Second oncologist asks FDA to wait on Provenge
Dr. Maha Hussain (left) is calling for an open access program for Dendreon’s Provenge prostate cancer vaccine (Sipuleucel-T) pending completion of an ongoing, 500 man clinical trial, She made this suggestion March 29 during the FDA Advisory Committee hearing after voting “No” on the vaccine’s efficacy. She followed up with a letter to the FDA reiterating her “No” position and again calling for an open access program.
Dr. Hussain is the second oncologist among 4 members of the panel who voted “No” to the efficacy of the drug who has followed up with a letter to the FDA.
A letter by Dr. Howard Scher to the FDA appeared earlier this month and was first printed on April 17, in the The Cancer Letter (see Scher to FDA about Provenge hearing). Dr. Hussain’s letter to the FDA also first appeared in The Cancer Letter, on April 27. Dr. Hussain writes:
It is with concern and professional obligation that I write to you as a member of the FDA’s Advisory Committee that recently reviewed Sipuleucel-T on March 29, 2007. My concerns relate to medical, scientific and procedural aspects of the meeting and the precedence that will be set for future reviews.
By way of introduction, I am an academic medical oncologist with expertise in GU oncology, extensive clinical trials experience and have been the PI of several NCI sponsored multi-center trials including randomized phase II and III trials. Currently, I am the PI of a Prostate Cancer Clinical Trials grant funded by the Department of Defense that focuses on phase I and II trials in prostate cancer. My experience also includes co-chairing the prostate cancer subcommittee
of SWOG overseeing development of national trials for advanced prostate cancer for the past 13 years. I have served as an ad hoc FDA consultant for several years and currently serve as a member of the Oncology Drugs Advisory Committee. I was a member of and chaired the ODAC special session on prostate cancer endpoints, March 3, 2005, and have been actively involved in the development of endpoints for this disease, a summary of which was recently presented at the 2007 Prostate Cancer ASCO meeting.I was one of the four members who voted “No” to whether the submitted data on Sipuleucel-T established “efficacy” or “demonstrated substantial evidence of benefit” in the intended population at the recent advisory committee meeting.
From the medical and scientific aspects the recommendations for approval that may be inferred
from the vote are based on data that can only be characterized at best as “suggestive” of possible benefit. As the discussant for Q5 regarding the persuasiveness of the efficacy evidence my comments are public record but to summarize my conclusion was that the data
presented is not conclusive. The context here is not “is the treatment promising” or “does it open the door for more immunotherapy research,” the context here is “is the treatment effective and are the results solid” such that this therapy should be offered as “The Standard
of Care” by physicians to thousands of patients with the confidence that their recommendations truly serves the best interest of the patients. First of all the lead trial (study 1) was a small trial by any standard with 127 patients in total of whom only 82 were treated with Sipuleucel-T. The study was not powered for survival nor was survival an end point. A post hoc analysis indicated a significant survival difference but there were no significant differences between the
Sipuleucel-T and placebo group with regard to any of the disease manifestations including PSA, time to disease progression (primary endpoint) or pain. This coupled with a clear imbalance in the arms with the control arm having more patients with bone and soft tissue disease thus potentially bulkier disease, more patients with higher Gleason scores, more % with prior chemotherapy and questions regarding the nature of the agent administered as the control (please see comments below), the small sample size, the fact that survival was not powered for and is a post hoc analysis could lead to a plausible conclusion that the observed survival
difference may be related to other factors or chance alone and not to the treatment effect. Please contrast this data with the two phase III trials (TAX-327 with 997 patients, SWOG -9916 with 770 patients) that led to the approval of docetaxel. Both of these trials had
very consistent results across them and conclusively demonstrated a survival advantage with notable effects on other disease manifestations.The sponsor presented a second “supportive trial” which was also a small prematurely terminated trial which showed about a 3 month difference in survival which was not statistically significant. The trial results were especially problematic since both arms had a poorer survival (15.7 and 19.0 months) than expected for asymptomatic patients and worse than the survival
observed in study 1. This occurred despite similar eligibility criteria to study 1. Furthermore, even the “est arm “Sipuleucel-T treated patients” had a median survival of (19 months) which is comparable to the “asymptomatic” subgroup of men treated on the mitoxantrone arm of the Tax327 trial (19.8 months, Berhold et al, ASCO Prostate Cancer Symposium 2007). Please note that mitoxantrone is not considered the standard first line therapy in general or for symptomatic
patients.This clearly raises concern regarding the true efficacy of the agent and reproducibility and reliability of the data hence the application in the intended population at large. Furthermore, considering that the “placebo” treated patients had an unexpected poor survival of 15.7 months, which is worse than the median survival of patients on mitoxantrone arm of the TAX-327 of 16.4 months (NEJM 04) which also included symptomatic patients, raising questions regarding a negative effect from the placebo thus leading to an apparent survival
benefit. Issues regarding CVAs, particularly in the intended population, are also of concern without mature toxicity data and in the context of inconclusive efficacy data.As you know, a definitive trial is in progress and is within 100 patients of achieving target accrual. This trial will lead to definitive answers as to the true efficacy and safety of this agent. These questions will never be answered if the decision regarding this agent is not
deferred at this time until all patients are accrued and data are mature, for obvious reasons.From the scientific and procedural aspects, in general, it would seem that at the end of the day what should determine a positive verdict in any therapeutic trial is the strength of the evidence as critically reviewed by an Advisory Committee with the proper expertise in the context at hand (ODAC in the case of a therapeutic cancer trial), with clear guidance on the questions posed to the committee within the framework of the regulatory guidelines and requirements of the FDA for approval. This needs to be coupled with an atmosphere that is conducive to an objective discussion and vote.
Another concern, based on this case, is the appearance of discordance in the burden of proof
required for regulatory approval between CBER and CDER. In the meeting regarding endpoints in 2005, ODAC reaffirmed the importance of powering trials for endpoints that measure true clinical benefit. But fundamentally here this particular agent did not even meet criteria for its primary endpoint.In conclusion, as physicians we owe it to our patients to maintain the highest scientific standards and rigor. We owe them our objectivity and the assurance that when we make recommendations for treatment that we are basing our decisions on strong conclusive
data. We need your help to ensure maintaining this high standard.
On this June 5 I am concerned that both Dr. Hussain and Dr. Scher are being villified by our community. I was among those giving public statements at the hearing, and yesterday I marched with the Raise a Voice rally at the Capitol. My support of Provenge is clear.
But, I find Dr. Hussain’s letter contains professional and reasonable arguments and facts. While I too am impressed by the three month survival, some of the evidence of diverging curves, other evidence at the hearing, the 13 to 4 vote, and some of the other arguments about probabilities raised above, etc., Dr. Hussain raises what I consider a fundamental concern: in essence, garbage in leads to garbage out, and it is possible the placebo and treatment groups were different enough at the get-go that we end up comparing apples and oranges. Statistical tests will not help us if the input data are fundamentally flawed. Frankly, that has concerned me ever since reading the background papers. I have come down on the side of letting patients take an informed and expensive risk, but I have respect and appreciation for Dr. Hussain.
Here is another point that has bothered me, and I believe it is fresh. Despite Dr. Christopher Logothetis representing expert opinion that median survival for men who are hormone refractory, metastatic but not symptomatic ranges from 14-22 months, a respected Case Western Reserve team found in a retrospective study that median survival of hormone refractory men with bone mets was 40 months. (Oefelein, Agarwal and Resnick). The difference is that the Case Western team counted from the time the men first became refractory, while the studies cited by Dr. Logothetis counted from the time the men entered trials, as I understand it, as did the protocol for the Provenge trials. I would like to know how the arms of the Provenge studies compared regarding how long the men had been refractory. If one group had on average been refractory for considerably longer, that would throw off comparisons. Such information might not be available for many of the patients. Absent such data, a small trial like the ones presented at the hearing runs the risk of not evening out such differences. That’s one of the kinds of problems Dr. Fleming was concerned about in his letter.
I believe we are wise to push for early, interim approval, but I respect the other side. They have a right to express their strongly held convictions just as we do. I Those who have threatened the two doctors deserve our contempt and scorn.
Comment by Jim Waldenfels — June 5, 2007 @ 9:38 pmI don’t think PSA Rising should be promoting the minority position of the FDA advisory panel on this, either on the medical level, or to preserve and expand Drs. Scher & Hussain’s turf as chemotherapy clinicians and bureaucrats.
Time to progression and other symptom measurements have always been surrogate endpoints for survival, in order to enable faster study results. Later data can also be valid, and more important.
The ultimate goals are survival and quality of life. Provenge provides both for PC patients.
Provenge is a “smart” drug treatment that works in cooperation with a patient’s living cell defenses. Like many advanced treatments, it is costly to implement and cannot be given away large scale, even at Dr. Hussain’s sudden urging. It is curious that she suggests both this and that the treatment’s approval by the FDA would undermine further studies. Valid follow-up studies, especially in regard to an even wider efficacy, are commonplace.
The entrenchment of the chemotherapy / radiation warfare industry despite its limited progress over the years is an unfortunate fact. The new territory opened up with immunological living cell treatment is a paradise in comparison.
My mother lived long with bunions. It was merely scar tissue on top of bone. Her brother died in agony — despite discreet “endpoints” — within two years from diagnosis of prostate cancer. Now a second and a third uncle have it. All symptoms and their measurements should matter less than the ultimate goals.
My hat is off to the Dendreon scientists for having worked long and successfully on this new individual-patient-specific immunological approach. I look forward to Provenge being approved by the FDA as quickly as possible.
This post originated on Investorvillage Dendreon board(admin).
Comment by Reverberator — April 30, 2007 @ 9:36 pmThis is easy - lets look at THE primary endpoint alone:
a) The chance that the 9901 TTP was by chance is less than 1 in 25.
b) The chance that 9902a TTP was by chance is less than 1 in 3.
c) the chance that both of these would happen if Provenge were no better than saline solution is 1 in 75. If you add the PSA Doubling Time results from PROTECT (p=0.04 or so - from memory) and the chance of Provenge being no better than placebo is less than 1 in 3750.
As for the “discrepancy between TTP and Survival” several comments:
a) How discrepant is it? On 9901 TTP it got p=0.08, while on survival it got 0.01. Would anyone really expect them to be the same? Clearly not - it is a long standing problem that all treatments get different efficacies on TTP than on survival. The problem here really is that traditional chemo typically has those p values reversed. The chemo has an immediate effect, but stops working shortly after it is given. This reversal in whether TTP or survival shows a stronger efficacy is undoubtedly a factor in oncologists dismissal. See next point.
b) it is ABSOLUTELY INCONTROVERTIBLE that vaccines take a while to kick in (e.g. even a flu vaccine takes several weeks to kick in and the flu isn’t manipulating the immune system the way cancer does). Add to this the time between randomization and when patients received provenge and you get 30-40% of the time to median TTP while the treated patients can progress as if they had had no treatment. So it should be NO SURPRISE that the p value for TTP should not be as good as the p value for survival.
So, now lets look at the chance that the survival results were by chance:
a) 9901 p value is 0.01. One chance in 200 that this was by chance.
b) 9902a p value is 0.33. One chance in 6 this happened by chance.
c) Ignoring PROTECT you still get 1 chance in 1200 that Provenge does not have an effect on survival. Add in PROTECT and the chance that Provenge has no efficacy is extremely low. 1 in 60,000. Let me repeat that - 1 in 60,000. Undoubtedly a critical statistician would make me pay a penalty (called a Bonferonni adjustment) for some of these factors - but even if he made me double them, the chance that this would be by chance is less than 1 in 5,000.
So why are oncologists so up in arms. Partly an internal FDA power struggle with a long history - and Scher/Hussein are clearly well attached to OOD/CDER. Partly that the story for Provenge is murky (missed endpoints etc - but people, including oncologists, seem to forget that missed endpoints is NOT a proof of lack of efficacy) - like it or not KISS is an important principle when selling a new idea. But it is NOT because the Provenge has less chance of efficacy than other drugs did when they were approved. They (traditional drugs) often have chances of being no better than placebo of 1 in several thousand.
But are you seriously proposing that a drug with undeniably and significantly fewer side effects and less than 1 chance in 5000 of being no better than saline should not be available to prostate cancer sufferers?
Comment by clarksterh1 — April 29, 2007 @ 2:32 pmThe bias and absurdity of your claim that “nobody has put forth any really convincing or adequate re-assessment of the data to show Provenge is effective” is laughable.
What about a 3-fold increase in Overall Survival at 3 years do you find hard to grasp. Honestly, a fifth grader would be hard pressed not to grasp the signifigance. Remember, this was achieved with only transient flu-like symptoms.
To help with your understanding, I have included a link to Dr.Daniel P.Petrylak’s November 2006 presentation at the ‘Chemotherapy Foundation Symposium’. In case you are unaware, Dr. Petrylak is considered to be one of the most respected Prostate Cancer specialists in the United States.
http://chemotherapyfoundation.org/professional_education/meetingarchives_tcf2006_main.html
Scroll about halfway down the page to “GU Cancers”, click on “view presentation” on the right.
His view is that Provenge is quite effective. Hopefully you possess the intellectual integrity to admit, after viewing Dr. Petrylak’s presentation, that you were mistaken or misinformed about the effectiveness of Provenge.
Comment by craig payne — April 29, 2007 @ 1:47 amI find the letters by Dr. Hussain and Scher disturbingly unprofessional. They were members of the FDA Advisory Committee that overwhelmingly found Provenge safe and effective. If safety was a concern I could perhaps understand their need to appeal to the public. But Provenge’s safety has never been in question. Their appeal merely questions Provenge’s efficacy. If the FDA asks Dendreon for more studies it will be at least three years before Provenge will be available for cancer sufferers. I, for one, may not be here then. I have to ask myself, what exactly is driving Dr Hussain to write such a letter? Her letter is a slap in the face of the fourteen of her peers (the other members of the Committee) that did feel Provenge has shown substantial evidence of efficacy. I am a physician and researcher and have reviewed the evidence: I am convinced that Provenge works. And as a prostate cancer sufferer I would not hesitate to take it and hope I will have access to it. Soon.
Comment by James714 — April 28, 2007 @ 6:15 pmBelow is from Businessweek magazine hitting the newstands on April 30th.
“So why, in trial after clinical trial, doesn’t this reaction eliminate the tumor? Dr. Glenn Dranoff, a vaccine expert at Boston’s Dana-Farber Cancer Institute, says there is evidence immune cells infiltrate the tumor and kill it from within, leaving a ball of scar tissue the same size as the malignant growth. “You don’t see a visible change in the size of the tumor, but the composition has been dramatically altered.”
Oncologists believe vaccines will work best at stopping cancer recurrences after initial surgery. These metastases are what usually kill the patient. Consequently, a growing cadre of oncologists say patients who have failed other treatments should have a chance to try these drugs. Dr. David F. Penson, a urologist at the University of Southern California’s Norris Cancer Center who has consulted for Dendreon, is convinced Provenge has extended the lives of his prostate cancer patients. “I don’t know what else could be doing it.” Equally important, he says, is the quality-of-life issue. “These are guys who have one or two years to live, and their only treatment option is Taxotere,” a chemotherapy so toxic that many men refuse treatment. With Provenge, “patients get infused on Thursday and play golf over the weekend,” says Penson.”
Comment by Robert L — April 28, 2007 @ 4:32 pmThe missed P value for TTP was .052. that is a very close miss. If p=.050 there would be no aurgument.
The two Provenge trials were designed to be pooled together. When pooled for survival, there was a statistically-significant survival benefit for Provenge over the control arm (p=0.011). When the Cox analysis was applied to the pooled data to correct for imbalances, the result was highly statistically significant at p=0.0006 (remember, p=0.05 is the accepted threshold for significance).
The pooled data and the Cox correction for the survival data on the second trial provide adequate “support” for the first trial, especially given the flexibility the FDA has used in determining what is supportive for other drug approvals.
The scientific community now recognizes active immunotherapies work differently than traditional chemotherapy drugs. The FDA and the National Cancer Institute sponsored a symposium earlier in 2007 focusing on cancer immunotherapies. Speakers from both organizations acknowledged the way clinicians and regulators have traditionally believed a cancer drug “should” work simply does not apply to active immunotherapies like Provenge. The Journal of Immunotherapy recently offered a peer-reviewed assessment of how cancer vaccines and related biologics should be evaluated under a difference clinical development paradigm.
There are many theories as to why this is the case, chief among them that survival is extended because these drugs slow the spread of the disease. Slowing the disease is not a broadly recognized surrogate endpoint for cancer therapy approval. But several classes of new therapies, many of them recently approved by the FDA, slow the growth of tumors far more often than they shrink them.
We first declared war on cancer in the 1970s. We’re making progress, but until the last decade this progress came only at a price of severe side effects. We are now so used to these side effects that when a prostate cancer chemotherapy drug like Taxotere is found by trial investigators to be directly responsible for the death of 1-2% of patients who take it, the side effects are called “acceptable”.
It was a great shame that the lead investigator for the first Provenge pivotal trial, Dr. Eric Small, had his flight cancelled by his airline so he was not able to join the panel in time. Dr. David Penson, however, has been an investigator on all three clinical trials for Provenge. During the public commentary section, he clearly articulated how his patients benefited. Dr. Penson came to the CTGT public commentary meeting of his own accord and did not discuss his testimony with the sponsor.
Perhaps more importantly, the administration of Provenge does not interfere with further treatment. This is not typical for other treatments for this patient population. Treatment with Taxotere extracts a significant cost, weakening many men so much they are not willing or able to take a second type of treatment. While Taxotere claims a benefit to quality of life as one of its advantages, that is only in comparison to another toxic chemotherapy drug.
Dr. Daniel Petrylak looked at the patients who did choose Taxotere after receiving Provenge comparing them to men in the control arm of the two trials who got placebo then took Taxotere. The survival difference was remarkable, 34.5 months compared to 25.4 months for patients randomized to receive placebo who went on to receive Taxotere, a difference of 9.1 months (HR = 1.90; p-value = 0.023). These data were presented by Dr. Petrylak at the 2006 Chemotherapy Symposium of New York.
Progression is a poor endpoint for cancer immunotherapies. In 2005, the FDA’s Oncologic Drugs Advisory Committee (ODAC) decided the only proper endpoint for oncology trials was survival. Dr. Scher was on that panel and agreed with the committee’s findings. Despite this, Provenge demonstrated a nominally statistically significant result in time to progression in its first trial.
Both the first (9901) trial and the pooled data demonstrated a p-value of p=0.01. This means that there is only a 1% chance the result is due to chance. Biostatisticians and regulators have arbitrarily chosen 5% (p=0.05) as the odds of a result being due to chance are too high for drug approval.
In order to prevent people from switching things up to get results they like better, biostatisticians force trial sponsors to choose in advance which single item they will measure to prove a clinical trial is successful. This is a very good rule, as long as it is not taken to extremes.
Eight years ago, the sponsors of the Provenge trial didn’t know any better and chose time to progression as that single item – the primary endpoint. time to progression was considered a wau to predict eventual survival. They nominally hit it for one trial and missed it with another. If they instead had chosen survival as that single item, then Dr. Hussain would not likely have written her letter and Provenge would likely already be on the market.
Nearly all of the time, when a sponsor switches endpoints around it is a problem. They often dredge data and choose some narrow portion of patients – a subgroup – and claim victory for the trial when that subgroup shows a benefit. This is quite common, and the FDA rightfully rejects these arguments for a whole host of reasons not particularly germane to this discussion.
It is important to realize that’s not what is going on here. Provenge demonstrated a survival advantage in all patients in the first trial and when all patients from both trials are combined into one analysis. All patients in the second trial saw a similar survival advantage once that trial was statistically corrected for imbalances.
Should prostate cancer patients be penalized for an eight-year old decision to make progression the primary endpoint? As Dr. Scher himself implies, sometimes you have to look beyond strict biostatistical rules and do what is right for patients. 13 panel members agreed with this point of view, and voted their belief that Provenge demonstrates substantial evidence of efficacy.
Comment by Robert L — April 28, 2007 @ 8:52 amThere was adequate evidence put forward at the Advisory Commettee that Provenge works…so much that 13 out of 17 experts agreed that it provides substantial efficacy.
First, an FDA Working Group, made up of many of the members of the CTGCT committee that sat on the committte, has submitted a revised way of measuring progression for vaccines that takes into account the “ramping up” necessary with a vaccine but not needed chemo.
Here’s the link > (I don’t know how to actually make it link)
It is also a myth that Provenge did not slow progression. It slowed it, even with the flawed model, with a 94.8% chance that the effect was due to the drug. The FDA arbitrarily requires 95%. Look at slide 7 of this presentation–you’ll see a clear separation at about week 17–a little late for the old model, but undeniable separation.
http://investor.dendreon.com/downloads/22568dndn.pdf
Second, chemo does not explain the survival benefit for one simple reason…more placebo patients progressed to chemo than did the drug group. Provenge is synergistic with Chemo…the median survival for Provenge + Taxotere was 35 months for AIPC patients! You should know that this is a doubling of normal survival rates.
In addition, the drug group had triple the chance of surviving 3 years, even more if you only look at prostate specific deaths in the trial. If you look at that slide show again on slide 10 you’ll see an eye popping HR curve…yes, almost 50% of the men were still alive at 3 years if you throw out deaths not related to prostate cancer. Compare that the Halabi nomogram that predicts 3 years survival at less than 20%. The efficacy is clear.
Finally, the two Provenge trials were meant to be pooled. Pool them and the 4.5 month median survival achieved a p value of .011, easily statistically significant, and that’s with 225 patients total; not huge, but hardly miniscule. Other drugs have been approved with smaller groups.
Provenge works, and this website should be pounding the table for approval. The huge short interest bet Wall Street has placed on this stock is not surprising; the lack of advocacy support for an effective, safe treatment for a hideous disease is very disheartening. The latest USTOO newsletter notes the the Provenge committee but then says the new info on hormone therapy is VERY important. Maybe the author had never been on hormone therapy. What is very important is extending the lives of men with late stage prostate cancer with 24 hours of flu like symptoms as the only side effects.
Please…get behind this drug!!!
Comment by frogmister — April 28, 2007 @ 3:42 amDr. Hussain’s declaration of conflict of interest involved her husband’s finances not her own. Check out the FDA website and you’ll see 6 or 8 waivers, some for sums larger than she declared. The chairman, James Mulé obtained a waiver too for a meeting next day. And most of the people on the committee were not obliged to declare any conflicts of interest they may have had.
Comment by admin — April 27, 2007 @ 8:31 pmI thought your web site was supposed to help Prostate Cancer patients. I’m disappointed that you published the biased letter without checking the background of the author. Maha Hussain has significant conflicts of interests against Dendreon, the maker of Provenge. According to the FDA web site, her husband owns stock in competing firms. She actually fell asleep during patients’ testimony at the Provenge Advisory Committee meeting. I don’t understand why you publish a biased letter from such a cold hearted and unprofessional person. Do you put Prostate Cancer patients whom you are supposed to help first or process/statistics first?
Comment by HH — April 27, 2007 @ 6:32 pm