I thought I'd travel back in time to recount for the investing public what Introgen has been promising and repeatedly failing to deliver with respect to applying to the FDA for approval of Advexin. It is truly astonishing to see how badly this company failed to deliver on its promises, and really makes one wonder how they are able to continue raising capital to keep the whole thing afloat. It is amazing how much "credit" biotech investors are willing to extend to management teams that have done nothing to deserve any credibility.
My sources are conference call transcripts, SEC filings and press releases.
The dramatis personae for this tragicomedy are:
David Nance, President and CEO
Max Talbott, Senior VP, Worldwide Commercial Development
Bob Sobol, Senior VP, Medical and Scientific Affairs
Various analysts who asked questions on the conference calls
And now on to Act I....
Introgen’s 2002 10K, filed March 31, 2003, lays the background for the story:
“We are conducting pivotal Phase 3 clinical trials of ADVEXIN gene therapy in head and neck cancer. Pivotal Phase 3 trials are typically the final trials required for FDA approval. We have completed a Phase 2 clinical trial of ADVEXIN gene therapy in non-small cell lung cancer, a category that includes approximately 80% of the various types of lung cancer, and are developing FDA registration plans.”
Later, they wrote:
“Based on clinical results from our Phase 1 and Phase 2 clinical trials, we are currently enrolling patients in and conducting two multi-national pivotal Phase 3 clinical trials that the FDA has reviewed, and if successful, will be used to support regulatory approval.”
As of the August 12, 2003, second quarter conference call, the company was clearly saying it would file the Advexin BLA in 2004. Max Talbott said:
“As discussed in previous calls it is our plan to file the BLA for ADVEXIN and head and neck cancer in 2004” and later reiterated “So our guidance has been and continues to be, and as I reiterated a few moments ago, that we will file the BLA in 2004 and we're on target for that objective.”
This is not “initiate the filing,” not “ask the FDA if we might file,” not “begin to think about whether or not we should file for accelerated approval” – no, it is crystal clear. Introgen said they would file the Advexin BLA in 2004. That of course means that the company expected to complete its phase III trials in 2004 and then put together the BLA filing and turn it over to the FDA.
On the third quarter call (November 12, 2003) nothing had changed. Max Talbott:
“All aspects of the Advexin development program are on track to enable the submission of our biological license application in 2004.”
David Nance was equally confident:
“As we have provided guidance previously, we and as Max Talbot just reiterated, we will be filing a BLA for Advexin next year in 2004.”
And so too on the next conference call, on February 27, 2004. David Nance commented: “We are moving closer to our goal of filing a BLA, Biologics (inaudible) license, application for ADVEXIN later this year” and of course Max Talbott sang the same tune:
“By way of an update today, I'm very pleased to report to you that all of our trials and development processes remain on track for filing of our BLA this year. In the very near future, we will begin our pre-BLA meetings with the FDA to prepare for a submissions filing later this year. During these meetings, we will be reviewing with the agency our chemistry, preclinical and clinical data, the latter of which will include Phase II and Phase III data.”
But by May 11, 2004 (the first quarter 2004 conference call), the story had already begun to change meaningfully. Now, Introgen would merely begin the filing of a rolling BLA submission in 2004. David Nance: “With respect to our lead product
ADVEXIN, we remain on track to begin the BLA submission this year.”
“As we have previously reported, we remain on track for the initiation of our BLA submission this year.”
And Bob Sobol:
“Well, as we mentioned, we, you know, planned to file, begin the filing process for the BLA in 2004 by the end of this year. And it is really the results of those meetings that we've mentioned that are planned for the FDA with the FDA over the next several months that will determine the BLA filing options that we will pursue. And also that will dictate the time lines for completing our Phase III trials.”
So in just three months, we’ve gone from submitting a BLA in 2004 (which implies that the phase III trials would have been complete and analyzed) to initiating a rolling BLA. Moreover, the phase III trials are still enrolling patients so they are, in fact, not even close to being completed. And furthermore – how could the discussions with the FDA have anything to do with “the time lines for completing” the phase III trials? The timelines for a clinical trial are determined by how many patients are to be enrolled, how quickly on finds and enrolls the patients, and how long it takes patients to reach the primary endpoint. The size and primary endpoint are specified in the protocol, and the rate of accrual has nothing to do with the FDA at all.
The next two conference calls (a post ASGT-ASCO call in Jun 2004 and the second quarter call in August, 2004) reiterated this meaningfully pushed back timeline of “initiating” the BLA filing by year-end 2004. But on the third quarter 2004 call (November 8, 2004), management made no mention about the initiation of the BLA filing by year end, despite the fact that it should have been nearly ready to go. And they did not address the issue even when asked directly about it!
A December 23, 2004 press release provided a further twist to the company’s prior guidance:
“Introgen announced that it has filed a Request with the U. S. Food and Drug Administration [FDA] to accept a "rolling Biologics License Application" (rolling BLA) for ADVEXIN. Introgen also plans to seek Accelerated Approval of ADVEXIN . . . . Introgen has decided to pursue Accelerated Approval for ADVEXIN. The company is requesting that the Accelerated Approval rolling BLA begin immediately, with the completion of the filing process before the end of next year.”
So the company failed to “initiate” the filing of its BLA by year-end 2004 – rather, it merely told the FDA it intended to file a rolling BLA for Advexin! As of March 14, 2005 (the fourth quarter 2004 conference call) the submission of the rolling BLA still had not yet started.
“Introgen filed a request for the submission of portions of an application, called a SoPA with the agency. SoPA term is used to describe rolling NDA's and BLA's. SoPA request is the first regulatory step of our rolling BLA accelerated approval process. In conjunction with the SOPA request filing, Introgen also submitted its first BLA technical selection to the ADVEXIN IND for a pre-review evaluation.”
A SoPA is defined as a “submission of portions of applications". Introgen had merely submitted a request to the FDA that it be allowed to submit the Advexin BLA in pieces, commonly known as a rolling BLA. Let’s be clear – this is NOT in any way the “initiation” of a rolling BLA submission.
On that March 2005 conference call, David Nance could not even articulate a cogent reply to an analyst who asked about the status of the phase III data. Mark Gross asked"
“My understanding from last year was that your plan was to file, to begin the BLA filing process at the beginning -- I'm sorry, at the end of last year, and to finish it roughly by the end of this year. And that was before you decided to file mainly on the Phase II data. Implicit in that is that you would have the Phase III data well before the end of the year in order to complete the BLA process based on the Phase III data, if that had been your decision. So I'd like to ask whether you still expect to have the Phase III data available before the end of this year?”
David Nance’s reply is worthy of being cited in its entirety:
“You know, there are a number of options that I may ask Max Talbott o comment on, but again, I think -- I think your analysis is flawed because it does not include the appropriate number of variables, and I'm not sure to be, you're a bright guy, of course, and to be fair, I'm not sure that anybody can -- could include the number of variables because there are so many moving parts. So, in late December, the reporting quarter, we announced that the Company had taken the decision to request an accelerated approval and we -- in this call and previously have laid out the rationale for that request, and I think that because of the complexities and the complexities, for example, will we do interim analyses? And if so will the agency allow us to do it on, you know, a number of patients, a certain number of patients that had been treated? And there are almost endless permutations of examples that indicate that you really, you know, we announce material events when they occur and we think that our strategy announcement and our filing in December speaks for itself.”
That is quite a long non-answer to a simple yes or no question – will the phase III data be out in 2005?
Also in March 2005, Introgen appeared to make a material mis-statement in its 10K filing:
“The design of our two Phase 3 clinical trials was agreed to by the Food and Drug Administration, or FDA, under its Special Protocol Assessment program, and we have received Fast Track designation for ADVEXIN therapy from the FDA.”
A special protocol assessment [SPA] is when the FDA and a company agree to the design of a phase III trial, then the company goes out and actually runs the trial – the SPA generally states that if the trial is successful, it will support approval of the drug in question. To my knowledge, Introgen had never previously stated that the phase III program was being conducted under an SPA. More on this detail later.
On the May 2005 conference call reviewing the first quarter of 2005, Max Talbott re-iterated the company's commitment to getting Advexin onto the market soon:
“The soon er that we can make this product available, the sooner victims of head and neck cancer will have a therapy to ease their suffering and perhaps prolong their lives . . . . As you know, we have announced the initiation of our rolling BLA process and our plans to seek an accelerated approval rolling BLA for ADVEXIN in head and neck cancer.”
Notice they did not announce the initiation of a rolling BLA – rather “the initiation of our rolling BLA process.” Max also noted “our phase III trials are continuing.” And once again, in response to a direct question about enrollment in those phase III trials, David Nance waxed unintelligibly:
“Our management believes that, we are well advised and it's just not in the interest of the shareholders we believe, to speculate on all the possibilities and options that are available to the Company as we move through the process with the Agencies. So I appreciate your curiosity, certainly, I appreciate that. And hopefully you and the other listeners can appreciate how committed the Company is to making sure that we successfully register ADVEXIN. And also utilize the options which are numerous that are available to us as part of the iterative process with the Agency.”
On the August 9, 2005 conference call, there was still no statement from the company as to whether or not it had actually submitted any portion of the BLA to the FDA. In fact, the company had not even said whether or not the Agency had approved its request for a rolling BLA. It is more of the same. From Max Talbot:
“I’ve previously described in detail our overall regulatory strategy for the registration of ADVEXIN for recurrent head and neck cancer, and our plans continue to be consistent with our previous guidance. We are in ongoing contact with the US Food and Drug Administration and are continuing to implement the regulatory plan that we described at the time of our biologic license application -- BLA -- request to the agency in December 2004.”
On that second quarter 2005 conference call, the SPA issue reared its head. In response to a direct question about whether or not the company had obtained an SPA since the 10K had explicitly stated an SPA was in place, David Nance responded:
“Okay. We do have a protocol assessment from the agency and have those documents that we’ve disclosed. It’s not a special protocol assessment. When we received the protocol assessment – correct me if I’m wrong, Max -- there was no “special” available."
And Max Talbott supported this claim from David Nance:
“No, you’re absolutely right. David, special protocol assessment provisions, I think, came along about a year after.” David Nance added: “Well, just for the record, it should be a protocol assessment, but it has all the bells and whistles of an SPA. We just had the value of it for 12 months or 18 months ahead of the standard term.”
So first the company had clearly stated in its SEC filing from March of 2005 that it had an SPA. When asked, they denied it and said their conversations with the agency took place before there was an SPA process, but they had a “protocol assessment” which has all the “bells and whistles” of an SPA. Well the main “bell and whistle” of an SPA is the written commitment from the agency that if a trial is executed in the way it was designed and the results are positive, then those results will support an approval. Do they have such a commitment or not? I think the answer to that question is clear. Oh, by the way, subsequent SEC filings have referred to a “protocol assessment” but not an SPA.
On the November 2005 all, the company did not answer a direct question about whether the rolling BLA submission would be completed in 2005 or not. In December 2005, yet another twist in the saga occurred when the company announced in a press release that it had made a “proposal to the U.S. Food and Drug Administration [FDA]to request permission to accelerate the initiation of an interim analysis of its randomized, controlled phase 3 ADVEXIN clinical trial data ahead of schedule.”
On the fourth quarter 2005 conference call, which took place almost exactly one year ago in March 2006, Max Talbott told us “I'm pleased to announce, that this proposal has been accepted by the agency who has endorsed expediting the analysis. FDA has additionally commented that the information from this safety analysis will be useful in the review of our BLA. We have also responded to multiple FDA suggestions that we consider doing previously unplanned interim efficacy analyses for one or both of the Phase 3 studies that will be useful in the approval of the Advexin BLA.”
And in a routine that had been played several times before, David Nance gave a non-answer to the very direct question “when are you going to file the last section of the BLA for Advexin?” David’s reply: “Max, you can comment if you want to. It will be brief, I'm sure, but we're not giving particular guidance. As you know, a BLA is completely filed when all the sections are in. We are providing data to the agency sequentially. We have a pending request for accelerated approval. We have a confirmatory trial strategy that is coming into place that Max has described to you with our interim efficacy analysis on page 3. I don't think there is an answer that we can give you for that particular question.” I think a better question would have been “when do you intend to submit the first section of the BLA for Advexin?”
Moving to the May 16, 2006 conference call, the company purported to give an update on the interim safety analysis of the phase III trial P301. Max Talbott said:
“We previously announced that we had not yet reached the predefined point of 109 survival events in the study even though more than enough patients have been enrolled for a sufficient length of time to achieve that point. We proposed to the FDA that we be allowed to accelerate the initiation of the analysis and the FDA has agreed to that. In addition, the actual analysis approach has been agreed to with the FDA, and we are confident that the comparative analytical approach that we are taking will result in findings that substantiate the safety of ADVEXIN.”
Now why would they be discussing the “analysis approach” with the FDA at this point when the statistical analysis is pre-specified in the trial protocol? And how is it possible that they are supposedly in the middle of a rolling BLA submission yet they are still discussing with the FDA which data from which trials is going to be part of that submission? I have been following the biotech industry for 10 years and I have never seen companies engage in discussions with the FDA about what data to include in a BLA or NDA AFTER the application has been filed.
Again, I think the only question to ask here is “has a BLA, rolling or otherwise, actually been filed with the FDA?” Max Talbott’s words on this call would suggest not:
“Since as part of our US rolling BLA efforts, we’ve completed or have nearly completed the other technical sections -- for example, the pre-clinical manufacturing of the application, we have all the critical elements of a registration document prepared with the exception of a specific clinical section addressing the Li-Fraumeni Syndrome indication. Even a clinical safety section would be available to us based on our over 600 ADVEXIN- treated patients.”
Notice the phrase “our rolling BLA efforts,” and not “our rolling BLA.” Also note his comment “even a clinical safety section would be available to us” – clearly implying that such a section does not yet exist, but it could exist, in theory, were someone to compile the safety data on the 600 patients who have received Advexin over the years.
In a July18, 2006 conference call, this thorny question about the filing of an Advexin BLA came up again: an analyst asked “what work remains to be completed, if any, to file in the United States for accelerated approval . . . in other words it appears for me that you have all of your data now, it has been analyzed, you know, what needs to happen now, if anything?!
And the answer is that there’s almost nothing left to do! Max Talbott answered “Basically just reaching agreement with the Agency, and what format they want it.” And he elaborated further
“It's administrative I have done it, well, I have done it nearly three dozen times on approved drugs both here and abroad, so this is something that over the last 35 to 40 years I have been doing at least once a year, and in many instances, it's just administrative, really. And so I don't mean to minimize the effort, but as far as the complexity is concerned, once we have reached an agreement with the Agency of the administrative format they want it in, then the hard work has been done. The discovery, the analysis, the correlation, the actual clinical trials themselves, those are fait accompli.”
Well once again, it is not exactly clear why if they are in the middle of a rolling BLA they would be having a conversation with the agency over the format of the BLA? But truly the most amazing thing we learned here is that “the discovery, the analysis, the correlation, the actual clinical trials themselves, those are fait accompli.”
Not so fast . . . less than one month later, on the second quarter 2006 conference call, everything seems to have come crashing to a halt. Now, all the data will be interpreted in light of some poorly articulated biomarkers. This, the company believes, will EXPEDITE the approval of Advexin, which in 2003 the company said was ready to go to the FDA in 2004! Max Talbott sounded triumphant:
“As we announced today, we have reached agreement with FDA to not only use these biomarkers in our analysis of our Phase II data, but also to incorporate these useful predictive tools in the interim efficacy analyses that we will be performing on our ongoing Phase III trials. This is an absolutely essential element of our accelerated approval enrolling BLA regulatory process. With FDA's previous invitations to consider interim efficacy analysis for the Phase III studies, we are now prepared, in conjunction with the FDA, to conduct these analyses. As we've indicated on several previous occasions, our BLA will utilize both Phase II and Phase III data for analyses. These analyses will be informed or are already in-hand biomarker intelligence and will allow us to provide package insert information specifically targeting patient characteristics.”
BUT WAIT – a few weeks earlier he told us “the discovery, the analysis, the correlation, the actual clinical trials themselves, those are fait accompli” and that all that stood in the way of a complete BLA filing was a question of the formatting of the BLA! Now they are going to have to engage in all sorts of new, non-prespecified analyses of phase III trials that have not even completed enrolling?
And read what the company was talking about – product labels! Despite not having completed phase III, not having released any of the interim analyses, not having any idea what the “biomarker” analysis of the phase III interim data will look like, and despite supposedly being in the middle of a rolling BLA submission for accelerated approval based on the uncontrolled phase II studies!
Max Talbott again:
“As mentioned during their remarks on the July 17 teleconference, Introgen and FDA are currently in the proces s of reaching agreement on the formats and mechanics to be employed in continuing the final regulatory activities. We believe that our available Phase II and soon-to-be-available Phase III data are more than sufficient for our regulatory approval processes. We believe that the package insert language, though, that we develop from these data will allow ADVEXIN to describe a superior safety and efficacy profile as compared to those profiles now available for existing recurrent head-neck cancer products.”
Later he said more:
“That's a good preface to the fact that the, I think what's really key about all of this is that we're, we applied the biomarker findings to the Phase II data, but clearly we had to get the agency's agreement to prospectively apply biomarker findings in the analysis, the interim safety analysis--excuse me, the interim efficacy analysis for the two ongoing Phase II trials. And that, I think, speaks to the issue of using these data in a prospective fashion to ask the right questions, to demonstrate the efficacy of ADVEXIN in both of these circumstances. I made an allusion to the fact of the package insert in my comments earlier today. Realize, of course, those of you that have been following us for a long time, these are ongoing trials, one of which is a monotherapy comparison, and the other which is the use of ADVEXIN in combination. So theoretically, then, as we move forward, not only would we have a monotherapy indication for ADVEXIN in recurrent squamous cell head-neck cancer, which Erbitux received earlier this year with 103 patients worth of data, I think. But it's very conceivable and likely, in fact, that the package insert will contain reference to combination use of ADVEXIN as well.”
And the old SPA issue came up again – again, Max Talbott:
“We will utilize what's called an SPA or Special Protocol Assessment to record and maintain all of these agreements, simply because the agency, I think, has long favored that approach. And it will be one which will, in fact, make our life a lot easier as we move into the actual approval itself.”
Now how are they going to get an SPA for a trial that was designed 5 years ago, has been enrolling patients over that whole time, and is not being subjected to multiple unplanned interim analyses?? The very idea defies the imagination! But David Nance threw some cold water on the conversation:
“I want to make sure that we are not announcing that an accelerated approval, based only on the Phase II data, is being announced, nor are we stating that the accelerated approval will require the Phase III data, and that the Phase III data might be used as a confirmatory analysis. So we're not saying anything. We're just saying other than we have agreed with the agency that we may use the biomarker data, and we're working out the precise details, and I wouldn't rule out either possibility.”
I think his comment says it all – “we're not saying anything” – that is exactly what Introgen has been doing for years. Not saying anything. So at year-end 2006, now 2 years after the BLA was supposed to have been filed, Introgen issued a press release announcing a conference call to “update its regulatory and clinical developments including its plans to begin the analyses of Phase 3 ADVEXIN trials. Management will comment upon the agreement between Introgen and the Food and Drug Administration for the statistical analysis plan of ADVEXI N phase 3 clinical trials to support product licensure for recurrent head and neck cancers.” On that call, David Nance said “Introgen and FDA have agreed on the statistical analysis plan for the ADVEXIN Phase III clinical trials to support product licensure for recurrent head and neck cancers. The analyses will incorporate p53 protein and other biomarkers. Our recently reported clinical biomarker data has provided extremely high statistical significance for both survivals and tumor response in p53 biomarker-defined patients. We plan to initiate the analyses of the Phase III ADVEXIN trials in early 2007.” So instead of filing a BLA in 2004, they will be beginning INTERIM analyses of the pahse III data in 2007!!
That brings us to yesterday’s fourth quarter 2006 conference call. Max Talbott put it on the line:
“The Company will begin the Phase 3 efficacy analysis in the second quarter of 2007. As we previously reported, a sufficient number of patients have been treated in the Phase 3 trial to provide us with meaningful efficacy data from these analyses. These efficacy analyses will be completed, and all remaining elements of the FDA registration submission will be concluded, recurrent head and neck cancer in 2007.”
He reiterated this guidance:
“One, we have formally amended the Phase 3 statistical analysis plan in preparation for opening of our study database. Two, we will begin the efficacy analysis of our Phase 3 data next quarter. Three, next quarter we will submit to FDA our final analysis set of the ADVEXIN Phase 2 data, to include our most recent biomarker findings. And, four, in 2007, we will complete the submission to FDA of all elements of the BLA for head and neck cancer.”
But when asked if the company would make the results of its phase III analyses public when complete, David Nance hedged:
“Yes, I just think, Bob, I [inaudible] my answer by the calendar date, so we've given a range of within two quarters. It's clear that the activities will ensue in the -- between those dates we mentioned and before the end of the year, and we'll provide the information to FDA, and, depending on the time in the year, we may publish. We will be making publications at conferences, as we usually do, and so, I'll say again, it's possible, depending on how the process goes and the precise timing between now and the end of the year.”
Mark your calendars. By the end of this year the Advexin BLA will be filed (we’ve heard that before). That means a 2008 review and decision. Hopefully, they have cobbled together enough data so they don’t merely get an RTF letter and we can all enjoy reading a detailed FDA review before they get skewered at an Oncology Drugs Advisory Panel. Either way, 2008 should see this story come to a close. Mercifully.
Disclosure: The author has a short position in INGN.
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