fandt lige et godt resume af casen:
Below are some facts and opinions developed over the past few years watching DNDN and the progress of Provenge:
1. 2004: Even though Overall Survival was not a prespecified endpoint in D9901, a logrank analysis of survival data at 3 years showed stat sig p = 0.01.
2. 2004/2005: DNDN peeked in D9902a to see if TTP and/or OS was supportive. Both failed. However, a standard back-stepping Cox analysis algorithm when applied to D9901 and D9902a resulted in highly stat sig OS results for both trials.
4. July 2005: A pre-BLA meeting with the CBER division of the FDA was held to present all available analysis results at that time. Dr. Pazdur was at that meeting and supportive of a BLA for Provenge per the below Q&A with Dr. Gold at the UBS Conference in Sept 2005 as reported by an attendee (Ackabaker):
"Q- Do you know of any precedents where FDA ok'd a drug missing primary endpoint but met secondary?
Mitch- We learned from our pre-BLA meeting that we had been overly conservative about the primary endpoint- that TTP should not have been a major focus- Pazdur sees survival as clearly the basis for approval- our TTP result with a .06 p-value is definitely "supportive"- though we never could have gotten full approval on it"
5. Nov 2006: The BLA was completed. For the first time, the FDA statisticians got to play with the submitted data. They found that the log-rank analysis for OS in D9901 was good. However, they also found a big hole in the Cox analysis. There were missing data leading to patients being excluded. Thus, the analysis for both D9901 and D9902a were on subgroups, not the entire ITT groups. Further, the excluded placebo patients appeared to live longer than the excluded treated ones. That meant that the findings of the Cox analysis might not be meaningful, or not meaningful enough to support licensure.
At this point, my guess was that Dr. Pazdur, without fully appreciating the intricacies of immunotherapy, likely felt that the statistical data fell far short of the acceptable standards that the FDA have been putting into place. Also, he might have felt that his previous flexibility in agreeing to let DNDN file a non-traditional BLA was misplaced. If it was up to him, he probably would have just issued a Refuse-To-File letter since without the Cox analysis, D9902a was not anywhere close to being supportive to D9901 and the OS logrank analysis for D9901 was both not pre-specified and post-hoc.
Again, I guess that CBER with their expertise in immunology trusted the data enough to argue for holding an Advisory Committee to discuss the data. There must have been lengthy discussions inside the FDA since the final decision to hold a meeting was not announced until very close to the date of the meeting itself in late March 2007.
6. Mar 2007: The AC was held. The safety vote passed 17-0. The efficacy vote started rocky and almost failed. Early voters stated that they thought the data had merit but the requirement of "Establishing efficacy" was too high to vote yes. Dr. Goodman, Director of CBER, stepped up and clarified that the requirement by law was only "Substantial Evidence of Efficacy". The voting was restarted, resulting in a 13-4 vote for efficacy.
7. Apr 2007: Drs Scher, Hussain and Flemming wrote letters to the FDA urging to delay approval. Dr. Scher's effort was aided by researchers at the NCI. Dr. Pazdur either started that effort or at least gave them the green light since Scher and Hussain were members of ODAC.
I wrote some early rebuttals to those letters on this board. Later, I helped a fellow called Wu, Rancherho and others to put together some of that contents and also contents from an independent letter by David Miller into a comprehensive letter that was sent to the FDA.
8. May 2007: The internal fighting at the FDA finished. Dr. Pazdur's side won the argument that the submitted data were sufficiently controversial that they should wait for a more definitive analysis from IMPACT. A CRL letter was issued asking for more efficacy data.
9. Mar 2008: The company, perhaps with help from the FDA, redesigned the IMPACT trials to change the alpha allocation method and the interim and final triggers for analysis. These changes were designed to both speed up the time line and to increase the chance of success for the interim look.
10. Oct 2008: The company announced that the interim look did not achieve stat sig but also gave the estimated HR at that time showing a trend of success for IMPACT. This board had many months of hand-wringing and bickering about how the final analysis will come out.
11. April 2009: The company announced that IMPACT had achieved stat sig. A new version of the BLA to be based on IMPACT as the pivotal trial will be filed in 4Q2009 with approval expected a maximum of 6 months afterward.
12. Some time in early 2010: Provenge approved. Well, ok, that's an opinion. Let's hope.
The delay decision, in hindsight with IMPACT data, is now known to be wrong but it was not unreasonable at the time given the nature of the data. From a data perspective, the faults could be laid at both DNDN and the FDA doors. In DNDN case, they were not careful enough with their data analysis, esp. the Cox analysis. In the FDA case, the decision makers did not have the wisdom and courage to follow the advice of the AC and their own internal people to approve.
No doubt a number of people involved in the delay of Provenge benefited handsomely from that. But we must remember that the opening for their success was the controversial quality of the data at that time. That was a hard and personal lesson for me. Even as I understood the science and trusted it, as observed at the ASM today, FDA approval is foremost about clean statistical data. That depends on factors beyond science, ie, trial engineering.
That's why, after the CRL, I spent much time learning to simulate IMPACT to see what factors could derail it or make it work. I shared some of that on the board as I was learning. I should also mention that P3analyze helped me much with certain aspects of statistics that I was not familiar with and firmed my thoughts on how the simulator should work.
In any case, just to repeat myself again, by focusing on the data aspect, it can be seen that the obstacles to approval as seen in 2007 will not be there in 2010 if the stat sig results of IMPACT hold up. So unless something else comes up, the default stance for the next BLA should be approval. Yes, JMO.
Below are some facts and opinions developed over the past few years watching DNDN and the progress of Provenge:
1. 2004: Even though Overall Survival was not a prespecified endpoint in D9901, a logrank analysis of survival data at 3 years showed stat sig p = 0.01.
2. 2004/2005: DNDN peeked in D9902a to see if TTP and/or OS was supportive. Both failed. However, a standard back-stepping Cox analysis algorithm when applied to D9901 and D9902a resulted in highly stat sig OS results for both trials.
4. July 2005: A pre-BLA meeting with the CBER division of the FDA was held to present all available analysis results at that time. Dr. Pazdur was at that meeting and supportive of a BLA for Provenge per the below Q&A with Dr. Gold at the UBS Conference in Sept 2005 as reported by an attendee (Ackabaker):
"Q- Do you know of any precedents where FDA ok'd a drug missing primary endpoint but met secondary?
Mitch- We learned from our pre-BLA meeting that we had been overly conservative about the primary endpoint- that TTP should not have been a major focus- Pazdur sees survival as clearly the basis for approval- our TTP result with a .06 p-value is definitely "supportive"- though we never could have gotten full approval on it"
5. Nov 2006: The BLA was completed. For the first time, the FDA statisticians got to play with the submitted data. They found that the log-rank analysis for OS in D9901 was good. However, they also found a big hole in the Cox analysis. There were missing data leading to patients being excluded. Thus, the analysis for both D9901 and D9902a were on subgroups, not the entire ITT groups. Further, the excluded placebo patients appeared to live longer than the excluded treated ones. That meant that the findings of the Cox analysis might not be meaningful, or not meaningful enough to support licensure.
At this point, my guess was that Dr. Pazdur, without fully appreciating the intricacies of immunotherapy, likely felt that the statistical data fell far short of the acceptable standards that the FDA have been putting into place. Also, he might have felt that his previous flexibility in agreeing to let DNDN file a non-traditional BLA was misplaced. If it was up to him, he probably would have just issued a Refuse-To-File letter since without the Cox analysis, D9902a was not anywhere close to being supportive to D9901 and the OS logrank analysis for D9901 was both not pre-specified and post-hoc.
Again, I guess that CBER with their expertise in immunology trusted the data enough to argue for holding an Advisory Committee to discuss the data. There must have been lengthy discussions inside the FDA since the final decision to hold a meeting was not announced until very close to the date of the meeting itself in late March 2007.
6. Mar 2007: The AC was held. The safety vote passed 17-0. The efficacy vote started rocky and almost failed. Early voters stated that they thought the data had merit but the requirement of "Establishing efficacy" was too high to vote yes. Dr. Goodman, Director of CBER, stepped up and clarified that the requirement by law was only "Substantial Evidence of Efficacy". The voting was restarted, resulting in a 13-4 vote for efficacy.
7. Apr 2007: Drs Scher, Hussain and Flemming wrote letters to the FDA urging to delay approval. Dr. Scher's effort was aided by researchers at the NCI. Dr. Pazdur either started that effort or at least gave them the green light since Scher and Hussain were members of ODAC.
I wrote some early rebuttals to those letters on this board. Later, I helped a fellow called Wu, Rancherho and others to put together some of that contents and also contents from an independent letter by David Miller into a comprehensive letter that was sent to the FDA.
8. May 2007: The internal fighting at the FDA finished. Dr. Pazdur's side won the argument that the submitted data were sufficiently controversial that they should wait for a more definitive analysis from IMPACT. A CRL letter was issued asking for more efficacy data.
9. Mar 2008: The company, perhaps with help from the FDA, redesigned the IMPACT trials to change the alpha allocation method and the interim and final triggers for analysis. These changes were designed to both speed up the time line and to increase the chance of success for the interim look.
10. Oct 2008: The company announced that the interim look did not achieve stat sig but also gave the estimated HR at that time showing a trend of success for IMPACT. This board had many months of hand-wringing and bickering about how the final analysis will come out.
11. April 2009: The company announced that IMPACT had achieved stat sig. A new version of the BLA to be based on IMPACT as the pivotal trial will be filed in 4Q2009 with approval expected a maximum of 6 months afterward.
12. Some time in early 2010: Provenge approved. Well, ok, that's an opinion. Let's hope.
The delay decision, in hindsight with IMPACT data, is now known to be wrong but it was not unreasonable at the time given the nature of the data. From a data perspective, the faults could be laid at both DNDN and the FDA doors. In DNDN case, they were not careful enough with their data analysis, esp. the Cox analysis. In the FDA case, the decision makers did not have the wisdom and courage to follow the advice of the AC and their own internal people to approve.
No doubt a number of people involved in the delay of Provenge benefited handsomely from that. But we must remember that the opening for their success was the controversial quality of the data at that time. That was a hard and personal lesson for me. Even as I understood the science and trusted it, as observed at the ASM today, FDA approval is foremost about clean statistical data. That depends on factors beyond science, ie, trial engineering.
That's why, after the CRL, I spent much time learning to simulate IMPACT to see what factors could derail it or make it work. I shared some of that on the board as I was learning. I should also mention that P3analyze helped me much with certain aspects of statistics that I was not familiar with and firmed my thoughts on how the simulator should work.
In any case, just to repeat myself again, by focusing on the data aspect, it can be seen that the obstacles to approval as seen in 2007 will not be there in 2010 if the stat sig results of IMPACT hold up. So unless something else comes up, the default stance for the next BLA should be approval. Yes, JMO.
11/6 2009 13:42 Hya 0
13385 Dendreon Annual Meeting notes
As usual, I attended the meeting and have compiled this post from my notes. I hope you find them useful, but really I got the idea for personal purposes. It is very handy to look back and see what changes as a company progresses.
CAVEAT
I am human, not a biotech professional, not an finance professional, and can't take notes as quickly as they speak. Mistakes will be made. When you really have to know, ask me for clarification, other attendees for other points of view, and get the official words from the company, the FDA, and the SEC.
PRE-MEETING
Dendreon holds its meetings in a conference room in its headquarters. This year they outgrew it (~200 people?) and added a set of chairs in the breakroom where the organic goodies lived. Take your pick. Live action, but theater seating; or a big screen TV but lots of good, free food. A couple of friends and I sat in the back of the theater. I like being able to watch the off-podium reactions. Free T-shirts to those who attended. That and the food were the closest things to dividends.
The following is not chronological, because I don't want to describe the various introductions and director's accolades.
OFFICIAL MEETING
Everything passed with a quorum of 79%. That took less than ten minutes.
While in control of the podium, the COB took the time to comment on the recent good news, but to also emphasize that there is no finish line. He said that there is every reason to believe that the FDA will approve Provenge, but that there is considerable work required for the application, commercialization, and the strategic growth of the pipeline and the company.
BUSINESS PRESENTATION
Mitch Gold, CEO and President, gave the presentation; which, was purposely abbreviated because most of the audience had already seen the data and might appreciate having more time for the Question & Answer section. For the most part he was correct. Much of what he presented was familiar to long term shareholders. For more details, I suggest cruising the press releases and commentary.
For those familiar with the company, Eduardo, one of the first public Provenge success stories, passed away. Before the treatment his prognosis was for about 18 month survival. He lived for 8 more years. I am glad that he allowed us to follow his progress.
The CEO mentioned 200 employees (which is more than last year and probably much less than next year), and that the company raised $220 million.
He briefly described the pipeline. Beside Provenge, the chart described Neuvenge (breast, colorectal, ovarian?), CEA (breast, colon, lung), CA9? (kidney, colorectal, cervical), and TRPM8 (small molecule - prostate). His primary message was that Provenge is just the beginning, and its success validates Dendreon's proprietary dendritic cassette technology. The Antigen Delivery Cassette is effective and relatively simple, from the physician's point of view. It is infusion (transfusion?) based medicine and takes about 30-60 minutes to administer. This keeps it within the current exam room facility rather than other transfusions which take hours and require separate facilities.
Provenge's initial label will cover approximately 100,000 patients annually. He showed the 9901 and 9902B data. (I was surprised to see curves on the 9902B data eventually collapse, and I am sure someone on the board can explain that.)
He emphasized that this is the first immunotherapy treatment for any cancer. It changes the paradigm and validates the technology. They look to build a big oncology company and are focused on commercialization, not selling the company.
Their target customers are the 5,000 oncologists and 3,000 urologists, who will be dealing with about 120 sales staff.
The company has approximately $351,000,000 in assets, which is a comfortable position from which to commercialize Provenge and possibly restart the pipeline.
He described the company as a compelling investment opportunity. They have 100% of the rights (which they'll keep in the US but partner ex-US), and they have a validated platform which has strong physician interest.
With that, he turned it over to Q&A.
QUESTIONS & ANSWERS (paraphrased)
? Provenge is used post-chemo and castration. Approval for earlier cases requires more and longer studies, especially if survival is the measure.
? Immune response is persistent, and booster shots boost the response, but the impact on survival is unknown. (first treatment CD54 rises five-fold, second treatment CD54 rises ten-fold, third treatment CD54 rises ten-fold)
? The company is not being built for a buyout. There are few oncology companies that haven't sold away their rights. Dendreon will be one of the few to retain their rights.
? Executives sold stock for personal reasons like diversification.
? Pipeline re-ignition (and as one person said, do you want to ignite a pipeline?) is limited by capital but will be addressed this summer.
? Dendreon will not promote off-label use of Provenge. (Are they even allowed to promote off-label?)
? The FDA responds to data, not advocacy. The physicians have gone from 30% awareness prior to the panel meeting, to 50% post-panel, to 93% today.
? The cassette's intellectual property protections probably run out in 2020.
? Typically, a drug takes 10 years and $1 billion to reach approval. Provenge took longer, partly because the paradigm for the approval process is being re-defined for immunotherapy.
? (There was an excellent question on reimbursement, but I distracted myself with a side-conversation and missed the answer except to hear "Medicare".)
? The manufacturing facility is built to at least 25%. The remainder takes 12-14 months (which I believe has already begun). The 25% is sufficient to begin revenue operation.
? Lots of companies are talking about cooperative group studies, Provenge plus this, Provenge plus that, etc. There is lots of interest and it is all good for the company. (and hopefully the patients)
? Neuvenge may work against breast, ovarian, and colorectal cancers in a similar or better fashion than Provenge. The downside is that the patient population is more fragmented and there is much more competition.
? (I was confused by the question and the answer.)
? The company intends to remain independent. With the pipeline operating, the company will look different. The COB stood up, agreed, and emphasized the point.
? The FDA is driven by data, not politics.
? The summer analysts' meeting will provide more details.
? The FDA provided crystal clear instructions about how to clear their internal concerns and Dendreon's manufacturing issues.
? The stock divot is perplexing, but he focuses on long term issues and value.
? Dendreon's products are aimed at making cancer chronic instead of life-threatening. The word "cure" is a tougher term.
POST MEETING
The meeting adjourned and the attendees milled around more than last year. The chief scientist, the COB, and the CEO were all very accessible and surrounded. Ask the other attendees for additional insights.
MY SUMMARY & CONCLUSIONS
The company has done well. They've championed an innovative technology through tough and contentious technical, regulatory, and financial waters.
They keep to the story line of an independent company working for the patients and relying on the FDA to approve based on the data provided. The patient population for Provenge is men with late stage prostate cancer. They leave it to us to speculate about off-label use and whether the FDA is influenced by politics or if the financial markets are influenced by criminals. It is hard to know if they are maintaining a story line while fully aware of improprieties, or if they are very naive. The realities of their situation are such that they have no incentive to act otherwise. It is up for us to make up our minds.
Usually, management message posturing is fine by me because it rarely changes the long term picture, but I was dismayed by management's dismissal of the trading improprieties. Amongst their many duties is to protect the shareholder interests. The stock divot directly affected shareholder interests, yet they do nothing about it. This is a fundamental task and job description that they choose to ignore. That would get many people fired in other jobs. But, so it goes.
I am encouraged by the strategy of independent growth. I am encouraged by the progress. I am discouraged by the delay which has allowed other companies to catch up. I am discouraged by the delay in the pipeline and particularly in the delay in treating breast cancer. The company may still grow significantly, but I now suspect that it will take longer and may be less extensive. Despite that, it continues to have enormous potential.
I may be inspired by management to sell a bit to diversify and realize some gains.
I also want to thank all of the men who risked their lives by entering the trials. I appreciate their efforts as an investor, but also as a middle-aged man. Thank you.
DISCLAIMER
LTBH since 2002 and optimistic based on data but pessimistic based on politics. (Copied from last year's notes and still true.)
As usual, I attended the meeting and have compiled this post from my notes. I hope you find them useful, but really I got the idea for personal purposes. It is very handy to look back and see what changes as a company progresses.
CAVEAT
I am human, not a biotech professional, not an finance professional, and can't take notes as quickly as they speak. Mistakes will be made. When you really have to know, ask me for clarification, other attendees for other points of view, and get the official words from the company, the FDA, and the SEC.
PRE-MEETING
Dendreon holds its meetings in a conference room in its headquarters. This year they outgrew it (~200 people?) and added a set of chairs in the breakroom where the organic goodies lived. Take your pick. Live action, but theater seating; or a big screen TV but lots of good, free food. A couple of friends and I sat in the back of the theater. I like being able to watch the off-podium reactions. Free T-shirts to those who attended. That and the food were the closest things to dividends.
The following is not chronological, because I don't want to describe the various introductions and director's accolades.
OFFICIAL MEETING
Everything passed with a quorum of 79%. That took less than ten minutes.
While in control of the podium, the COB took the time to comment on the recent good news, but to also emphasize that there is no finish line. He said that there is every reason to believe that the FDA will approve Provenge, but that there is considerable work required for the application, commercialization, and the strategic growth of the pipeline and the company.
BUSINESS PRESENTATION
Mitch Gold, CEO and President, gave the presentation; which, was purposely abbreviated because most of the audience had already seen the data and might appreciate having more time for the Question & Answer section. For the most part he was correct. Much of what he presented was familiar to long term shareholders. For more details, I suggest cruising the press releases and commentary.
For those familiar with the company, Eduardo, one of the first public Provenge success stories, passed away. Before the treatment his prognosis was for about 18 month survival. He lived for 8 more years. I am glad that he allowed us to follow his progress.
The CEO mentioned 200 employees (which is more than last year and probably much less than next year), and that the company raised $220 million.
He briefly described the pipeline. Beside Provenge, the chart described Neuvenge (breast, colorectal, ovarian?), CEA (breast, colon, lung), CA9? (kidney, colorectal, cervical), and TRPM8 (small molecule - prostate). His primary message was that Provenge is just the beginning, and its success validates Dendreon's proprietary dendritic cassette technology. The Antigen Delivery Cassette is effective and relatively simple, from the physician's point of view. It is infusion (transfusion?) based medicine and takes about 30-60 minutes to administer. This keeps it within the current exam room facility rather than other transfusions which take hours and require separate facilities.
Provenge's initial label will cover approximately 100,000 patients annually. He showed the 9901 and 9902B data. (I was surprised to see curves on the 9902B data eventually collapse, and I am sure someone on the board can explain that.)
He emphasized that this is the first immunotherapy treatment for any cancer. It changes the paradigm and validates the technology. They look to build a big oncology company and are focused on commercialization, not selling the company.
Their target customers are the 5,000 oncologists and 3,000 urologists, who will be dealing with about 120 sales staff.
The company has approximately $351,000,000 in assets, which is a comfortable position from which to commercialize Provenge and possibly restart the pipeline.
He described the company as a compelling investment opportunity. They have 100% of the rights (which they'll keep in the US but partner ex-US), and they have a validated platform which has strong physician interest.
With that, he turned it over to Q&A.
QUESTIONS & ANSWERS (paraphrased)
? Provenge is used post-chemo and castration. Approval for earlier cases requires more and longer studies, especially if survival is the measure.
? Immune response is persistent, and booster shots boost the response, but the impact on survival is unknown. (first treatment CD54 rises five-fold, second treatment CD54 rises ten-fold, third treatment CD54 rises ten-fold)
? The company is not being built for a buyout. There are few oncology companies that haven't sold away their rights. Dendreon will be one of the few to retain their rights.
? Executives sold stock for personal reasons like diversification.
? Pipeline re-ignition (and as one person said, do you want to ignite a pipeline?) is limited by capital but will be addressed this summer.
? Dendreon will not promote off-label use of Provenge. (Are they even allowed to promote off-label?)
? The FDA responds to data, not advocacy. The physicians have gone from 30% awareness prior to the panel meeting, to 50% post-panel, to 93% today.
? The cassette's intellectual property protections probably run out in 2020.
? Typically, a drug takes 10 years and $1 billion to reach approval. Provenge took longer, partly because the paradigm for the approval process is being re-defined for immunotherapy.
? (There was an excellent question on reimbursement, but I distracted myself with a side-conversation and missed the answer except to hear "Medicare".)
? The manufacturing facility is built to at least 25%. The remainder takes 12-14 months (which I believe has already begun). The 25% is sufficient to begin revenue operation.
? Lots of companies are talking about cooperative group studies, Provenge plus this, Provenge plus that, etc. There is lots of interest and it is all good for the company. (and hopefully the patients)
? Neuvenge may work against breast, ovarian, and colorectal cancers in a similar or better fashion than Provenge. The downside is that the patient population is more fragmented and there is much more competition.
? (I was confused by the question and the answer.)
? The company intends to remain independent. With the pipeline operating, the company will look different. The COB stood up, agreed, and emphasized the point.
? The FDA is driven by data, not politics.
? The summer analysts' meeting will provide more details.
? The FDA provided crystal clear instructions about how to clear their internal concerns and Dendreon's manufacturing issues.
? The stock divot is perplexing, but he focuses on long term issues and value.
? Dendreon's products are aimed at making cancer chronic instead of life-threatening. The word "cure" is a tougher term.
POST MEETING
The meeting adjourned and the attendees milled around more than last year. The chief scientist, the COB, and the CEO were all very accessible and surrounded. Ask the other attendees for additional insights.
MY SUMMARY & CONCLUSIONS
The company has done well. They've championed an innovative technology through tough and contentious technical, regulatory, and financial waters.
They keep to the story line of an independent company working for the patients and relying on the FDA to approve based on the data provided. The patient population for Provenge is men with late stage prostate cancer. They leave it to us to speculate about off-label use and whether the FDA is influenced by politics or if the financial markets are influenced by criminals. It is hard to know if they are maintaining a story line while fully aware of improprieties, or if they are very naive. The realities of their situation are such that they have no incentive to act otherwise. It is up for us to make up our minds.
Usually, management message posturing is fine by me because it rarely changes the long term picture, but I was dismayed by management's dismissal of the trading improprieties. Amongst their many duties is to protect the shareholder interests. The stock divot directly affected shareholder interests, yet they do nothing about it. This is a fundamental task and job description that they choose to ignore. That would get many people fired in other jobs. But, so it goes.
I am encouraged by the strategy of independent growth. I am encouraged by the progress. I am discouraged by the delay which has allowed other companies to catch up. I am discouraged by the delay in the pipeline and particularly in the delay in treating breast cancer. The company may still grow significantly, but I now suspect that it will take longer and may be less extensive. Despite that, it continues to have enormous potential.
I may be inspired by management to sell a bit to diversify and realize some gains.
I also want to thank all of the men who risked their lives by entering the trials. I appreciate their efforts as an investor, but also as a middle-aged man. Thank you.
DISCLAIMER
LTBH since 2002 and optimistic based on data but pessimistic based on politics. (Copied from last year's notes and still true.)
