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My wife just looked over my shoulder and said, "Hows it going?" Thank goodness for a moderated board...!
Battle of the midway to $3.00. Pretty impressive.
Max Pain. People will deny it, but it seems to apply to the majority of OpExes I've watched..
I believe they said they will consider applying for AA if the data merits it -- in so many words.
Whether the data will merit it is TBD. We still haven't seen the bottom line data.
I was born in Limestone, population 2,314 at the 2010 census.. :o)
Since we may not be stat. sig. on anything, we wouldn't be granted AA based on OS in any case. The question is, will we meet and/or exceed the requirements of an AA application. Note Mojo's recent post.
I don't know if we apply for AA. I'm more interested in the criteria and the possibilities at this point.
...that is reasonably likely...
Based on your citation, your earlier example of an AA aproval and the three examples of AA approvals that I found and posted so far, the argument that AA requires stat. sig. in a primary (or secondary} endpoint would appear to be untrue.
Another single arm study that got AA.
http://www.hematology.org/News/2009/4293.aspx
On September 24, 2009, the Office of Oncology Drug Products granted accelerated approval to pralatrexate injection (Folotyn™, Allos Therapeutics, Inc.) for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This approval was based on an overall objective response rate observed in a single-arm trial. As a condition of the accelerated approval, randomized, controlled trials are required post-approval to verify and describe the clinical benefit of pralatrexate in PTCL.
Trial PDX 008 was an open-label, multicenter, international trial that enrolled 115 patients with PTCL who had relapsed or had progressive disease following prior therapy. The median number of prior systemic therapies was 3 (range 1 to 12). Twenty-four percent of patients did not have an objective response to any previous therapies; 63 percent did not have an objective response to the most recent prior therapy.
One hundred and nine evaluable patients received pralatrexate at a starting dose of 30 mg/m2 administered as an intravenous push over three to five minutes once weekly for six weeks followed by a one week break (1 cycle). In addition, each patient received vitamin B12, (1.0 mg IM) every eight to 10 weeks and a daily administration of folic acid (1.0 – 1.25 mg orally). Imaging scans to assess disease status were performed at week 7 (end of cycle 1) and subsequently at 14-week intervals. Patients who had tumor responses or stable disease continued to receive additional cycles until disease progression or unacceptable toxicity.
Responses were assessed by an independent central imaging review committee using the International Workshop Criteria (IWC) for malignant lymphoma. The overall response rate (complete response plus complete response unconfirmed plus partial response) was 27 percent (95% CI: 19%, 36%). The median response duration was 9.4 months (range: 1-503 days). Thirteen patients (12% of 109 evaluable patients) had response durations = 14 weeks; the median response duration of these patients has not yet been reached (range: 98 to 503 days). Six of these 13 patients achieved complete responses, one patient had a complete response unconfirmed, and the remaining six patients had partial responses.
Example of a recent AA approval:
On October 26, 2009, the U.S. Food and Drug Administration granted accelerated approval to ofatumumab (Arzerra™, GlaxoSmithKline) for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The approval was based on a clinically meaningful and durable overall response rate (ORR) observed in a single-arm trial (Hx-CD20-406). As a condition of accelerated approval, subsequent randomized trials are required to verify and describe the clinical benefit of ofatumumab in CLL.
Hx-CD20-406 was a single-arm, multicenter trial in 154 patients with relapsed or refractory CLL. Accelerated approval was based on the results of a pre-specified subgroup of 59 patients who were refractory to both fludarabine and alemtuzumab. Drug refractoriness was defined as failure to achieve at least a partial response to, or disease progression within six months of the last dose of fludarabine or alemtuzumab. The primary efficacy outcome was durable ORR as determined by the 1996 National Cancer Institute Working Group (NCIWG) Guidelines for CLL.
In the Hx-CD20-406 trial, patients received an initial 300 mg dose, followed one week later by 2,000 mg weekly for seven doses, followed four weeks later by 2,000 mg every four weeks for four doses (maximum of 12 doses). All doses were administered by intravenous infusion.
In patients with CLL refractory to both fludarabine and alemtuzumab, the median age was 64 years (range 41 to 86 years), 75 percent were male and the median number of prior therapies was five. Eighty-eight percent received at least eight ofatumumab infusions and 54 percent received 12 ofatumumab infusions.
The investigator-determined ORR in patients with CLL refractory to fludarabine and alemtuzumab was 42 percent (99 percent CI: 26, 60) with a median response duration of 6.5 months (95 percent CI: 5.8, 8.3). There were no complete responses. Supportive information included anti-tumor activity observed in a multicenter, open-label, dose-escalation study (Hx-CD20-402) conducted in patients with relapsed or refractory CLL and additional patients enrolled in the Hx-CD20-406 trial.
Depends on how wrong I was about the share price. (It's a big trip from London.) If dia76ca is right @ about $30.77? Heck yeah, I'm there... ;o)
You wrote: my note - you'd have to be naive to believe there won't be a warrant kicker or else funds will be reluctant to participate.
I wrote to point out that PPHM may have attractive alternatives to finance their business that don't include warrants. Everything else has been trader talk. It's not my thing.
Done with this thread.
You think the current dip in stock price matters to an investor? Corcept will do very well for patients and the patient, IMHO.
As a rule, I don't trade.
I posted the wrong link initially. I since updated the link. Look again.
UPDATED - Look at the recent Corcept deal. In this market of uncertain returns, advantageous deals are being made - for both parties.
http://www.streetinsider.com/Corporate+News/Corcept+%28CORT%29+Sells+Synthetic+Capped+Royalty+on+Future+Sales+for+%2430M%3B+Terminates+CEFF+with+Kingsbridge/7636535.html
BSR will release an audio recording of an interview with the CEO of Corcept in which he details the deal in a few days. Members have access now. By agreement, I can't tell you the BSR content. You should keep your eyes open for the interview when it goes public -- sometime at the end of next week.
It's pretty interesting and shows what can be done if one thinks creatively in the current market.
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.
Pardon my French: Holy shit.. I'd call that latitude.
Wow... That's a gem of a citation.
Ex,
I was there for the whole thing. Enlightening, to say the least. PPHM will have to navigate the FDA -- regulations and people. Glad we have Garnick to skipper the ship.
They say that they will answer. Let's see what they say.
The email I sent to the FDA:
Background
I'm monitoring a PIIb clinical trial in NSCLC.
The trial was multi-center, randomised and double-blind for the primary endpoints.
The primary endpoints are ORR and PSF.
The secondary endpoint is MOS.
The trial has three arms. One docetaxel, the other two are treatment arms at two different doses.
Question 1
Does Accelerated Approval require statistical significance to file? For primary endpoints only?
For example:
Question 2
If the primary endpoint is not statistically significant, is AA possible if a secondary endpoint of MOS is extremely good. What if MOS exceeds the control arm by, say 100-200 percent, would AA be possible or not?
Question 3
If a trial is blinded for the primary endpoints of ORR and PSF but not for the secondary endpoint of MOS, is the MOS data considered less reliable due to the potential of treatment bias?
Question 4
Does the FDA consider multi-centered trials that use foreign countries to be less rigorous or more suspect (corruption/data tampering) than those that use US sites exclusively? Are trial sites in Georgia (Russia) and/or India a cause for concern at the FDA?
Was it the proscriptive endpoint? Were they testing with the idea of filing on safety as opposed to efficacy?
Ex,
Generally, I believe you are correct but I'm looking for a definitive source of information on this. To wit: I called the FDA this morning. Turns out, you can email the FDA questions and they will return answers. I've sent one off which covers all of these points. I'll report when I get an answer.
The question I still have is whether or not a secondary endpoint can be the basis of an AA approval if the primary endpoint isn't stat. sig.. In particular, if that secondary endpoint is survival. I'm still looking for the answer.
I expect the survival data to excel but I'm a bird in the hand kinda guy. Excellent survival data should lead to a good partnering deal regardless of AA.
So I'm not overly concerned, big picture.
Article specific to NSCLC Approvals - an easy read with lots of info.
http://www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/ucm120832.pdf
I would caution those that might misunderstand, the lower standard of proof in AA relates to the choice of less certain endpoints -- OOR/PSF vs. OS, for example.
The texts I've read refer to "significant" proof of efficacy in relationship to AA. I take that to mean statistically significant. If I'm correct in my assumption, from what I'm reading, AA does not carry a lower standard of biostatistical proof.
If you thought I was disagreeing with Dew on this point, I was not. I don't yet know enough about it to say for sure one way or the other.
I was disagreeing with Dew on whether one could say the trial failed to achieve statistical significance based on top-line numbers. We've seen how far those numbers can shift in three short months.
We should know very soon. Meanwhile, games will be played.
Another recent article - crossover trials that aren't statistically significant, but actually are! New approach to statistical analysis. Very interesting.
http://www.aacr.org/home/public--media/aacr-in-the-news.aspx?d=2808
June 1, 2012
“The crossover design of the trial meant that our final analysis using conventional statistical methods indicated no ‘statistically significant’ effect of sunitinib on overall survival, because the long-term survival interpretation was shifted by the activity of the drug in patients who received sunitinib after crossover. However, we expected this and also assessed overall survival using a statistical method to model what might have happened in the absence of crossover,” said Demetri. “We found that sunitinib conferred a clear statistical benefit on overall survival. This really is key; it shows that we can design clinical trials that indicate a drug works and offer that active therapy to patients from the placebo arm of the trial — this protects the interests of patients and yet allows the study to provide rigorous proof of the safety and efficacy of the study drug, in this case sunitinib.”
They'll need to partner, IMO. The PIII costs will be multiples of the PII costs.
Worth Reading 2011 Article
Accelerated Approval of Oncology Products: The Food and Drug Administration Experience
http://www.topra.org/sites/default/files/assets/pdf/2011_mar_-_jnci_aa_of_oncology_products_fda_experience.pdf
Especially note Table 2 - the number of treatments that were granted AA based on single arm trials -- that is to say, trials in which a bias was present but the treatments were approved anyway.
I suspect that PPHM (Garnick) did the trial this way to speed up their time to filing for approval, provided they succeed in producing approvable data. Had they made MOS the primary endpoint, we'd still be two years from data and the possibility of a partnership. The dilution would have been brutal.
Based on top-line numbers? That's interesting. I'll keep it in mind...
Please show me proof that the second-line PIIb missed it's primary endpoint.
Factually incorrect.
Accelerated Approval: What's Needed?
The bar is actually lower than for regular approval. For Example:
August 9, 2012
Talon Therapeutics (TLON) today announced Marqibo received accelerated approval from the U.S. Food and Drug Administration for the treatment of adult patients with Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies. This indication is based on overall response rate. Clinical benefit such as improvement in overall survival has not been verified. Marqibo is administered at a dose of 2.25 mg/m2 intravenously over 1 hour once every 7 days. Marqibo has different dosage recommendations than non-liposomal vincristine sulfate.
www.benzinga.com/news/12/08/2820915/talon-therapeutics-marqibo-granted-accelerated-approval-by-fda#ixzz24kramy3g
A quick search of the requirement for AA will show that approval is based clinical need and on less stringent biostatistical benchmarks. For example:
http://jnci.oxfordjournals.org/content/96/20/1500.full
In 1992, Accelerated Approval Subpart H was added to the new drug application regulations. This addition allows accelerated approval of drugs for serious or life-threatening diseases if the drug appears to provide a benefit over available therapy; the benefit is determined by the drug's effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on evidence of an effect on a clinical benefit other than survival. Drugs granted accelerated approval for which uncertainty exists as to the relation between the surrogate endpoint and clinical benefit or between the observed benefit and ultimate outcome must be studied further by the applicant to verify and describe the drug's benefit. The FDA expects that confirmatory studies to demonstrate that treatment with the drug is associated with clinical benefit will usually be underway at the time of accelerated approval, though that is not a specific requirement. If confirmatory studies are not performed with due diligence or do not demonstrate clinical benefit, the Code of Federal Regulations describes a mechanism for removing the drug from the market (2).
Said differently, stat. sig. is not required. What is required?
In general, the FDA has considered an effect on survival or relief of patient symptoms as evidence of clinical benefit in oncology. Objective tumor response rates and time-to-progression have often been viewed as surrogate endpoints that are reasonably likely to predict clinical benefit. Objective response rates and/or time-to-progression have been accepted as evidence of clinical benefit in some circumstances—for example, when relatively nontoxic products are evaluated, such as hormonal therapies for breast cancer and some biologic products. Durable complete responses have been accepted as evidence of clinical benefit in hematologic malignancies when response has been associated with an established clinical benefit parameter, such as improved survival, reduced rate of infection, or reduced need for transfusion (3–5). These endpoints have also been accepted for other malignancies, such as testicular cancer, because the response was of sufficient magnitude and duration that it appeared to be associated with improved survival.
In other words, it's no one thing. The FDA has flexibility when considering AA for serious, unmet needs.
We'll have to see the bavitaximab's 1st-line, bottom line numbers before we'll really know, but it's comforting that the strong topline numbers for the primary endpoints were based on independent investigator reads and that MOS for the treatment arms has clearly gone over 100% improvement over docetaxel control arm of the study.
AA is clearly a possibility if the bottom-line numbers stay consistent with the top-line numbers.
How many AAs can you find that were based on open-label trials (i.e., where the issue of possible bias didn't prevent the FDA from granting AA)?
Are treatments granted AA measured by the same high standard that the FDA requires for regular approval?
No.
jco.ascopubs.org/content/21/7/1404.ful.pdf+html
In 1992, Subpart H was added tot he new drug application (NDA) regulations to allow accelerated approval (AA) for diseases that are serious or life-threatening when the new drug appears to provide benefit over available therapy, but under situations when the demonstrated benefit did not yet meet the standard for regular approval.
Lots of misinformation flying out there. Don't be a lemming.
How many oncology treatments have been FDA approved based on open label trials? How worried should we be re: the unblinded data? Remember, this PIIb is a registrational trial.
I recall Provenge had a delayed action because it took time to stimulate an immune response.
Mike, I'm pretty sure it wasn't meant for you. Generally, shorts will be shorts. It's like a political debate- there's no end to counterpoint. Better to let the data speak for itself. If good, as most of us here believe it will be, the shorts may (will) continue their games but they will have to do it from a higher share price. This battle will never end until PPHM gets bought or is sitting on a pile of cash and has significant free cash flow - AKA until they have the FU money.
Agreed.
Typo = second-line
From Corsica.
"Naturally, we ASSUME that the May 2012 for the ad one-line NSCLC trial was again not based on independent central review..."
These guys call themselves biotech investment researchers? The key verifiable fact supporting the dismissal of the 2nd-line data in the article and they got it wrong. All they had to do was read the freakin' press release! I guess that was too much work for such a prestigious outfit as Apsara Biotechnology Research. Why would anyone trust any of their other assumptions?
Hatchet job. Transparent.
HR, p-value TBD. Significance, TBD. FDA reaction to the data, TBD.
Close was 2.91 according to Nasdaq.
OpEx is today. I don't expect to move until a few days into next week at the earliest.
Considering my lousy trading skills, you should not take that to the bank.