Friday, November 27, 2015

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.

Saturday, November 14, 2015

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.

Thursday, March 12, 2015

The FDA Feigns Activism

On March 6th 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 4th, 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

Tuesday, March 3, 2015

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.