There’s an excellent article in the current issue of Internal Medicine News, relating to an emerging controversy over the regulation of cancer tests.
“I think the current FDA regulations are awful. New diagnostics should be addressed the same way as new therapeutics,” said Dr. Daniel F. Hayes, professor of internal medicine and director of the breast cancer program at the University of Michigan, Ann Arbor.
“If we use diagnostics to make clinical decisions, then why not use a test that’s as reliable and accurate as a new therapeutic? A bad test is every bit as bad as a bad drug,” he said.
There are many new types of emerging cancer tests.
1. Combining blood tests for CA-125 with transvaginal pelvic ultrasound for diagnosing ovarian cancer, e.g.
2. A 21 gene PCR-based assay (Oncotype DX) to help guide the choice of postoperative, adjuvant therapy (generally chemotherapy vs hormonal therapy) for estrogen receptor positive, node negative breast cancer.
3. The OncoVue test to estimate a women’s risk of developing breast cancer.
The controversy discussed in the Internal Medicine News article essentially has to do with the issue of when is a new test “ready for prime time” and who is empowered to make this determination.
In the U.S.A., the FDA regulates drugs, devices, and test kits. It does not regulate so called “in house,” laboratory-developed tests (LTDs), also referred to as “home brew tests.” The clinical laboratories which perform these tests are regulated by state licensing agencies and also through the CLIA (clinical laboratory improvement amendments) program, administered by the Centers for Medicare and Medicaid Services.
Some voices (e.g. Dr. Hayes, quoted above) are saying that LTDs deserve much more stringent regulation, and Genentech has proposed that the FDA regulate those tests which pertain to drug selection in cancer treatment.
The Internal Medicine News article discusses the Genentech iniative:
Although the controversy has simmered for several years, the biotechnology company Genentech turned up the heat in December with a citizen’s petition it submitted to the FDA. The petition asked the FDA commissioner to “require that all in vitro diagnostic tests intended for use in drug or biologic therapeutic decision making be held to the same scientific and regulatory standards, regardless of whether the tests are developed and sold by device manufacturers as diagnostic test ‘kits’ or are developed by clinical laboratory companies for in-house testing.”
Genentech’s petition continued, “Currently, FDA regulates in vitro diagnostic tests in kit form, but not LDTs [laboratory-developed tests].” (See box.)
Citing a University of Washington Web site that listed nearly 600 labs running tests for more than 1,300 diseases or conditions as of last November, the petition noted that the number of LDTs on the U.S. market grew significantly in recent years.
The petition also cited several unapproved LDTs that were being used to guide prescribing of cancer drugs marketed by Genentech. These included tests for the HER2 protein to identify patients with breast cancer that should be treated with trastuzumab (Herceptin), a test to predict response to rituximab (Rituxan) in patients with follicular non-Hodgkin’s lymphoma, and a test to distinguish squamous from nonsquamous non-small cell lung cancer to identify patients who should receive bevacizumab (Avastin).
In a written comment on the petition, Ms. Javitt and Kathy Hudson, Ph.D., director of the Genetics and Public Policy Center, said, “We believe that FDA has jurisdiction to regulate all laboratory developed tests as medical devices and should exercise this authority.”
They added that the “FDA’s current failure to regulate LDTs—in particular genetic tests that are used in drug or biologic therapeutic decision making—threatens public health, creates serious inequities in the marketplace that disincentivize innovation, and impedes the success of personalized medicine.”
Others offered different points of view. Dr. Margaret Gulley, a University of North Carolina pathologist stated:
“there is no need for LDTs to be subjected to an extra, expensive process of vetting by the FDA. Adding another layer of scrutiny would be extremely costly for both the government and for testing labs. Yet it would be questionable if it would improve patient care.”
A different UNC pathologist, Dr. Karen Weck agreed, stating:
“Physicians base medical decisions on the literature and on recommendations from medical groups. The medical community does a pretty good job of regulating itself”
Also in agreement was a University of Pittsburgh pathologist, Dr. Jeffrey Kant:
“The system, as it’s been operating, hasn’t failed the public in any massive way. I’m not aware of any public health disasters [in the United States] associated with molecular tests in mainstream laboratories,” Dr. Kant said.
There are currently in excess of 180 drugs approved for use in cancer. There is an ongoing explosion in the introduction of new drugs for cancer treatment. While very welcome, this poses great challenges for the health care system. Almost all new drugs introduced for cancer treatment cost between $3,500 and $12,000 per patient per month. Almost all new drugs provide negligible benefit to the average cancer patient, while providing profound benefit to a select few.
The rapid expansion of therapy options poses difficult challenges for physicians, drug companies, insurance carriers, Medicare, and the FDA, who must determine when, how, and to whom cancer therapies are to be administered. For the individual cancer patient, the question is more immediate – “Which cancer therapy is best for me?” For the health care system (whether private or public) the biggest problem is exploding cost:
In the UK, treatments are already being judged not simply on the traditional standards of “safety and effectiveness,” but increasingly on cost-effectiveness:
The above concerns have already been addressed, to an extent, in the American Recovery and Reinvestment Act, recently signed into law by President Obama.
The following is a quote from the above article:
“A portion of the House bill reportedly retained in the Senate’s proposed $789 billion compromise version calls for the creation of a federal agency that would help coordinate research on “comparative effectiveness,” a wonky term that means determining which treatments work better than others.
“To proponents, such research would improve quality of care and reduce health costs by limiting the use of drugs and treatments that do not work well. They contend the $2 trillion the country spends on health care would be better spent if government knew how well various drugs and treatments worked.”
The current treatment paradigm in cancer, which dates back to the 1950s, is to perform gargantuan prospective, randomized trials to determine the “best” treatment for the average patient, in a disease notorious for its heterogeneity, where what is “best” for one patient is often “worst” for a different patient, with ostensibly the same disease. If prospective, randomized trials to identify the “best” treatment for the average patient were an effective strategy for making progress, then we should have seen marked improvement in the treatment of metastatic breast cancer, where probably in excess of 100,000 patients have been entered into these trials. Yet 35 years ago the median survival was 2 years and it is still 2 years today. And a single “best” drug regimen to give to the average patient has not been identified, as evidenced by the National Cancer Institute’s decription of “state-of-the-art” therapy, which lists 26 different drugs and drug combinations as being equally efficacious, with no conclusive data to indicate whether single agent or drug combination therapy is superior.
So how are drugs selected, in the real world?
Two different studies have shown that drug selection is correlated with the amount of profit made by the prescribing oncologist.
In summary, both in terms of cancer care affordability and cancer care effectiveness, what is urgently needed is some method of matching individual drugs and drug combinations to individual patients.
Matching treatment to patient: Molecular vs. Cell Culture Tests
There is currently a vast effort to develop laboratory tests to match cancer treatment to cancer patient. However, all of the technologies under study in major universities, the pharmaceutical industry, and cancer centers are based on so-called “molecular” methodologies, which basically means studying the building blocks of the cancer cell (DNA, RNA, proteins), as opposed to taking a portion of the living (“viable”) tumor, putting living/viable cancer cells into a laboratory cell culture plate, and directly adding anticancer drugs to these cells to determine which drug(s) work best against an individual patient’s cancer. There are advantages and disadvantages to both approaches (“molecular” versus “cell culture”), but what is important is that all of the effort (and all of the funding) has, for the past 20 years, been going to the development and testing of “molecular” approaches, with nothing of consequence going to support the development and testing of the “cell culture” approaches.
I published the following editorial response in the Journal of the National Cancer Institute, in 1992:
“National Cancer Institute (NCI) program solicitations have no business offering such outrageous guidelines as “cell culture assays with cytotoxic end points that do not offer a distinct advantage over models in current use are not encouraged” (NCI Anticancer Model Development PA-91-90). The last decade has produced such a large volume of such a priori censorship in study sections that American investigation into cell culture assays using fresh tumors has been effectively extinguished, at least in research supported by the public sector. I am becoming convinced that drug screening will never be moved from the clinic into the laboratory until our patients begin to demand it, which they one day surely will.” (Weisenthal, LM. J Natl Cancer Inst 89:1284, 1992).
The reasons for the abandonment of research into cell culture testing are fairly simple to understand, in retrospect. There had been great enthusiasm for developing cell culture testing methods in the late 1970s and early 1980s. These methodologies were all based on measuring inhibition of cancer cell growth as the test endpoint. Cancer was considered to be a disease of disordered cell growth and cancer drugs were thought to work by inhibiting cell growth. Assays based on measuring cell growth were plagued with problems and artifacts, which led to great disillusionment. My own contribution to this field was the development of an assay based on the alternative concept of cancer cell death (as opposed to inhibition of cancer cell growth). However, timing is (almost) everything, and it was not appreciated, at the time, that cancer is very much a disease of disordered cell death (as opposed to disordered cell growth) and that most of the anticancer drugs work by promoting cell death, as opposed to inhibiting cell growth. Faced with the unavailability of funding, American investigators were forced to leave the field of cell culture testing or were forced into the private sector.
These technologies are largely non-proprietary and in the public domain. They are labor intensive, refractory to automation, and there is no serious money to be made by anyone in providing these tests as a service to patients. There is a compelling body of published data to indicate that these tests are usefully accurate in distinguishing between “good” and “bad” drugs, on an individual patient basis.
It is now possible to test virtually all of the major classes of anticancer drugs (with rare exceptions, such as pemetrexed/Alimta). We can test traditional cytotoxic drugs, biologic response modifiers, such as IL-2, the newer “targeted” kinase inhibitors (e.g. erlotinib, sorafenib), and we can test antivascular drugs, such as bevacizumab (Avastin) and small molecule antivascular drugs. We can use cell culture methodologies to custom tailor complex treatment regimens for individual patients, based on combinations for the above classes of drugs, where the tests indicate that such combination therapy would be most appropriate. Of equal importance, we can identify drugs which should be avoided, as they are much more likely to cause harm, than to help.
We and other laboratories have been largely unsuccessful in attempting to convince cooperative oncology groups to partner with us to perform clinical trials to prove that these methodologies can improve the overall success of cancer treatment and to reduce the horrendous personal and system costs associated with ineffective treatment. As there is no serious money to be made in non-proprietary laboratory testing, there is negligible interest on the part of investors to sponsor such trials.
What is urgently needed, in order to motivate others, with superior resources and superior talent, to jump start the development and application of fresh tumor cell culture technologies, is an open, transparent clinical trial.
The trial design I have in mind would be the following:
Select 6 different types of advanced cancer. I would recommend: (1) platinum-resistant ovarian cancer, (2) unresectable pancreatic cancer, (3) stage 4 adenocarcinoma/alveolar cell carcinoma of the lung, (4) relapsed acute non-lymphocytic leukemia, (5) stage 4 colorectal cancer, and (6) Stage 4 breast cancer. In each disease, randomize patients between receiving “physician’s choice” therapy and assay-directed therapy, where the therapy to be administered may consist of any FDA-approved drug or drugs, which could include traditional cytotoxic drugs, biologic response modifiers, “targeted” kinase inhibitors, antivascular drugs, and resistance modifying drugs, such as high dose tamoxifen, DMSO (for the antivascular drugs), and celecoxib. The endpoint would not be progression-free survival but would be overall survival, as patients randomized to each arm could receive 2nd and 3rd line “physician’s choice” or “assay directed” therapy, respectively. Other important endpoints would be toxicities, quality of life, and overall costs of treatment. Assuming, for example, that assay directed therapy proved to be superior, one could then calculate cost effectiveness, based on cost per year of useful life saved. All results of the study would be transparent (protecting patient privacy) and in the public domain. Note, also, that patients in the “physician’s choice” arm of the study would be eligible to have their tumors sent for any ancillary (e.g. “molecular”) tests desired by the patients’ physicians, they would only be enjoined from receiving cell culture-based tests.
I have been doing this, full-time, for 30 years. I know that it works. My referring oncologists know that this works. Our patients know that this works. These methodologies have the potential to immediately improve the results of cancer treatment, immediately improve the process of drug development and clinical trials, and contribute to containing the exploding problem of exploding costs associated with ineffective drug treatment. But no one else will believe it, without a rigorous clinical trial, which no one has yet been willing to support, despite the enormous human and financial upside, in the event of a successful outcome.
I estimate the overall cost of such clinical trials to be in the neighborhood of $10,000,000 per disease studied. The greatest share of this would go for the payment for the cancer drugs to be used in the treatment of the patients, as in many cases, private insurance or Medicare may be unwilling to pay for the drugs determined to be of greatest value to the patient, on the basis of the testing procedures, even though these agencies stand to realize substantial overall savings from the avoidance of costly, ineffective treatments.
The issue is this: where will the money come from? It’s very easy for Genentech to demand that clinical laboratories sponsor the same sorts of clinical trials as are performed for new drug approval. Their proprietary cancer drugs cost a few dollars per dose to produce and sell for $5,000 to $10,000 per patient per month and produce billions of dollars per year in profits. There are negligible profits to be made in labor-intensive, non-proprietary laboratory tests.
So here is the issue for consideration:
What type of “validation” should be required of laboratory tests used to assist the physician and patient in their choice of cancer treatment?
I’ve got my own ideas, but I’d like to hear what others may have to say.
- Larry Weisenthal/Huntington Beach CA