than any existing drug doublet in use today. If they were approved for all lung cancers today the use of the myriad of doublets of far more toxic drugs would disappear overnight. In the meantime, many patients who might benefit from these drugs are getting old hat treatment. But when the family members and friends of physicians are diagnosed with lung cancer, these physicians find a way to get the new drugs to them using any loophole possible.

The FDA will eventually approve both drugs for all subtypes of advanced lung cancer and even as a first line treatment. They will have no choice. But they will do it in their own good time. Meanwhile, thousands of patients with lung cancer will die without the chance of getting access to these drugs to extend their useful lives. If the FDA really wants to be considered an activist, they should approve these drugs for all lung cancer patients now. 

-Vincent T. DeVita, MD

Worth a Read

Last week two articles related to cancer care caught my eye. Both were well written, and both spoke to problems in the delivery of cancer care in this country. The first, by Len Zwelling, speaks to the decline of dynamic and creative research at MD Anderson (but a problem typical of other institutions). (I found it so interesting that I'll forgive him for spelling my name wrong.)

The second was an Op-Ed by journalist Laurie Becklund called "As I Lay Dying," which appeared in the LA Times February 20th. Becklund, who was dying of stage IV breast cancer when she wrote it, takes on, among other things, the system of cancer care. She's right on a number of counts, but I was particularly struck by a paragraph about the FDA:

The medical establishment tells me I have “failed” a number of therapies. That's not right: The establishment and its therapies have failed me. The system we live in as metastatic breast cancer patients is simply not designed to deal with the cycle we are living and dying in. The estimated 40,000 women (and a few men) who die annually can't wait years for FDA-approved, “gold standard” clinical trials. We're dying now.

I wish more patients realized this and put pressure on the FDA to make drugs available for patients more quickly. Many, like Becklund, who died February 8th, don't have time to waste.  

The New Edition of Cancer: Principles & Practice of Oncology is here

The 10th edition of Cancer: Principles & Practice of Oncology is out. It's the only cancer textbook that is continuously updated online and searchable by a hand held device.

Helping Primary Care Doctors Manage Cancer Patients

In the long term, much of cancer care will be in the hands of primary care doctors. Given that reality, we realized we needed to do a concise, crisp and up to date version of Cancer: Principles and Practices of Oncology for primary care doctors. Our new book--Oncology in Primary Care--comes out May 1, 2015. Dr. Michal Rose of Yale joins us as an editor on this one. I'm biased of course, but I think it turned out well.

Research--The Moving Parts

In the process of going through transformation, the American Cancer Societyonvened a group called Research 3.0 that made recommendations to the ACS Board about how to transform its research programs in the next decade. It is worth looking at Research 3.0 to examine how it will affect two of the moving parts of research programs, the investigators who do the research and the grants or other instruments that support their research.

A good place to start is by defining what we mean by research. How does Clinical Research differ from Basic Research; what is Translational Research, and what do we mean by applied research and applied science? 

Louis Pasteur said there is no such thing as applied research, only research and the application of the results of research. The latter is applied science; the application of what we know to diseases. The failure to distinguish between research and applied science causes much confusion when trying to interpret science budgets and could potentially be a problem in interpreting the recommendations of Research 3.0. 

Research is really a methodology. All good research is characterized by the use of strong inference, a term coined and described in detail by John Platt in 1964 (1). It involves setting up alternative hypotheses, the designing of an experiment or experiments that will exclude one of the hypotheses, developing new hypotheses and repeating the process until only one hypothesis remains standing. 

In other words it involves keeping the facts and throwing away hypotheses!

This is true in the clinic as well as in the laboratory but this is not easy to do.  Many researchers get attached to their hypothesis and design studies to prove it not disprove it. Because of this, the literature is filled with studies defending hypotheses that could have been easily disproved in a properly designed study. 

All good researchers use strong inference to ask fundamental (basic) questions regardless of the size of the particle under study. Science administrators have struggled for decades trying to define the difference between clinical research and basic research but, as you can see, there really is none, methodologically speaking, if both are testing hypotheses using strong inference.

 It is easier to test hypotheses in the lab where experiments can sometimes be set up and completed in days or weeks compared to years for clinical studies.  

But there are some classical examples of fundamental (basic) research in the clinic in Bernard Fischer's studies testing the hypothesis that lymph nodes were not a barrier to metastases in breast cancer but a sign that a tumor had already spread (2) and in the experiments that proved you could cure childhood leukemia and advanced Hodgkin's disease with combination chemotherapy in adults (3, 4). 

    It is also much more difficult to design experiments to exclude a hypothesis in the clinic when the particles are whole humans who can talk back to you.

     When I was Director of NCI's Treatment Division, I reviewed about 1,500 of NCI's clinical protocols looking for those that were using strong inference. Only 5 to 10% of them were actually testing a hypothesis; the rest were applied science. There is nothing wrong with applied sciences as long as it is identified as such. 

    But when good scientists are offered examples of applied science as clinical research they are understandably confused at what passes for research by clinicians.

   Finally, translational research was a term introduced by my successor as NCI Director, Sam Broder. It simply refers to laboratory research that has visible potential applications in the clinic, although the time span from discovery to application is never clear. 

    At the time he coined the phrase, in the early 1990s, it was often difficult to see the clinical application of a study of what might have been an obscure molecule. 

    Translational research has lost much of its meaning today since virtually all laboratory science has visible clinical applications and most grants are categorized as translational research. But translational research is different from applied science because it involves the use of strong inference.

     So what are the major moving parts of Research 3.0? The most important recommendation was to urge the ACS CEO to double the funds devoted to research in the ACS budget over 5 to 7 years. That requires no explanation. It does require that the ACS raise substantially more funds.

     The extramural grant program will be the main beneficiary of any increase in funding and the recommendations of research 3.0 for the extramural research program are shown in Table 1. 

    There are two points to be made from Table 1. 

    The first is that 50% of extramural funds are to be devoted to basic science. Presumably, this means all studies asking fundamental questions , using strong inference, whether they take place in the laboratory or the clinic. 

    

    The second point is the awards in this category will be made only to those in their early careers, under the age of 45. The logic for this is that in order to assure the future of research we need to assure that young scientists are provided the stable support they need to encourage them to stay in the field.     

    But it can be argued that supporting young investigators is really the job of the NIH and NCI as the ACS's research program is too small to affect the nation’s long term needs of young scientists, and NIH and NCI have special programs for young investigators. 

    In addition, other organizations like the American Association for Cancer Research, the American Society of Clinical Oncology (ASCO) and the ASCO Foundation and others have substantial special grant programs for young investigators.

     It can also be argued that the ACS should be focused on discoveries that help us to eradicate cancer. In that case,discovery knows no age barrier and major discoveries have been made at both ends of the age spectrum.  By recommending age discrimination in awarding grants, the ACS could be hindering progress toward its basic goals. 

    Most of the movers and shakers in the cancer field are over the age of 45. With an age cut off they are excluded from access to ACS funds. Removing the age limit does not exclude young investigators from applying and the best of them do very well.

     My favorite example of great research at the nether end of the age spectrum was the discovery that information is transmitted by DNA not proteins which laid the foundation for Watson and Crick’s work on the structure of DNA and the molecular revolution that followed (5, 6).

     It was made by a retired scientist at the Rockefeller University, Oswald Avery, and has often been referred to as the most important discovery that never won a Noble Prize. Linus Pauling won his Noble Prize for work he did in his 50s. And he was the close runner up to Watson and Crick for the discovery of the structure of DNA or he might have been the first person to win three individual Nobel Prizes. He continued working productively in the lab into his 80's. 

    E. Donnall Thomas and Joseph E. Murray won a Nobel Prize for the definitive and fundamental clinical research they did on organ transplantation while  in their 50s and 60s.

     True in mathematics, if you haven't done anything major by the time you are 40 you probably never will. Not so in biology. Biology is very complex and it takes time to develop the insight and wisdom to solve biological problems. Leo Szilard the famous nuclear physicist, who gave us the nuclear chain reaction, decided at age 47 to become a biologist. 

    After that, he quipped, "I never had a decent bath". While a physicist, Szilard thought through the mathematics of a problem while soaking in a bathtub and could solve complex problems in one bath.

     But when he became a biologist, he said, he often had to interrupt his bath to go look things up! 

   Senior physician-scientists do much of the best work in clinical investigations as was the case with Donnall Thomas and his work on allogenic marrow transplantation. They need years of experience to marshal the resources to design and carry out novel clinical experiments that use strong inference.

     The remaining half of funds, as shown in Table 1, will be in support of grants in response to RFAs that will attempt to align our supported research with ACS mission critical questions. But notice that half of those funds will go to mission critical questions in "applied research" or, strictly speaking, applied science. These monies will not support fundamental research, the lifeblood of discovery. 

    In this category of applied science no age restriction will apply. Finally, the other half of funds allocated in response to RFAs will go to support in areas designated as mission critical but these funds will also be restricted to young investigators receiving research scholar awards. 

    All in all, 75% of ACS extramural research funds will be allocated to young investigators. The 25% for which scientists of any age are eligible would be funds devoted to the application of the results of research, or applied science, not discovery. 

    

    Much of research today is called “Big Science” because addressing major issues often requires millions of dollars typically not provided in small research grants like research scholar awards provided by the ACS. The type of support instrument to foster discovery has been a subject of heated debate for years. At the NIH the preferred grant instrument is called the RO-1. The RO-1 grant has supported investigator-initiated research, ideas springing from the fertile mind of a single scientist, and is typically a grant to support a small laboratory run by a single investigator. 

    ACS research scholar awards are similar to RO-1 grants.  Research 3.0 recommended the ACS reexamine the use of large program project grants to  accommodate the collaborative nature of science these days. 

    These grants would support teams of scientists each doing a part of a project focusing on one area, or a specific tumor. These kinds of grants are large and expensive and their resurrection will depend on the ability of the ACS to raise the funds to support them or require a reduction in the support for research scholar grants.

     There is often conflict between program directors who want to see the science of their programs advance quickly, and need a more structured approach and those who feel that investigator initiated research remains the future of science. 

     This is not a new issue. Years ago, when the author was Director of the NCI and the National Cancer Program, the institute faced criticism for syphoning monies away from RO-1 grants into other instruments to support research. The other instruments were Program Project grants (PO-1), of the type recommended by the Research 3.0 group, and even research contracts, an instrument generally disliked at the NIH and research universities because it implies external direction of the scientist doing the work.

    To address this question we designed a special study (7). The NCI assembled a panel of elite scientists who were experienced in both laboratory and clinical sciences and asked only that they meet and deliberate to identify what they thought were the ten to fifteen most important advances in cancer science and medicine in the preceding 20 years. 

    After several weeks of in person and phone meetings, they identified 13 different discoveries. We then thanked them for their work and disbanded the committee and hired an external contractor to work backwards from each discovery, and the papers they produced in the scientific literature, to the funding instrument that supported the initial work. As a measure of the quality of the selected topics, scientists in six of the thirteen areas selected have since gone on to win a Nobel Prize for their work. Since at the time ACS was the source of support for only 4.3% of the identified work, only NCI funding instruments were studied.

     The results were surprising. No single grant mechanism dominated. Many different mechanisms supported the traced work. This is shown in Figure 1. It shows the percent of NCI supported trace papers by funding mechanism and type of advance. For studies considered laboratory based, three mechanisms dominated; the RO-1 grant, the NCI Intramural Program and the surprising one, the research contract. But even the P-30 grant, which is the cancer center support grant, through its pilot project grant mechanism, supported the initial work of one investigator who went on to win a Nobel Prize. Only the R-10 grant, which supported the clinical trials program, did not, by definition, play a role in laboratory based studies. 

    For the clinical advances, the dominant grant was the program project grant, the P-01, followed by the R-10, the P-30 and NCI intramural program and only then the RO-1 grant which has not been a support instrument that has worked well for clinical investigations. 

    Finally, fundamental advances in epidemiology were most often supported by research contracts with equal but lesser support coming from PO-1 and RO-1 grants and even cancer center core grants.

     Actually this was a data rich study and is presented here in its most simple form to illustrate the central message that research flourishes when there are multiplicities of ways of supporting it. This is due to the fact that different kinds of projects require different types of support to carry them out at different times in their evolution. One shoe doesn’t fit all. This is especially true in the era of big science.

    The most surprising finding was how often the research contract, often considered an inferior instrument, played an important role in the identified projects. This may be due to the tight focus and flexibility contract support provided to investigators that allowed research projects to move forward more rapidly. 

    These findings highlight the importance of the recommendation that the ACS re explore different grant mechanisms to match the needs of modern research.

   There is another important point about larger project grants. While more senior scientists  generally direct them, because they have the experience to coordinate complex projects, they often include support for young scientists as part of the project. This important means of support is often overlooked and needs to be considered one of the other ways to support young scientists in the age of modern science. 

    The Research 3.0 recommendation that 25% of funds go to support mission critical areas in applied science, with no age restriction, is important but needs clarification of the definition of applied research to be sure it includes projects that support fundamental research with clinical application, or translational research, not just applied science.

    Everything we do that works was developed through research.

 As volunteers for the ACS we need to be reminded of this when the temptation is to shy away from research support in favor of programs to provide access to care.

    As sophisticated as cancer care has become it is still what Louis Thomas referred to as “half way technology” (8). In this sense, cancer is unique as a discipline. Other fields are much more settled in their ways, able to focus on one organ or a small group of disorders affecting one organ, not the hundreds of entities affecting every organ in the body . The cancer field is unsettled and is likely to be that way for some time. 

     While the ACS spends about fifteen percent of its budget on research only about ten percent is devoted to its most visible component the extramural research grants. Yet the majority of donors think their donations are going to support research. 

    There could be a better balance of resources between what we know works and the allocation of resources to research programs that can deliver the next generation of advances.

    Research 3.0, in its totality, represents the beginning of a major new thrust for ACS in the area of research support. If the society can double the funds in the research program in the next 5 to 7 years, and broaden the ways it supports research to match the extraordinary pace and opportunities of modern research, it will play an increasingly important role in unraveling the mysteries of cancer and fulfill our mission to create more birthdays, and meet the expectations of our donors and volunteers.

    If we want to finish the fight we need to devote more money to research and fund the movers and shakers who are doing the cutting edge research in the field.

References

1) Platt JR. Science, Strong Inference -- Proper Scientific Method (The New Baconians). Science Magazine 1964;146(3642)

(2) Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233-41.

(3) Frei E III, Karon M, Levin RH, et al. The effectiveness of combinations of antileukemic agents in inducing and maintaining remission in children with acute leukemia. Blood 1965;26:642-56.

(4) DeVita VT Jr., Serpick AA, Carbone PP. Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 1970;73:881-95.

(5) Avery OT, Macleod CM, McCarty M. Studies of the chemical nature of the substance inducing transformation of pneumococcal types: induction of transformation by a desoxyribonucleic acid fraction isolated from pneumococcus type III. J Exp Med 1944;79:137-58.

(6) Watson JD. The Double Helix – A Personal Account of the Discovery of the Structure of DNA. 1968.

(7) An Assessment of Factors affecting Critical Cancer Research Findings; NIH Publication No. 90-567, May 1990.

(8) Thomas, L. The Lives of a Cell: Notes of a Biology Watcher, 1974, Viking Press.