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Got it.
Slide 15 show that neither treatment arm of 2nd Line trial have evented yet.
I think Elan or Dendreon decided to bar AF from a conference once. He raised a stink and they let him in.
St.SR's point deserves to be revisited.
post# 89772
What is Cotara worth if it is sold outright after the FDA replies with a P3 decision? Any estimates? I understand that the paved path would be partnering, but wouldn’t the proceeds of a Cotara sale coupled with the recent loan provide enough capital to at least give the impression that Peregrine could go it alone?
Firechief, corporalagarn, how would you evaluate the idea of selling Cotara to fund Bavituximab's PIII/PIV -- allowing PPHM to enter into the semi-dark of a full-blown, randomised, double-blind PIII/PIV with survival as the primary endpoint? Would you risk clinical failure to maximise your return on the other side of a successful clinical trial?
Could they sell it for enough to make going it alone possible?
The more I think about it, Peregrine has to partner. There's no other way PPHM can afford a PIII/PIV clinical trial -- and enrolment in a PIII/PIV is pretty much required before a company can be granted AA. The FDA may even require interim data from the PIII/PIV to grant the AA.
So AA cannot be something Oxford is counting on.
I agree with Firechief and Corporalagarn, Oxford has to be confident that a deal is afoot.
UPDATED
KT,
To me, the loan makes sense from a negotiating point of view only if the company has determined for itself -- and Oxford agrees -- that they have the ability to file for AA.
If they can't apply for AA and no acceptable deal can be reached, PPHM suddenly has no path to a PIII and they will struggle to pay back the $15M loan. They still have the possibility of a Cotara deal but, similarly, they will have lost negotiating leverage (made themselves vulnerable) having taken on the burden of the loan without a pathway to AA and revenue.
With AA they have a pathway to substantial revenue in less than a year.
Even with an AA application, there is substantial risk of regulatory and, ultimately, clinical failure, so they should partner to mitigate that risk.
Interesting graph. Looks like we have an initial response, maybe from the carboplatin and paclitaxel therapy. We seem to fall off a cliff around six weeks in, then at 8 weeks we plateau. Eight weeks was the time the immune response began to kick in for the other immunotherapeutic biologic from FTM's article.
I wonder if the immune response wasn't too late in the advanced disease therapy for the immune effect to make a big difference in the signal seeking 1st-line trial...
Reading tea leaves, could be useless. Probably is.
Today I sent Tustin FTM's article on the delayed response of tumours to immunotherapy. I decided it wasn't worth the chance of them not being aware of the development in light of their continued use of RECIST to evaluate tumours. It may be a waste of my time and theirs, assuming they already know the issue. On the other hand, there has been no indication that they are aware of it and I thought it best not to leave it to chance.
Totally in the PNWMBWK column. (ProbablyNotWorthMuchButWhoKnows?)
They're using RECIST. PPHM may need to rethink that given that disease progression in immune stimulatory therapies can give misleading signals using RECIST criteria.
Yes. They do that because the AA would cover 2nd-line (or in some cases 3rd-line) patients. (You can't get AA for 1st line.) But try to enrol a confirmatory trial once you've gotten AA ... a little tough. So they enlarge the patient base by using non-refractory patients for the confirmatory trial because they are not eligible for the AA approved treatment. It causes some problems, but it's one way they've been tackling the problem of slow to no enrolment in confirmatory trials.
Note the Oncology Drug Advisory Committee transcript from March 12, 2012. Dr. Pazdur addresses the issue specifically. P 37, lines 16-18.
http://www.fda.gov/ohrms/dockets/ac/cder03.html#OncologicDrugs
(It's a few down on the list)
The March 12-13 meeting. It should contain a wealth of information on AA. Thanks for hunting it down!
It's a long two documents if people want to jump in and read, would be great. I'd guess they have votes and summaries along the way, if someone wants to hunt them down.
Let's all work off the PDF download so we have consistent page numbers.
THAT, it a brilliant find.
PG,
I don't think it matters what happens tomorrow. The weighing machine will take over eventually. If we succeed, you will want a plan for when irrational exuberance takes hold and sends us into the stratosphere...
On top of that, the article cited goes on to detail the AA of several biological products and drugs. If anybody has any questions regarding the author's intentions they can contact him. He posted his details at the bottom of the article:
Correspondence to: Ramzi Dagher, MD, HFD-150, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 1451 Rockville Pike, Rockville, MD 20852 (e-mail: dagherr@cder.fda.gov)
The language appears to be very similar.
Sec. 601.40 Scope.
This subpart applies to certain biological products that have been studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit to patients over existing treatments (e.g., ability to treat patients unresponsive to, or intolerant of, available therapy, or improved patient response over available therapy).
Sec. 601.41 Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity.
FDA may grant marketing approval for a biological product on the basis of adequate and well-controlled clinical trials establishing that the biological product has an effect on a surrogate endpoint that is reasonably likely, based on epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this section will be subject to the requirement that the applicant study the biological product further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. Postmarketing studies would usually be studies already underway. When required to be conducted, such studies must also be adequate and well-controlled. The applicant shall carry out any such studies with due diligence.
Thanks. Reading it...
Found this already: The applicant shall carry out any such studies with due diligence.
Hmmm...!
http://jnci.oxfordjournals.org/content/96/20/1500.full
DISCUSSION
Although Subpart H regulations state that post-marketing studies to confirm clinical benefit would “usually be studies underway” at the time of accelerated approval, this has not always been the case and is not a requirement (2). However, the FDA believes that the design of these studies needs to be part of a comprehensive drug development plan that is discussed with the FDA early in the development process. A continuous dialogue between the sponsor and the FDA should exist during the conduct of confirmatory studies, with strategies in place for alternative studies if those originally proposed fail to demonstrate clinical benefit.
and
Both single-arm studies and randomized studies may provide evidence to support accelerated approval. It is useful to discuss development plans including the design, conduct, and analysis of confirmatory studies with the FDA early in the development process. These studies are viewed as part of a comprehensive drug development plan that includes studies that might lead to accelerated approval and the confirmatory studies.
* * * * *
Peregrine had already run an open-label, PII NSCLC trial plus another, separate PII trial with essentially the same docetaxel treatment protocol as the ongoing PIIb. The second, docetaxel based trial, reported a 10.9% complete response rate in Advanced and Metastatic Breast Cancer.The results have been published in a number of scholarly articles.
http://scholar.google.co.uk/scholar?q=bavituximab+Advanced+Breast+Cancer+docetaxel+complete+response&hl=en&as_sdt=0&as_vis=1&oi=scholart&sa=X&ei=fgtAUNSfCIGg0QXfgYHADQ&ved=0CB0QgQMwAA
Those PIIs (and others) may have formed the basis for the initiation of a comprehensive plan process like the one described above.
From earnings calls and presentations we know that Garnick worked through the trial designs of the two PIIb trials with the FDA and has been in repeated contact with the FDA since the process began. What exactly is going on in those meetings hasn't been disclosed, but from the beginning of the randomised trial he has talked about the possibility of AA if the data came in as a home run.
Since the trials began it has become clear that bavi's MOA unblinds the immune system allowing a immune response to cancer cells (note Thorpe's May presentation). From papers recently posted on this board you can see that treatments that stimulate an immune response have a delayed effect that can be misleading if tumours are being analysed using RECIST -- which is what the bavi PIIb trials used.
Given the extraordinary survival results that are clearly developing, the federal mandate of AA, the FDA's ability to be flexible evaluating AA approval criteria, the updated understanding of bavi's MOA and Garnick's continuing discussions with the FDA, I don't think it's unreasonable to think AA is a possibility this time around.
OTOH, It's a given that the FDA is not a charity and isn't going to give AA minus what it considers a "reasonable" indication of clinical benefit and safety.
AA? TBD.
Mag, I hope you aren't short. It could get brutal for you if you are in a very short period of time.
Denileukin diftitox (Ontak) was granted accelerated approval in 1999 for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the interleukin 2 receptor. Approval was based on results from a randomized study that compared 9 µg/kg/day versus 18 µg/kg/day (given for 5 consecutive days every 21 days) in 71 patients with persistent or refractory disease (26). The objective response rate for the two treatment arms combined was 30% (95% CI = 18% to 41%), with no statistically significant difference in objective response rates between the two arms. The post-approval phase 4 commitment, which was initiated before accelerated approval was granted, is for a randomized, three-arm study with 1 : 2 : 2 randomization to placebo, 9 µg/kg/day, or 18 µg/kg/day that is currently accruing patients in North America, Europe, and Australia.
I'm not sure that based on an n=11 AA approvals "based on studies with active comparator groups" between that a subset of those 11 AAs is going to give me any confidence in a statement like "it's never happened before, therefore it's de facto FDA policy."
Clearly the FDA is granting AA on a basis other than statistical significance in some cases - even in randomised trials with active comparator arms. We don't have enough information -- enough examples -- to know whether or not the FDA has a de facto policy on SOC / SOC+ yet. Unless there is a document that states the policy.
http://jnci.oxfordjournals.org/content/96/20/1500.full
I really do have to go now. Family, I've already stayed to long...
On BV you wrote: PPHM longs continue to promulgate the canard that accelerated approval in second-line NSCLC possible based on a phase-2 trial that missed its primary endpoint. This has never happened in FDA history, as far as I know.
Are you talking from your experience or from conversations you've had with authorities or documents you have read?
Citations would be helpful.
Stifel hasn't happened yet. Citation?
Untrue.
Abstract
On August 19, 2004, pemetrexed for injection (Alimta); Eli Lilly and Company, Indianapolis, IN, http://www.lilly.com) received accelerated approval as monotherapy for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had received prior chemotherapy. Approval was primarily based on a single, controlled, unblinded trial. Five hundred seventy-one protocol-eligible patients were randomized to receive either pemetrexed or docetaxel (Taxotere); Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharmaus.com). The primary efficacy end point was overall survival. The median survival times were 8.3 months in the pemetrexed arm and 7.9 months in the docetaxel arm. Neither superiority nor noninferiority for overall survival could be demonstrated, the latter because a reliable and consistent survival effect of docetaxel could not be estimated and because of significant crossover of pemetrexed-treated patients to docetaxel after tumor progression. Comparable response rates, 9.1% for pemetrexed and 8.8% for docetaxel, times to progressive disease, and progression-free survival times supported the conclusion that an effect of pemetrexed on survival was reasonably likely, however. In addition, pemetrexed was felt to have a more favorable safety profile than docetaxel. Of greatest importance, pemetrexed caused significantly less neutropenia, febrile neutropenia, neutropenic infections, and need for granulocyte/macrophage colony-stimulating factors.
Citation provided by MJ
So, average price of the Alien Abduction Gang: $12.18
Average price of the Abduction Gang's Insane group: .45 (you're surely being generous there, H...)
And the new OB Simn --> $6.315! Adjusted by the LOOF-LIKE Adjustometer, (divide by two) and the new prediction is ... wait for it ... $3.16!
Which puts my $3.13 prediction closest.
Then again, you're assuming that they weren't abducted...
Got me laughing out loud. Good point. :o)
As you can see from my prediction, I've cut it by a little more than that. ;O) I like the experiment. I'm dying to see what the price is on the 31st. I hope I'm the biggest loser in the bunch! (Don't expect to be, but I'd love to be.)
I think Loofman should update whenever there's a different "loof-number."
Long ago, when my wife was in business school, she read me part of a paper that argued, in essence, that the majority is right the vast majority of the time.
It's how I discovered PPHM ... looking for the board with the most activity.
When I see Loof's posts and the updates to the average price and his loofly calculation, I think, "Interesting. Let's see how close we are on the 31st..."
For me, it's entertaining. Could it be more than that?
Makes a lot of sense.
UPDATED with note on KM curves, delays and the repercussions on the Hazard Ratio
A different immune stimulatory protocol got this eye-popping result from the 2nd paper FTM posted tonight:
http://jnci.oxfordjournals.org/content/102/18/1388.full.pdf+html
Photographs of a case study of the first novel tumor response pattern (Figure 3, D) show that tumor burden initially increases (day 84) and then decreases (day 112) to a complete response (day 503).
Tumor burden increased for almost 3 months.
Tumor burden began to decrease starting at almost 4 months
Complet response achieved after 16-17 months
It's not bavituximab, but it does illustrate the delay in apparent effect that can happen when immune stimulatory therapy is used.
(its late, my english is deteriorating.)
RCJ, this one's for you!
overall survival
A delayed separation of Kaplan–Meier survival curves is
observed in almost all randomised immunotherapy trials, and
may occur months after the start of treatment.
The delayed separation of the KM survival curves also affects the HR. Traditional HR doesn't work. The end of the paper is very interesting. Note the last graph where the delay's impact on the HR is demonstrated.
From FTM's article, part of the reason radiological scans could be confounding when treatment stimulates the immune system:
(refer back to FTM's original post for the URL)
antitumour response
Following treatment with immunotherapy, changes in tumour
burden may be the consequence of three scenarios; (i) in
patients that have an objective response, the tumour is invaded
by immune cells and inflammatory cells and metastatic lesions
decrease in size; (ii) in patients with tumour progression,
metastatic lesions increase in size and (iii) in patients where
tumour lesions become heavily infiltrated by immune and
inflammatory cells, there may be an initial increase in tumour
burden. In the case of the latter scenario, the increased burden
is an indicator of an antitumour response, but would be
defined as progressive disease according to existing Response
Evaluation Criteria in Solid Tumours (RECIST) or World
Health Organisation (WHO) criteria.
In our case where we use RECIST to evaluate tumour size, growth and shrinkage, our ORR and PSF numbers may fundamentally misrepresent the ultimate therapeutic effect. Which could explain why our MOS numbers appear to be exceeding the MOS numbers one might have projected based on our ORR and PFS surrogate endpoints. How much our MOS could exceed expectations has yet to be seen...
B, the issue was addressed in this article written about 5 years subsequent to the article you cite.
http://www.topra.org/sites/default/files/assets/pdf/2011_mar_-_jnci_aa_of_oncology_products_fda_experience.pdf
Written on January 17, 2011
The Conclusion
Lack of due diligence in conducting confirmatory trials is a serious concern that has threatened the continuation of the accelerated approval process. Before the FDA grants accelerated approval of a new indication for a drug, the pharmaceutical company is required to commit to a confirmatory trial protocol submission date (if one was not already submitted), a confirmatory trial com- pletion date, and a study report submission date. Accelerated approval is granted only if the FDA agrees that these timelines are reasonable. Until recently, the only option available to the FDA for addressing a lack of due diligence by the pharmaceutical company in keeping these commitments was to revoke the accelerated ap- proval. However, removing a drug from the market solely because of lack of due diligence when the only available evidence of efficacy is that the drug is reasonably likely to have better clinical benefit than available therapy may be an appropriate sanction against the pharmaceutical company but may not be in the best interest of cancer patients. Thus, this is not an attractive option and has never been done for an anticancer drug. The US Congress has recently addressed this problem by passing the Food, Drug and Cosmetic Act of 2007 (9), which gave the FDA authority to assess monetary penalties up to $10 million on pharmaceutical companies for lack of due diligence in completing confirmatory trials for drugs granted accelerated approval (10). The FDA believes that this will be an effective new tool for dealing with lack of due diligence.
Sorry, had to put my girls to bed. Adjusting to the start of the school year.
Yes, I downloaded the whole article without a problem. Thanks. If you want it I can send it to you.
Just read the article more carefully. Really good stuff.
UPDATED: Time from AA approval and regular approval averages 3.4 years. That's time to sell a fair bit of bavituximab which is why, if it is at all possible, it would be the way to go initially.
http://www.topra.org/sites/default/files/assets/pdf/2011_mar_-_jnci_aa_of_oncology_products_fda_experience.pdf
Bottom page 7.
Among the 15 accelerated approvals that were converted to regular approval, the median time from accelerated approval to regular approval was 3.4 years (range = 1.0–12.6 years) and the average time was 4.6 years. The five longest intervals between accelerated approval and successful conversion to regular approval were 12.6, 9.7, 8.1, 7.5, and 7.4 years. Among the 12 accelerated approvals that have not been converted to regular approval, the four longest intervals from accelerated approval to July 1, 2010, are 6.4, 5.5, 5.5, and 4.7 years.
Agreed.
cj,
I've been using a more conservative number. I put us at 11.4 months MOS now.
RJ,
There's your answer to the immunotherapy debate. Bluster isn't proof of anything. Well, it's not proof of an argument.
Wouldn't they need a confirmatory trial for regular approval? AFAIK, that's the norm.
I think AA application even if MOS is stat. sig. or they bite the bullet, do the PIII with a partner and we find out how it goes (OS) in 3.5-4.5 years, length of time depending on enrollment speed.
Thurly's Current 2nd-Line MOS Projection
For both the high and low dose treatment arms: 113% improvement in MOS over the docetaxel monotherapy arm.
MOS has not yet evented in either treatment arm. Percentage improvement over the control arm, which has evented, continues to increase...
FWIW
Stifel Nicolaus Healthcare Conference date and time.
http://www.veracast.com/webcasts/stifel/healthcare2012/55112488.cfm
September 5, 2012 at 2:40 PM (ET)
Speaker:
Mr. Stephen King, President & CEO
Will be webcast.