Need an efficient process for obtaining transformative drugs before approval

[huntingonthebluffs]

As we continue to learn about the development process / progress on ImetelChat that Geron is struggling through with it’s j”transformative” drug Imetelstat and our own personal difficulties trying to procure the drug as life slipped away, I think and hope there must be more that could be done here. Many thousands are in the same situation we were in 18 months ago and will likely die before the drug is approved unless given paths and options to obtain the drug.
It appears challenging to many of us and even some of you with much knowledge and experience in drug development and especially Imetelstat as to why, even after given ODD status in 2015 for MF and MDS, people with only time for one last opportunity at finding a drug that will help them, have no apparent path assuming the time they have left. While I suspect I am less than accurate on my views and assumptions, the fact remains, for end of life situations that have a decent probability of a longer life and even a cure, much more needs to be done in this space. More options are needed for obtaining possible transformative drugs for end of life patients.
I’m wondering if it might be a worthwhile idea to make it a thread on ImetelChat to attempt charting processes to obtain this drug while still in clinical trial process, etc. Some highlights might be what the steps to take, likely timeframes, odds to obtain Imetelstat, probable costs and locations, best avenues to try, legal implications and how to mitigate legal responsibility of providers, results of attemps, etc. etc. With the many brilliant minds and many connections on ImetelChat, I would bet a way could be found through this maze.
Hopefully this thread could help people suffering from MF, MDS, AML, etc, Otherwise their situations become quite hopeless even when positive that a drug exists with a significant probability of slowing or curing the diseases. This failure becomes even more staggering when we realize that powerhouses like the FDA, JNJ, Jansen Biotech and thousands of top notch doctor’s, labs and domestic and international institutions are involved. I realize there are competitive issues and risks here, etc., but surely there must be a timely way through it. Thank you.

[Fishermangents]

Hunt, this is a great call. I grant my support to your plan. It can be a thread (like this one) or even a seperate forum within ImetelChat. Maybe start with a thread.

The point you raise is very true. At the same time the people at EMA and FDA do share your vision. That's why I have the feeling that some kind of fast track is around the corner. However, what we need to keep in mind is that telomerase inhibition is a new area, meaning that there may be a tendency that doctors and regulators might need a bit more time then usually for a drug that follows are more common MoA.I am not sure (how can I...), but that may an explanation for the situation you describe.

To follow your suggestion: where to start? Why not with the FDA iself? They have defined the following procedures to get drugs faster to market:

Speeding the availability of drugs that treat serious diseases are in everyone's interest, especially when the drugs are the first available treatment or if the drug has advantages over existing treatments. The Food and Drug Administration has developed four distinct and successful approaches to making such drugs available as rapidly as possible:

Priority Review
A Priority Review designation means FDA’s goal is to take action on an application within 6 months.

Breakthrough Therapy
A process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.

Accelerated Approval
These regulations allowed drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.

Fast Track
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

link: http://www.fda.gov/forpatients/approval ... 041766.htm

I will check the same at EMA and will post it later on.

[Fishermangents]

Btw: what we could do is the create a subforum and start a thread for each of the fast track procedures as soon this thread becomes too busy and needs better organisation of topics and responses.

[Fishermangents]

The EMA currently has two procedures to speed up to path of a new drug to the patients:

Accelerated assessment
EMA’s accelerated assessment procedure allows for a faster assessment of eligible medicines by EMA’s scientific committees. Rapid assessment of medicines in the centralised procedure that are of major interest for public health, especially ones that are therapeutic innovations. Accelerated assessment usually takes 150 evaluation days, rather than 210.

Conditional marketing authorisation
Conditional marketing authorisation allows for the early approval of a medicine on the basis of less complete clinical data than normally required, if the medicine addresses an unmet medical need and targets a seriously debilitating or life-threatening disease, a rare disease or is intended for use in emergency situations in response to a public health threat.

Links:
http://www.ema.europa.eu/ema/index.jsp? ... 058004d5c1
http://www.ema.europa.eu/docs/en_GB/doc ... 190556.pdf

The Conditional Market Authorisation seems to be a bit similar to the FDA's Accelerated Approval.

[Fishermangents]

The problem I have is that we don't know if Geron/JnJ have applied for some kind of fast track as we speak. I suppose they will not announce it when they do the application. We will only know about it when the decision has been taken, positive or negative. Maybe we will never know a negative decision? The assumption here is that the drug owner should apply for it. The FDA or EMA do not propose for a fast track themselves.

[Fishermangents]

So I checked the EU Regulation (EC) No 507/2006 dealing with Conditional Marketing Approval (CMA). To start with the question: does imetelstat meet with the basic criteria for CMA and therfore: is it reasonable to think that Geron/JnJ has applied for CMA? The regulation says:

Aricle 2 - Scope
This Regulation shall apply to medicinal products for human use that fall under Article 3(1) and (2) of Regulation (EC) No 726/2004 and belong to one of the following categories:

1. medicinal products which aim at the treatment, the prevention or the medical diagnosis of seriously debilitating, diseases or life-threatening diseases;
2. medicinal products to be used in emergency situations, in response to public health threats duly recognised either by the World Health Organisation or by the Community in the framework of Decision No 2119/98/EC;
3. medicinal products designated as orphan medicinal products in accordance with Article 3 of Regulation (EC) No 141/2000.

Nr 1 and 3 apply for imetelstat, so the answer is: yes, it is reasonable to think that Geron/JnJ has applied for CMA. The next question is if they actually did it.

Then Article 3 says:
"A request for a conditional marketing authorisation may be presented by the applicant together with an application in accordance with Article 6 of Regulation (EC) No 726/2004. The request shall be accompanied by details showing that the product falls within the scope of this Regulation and satisfies the requirements laid down in Article 4(1)."

Article 6 of (EC) No 726/2004 describes the regular application for "the authorisation of a medicinal product for human use" (i.e. market approval). That means that Geron/JnJ could apply for market approval AND CMA at the same time.

Article 4 - Requirements
1. A conditional marketing authorisation may be granted where the Committee finds that, although comprehensive clinical data referring to the safety and efficacy of the medicinal product have not been supplied, all the following requirements are met:
(a) the risk-benefit balance of the medicinal product, as defined in Article 1(28a) of Directive 2001/83/EC, is positive;
(b) it is likely that the applicant will be in a position to provide the comprehensive clinical data;
(c) unmet medical needs will be fulfilled;
(d) the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.
2. For the purposes of paragraph 1(c), ‘unmet medical needs’ means a condition for which there exists no satisfactory method of diagnosis, prevention or treatment authorised in the Community or, even if such a method exists, in relation to which the medicinal product concerned will be of major therapeutic advantage to those affected.

Also on the basis of the regulation itself it seems that imetelstat meets the necessary requirements.

Finally, article 10 'Agency advice prior to marketing authorisation application' says the following:
'A potential applicant for a marketing authorisation may request the advice of the Agency on whether a specific medicinal product being developed for a specific therapeutic indication falls within one of the categories set out in Article 2 and fulfils the requirement laid down in Article 4(1)(c).'

So Geron/JnJ could have asked for advice whether or not imetelstat may be eligible for CMA and if it complies with the requirements mentioned in article 4(1). It seems that imetelstat complies with all of these requirements.

So is it reasonbable to believe that Geron/JnJ has seeked for advice already? And if so: would this advice have been positive or not?

Links:
(EC) No 726/2004: laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
Link: http://eur-lex.europa.eu/LexUriServ/Lex ... 033:en:PDF

(EC) No 507/2006: on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council
Link: http://ec.europa.eu/health/files/eudral ... 507_en.pdf

[huntingonthebluffs]

Wow, you are amazing Fishermangents! It is impressive that you can pull so much information together from so many sources and put it into something coherent that a person like myself can comprehend. Thank you again for your thoughts and efforts here and doing the heavy lifting on this board.

So it would seem that Geron/JNJ “could have” applied and likely obtained by now additional designations and conditional marketing approval via the EMA which has a faster assessment / approval to the FDA. Given what I understand about Imetelstat, I would believe this all could have been accomplished by now. There must be other criteria being applied by Geron/JNJ that proceeding in these areas would not be prudent (e.g. inadequate understanding of MoA) or not in their best interests, etc. It is easy to be judgmental here so leave it at that. Maybe a question at the next quarterly report would be in order.

Assuming the company sponsors are not motivated to veto all requests for Imetelstat prior to approval, I would want to defer to your thoughts and judgment on how to proceed on charting processes on your website. Your thoughts on starting here and possibly moving to subforums, or several threads, etc. all make sense to me, just know you are best provide guidance.

I really liked your thoughts on documenting the regulatory aspects first. So impressive how you plowed through the material AND reached conclusions on what we might expect to happen / be happening. I also wonder if there is some way to petition the FDA/EMA to add more lenient methods than CMA. This might be too scary for some as red tape has it’s merits.

I would also be interested if there are any effective organizations out there for inter-mediating through the “maze” for such requests. It is virtually impossible for anyone but the rare exception to get there on their own. FDA / EMA agencies are helpful here on expediting when requested, but what if not being requested by the sponsor? And what if the sponsor is just not cooperative on any foray to obtain the drug outside the clinical trials? Hopefully we are not wasting efforts here.

[biopearl]

Fish, kudos for assembling and analyzing this info in such a cogent fashion. CMA was developed so drugs like Imetelstat would not languish. Janssen is too savvy to not be tuned to the most efficient path to approval. We have a window into to evolving approval process via the EU/COMP/CHMP agendas and reports. We need to follow these closely. bp

[cheng_ho]

"Right to try" laws have been passed in many states (including NH) that give doctors of terminally ill patients the right to use ANY drug that is even in Phase I.

[huntingonthebluffs]

Right to try laws are a start, but like many things in this effort are "more symbolic than effective" per some news reports. Hopefully that is improving. A few quick reports via Google are:

http://www.usnews.com/news/articles/201 ... bypass-fda
https://www.washingtonpost.com/national ... story.html
https://www.sciencebasedmedicine.org/th ... -try-laws/

All parties involved (FDA, pharma company, doctor, hospital, state, etc.) have an approval process, which takes time, can disapprove based on their own criteria. Not saying this doesn't have some merit, but for anyone trying to get through the maze, will find this a daunting effort and given time is of the essence, most likely to not be successful.

[biopearl]

Fish, thanks for your great work on this. Can you help me clarify one thing? Under Article 4 it says <<A conditional marketing authorisation may be granted where the Committee...>> Which committee does this refer to? COMP or CHMP? or other? What I am trying to get at is since we know ODD was granted in Nov of 2015 and the fastest timeline possible is 150 days... we have exceeded the 150 day timeline since Nov. Of course we don't know when the clock starts when the application is received or when it receives first action, probably the latter. If the presumed (by me) July recommendation (assuming it was positive or acted on at all), goes to the CHMP for approval (does it have to? or can the COMP approve?) (assuming that's when they meet) in Sept that would (slightly) exceed the 270 day timeline but might be what we are waiting for. I can only think they didn't go the 150 day route because they were waiting for data but since the July ODD meeting took up Imetelstat that maybe the data became available and there could be action taken. Or if the COMP has the power to approve (which is what I am really trying to find out) then its already done. Pure speculation but maybe someone can check my math. bp

[Fishermangents]

Bio, in Article 3 sub 2 of (EC) No 507/2006 it says:
"The Committee for Medicinal Products for Human Use, hereinafter ‘the Committee'"
So everytime you see 'the Committee' in this document it refers to 'The Committee for Medicinal Products for Human Use'. That committee that also decides on regular market approval.

Btw: here are the links to the two regulations:
(EC) No 726/2004: laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency
Link: http://eur-lex.europa.eu/LexUriServ/Lex ... 033:en:PDF

(EC) No 507/2006: on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004 of the European Parliament and of the Council
Link: http://ec.europa.eu/health/files/eudral ... 507_en.pdf

[Fishermangents]

Bio, ODD decision making is separate from the decision making on market authorization. The only thing the ODD Committee does is earmarking certain drugs as an orphan drug (serious disease, small patient population, no good drug avaiable). Once in a while they check if the drug is still ODD-valid. Market authorization is not part of that. They only need to stay convinced that the product is safe and effective based on the data that are available to them. An intermediate update by JnJ can be part of that process. Btw: a market approved drug can still by ODD. And can lose ODD if the drugs profile appears not to be so positive over time. Then it loses ODD, but it doesn't lose market authorization. (unless something is very wrong with the drug...)

Obviously JnJ did a good job in convincing them. And obvioulsy we can consider the positive ODD decision as some kind of formal confirmation of the validity and credibility of these data (which are basically the Mayo data).

So the line of development in the EU could be:
- ODD
- Conditional Market Authorization (with or without Accelerated Assessment)
- Market Authorization

[biopearl]

Fish, thanks for clarifying all of this, it is very helpful to me. Regards, bp

[cheng_ho]

Absolutely correct that current "right to try" laws are just symbolic. The problem is that sick and old people are sick and old, it's hard to organize them for effective action... perhaps we need a "Dalek" line of more aggressively designed wheelchairs.

Some state reps in NH are pushing for an explicit "nullification" law that would remove FDA powers over the terminally ill within the state.

[Fishermangents]

Cheng: that would create unacceptable risks for patients who may take uninformed decisions out of desperation.

[huntingonthebluffs]

Here is the thing, has anyone, anywhere been able to work through the maze and obtain Imetelstat or any pre-market approved drug for terminal patients? If there are examples out there that could be shared without violating a confidentiality or some other similar agreement, could they please provide the process they followed and any related considerations or exceptional actions required. If there is no response here, then much still is required and it makes our task even more daunting but none the less, hopefully still worthwhile.

[cheng_ho]

Fisher, right now if you have pancreatic cancer etc. you face absolutely certain death. It is ridiculous to pretend that we are "helping" patients by forcing them to die in approved ways

The underlying issue is simple... do you own your own bloodstream, or do the "important people" who are important because they have FDA-granted profits? If we used your logic, we would never have had air or space travel, because it would never have been safe enough to do the first human flights.

[huntingonthebluffs]

I had hoped for more inputs on what others have done in efforts to obtain Imetelstat prior to marketing availability or being selected for a clinical study. Based on no other posts, probably means there have been no instances to share or are limited by confidentiality agreements.

For what it’s worth, I can share the following regarding our experience. Unfortunately, I was at best, a “naive layman” in our endeavor to obtain Imetelstat for a relative. The relative was at the end of a long battle with MF when we began trying to obtain access to Imetelstat for him.

Our expectations: 2-3 months to achieve access. Reality: in the 6 months we had, we were not even close to success. My lack of understanding / tentativeness on how to proceed and of how serious his condition was becoming didn’t help but honestly, I’m not sure just how long it would have taken.

We first requested assistance via an email appeal to Dr. Tefferi (not his doctor) at Mayo, but received no response. We then requested assistance via email from his hemo doctor at Mayo, which, in hindsight, I believe was the correct choice to begin this effort.

However, and to his credit, the doctor expressed concerns for his patient’s health and indicated trying a drug such as Imetelstat could be risky. He personally had patients that tried it “unsuccessfully”. He said, it was not something just anyone could use and expect good results and he said if it was effective in all patients with MF, our relative would have been among the first to receive it.

His doctor was willing to try to get him into the phase 2 clinical study if his nutritional health improved and he met the CT criteria, unfortunately he died 6 weeks before the study started and over three months before the first patient was treated in September of 2015. The CT was probably never an option for him especially since he had his spleen removed early in 2015.

So while for our relative and for us, our efforts were unsuccessful, in thinking about the process, this would be a summary:

We found in hindsight, our best approach would have been to work / dialogue directly with his doctor as soon as possible. Even if the doctor was not in favor of using the drug, he would have been our best chance for getting through the authorizations from the hospital, FDA and Jansen Biotech, etc. Our relative could have then reevaluated at a later time, assuming they had authorization, if using this drug was still the course they wanted to take. This is naturally a long process as all parties in the sign off chain are very busy and deliberate to assess the merits of the request, so waiting to go through this process was a mistake for us.

We also sought assistance via a pilot program through NYU but found that it would only include a small handful of drugs at first, and then only drugs that are already well into stage 3 trials. We were advised to seek help via the links below as the quickest connection to the imetelstat team. However on trying these links, we found they pointed back to the treating physican as the starting point.

http://www.janssenpharmaceuticalsinc.co ... assistance
and

1-800-Janssen, or janssenmedinfo@its.jnj.com


We were not aware of “Right to try” laws at the time so that would be an obvious area to investigate further.

Looking at this process now and while I am sure I’m over simplifying, I think if selected “panels” existed (such as was the goal of the pilot project at NYU) to help patients obtain these drugs, it might be the most effective approach. In my mind, these panels would be a group of people with the staff, knowledge base, experience and credentials to interact with patients, lawyers, treating physicians, the FDA, drug sponsors, etc. to efficiently / effectively navigate through the “process” of obtaining drugs for patients requesting them.

[Fishermangents]

Hi Hunt, thanks for telling your experiences. I think you are right about going through your own physician first. For a doctor like Tefferi it is an important reference and also a gate to prevent every single individual to contact him directly. I am not sure from you story if the own doctor of your relative has tried to reach out for Tefferi also. It seems that your relative's doctor was on the right way by trying to put his patient into a CT, but the your relative's condition was simply too weak. It also seems that the development of the CT's was still in its beginning and the actual enrolment and infusion was not really started up broughtly. That means that hospitals don't have the channels and administrative tools yet to start infusing based on 'the right to try'. I have no experience with that, but I can imagine that a hospital needs to comply with quite some legally binding requirements in order to apply a new medicin on that basis. Then JnJ needs to agree too.

The other thing is that the 'right to try' legislation is new and hardly tried in the legal sense. At least I am not aware of existing cases. Your last point makes sense, although also here it seems it was just too early for imetelstat to be included in this NYU trial. Setting up such panels (or special patient groups grouped around a specific disease category or medicine), as you suggest would be a good idea, though. It can be done regionally so forces can be joined and costs can be shared (e.g. legal). Such a group will then collect experiences with all issues involved and develop channels towards hospitals, insureres and pharma's, so a single patient doesn't need to invent the wheel again. This would also take a large burden from the treating doctors, who often are simply too busy to spent so much extra time to a single patient.

Thanks for sharing this with us, much appreciated!