The Problem with Accelerated FDA Approval

In Phase I trials researchers test an experimental treatment in a few patients for the first time. The purpose is NOT to see if the treatment kills cancer cells, but only to:

• evaluate the drug's safety
• determine a safe dosage range
• identify side effects

What if the patients in a Phase I trial experience shrinkage of their tumors? Should this speed up FDA approval of the trial drug?

As explained in a NYTimes article, PLX4032 caused tumor shrinkage in nearly all the 32 patients with advanced melanoma who were treated in the Phase I trial. For most, the reprieve lasted less than a year. But life expectancy with advanced melanoma averages 8 months and quality of life can be miserable. Some patients nearing death improved enough to get out of bed and off oxygen for awhile (the so-called Lazarus effect)

Oncologists appealed to the FDA to provide accelerated approval for PLX4032 that would allow Roche to sell the drug, as long as it proceeds with the Phase II trial. For understandable reasons, Roche resisted: 

• Doing so would handicap patient accrual for the $100 million Phase II trial. What patient is going to enter a trial with a 50% chance of getting standard therapy (with its notoriously high toxicity and low efficacy) if they can receive the promising new drug "off label"? 
• Other companies are developing similar drugs. Roche needs the Phase II trial results to get FDA approval for a broader market than patients at the end-of-life.  

Understandable. But is witholding accelerated approval ethical?

Comments

[Steven Walker]

In this case, neither the randomized trial (which is actually medically and scientifically meaningless), nor withholding the drug from patients who can't qualify for a trial (which is most of them) is ethical. Under all of the various international guidelines for conducting human clinical research, putting patients at risk to answer a question that we already know the answer to is unethical. The Phase III trial is being run primraily to satisfy the rigid, formulaic and in many cases scientifically obsolete requirements imposed by the FDA's Office of Oncology Drug Products for most cancer drugs since about 2003. Roche is actually more concerned about the FDA refusing to approve the drug than they are about acceptance of the drug by oncologists. The now available treatment options for metastatic melanoma are so poor, acceptance by oncologists of PLX4032 for patients exhibiting the requisite genetic mutation would be immediate. There is much more than meets the eye with this one, and most of those things are problems at the FDA. PLX4032 is far better than the existing approved drug, dacarbazine, it is being tested against. The cost of this mess will be the premature, painful deaths of thousands who will die waiting for this drug. Combining all the available clinical trial slots for patients to access PLX4032 will serve only about 400 patients over the next two years; but more than 8,600 patients die from metastatic melanoma every year. Ask them if denying them this drug is ethical.

[Wendy S. Harpham, M.D.]

Dear Steven,
As you'll see in my next post (posted earlier this evening), I've been leading up to the idea that we need to be pushing for improvements in how we run clinical trials. The gold standard of the 20th century just doesn't cut it with 21st century science. This is a tough but do-able challenge.

The greater challenge is dealing with the politics and economics that are interfering with the goal of helping patients.

With hope, Wendy

[Stacey Kliewer]

My wife was diagnosed with stage IV metastatic melanoma in December 2009. In January 2010 a 10cm tumor was removed from her left armpit. In September 2010 two tumors appeared on her left lower lung lobe. She was tested for the Braf gene early in October 2010 - she was positive for the Braf. Our Oncologist attempted to get her onto the PLX4032 trial. However, her required EKG test excluded her (barely). So, she was not accepted on the trial. So we were told to surgically remove the two tumors in her lower left lobe (1 at 3mm, second one at 10.3 mm). Surgery was scheduled for November 10th, 2010. However, a required Pet scan (for surgery) was done on Oct 21-10 only to show a "hot-spot" around her left L5 spinal area. Thus, surgery was canceled until an MRI of the area can be performed to verify or disprove further melanoma metastases. We are now waiting for that. We have been informed informed that if the MRI verifies the Melanoma has metastasized to her spine, surgery on her lung will not occur and there is nothing further they can do.
Considering she has the required Braf gene that is required for the PLX4032 to work - it seems very unethical to withhold this drug from her. Like really, what do we have to loose? Why would they not allow her to at least take a compassionate Ipi or PLX4032? This is very disturbing when the Phase 1, 2 and 3 trials so clearly show / give some hope - at least something better than the obvious if nothing is done!
Is there anything we can do to help push approval along? We would be willing to go public - or anything to help. Or, does anyone have any other ideas (other than planning a funeral)? We live in Canada.

[CHRIS NOLAN]

MY SISTER IN-LAW HAS STAGE 4 MELANOMA AND TRIED THE INTERFERON TREATMENT ONLY TO FIND HER LIVER TUMOR GREW 30% AND SHE HAS MORE LUNG TUMORS AND NOW A PELVIC TUMOR.
BRAF COULD POSSIBLE GIVE HER THE TIME WE ALL HOPE FOR HER. BRAF NEED TO BE MADE AVAILABLE TO STAGE 4 PATIENT. TIME IS OF THE ESSENCE!!

[John]

I like many others on this post have a relative that has been given a stage IV metastatic melanoma diagnosis (with metastasis to liver, both lungs, and several brain mets). Also, like many, we have been told that the patient is not now eligible for the trial (actually this is the GSK trial because it is the only trial currently available for brain mets). I am searching for a solution, like many others. It seems that, with support of the drug maker, an application could be made to the FDA. Without the drug maker's support, this option does not seem viable. Any suggestions would be greatly appreciated.

[Wendy S. Harpham, M.D.]

Dear John,
You are wise to reach out to people who have been fighting this fight. Starting points might include Abigail's Alliance [www.abigail-alliance.org] and the National Coalition for Cancer Survivorship [www.canceradvocacy.org]
With hope, Wendy

[Wendy S. Harpham, M.D.]

NYTimes reports today that the FDA has approved ipilimumab for metastatic melanoma. Wendy

[John]

Wendy,

Thanks so much for the info. I am learning here and will not give up for my family.