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Am I Missing Something Or Is The FDA Dysfunctional?

|Includes: Provectus Biopharmaceuticals, Inc. (PVCT)

On the Premium Service side of Trust Intelligence, we were discussing the article about Lilly's Cyramza that I appended at the end of this one. It is one of the first of many we will see come out of the ASCO Meeting that started on May 30th and ends on Tuesday June 3rd, the day that Provectus will hold a Conference Call to explain it research plans.

See this link for details about the organization and the meeting, as well as to search the Abstracts (the summaries of the scientific papers that will be presented during the convention).


The reason I am writing about a cancer drug, other than PV-10, is to show the kind of drug the major pharmaceutical companies are developing to treat cancer and how the FDA deals with them.

Lilly's Cyramza (ramucirumab) is an anti-angiogenesis drug that is already approved to treat patients with gastric cancers that have failed chemotherapy. (The article at the end of this piece reports data collected to get the drug approved for lung cancer, too). Cyramza works by reducing the blood flow to the tumor, retarding cancer growth and thereby prolonging survival. Eight mg/kg of body weight is given to patients every two weeks. I have not been able to find pricing information, but a similar anti-angiogenesis drug, Avastin, costs between $4,000 and $9,000 per month, depending upon a patient's body weight.

That is a high, price but patients could be more than willing to pay if they have the money... and they certainly would like their medical insurance to pay... except it is not as simple as that. In fact, it is not an expensive treatment because the patients treated tend not to survive very long. Phase III trial date on these gastric cancer patients proved that Cyramza worked but only increased survival by 1.4 months (~42 days). This means that the average patient had 3 or 4 infusions at (probably) $6500 each or about $20,000 to $25,000 for an extra 42 days of life. Another measure of efficacy was also significant in Phase III trials for gastric cancer: Cyramza increased progression-free survival from 1.3 months to 2.1 months, in other words, by ~ 24 days. Yes, that is days, not weeks or months, much less years. But the Phase III trial data showing this minimal benefit was statistically significant.

It is difficult and morally uncomfortable to put a value on an extra day of life. If you have the money, an extra day or month may be worth a small fortune. On the other hand, what is the quality of these extra days, bought by taking a drug like Cyramza, which has a too-typical cancer drug "safety" profile. Safety is in quotations because the profile, as with most cancer drugs, is about the many ways the drug is dangerous. It is just a bit less dangerous than doing nothing to combat the cancer, which will kill the patient.

How will the Cyramza patient be feeling during their few extra days?

While doctors will try to minimize and treat the side effects, many patients will be made to feel sicker by the treatment. Side effects include:


Arterial Thromboembolic Events.


Infusion Related Reactions.

Gastrointestinal Perforation.

Impaired Wound Healing.

Patients with Child-Pugh B or C Cirrhosis.

Reversible Posterior Leukoencephalopathy Syndrome.

"The labeling for CYRAMZA contains a Boxed Warning regarding increased risk of hemorrhage, including severe and sometimes fatal events. CYRAMZA should be discontinued in patients who experience severe bleeding. The most commonly reported adverse reactions (all grades) in REGARD, occurring in at least 5 percent of patients receiving CYRAMZA and at a rate at least 2 percent higher than those receiving placebo, were hypertension (16% vs. 8%), diarrhea (14% vs. 9%), headache (9% vs. 3%), and hyponatremia (6% vs. 2%). The most common serious adverse events with CYRAMZA were anemia (3.8%) and intestinal obstruction (2.1%). Red blood cell transfusions were given to 11% of CYRAMZA-treated patients vs. 8.7% of patients who received placebo. Across clinical trials of CYRAMZA administered as a single agent, clinically relevant adverse reactions (including Grade greater than or equal to 3) reported in CYRAMZA-treated patients included proteinuria, gastrointestinal perforation, and infusion-related reactions. In REGARD, according to laboratory assessment, 8% of CYRAMZA-treated patients developed proteinuria versus 3% of placebo-treated patients. Two patients discontinued CYRAMZA due to proteinuria. The rate of gastrointestinal perforation in the REGARD trial was 0.8% and the rate of infusion-related reactions was 0.4%. This is not a complete list of adverse reactions."

Read more: Lilly's CYRAMZA™ (ramucirumab) Becomes First FDA-Approved Treatment for Advanced Gastric Cancer After Prior Chemotherapy

FDA View?

"The FDA granted Cyramza priority review because the drug demonstrated the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cyramza also was granted orphan drug status because it treats a rare disease or condition."


In the report at the end of this article, the author explains that Lilly has shown that Cyramza plus Taxotere (a combination that will likely cost the sum of the prices of the drugs) will prolong survival by 45 days, in a subset of lung cancer victims. Of course, with another cancer drug, more nasty side-effects are added. To the Cyramza side-effects, add those of Taxotere.

Side effect of docetaxel (Taxotere)

The most serious adverse reactions:

Toxic Deaths




Fluid Retention

The most common adverse reactions across all TAXOTERE indications are infections, neutropenia, anemia, febrile neutropenia, hypersensitivity, thrombocytopenia, neuropathy, dysgeusia, dyspnea, constipation, anorexia, nail disorders, fluid retention, asthenia, pain, nausea, diarrhea, vomiting, mucositis, alopecia, skin reactions, and myalgia. Incidence varies depending on the indication.


PV-10 injections have no significant side effects & can eliminate 50% of tumors

And yet, with PV-10, the FDA is more concerned about pain, itching, minor bleeding, or changes in discomfort, even though treatment tends to be successful. PV-10 injections that work best cause blistering as PV-10 kills cancer cells. The dead cells then stimulate the immune systems of the patients to recognize cancer cells and kill them elsewhere.

I am left wondering about the rationality of the obviously conservative FDA Committee that declined to grant PV-10 Breakthrough Therapy Designation (BTD), given the expensive and dangerous drugs the FDA approves that provide only marginal (even though statistically significant) benefit.

PV-10 has an outstanding safety profile and can be used with old, weak, and immune-compromised patients without killing them or ruining their quality of life. The Provectus drug is more effective killing cancer in solid tumors than other available drugs and it has an immune effect that the FDA acknowledged in the BTD Decision Letter.

The FDA also knows that its own regulations allow the FDA to remove BTD status if subsequent research indicates the BTD Drug is not better than what is available. In other words, if they had granted BTD status to the apparently safe and effective PV-10, it could have been removed if subsequent research proved that it was not a better treatment than already available, sending PV-10 to a normal Phase III trial. Therefore, the risk of BTD approval to patients was ZERO. And if PV-10 proved to be better than the exiting treatment, the reduced time until NDA approval and faster commercialization of PV-10 would have meant that lives would have been prolonged.


When you take the FDA Decision, by itself, it is easy to understand that they are asking for more data on pain, bleeding, etc. We can presume that the FDA are knowledgeable experts who are concerned with the welfare of patients, wanting to be sure to approve only the worthwhile drugs.

Then, if you are like me, you think:

Granting BTD status is not approving PV-10. Granting BTD is just speeding PV-10's regulatory progress.

The FDA, post BTD approval, could have required another trial to measure anything the FDA desired, and PV-10's BTD status could have been removed, if the added research results indicated that the drug did not meet FDA's requirements.

If you are like me, you have trouble understanding the FDA rejecting BTD for PV-10 and approving BTD and NDAs for expensive and dangerous cancer drugs that extend life only matter of weeks, not even months, and make the patient feel sick during their "extended" lives.

Look at the Complete Response (CR or elimination of tumor) of Melanoma drugs



50% PV-10 (in the all-tumors-treated group)

20% T-Vec

7% Taflinar

10% Yervoy+nivolumab

9% Taflinar+Mekinist

2% Zelboraf

9% Lanbrolizumab

2% Yervoy

1% nivolumab

1% Mekinist

So, you tell me.

I am crazy or is the FDA dysfunctional?

Or is the FDA political and influenced by.....?

Here is the article about the minimal benefit that Cyramza provides in lung cancer.


ASCO: Cyramza Boosts Survival in NSCLC

Published: May 31, 2014

This report is part of a 12-month Clinical Context series.

By Michael Smith, North American Correspondent, MedPage Today

Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

CHICAGO -- An investigational targeted agent, combined with standard second-line chemotherapy, extended survival in patients with advanced non-small cell lung cancer (NSCLC), a researcher said here.

In a phase III randomized trial, ramucirumab (Cyramza) combined with docetaxel (Taxotere), also extended the time before the disease progressed, according to Maurice Perol, MD, of Léon-Bérard Cancer Centre in Lyon, France.

It's the first time in a decade that a new drug has shown a survival benefit in second-line NSCLC, Perol said at the annual meeting of the American Society of Clinical Oncology.

But other experts were divided on its value, because the overall and progression-free survival benefits -- while statistically significant -- were small in absolute terms.

Roy Herbst, MD, PhD, of the Yale Cancer Center in New Haven, Conn., said he is "pretty high on that drug," largely because he thinks the benefits are "quite extraordinary" compared with the risks.

"In second line, I find the data quite compelling," he added. "It is one of the top five important things in lung cancer this year."

On the other hand, Don Dizon, MD, of the Massachusetts General Hospital Cancer Center in Boston, said the drug's benefits are probably not enough to get it through the regulatory process.

"I wouldn't use it if it were approved," he said, "but I don't think it can get approved on these data."

Ramucirumab is a recombinant human monoclonal antibody that blocks a receptor involved in building new blood vessels in tumors, thereby slowing their growth.

The REVEL trial tested the drug in combination with docetaxel, versus docetaxel alone, in 1,253 patients with stage IV NSCLC who had progressed either during or after previous treatment.

The top-line results were:

A 1.4-month increase in median overall survival (OS), from 9.1 to 10.5 months, among patients on the combination therapy (hazard ratio 0.857 for death favoring the combination, P=0.023)

A 1.5-month increase in median progression-free survival (NYSE:PFS), from 3.0 to 4.5 months, for patients getting the two drugs (HR 0.762 for progression, P<0.0001)

An increase in the objective response rate, from 14% for docetaxel alone to 23% with the combination (P<0.001)

The most common grade 3 or great adverse events associated with the combination were neutropenia, febrile neutropenia, fatigue, leukopenia, hypertension, and pneumonia

The rates of treatment-emergent adverse events that led to death were similar between the arms

But there is an ongoing debate over the value of new drugs, when the benefits are small and costs are likely to be high, commented Mark Kris, MD, of Memorial Sloan-Kettering Cancer Center in New York City.

"This trial is one of the more problematic ones," he told MedPage Today, because the improvements in OS and PFS were so small.

"We have to wonder, with the toxicity seen and the likely cost of the drug in addition to standard therapy, is it going to be worth it?" he said.

But he added, "we need more drugs and even drugs with a tiny benefit," noting that other drugs with small absolute benefits have been approved and are in use.

Indeed, the OS benefit was not "dramatically different" from what is seen in first-line therapy with bevacizumab (Avastin), according to Thomas Lynch, MD, also of the Yale Cancer Center.

"If this drug were approved tomorrow," he told MedPage Today, "I would certainly look at it as an option for patients. Any kind of survival benefit is unique" in these patients.

"This represents an improvement in outcome," Lynch said.

The big question, he added, is whether it's possible to winnow out patients for whom the drug is highly beneficial.

"My suspicion is that, whether the FDA requires it or not, I think payers are going to increasingly ask that we use these drugs in patients who will benefit from them," Lynch said.

The study was funded by ImClone Systems, a subsidiary of Eli Lilly.

Perol disclosed relationships with Pfizer, Roche, Boehringer Ingelheim, Genentech, and Eli Lilly.

Some co-authors reported relationships with Eli Lilly, Clovis, AstraZeneca, Roche, Boehringer Ingelheim, Astellas Pharma, and ImClone Systems.

Some co-authors reported being employees of Eli Lilly and/or holding company stock.

Primary source: American Society of Clinical Oncology

Source reference: Perol, M, et al. "REVEL: A randomized, double-blind, phase III study of docetaxel (NYSE:DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (NYSE:PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy" ASCO 2014;Abstract LBA8006.

Disclosure: I am long PVCT.