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LE Magazine September 2007

Life-Saving Cancer Drugs Not Approved by the FDA

By William Faloon and Donna Pogliano

How Many Lives Have Been Needlessly Ended?

Phenoxodiol’s minimal toxicity, demonstrated anti-tumor activity, high specificity for tumor cells, ability to enhance the effectiveness of therapy with various chemotherapy agents, and efficacy in reversing chemoresistance, would seem to meet the “chicken soup test,” thus conferring a significant probability of benefit without much potential for harm.

Every month, more than 1,000 women succumb to ovarian cancer. Advanced prostate cancer patients who have exhausted the conventional therapies presently available to them are left with little hope for survival and a dismal quality of life. Phenoxodiol was discovered in April 2002. If phenoxodiol turns out to be even partially effective, the delay in getting it into the hands of the cancer patients who so desperately need it will have meant countless sacrifices in quality of life. The number of needless, untimely deaths caused by this delay could number over one million. Why do we have a problem with earlier access to such promising therapies? This is disgraceful.

Promising Bone Cancer Drug Still Not Approved!

The day May 9, 2007 has been called “Black Wednesday” by the Wall Street Journal based on the FDA’s refusal that day to approve two highly promising cancer drugs.16

One of these drugs is JunovanTM, which was developed to improve outcomes for patients with high-grade non-metastatic osteosarcoma, the most common form of bone cancer.17 The FDA’s Oncologic Drugs Advisory Committee (ODAC) recommended against approval of Junovan™ for advanced-stage patients. The final decision on Junovan™ may come in late August 2007.18

Although many cancer patients suffer from bone metastasis secondary to other types of cancer elsewhere in their bodies (such as in the breast, prostate, or lung), primary bone cancer is relatively rare. Only 400 to 1,000 new cases of the form of bone cancer known as osteo-sarcoma are diagnosed annually in the United States; a similar incidence of osteosarcoma exists in Europe. Osteosarcoma accounts for about 3-5% of childhood cancers and has an overall five-year survival rate of only 60-65%.17,19

How Junovan™ Works

Standard cancer treatments include surgery, chemotherapy, and radiation therapy. Junovan™ is a “biologic therapy” or “immunotherapy.”19-21 Biologic therapies or immunotherapies use the patient’s own immune system to fight cancer by boosting, directing, or restoring the body’s natural defenses against cancer.20

Junovan™ is a synthetic derivative of a naturally occurring component of bacterial cell walls called MTP-PE (muramyl tripeptide phosphatidylethanolamine).17 It is an immune system stimulator designed to destroy cancer cells by activating macrophages present in the patient’s tissues.21 Macrophages are a type of white blood cell. Macrophages release substances that stimulate the immune system, and they also have the ability to take in and destroy foreign substances such as bacteria and tumor cells.22 Junovan™ is administered by intravenous infusion.17

The Statistics Don’t Tell the Story

To understand the impact of the potential refusal of the FDA to approve Junovan™, it’s necessary to understand the impact of osteosarcoma on those patients who are diagnosed with this insidious type of cancer.

Because osteosarcoma usually develops from osteoblasts (bone-forming cells), it affects mainly children and young adults between the ages of 10 and 25, whose long bones undergo a period of rapid growth during adolescence. In children and adolescents, tumors appear most often in the bones around the knee.19

In Phase III clinical trials with non-metastatic, localized osteosarcoma, Junovan™ demonstrated a clear reduction in the risk of recurrence and death, yet the FDA committee hung its hat on a statistical difference of 1% (94% certainty versus 95% certainty) in the probability of efficacy to justify a 12-2 “no” vote.23 Not a single comment was made about the immunologic clinical data supporting the efficacy of this agent.16 Statistics were the main consideration by the FDA panel in making its decision to recommend against approval of Junovan™.

In October 2006, IDM Pharma, Inc., the pharmaceutical company now completing the development of Junovan™, submitted a New Drug Application to the FDA, seeking approval for its use in patients with newly diagnosed resectable high-grade osteosarcoma following surgical resection (surgical removal of the cancer in the affected bone) in combination with multiple agent chemotherapy. The Phase III study, which provided the evidence of Junovan’s efficacy and safety, was supported by 17 Phase I and Phase II studies that preceded it, and was conducted by a different pharmaceutical company than the one that began its development.23 Studies that date back to the late 1980s, conclude that the systemic administration of MTP-PE rendered the blood monocytes of cancer patients toxic to cancer cells.24 Thus began a long and arduous study of the possibilities of using MTP-PE as an agent in an immunologic strategy to activate the patient’s own immune system to marshal its defenses against cancer.

When the FDA application was submitted, there was optimism that Junovan™ would bring new hope of survival for osteosarcoma. When the “no” vote was issued by the FDA committee, it was again emphasized that there have been no new treatments for this type of cancer in over twenty years, and that there is a significant unmet need for safe and effective treatments to help these young cancer patients.21

The principal investigator in the Phase III clinical trial cited in the New Drug Application was Dr. Paul Meyers, Vice Chair of Pediatrics at Memorial Sloan-Kettering in New York City.25 It was the largest Phase III trial studying osteosarcoma to ever be published, reporting data on 678 newly diagnosed patients who fit the criteria of the study, i.e., non-metastatic cancers that were of a size and in a location where they could be removed by surgery and that were staged as high-grade rather than low-grade.21

Dr. Meyers was quoted as saying that despite advances in surgical and chemotherapeutic approaches, the outcome can be very poor for a substantial proportion of patients and Junovan™, if available to patients, will provide physicians with a new tool that has significant potential to improve outcomes and most importantly, survival.21

The Phase III trial on which the FDA application was based demonstrated a relative reduction in risk of recurrence of 25% and a relative reduction in the risk of death of 30%. These findings were considered by the researchers to be clinically meaningful in a pediatric population where the longer the survival, the greater the chance that the patient is cured of cancer.26

When osteosarcoma recurs, it is usually within two to three years after the completion of treatment. Later recurrence, though possible, is rare.20 A typical standard course of treatment for the average patient takes place over a period of 29 weeks or longer, depending on how quickly the patient responds or recovers from surgery or other therapy.27

In a typical treatment regimen, surgery is usually preceded by 10 weeks of chemotherapy and followed by 18 more weeks of chemotherapy.27 Other commonly used chemotherapy agents include doxorubicin, cisplatin, ifosfamide, and etoposide.28 The median follow up time in the latest Phase III study was almost five years so that any recurrence that was likely to happen could be included in the statistics.21

Despite this very thorough and convincing evidence of Junovan™’s efficacy with minimal adverse events, the FDA sent IDM Pharma and its team of researchers back to the drawing board, apparently to achieve another 1% probability of efficacy, without regard to the impact on the children and families struggling with the human side of suffering.


The clinical trial procedure depends on the ability of the pharmaceutical company to finance clinical trials and to recruit patients to participate in them. Many promising trials need to be halted due to lack of adequate funding or inability to recruit enough patients to make up an acceptable group of patients to form the study and/or control groups.

Patients can help bring new drugs and treatments to the marketplace by participating in clinical trials that fit their disease state, prior treatment profile, and eligibility status. Patients should ask questions to be certain that they are not sacrificing a proven treatment protocol for one which has little potential to help them, and they should ask questions until they thoroughly understand the details of the trial and how it will affect their disease management strategy. It is also important to verify that all patients in the study receive some form of active therapy and that no group will receive a worthless placebo.29

Clinical trials on promising anti-cancer drugs are done in three phases, with Phase I trials being conducted to establish dose-limiting toxicity, Phase II trials proceeding to establish effectiveness in a limited number of patients, and Phase III trials advancing to include widespread study populations and to gather data to make comparisons between the effectiveness of the new treatment versus current protocols.29 Normally, application to the FDA (a New Drug Application, or NDA) for approval takes place after Phase III clinical trials have demonstrated that the new agent, procedure, or protocol is superior to the current standard of treatment in terms of effectiveness and/or tolerability. Only after FDA approval can the new drug or treatment be marketed and made available to the general public, even if such a treatment is approved in another country considered to have advanced medical care by our standards. Medicine clearly has geographical boundaries—drugs and devices approved in the USA may not be approved 10 feet beyond the US border into Canada, and vice versa. Drugs such as Taxotere®—considered to be the most active agent in breast, prostate, head and neck and lung cancer and an approved drug in Europe—were not made available to cancer patients in the USA until the FDA granted its approval. This “process” took approximately five additional years.

Beyond the Statistics: The Human Side of Suffering

In the Phase III study of Junovan™, adverse events associated with its use were generally mild to moderate, including flu-like symptoms such as chills, fever, nausea, vomiting, muscle pain, headache, fast heart rate, hypotension or hypertension, fatigue, and shortness of breath. These discomforts are consistent with the activation of monocytes and macrophages by Junovan™, since flu-like symptoms are known to follow cytokine release.21 These minimal side effects are probably unavoidable, since they are thought to be associated with the biological activity that causes Junovan™ to work. Since high-dose, multiple-drug chemotherapy was used in the Phase III trial along with Junovan™, some patients did experience severe adverse events, but they were those typically associated with the chemotherapy, as opposed to the Junovan™ administration.17

For those who are diagnosed with the stage of cancer that Junovan™ is designed to treat, non-metastatic Stage II cancers, the prognosis is relatively good. With standard therapy combining surgery and chemotherapy both before and after the surgery, patients without detectable metastases have about a 60-65% survival rate. This survival rate has remained stable since the mid-1980s because the standard of treatment has remained static, with no new innovations to improve the odds.21

The Phase III clinical study of Junovan™ is supported by 17 Phase I and Phase II clinical studies in which an additional 248 patients received at least one dose of Junovan™. The survival data show that with the addition of Junovan™, the survival rate at six years jumps from 66% (with a range of 59% to 73%) to 77% (with a range of 72% to 83%), yet the FDA’s committee failed to recommend approval of Junovan™.

The FDA is charged with the duty of protecting the public from the hazards of potentially dangerous or damaging foods and drugs. Protecting the public without regard to any reasonable degree of common sense at the cost of their very lives is not, and should not, be included in the job description of the FDA!

Promising Melanoma and Leukemia Drug Still Not Approved!

Metastatic melanoma and chronic lymphocytic leukemia (CLL) often prove fatal. A unique drug called Genasense® has been developed by a small pharmaceutical company to combat these and other cancers. The FDA has refused to approve it, ignoring compelling evidence of the drug’s efficacy.30

Genasense® is an “antisense” drug. Antisense drugs work by targeting one or more proteins in cancer cells responsible for cellular proliferation, drug resistance, or other mechanisms that have given cancer cells a survival advantage.29

Genasense®, for example, targets bcl-2, a protein that functions to protect cancer cells from cell death (apoptosis). Genasense® blocks the bcl-2 protein, removing this cancer survival mechanism, therefore causing death of the cancer cell. There is very little potential for side effects because normal cells don’t exhibit the large quantity of bcl-2 that is characteristic of cancer cells.31

Administered intravenously, Genasense® is designed to be used synergistically with a wide range of anti-cancer therapies, including chemotherapy, radiation, monoclonal antibodies, and immunotherapy agents.31 The goal of anti-cancer therapy is to introduce toxic substances that induce apoptosis in cancer cells, while suppressing substances like bcl-2 that prevent cancer cells from dying.29

The bcl-2 protein has the ability to protect cancer cells from signals sent by a variety of chemotherapy agents that promote apoptosis. Therefore, co-administration of Genasense® with other agents and therapies is a strategy designed to enhance, rather than compete with, other forms of anti-cancer therapy. A host of commonly used chemotherapy drugs and other agents have already been tested in clinical trials in combination with Genasense®.31


Genasense® Research

Genasense® research dates back to 1997, when the Journal of Pharmacology and Experimental Therapeutics reported on a study in mice that looked at its effect on the bcl-2 protein.32 Genta, the pharmaceutical company that developed Genasense®, has plans to conduct clinical trials on cancers such as melanoma, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, prostate cancer, colon cancer, and lung cancer.31

Because of the potential to increase the cancer-killing activity of many standard anti-cancer therapies, and because it has potential to work in so many different types of cancer, Genasense® holds promise for a diverse group of cancer patients, some of whom have exhausted standard chemotherapy options.31

Take for example the description of the effect of Genasense® on a patient who enrolled in a clinical trial described in the October 1999 issue of Seminars in Hematology.

Preclinical toxicity studies had already established that G3139, as Genasense® was called at that time, was well tolerated with minimal toxicity. But most interesting was that one human being suffering from Stage IVB follicular lymphoma achieved a complete clinical and radiologic response that had already lasted more than two years at the time of publication.33

Subsequent studies have confirmed the activity of Genasense®. In the February 2007 issue of the Journal of Clinical Oncology, a study conducted at 100 centers around the world and involving patients with advanced chronic lymphocytic leukemia (CLL) was reported. These were patients who had relapsed on prior chemotherapy regimens. The study compared Genasense® in combination with fludarabine and cyclophosphamide (two established drugs used in CLL) with a control arm in which the two chemotherapy agents were used without Genasense®. The findings showed that 17% of patients in the Genasense® plus chemo arm achieved a complete or partial response, as opposed to 7% of patients who were treated only with chemotherapy.34,35

Furthermore, the durability of the remissions in the patients who received Genasense® was significantly longer. The duration of the remission exceeded 36 months on average in the Genasense® group, as opposed to 22 months in the group receiving chemotherapy alone. An impressive 70% of the patients who received Genasense® in combination therapy were alive at three years, versus only 38% for the patients who did not receive Genasense® combination therapy.34,35 This is convincing evidence, but apparently not sufficiently convincing for the FDA panel.

David and Goliath and the FDA’s Error

The FDA’s decision on Genasense® seems to be the ultimate in bureaucratic incompetence and an unbelievable injustice to the cancer patients who are waiting for the marketing of this promising drug.

The researchers had randomized, controlled clinical trials demonstrating that Genasense® confers a benefit to patients in the clinical setting, and both primary and secondary endpoints were achieved in Phase III clinical trials. Accordingly, on March 1, 2006, Genta submitted a New Drug Application requesting approval of Genasense® with fludarabine and cyclophosphamide for the treatment of patients with relapsed or refractory CLL.36 In September, 2006, the FDA’s committee voted 7 to 3 against the recommendation for approval of Genasense®. None of the members of the committee were CLL experts, and there are allegations of conflict of interest in two of the voting members.30

In a follow-up meeting, Genta presented information regarding the clinical benefit of Genasense®, enlisting CLL experts to help plead their case. Still, the FDA insisted that the long-lasting disappearance of disease demonstrated by the clinical trials was a “theoretical construct” and not grounds for approval.30

The FDA’s committee finally acknowledged the complete responses in the CLL patients, but was still unmoved despite the unanimous appeal of the leukemia experts requesting approval. The FDA subsequently rejected Genasense® after suggesting that the small, financially struggling company just give the drug away under their expanded access program. Genta responded that they could not afford to give it away, and that the FDA non-approval was therefore a denial of patient access to Genasense®. Ironically, the FDA’s mantra is that the best avenue to patient access to new drugs is through approval, yet they refused to approve Genasense® despite compelling evidence of its efficacy and benefit to patients.30

Genta filed an appeal of the FDA’s decision in April 2007, but they were forced to reduce staff so they could stay in business long enough to appeal the FDA’s decision. Approval for use of Genasense® for treatment of melanoma was similarly denied. This was the result of an apparent mathematical error on the part of the FDA in analyzing the data. Genta is filing a complaint under the Federal Data Quality Act to correct the record, but meanwhile, melanoma patients have the same access to Genasense® as leukemia patients—NONE, except through clinical trials, which are continuing despite all adversity.30

This is the classic story of the small struggling company up against an unreasonable and often insensitive government bureaucracy. Caught in the middle are millions of patients and multi-millions of their loved ones. There is a saying that “he who saves one life saves the world.” Apparently, the FDA’s committee does not have this as part of its philosophy. This “process” needs to be drastically altered, and now, before more lives are prematurely ended.

Promising Kidney Cancer Drug

Renal cell carcinoma (RCC), or carcinoma of the kidney, is a difficult form of cancer to treat. Approximately 25% of the estimated 51,000 diagnosed this year with kidney cancer will present with advanced disease—defined by locally invasive disease to distant metastatic disease at the time of diagnosis.1,37

The prognosis is generally dismal, and only 20% of such patients survive five years. Estimated deaths in the USA in 2007 from RCC approach 13,000.37 The incidence of this form of cancer is highest in people between the ages of 50 and 70, with more men affected than women.

Enter Torisel™ (temsirolimus), being developed by Wyeth Pharma-ceuticals for use in patients with advanced RCC. Recognizing an international need for new therapies to prolong the lives of kidney cancer patients, Wyeth submitted both a New Drug Application to the FDA, and a marketing authorization application to the European Medicines Agency in October 2006.37

Torisel™ was previously granted FDA fast-track designation in July 2004 and was granted the agency’s “orphan drug” designation in December 2004. Torisel™ also received Orphan Medicinal Product designation for the treatment of RCC in the European Union in March 2006, prior to the application date.37

Evidence of Efficacy

Torisel™ inhibits a protein that regulates cancer cell growth and proliferation and cell survival. It was the first drug of its kind to be submitted for FDA approval, a landmark drug which uses a very different strategy to target cancer. Torisel™ works by fooling cancer cells into thinking they’re starving. The tumor population, believing that it lacks sufficient nutrients for growth, stops dividing.38

Phase III clinical trials involving 626 patients indicated that the drug conferred improved survival in terminal RCC patients, with an increased survival of 3.6 months, or nearly 50%. Patients randomized to Torisel™ survived 10.9 months, compared with 7.3 months for patients who received interferon-alpha alone. Interferon-alpha is a traditional treatment for kidney cancer.39

In this study, adverse effects included weakness, loss of energy, and anemia. Those patients randomized to treatment arms lacking interferon had fewer adverse effects than the patients who received Torisel™ alone, so at least some of the adverse effects might be attributable to the interferon-alpha.39

Given these Phase III clinical trial results, there was optimism that approval by the FDA would quickly be forthcoming. Like the other drugs profiled in this article, cancer patients had to be in an advanced stage of the disease to participate in the clinical trials. The fact that these drugs are showing clear survival benefits when cancers are at such a difficult-to-treat juncture implies that these drugs could be more effective if allowed to be used in early-stage cancer patients. The FDA, however, ignores this basic understanding of biologic systems. Any disorder—be it cancer, diabetes, heart disease, Alzheimer’s, obesity, and even global warming—is always more successfully treated when therapeutic measures are initiated early, in contrast to waiting until the end-stages of the condition. It’s just plain common sense.

The Death Toll

In May 2007, it was announced that although Wyeth Pharma-ceuticals expected FDA approval as early as April 2007, it was not to be. In fact, the FDA extended its review of Torisel™ until July 2007 to examine additional data on tumor evaluation. Wyeth’s presentation on the efficacy of the new drug concentrated on overall survival, while the FDA decided that the efficacy of the drug should also be measured by its effect on tumor progression.40 Certainly, the patients themselves would side with the pharmaceutical company, and not the FDA.

Since many renal cell carcinoma patients die within three months of diagnosis, Torisel™ brings a ray of hope in a sea of hopelessness for prolonging patients’ time on this earth. For a time, the FDA seemed to turn a blind eye to these patients while insisting on still more data. Their delay denied RCC patients a few additional months of life that might have resulted in their being around— to see their children graduate from college, get married, celebrate anniversaries with beloved spouses, or do anything they always wanted to do before they died.

But just as this article was going to press, the FDA approved Torisel™ for use in patients with advanced kidney cancer. The drug is expected to be available to patients in 2007.41 The hopes and dreams of patients and their loved ones, as well as the very loss of life, often seem secondary to the bureau’s mission to protect the public at all costs. But today, at least patients with advanced RCC have a hope for prolonged survival that they didn’t have yesterday.

Our upset remains with the thousands of kidney cancer victims and the similar scenarios involving patients with other types of cancer who needlessly or prematurely died and continue to die while the FDA delayed, and continues to delay, approving drugs that deal with drastic illnesses.

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