ImetelChat

Orphan drug designation
I’m sorry about this being so long, edit as necessary if you keep it up. It has been a weighty subject for me for a long time and I suspect many suffering with the diseases of MF and MDS as well. What does ODD really mean and why haven’t we seen more attention on this aspect of getting Imetelstat to market? I would certainly admit my very limited understanding of what is taking place in the process of getting Imetelstat to market but shouldn’t more have more been done with the ODD option?
It just seems to me that given Imetelstat has ODD status for MF and MDS, JNJ / Jansen / Geron should be able to obtain a faster path to marketability of Imetelstat for those diseases as an OD. Maybe it just takes too much bandwidth on their parts to focus on it. In one of the web articles noted below. It doesn’t appear that JNJ / Jansen / Geron have pursued doing that as smaller / shorter studies could have been used, etc. I would guess they are taking advantage of the incentives provided by the FDA for those drugs with ODD and I would think we should have seen more results by now, versus the massive studies and years to the goal line. It looks like maybe the incentives were the main reason for obtaining ODD versus getting the drug to those most in need, while just staying the course for the big picture.
I found the process of approval to obtaining Imetelstat almost impossible to follow when trying to obtain for a relative (now deceased). But for us, it traced back to the primary physician who it seems needed to make the request and go through a loosely set of channels and roadblocks However, getting the primary physician to do this was impossible for all sorts of reasons, including concerns for the patient, time, legal considerations, etc. All of this is understandable but very frustrating and since the Orphan Drug Act and various enhancements and changes along the way, seems to me a cleaner fast track should have evolved by now for those in need and lessen the burden on the primary physician.
One path I took, might be of interest to some, following reading an article by Katie Thomas for the NY Times:
URL:http://psychologyofmedicine.blogspot.co ... panel.html
Katie replied the following to my request for assistance:
“The program is a pilot program and will only include a small handful of drugs at first, and then only drugs that are already well into stage 3 trials.
For the other Janssen experimental treatments, people will still have to go through the old channels of making a request, and it won't go through NYU.
The best advice I would have is to start here and see if someone can point you in the right direction:
http://www.janssenpharmaceuticalsinc.co ... assistance “
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One of the items on the referenced above indicated the following in the section about “Cost:”
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The government has implemented steps to bring down these high research and development cost by providing subsidies and other forms of financial assistance to companies that produce orphan drugs. The largest of this assistance comes in the form of tax breaks that can be as high as 50% of research and development costs.[23] Orphan drug manufacturers are also able to take advantage of the small customer base to cut cost on clinical trails due to the small number of cases to have smaller trials which reduces cost. These smaller clinical trials also allows orphan drugs to move to market faster as the average time to receive FDA approval for an orphan drug is 10 months compared to 13 months for non-orphan drugs. This is especially true in the market for cancer drugs as a study in 2011 found that between 2004 and 2010 orphan drug trials were more likely to be smaller and less randomized then their non-orphan counterparts but still had a higher FDA approval rate, with 15 orphan cancer drugs being approved while only 12 non-orphan drugs were approved.[24] This allows manufactures to get cost to the point that it is economically feasible to produce these treatments. These subsidies can total up to 30 million dollars per fiscal year in the United States alone.

Web article here: https://en.wikipedia.org/wiki/Orphan_drug
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Another web item talked about access to OD’s before receiving a marketing approval
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Full article here: Incentives to orphan drugs providers in terms of R&D, intellectual property and marketing
Granting orphan drugs status may enable the sponsor to obtain the following advantages for the development of the product :
• a 50% tax credit on the cost of clinical trials undertaken in the USA ;
• a seven year period of marketing exclusivity following the marketing approval ;
• some written recommendations provided by the FDA concerning clinical and preclinical studies to be completed in order to register the new drug ;
• a fast-track procedure for the FDA to evaluate registration files ;
• The availability of orphan drugs to patients before being granted a marketing approval is possible. In some cases of compassionate use, a Treatment Investigational New Drug (t-IND) may be obtained under specific conditions :
o The drug must be intended for the treatment of a serious or life-threatening disease ;
o No alternative drug or treatment must be available ;
o The product must be in the process of clinical trials and in an active phase of marketing approval.
For this latter reason, t-INDs are granted for a limited period of time.

Web article here:
http://www.orpha.net/consor/cgi-bin/Edu ... NDRUGS_USA
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Hi Hunt, thanks for your telling post. I guess we all would like imetelstat out of its box asap in order to help suffering patients... Your post certainly reflects the frustrations and powerlessneess in these terrible, heartrending cases.

The key of ODD benefits are as you mentioned; pretty straight forward, it seems. But it is not so clear how decissions about t-IND's are taken. I guess it will be a negotiation between the doctor/hospital, the patient and the pharma. Maybe costs and legal aspects are invovled too.Your personal experience tells a lot. The time a primary physician has to spend on such a case can indeed be a limiting factor.

Re. Geron/JnJ and ODD: the problem is that we don't see what is actually happening with the ODD status behind the screens. The element of technical assistance during the elaboration of the file as well as simplification of administrative procedures are not visible for the outside world. I assume that these actions all are taking place as we speak.

We also don't know if t-IND's are already being applied in certain cases as those may have happened under a strict protocol of confidentiality. We should realize that IF something goes wrong in a case of t-IND it can bring the whole imetelstat operation in danger once this reaches the public in an uncontrolled way. That may put the lives of many other patients at risk. So pharma's probably will think twice before they take that risk. I think these are very difficult decissions.

Thanks Fishermangents for your reply and always very good thoughts, all of which reflect and educate us on the challenges faced by the principals.
I would reflect that given we on the outside recognize the awesome capabilities and potential of Imetelstat, how much more might they on the inside know what they have in this science and want to find the optimum methods to getting this to patients who are “time critically” in need. I suspect thousands of people with MF have died even while the Phase II study has been in plan/progress and much of the while an ODD was in play. Each of those people were facing certain death with the status quo offerings providing no hope of remission or cure, the clock was/is ticking for all with this disease.
Depending on one’s perspective (patient, family member, doctor, pharma, etc.) this situation likely looks different, but I would share my perspective to add one hopefully typical example of an MF patient’s life as I saw it. My brother-in-law was diagnosed with the MF. As an aside, he was a Vietnam vet who was sprayed with Agent Orange several times. These vets are now found to have a disproportionate ratio of MF His ancestry reflected very long lives so dying at age 69 was exceptionally young in his family. He had a very storied life with a strong constitution and desire to live and contribute to society. Once diagnosed, he and his wife (my younger sister) made more than 75 trips (over 1200 miles round trip) to the Mayo Clinic in Rochester, MN and several times with other various family members in tow.
Different treatments were tried over the 5-6 years of his life with the disease. I think I recall treatments included pamolinomide, chemo, lenalidomide, etc. with lessening affect, while transfusions increased with his spleen becoming so large that it had to be removed in February 2015. Complications arising from this surgery signaled the beginning of the end. So towards the end of his treatments and life, he lost ground quickly over the last 9 months or so. Once his spleen had been removed, I believe he was no longer going to be considered a candidate for the Phase II MF study but we hoped there would still be an opportunity for treatment with Imetelstat as he and his case were well understood at the clinic given his history of treatment there.
So in the final 6 months, he refused a stem cell transplant as too risky (hindsight can’t help us on this one) and held to his hope that he could be treated with Imetelstat. His view was that even if he only had a 50-50 chance or less of the drug helping him, he had no other options that could save his life; he had nothing to lose and possibly offering something in terms of patient study results. Life is not a dress rehearsal and everyone would know it was a calculated “gamble”. Signing confidentiality and legal liability agreements was not a problem or concern for him or his family. The fact that Imetelstat might not work for him was not something he could wait to find out about and he died in June, 2015.
We understood the issue with something going wrong in a loosely controlled environment and jeopardizing ultimate success and delivery to market, regardless, we worked hard to find a way but could find no options and even if there was a “secret” way, I think we might have had a good chance of uncovering it being associated with care providers at Mayo and our desire to leave no stone un-turned. His death was a great loss to his family and community while the complexities of his care over the years and especially last few months is something one would not wish on their worst enemy and most can’t imagine.
Extrapolating to the big picture of it all, thousands of people are likely suffering the same ugly demise. While we have been close to one case, it is not too difficult to understand what all these people must eventually go through. And to us it seemed like such a shame, like being in a room and dying of thirst all the while knowing that in the room next door there are thousands of gallons of drinking water.
So should a death before FDA approval be more of a problem than after approval? Of course, that seems to be the case but technically maybe it shouldn’t as most with MF are facing a death sentence given the status quo. Then it seems there should be a reasonably uncomplicated process to obtain the OD. A process that is documented and people can follow to obtain the drug in a short amount of time, maybe a month or two. And that is handled confidentially but also not impacting outcomes of clinical trials in plan / process, by those who govern over the trials and test results.
The FDA, pharma and medical communities have had years to work this out and it makes us wonder how humanity seems to be prioritized so far below the science. Quite possibly it’s just my ignorance, but is there a common sense element missing here? With all the highly intelligent people involved, certainly the proper framework could be defined to handle the situation given the patient has knowingly made the best decision for themselves, especially given the consequences of taking it and possibly recovering versus not taking it and dying.
Finally, through all the frustrations encountered, we acknowledge and are keenly aware of a doctor’s concern for and of losing long term patients, even good friends as they have worked together for years to survive the disease. We know it is with great care and concern doctor’s watch over the patient’s situation. We are very appreciative of their efforts and cannot fully express what that has meant to the family. Mayo’s is truly the best from top to bottom, doctors to staff, administrative to support staff, to people throughout Rochester, MN.

Hi Hunt, thanks for this very touching story....Life certainly is not a dressed rehearsal. Sometimes people first need to get very sick before this is well understood. I feel with you and your sister. Let's hope that access to imetelstat will getting more easy as soon as possible for those who still stand a chance. Although we may not see it yet with our own eyes, ODD will help in the work behind the screens. Ethics and new drugs (and the pharma industry in general) not always go hand in hand unfortunately, to say the least.

Okay, thanks again for your perspective as it certainly reflects our experience regarding accessibility to the drug outside of a CT. ODD should be considered primarily beneficial to the businesses involved and possibly those participating in related CTs. Others with the disease and not fitting the CT acceptance criteria, etc. would most likely benefit only indirectly (if they survive long enough) as the drug should achieve a faster path to market. We were completely missing the purpose and primary focus of the ODD. Hopefully some day in the future there will be a functional process to request and receive ODD drugs like Imetelstat.

Hunt, very sorry to read about your brother in law. I fault the FDA and the unreasonable "hold" that was placed on Imetelstat. Scarlett had a vigilant approach to the liver function abnormalities with a panel of hematologists monitoring the status of patient with abnormal LFTs. Once the hold occurred all patients who did not show some positive effects (very tightly defined) were taken off drug. This included CI (!!) patients and the two MM patients. The result was a one year delay that resulted in many ramifications. My opinion only: 1. We would have a drug on the market now with completion of the second Mayo study (which was canceled), 2. We would know more about the effects in the myeloma patients. 3. Geron might not have been driven into the arms of Janssen. History. bp

Bio, agreed regarding the negative impact of the hold for patients. But I can't completely follow your third comment regarding JnJ. As far as I know JnJ was already talking with Geron way before the hold was installed. So it seems likely that Geron would have signed up with JnJ anyway, also if the hold wouldn't have taken place. Secondly, don't you think it is something positive for Geron being in the arms of JnJ?

Fish, true they were talking. My only point was that an ongoing study with multiple clinical sites, many more enrolled patients and a clear path to approval one year earlier would have strengthened Geron's negotiating hand considerably and perhaps affected the choice of partner (Janssen no doubt the best but the second best might have sweetened the deal, you get my drift...competition for a much more valuable asset based on the above factors. Yes, I think the FDA was punitive re Geron and did not facilitate this drug, to Hunt's point. bp

Look at it from the bright side: due to the hold the FDA had the opportunity to take a close look at safety. And they lifted the hold completely. How big is the chance we'll get another one? Not so big I'd guess. That means a lowered risk for the approval path.

Fish, I can agree and I love your optimism. But if the FDA has had such a close look than where is our BAT designation? I agree that approval is very likely. The delay however is to me astounding in light of the very scrutiny you refer to. If submission requires a completed study, CT site informs us that top line data waits until Nov 2017. I think the delays have been problematic and if ever there was a case for simultaneous approval with a requirement for further ongoing study this would be it. We are dealing with a fatal disease and patients on Imetelstat are their own controls, having failed all else. Surely the quick time to CR and PR and CI translates to improved survival for an identifiable subgroup. Unless a patient who is a Jakafi failure can enroll in a clinical study they have a short life expectancy indeed. This drug cries out to an unhearing FDA for special status. Regards, bp

We need to change the whole system and make the medical industry more like the computer industry. It is criminal for terminally ill patients to be denied the right to try new therapies. It come down to this: do WE own our selves, or does the FDA/Pharma complex?

http://www.strike-the-root.com/51/walker/walker6.html

Wasn't there some new legislation in the US on compassionate use?