phone conference with Dr. Bihari

A board to discuss Low Dose Naltrexone (LDN) as a treatment for Multiple Sclerosis

Postby HarryZ » Mon Sep 06, 2004 8:14 pm

Daunted,

There was recently a very small trial on statins (using only 30 patients)... and immediately following it, there were a flood of posts on the various forums reporting that many doctors were willing to consider statins for MS patients.


Statin drugs are very well known by docs and if a small trial like this gets published, the info is going to be far more accepted. Naltrexone, from what I have read, isn't well known at all so it would likely take more than just one small trial to convince docs to consider it.

The trial of statins was ONLY 6 months LONG and it was UNCONTROLLED.


That's why most neuros wouldn't likely prescribe or consider it at this time.

LDN doesn't even have that level of evidence- and such an experiment obviously doesn't cost close to 5 million dollars- sheash, using finn's numbers from before, it could cost around $300,000.


And that brings up a very big question. How is it that a statin drug, which in the past has had absolutely nothing to do with MS, gets a small trial done on MS patients while LDN, which has been used by thousands on MS patients for a couple of years, can't get anyone interested? It simply doesn't make any sense and you have to wonder what is going on in the background in the drug research world. Why do statins, out of nowhere, get the attention of the NMSS but this same organization writes a scathing report in commenting on LDN without doing any kind of investigation into it? Too many questions and no answers!!

Why Dr. Bihari hasn't published his findings from his 31 patients, is unclear. Serial MRIs are nice but Swank got his research published without a control group or radiological evidence- the limitations are clear but the possibilities are illuminated.


I really don't know why Bihari hasn't pursued a research route on LDN but I suspect because his age and lack of resources may be the reason. Supposedly he has some 300 patients on LDN at the moment. If any readers out there have an answer to this, I surely would like to hear it!

As far as the FDA, Harry, I just have to disagree with you. Formal approval of LDN for MS might never be necessary.


If LDN is ever to be used and advertised for MS , FDA approval would be paramount. The FDA is quite strict about how a drug can be presented and from what I understand, you would not be able to mention LDN and MS in the same sentence without approval. At this stage of the game it is a mute point because unless LDN becomes far better known to the docs it won't even make it to the "off label" possibility. I continue to read about MS patients mentioning LDN to their neuro or GP and getting the response..."I've never heard about it." And that brings us back to the requirement of small initial trials to make it better known...but until now it just hasn't happened! And again I ask...why not? How can the statins or minocycline get these off label trials so quickly?

But I just think it's false that if a reasonable pilot of LDN could be
done for less than $5 million, it would already have been done- because it would cost less than 1/10th of that to perform a trial equivalent to the statin trial I mentioned above.


And that just brings up the same question as to "why not?" What' missing in the LDN equation that these other drugs have and LDN does not?

Again, I take LDN, but this is where we are in terms of science, not belief.


Yes, that pretty much sums up the current LDN situation. Up until now, all of the demand for LDN clinical trials is coming from those who are using it. It should be coming from the world of MS medicine but it certainly isn't. That may change soon but it is a very slow process.

Harry
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Postby Janice » Tue Sep 07, 2004 7:21 am

Group:
I've read all the responses, but I haven't heard from anyone who has actually had a consult with Dr. Bahari to see if it was felt that he brought anything special to the table. I also think $500 is too $$$, especially since I found out my insurance will not pay for phone consultations. Therefore, I also have a call into Dr. Scott's office in LaCrosse, WI who was recommended on this site. (He's half the price of Bahari) From what I'm hearing, it doesn't seem to matter who you talk to , just that you get LDN from a reputatable pharmacy like Skip's, and try it at the prescribed dose.
Is that about it?
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Postby finn » Tue Sep 07, 2004 12:11 pm

Sorry, time to leave the board.

-finn
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Postby HarryZ » Tue Sep 07, 2004 7:51 pm

Finn/Daunted,

I think that there is no conspiracy behind the fact that LDN is not always taken that seriously by MS professionals. Probably the situation is in most cases due to lack of valid preclinical studies and publications.


After what I have discovered in the past two days, this is likely very, very true.

First of all, I would like to comment on the FDA approval process part of this thread. I obtained information from a close contact who has had a number of dealings with the FDA. I also went to the FDA website and spent a long time reading from various sites last night, using Google a lot.
I also called the Merck Pharmaceutical company today and spoke to their Customer Information department.

For a new drug, the FDA requires the company to perform animal safety studies and then Phase I, II and III clinical trials. Phase I is where the drug is given to a healthy individual to look at safety and tolerance.

Phase II the drug is given to a small number patients who have the disease to initially test for safety and efficacy.

Phase III usually involves multi center, large numbers of patients and the FDA likes to see at least two year duration trials. They also want the company to submit data from two separate trials in order to duplicate the positive data. One glitch in this is that a company could conduct 10 trials and have two that were successful...and the FDA will only get data from the two successful trials. The FDA has instituted a law that all clinical trial research done must be made available on the internet (Clinical trials.gov) to ensure that all the trials are made public but there is no penalty if the particular company fails to comply!!! Go figure! And the latest data showed less than 50% compliance by the pharmas.

This kind of process can cost up wards of $ 70-100 million dollars.

Now, if the original company who made Naltrexone decided to try and get FDA approval for LDN, the process becomes much less expensive. This company could get approval cheaper and faster than anyone else because they could refer to prior IND (investigative new drug) information which they own. This would allow them to probably avoid having to repeat animal studies and maybe even Phase I studies and so it is feasible that they could maybe get FDA approval for 5-10 million dollars.

So I decided to check on the FDA site and saw that in 1994, Merck and Dupont were co-sponsors of updating the patent on Naltrexone. So I called Merck and asked them about the drug. The lady checked and said she had absolutely no information that Merck was ever associated with Naltrexone and when she looked into her Physicians Reference Manual, she told me that Naltrexone wasn't listed!!!! I couldn't believe what I was being told but certainly wasn't in a position to challenge her. So is this one reason as to why LDN is totally unknown to most physicians?

Also, if the original manufacturer of Naltrexone ( I still don't know who that is) gave their IND info to another company, Animal and Phase I studies could likely be avoided and obtaining FDA approval might be in the $ 10-20 million cost range. But this would have to be done by a large pharmaceutical company who already had a very well established research structure in place and had worked extensively with the FDA.

Otherwise, a much smaller company would have to go through the entire process and huge costs and even worse, hire a consultant firm experienced in this kind of work. That could escalate the costs up to $ 100 million very easily.

So you see, there appears to be a number of variables involved in getting FDA approval for a drug and depending on who does the trials will determine the eventual costs.

And that leads me back to the questions of my previous message as to why nobody has done anything at all to look at LDN. And Finn, your statement at the beginning of this note might be the answer. Who knows?

I could spend hours and hours researching this more but at the moment don't quite have that kind of time.

If anyone else would like to track down the original manufacturer of Naltrexone, please let me know what you come up with. Perhaps I simply missed the answer by not reading accurately enough.

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Postby mscaregiver » Wed Sep 08, 2004 6:08 am

Perhaps the name "Naltrexone" is why Merck said they had no info Harry, From what I found this morning it seems Du Pont Pharmaceudicals ( formerly Du Pont Merck) has had a long (20 year) association with Naltrexone under the names , Trexan and ReVia.

http://www.fda.gov/cder/foi/nda/2000/75-434_Naltrexone%20Hydrochloride_chemr.pdf

Revia was approved on Nov 20th , 1984 by Dupont Pharmaceuticals ( previously known as Du Pont Merck)


--------------------------------------------
On a side note, I came across this numerical reference on this site :

http://www.ldners.org/Articles/Brattleboro_Reformer.htm

Bihari is treating 395 MS patients with low dose naltrexone. He said a survey of around 100 pharmacies across North America showed almost 16,000 prescriptions for low dose naltrexone being used to treat the disease. He said unscientific research shows a 98 percent rate of stabilization in MS patient.

-----------------------------------

As for the origin of Naltrexone I am still searching..

Take care, Philip
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Postby HarryZ » Wed Sep 08, 2004 6:46 am

Philip,

Perhaps the name "Naltrexone" is why Merck said they had no info Harry, From what I found this morning it seems Du Pont Pharmaceudicals ( formerly Du Pont Merck) has had a long (20 year) association with Naltrexone under the names , Trexan and ReVia.


Thanks for the info. During the call I advised the Merck rep to look under the name "Revia" as well and she still found nothing.

Revia was approved on Nov 20th , 1984 by Dupont Pharmaceuticals ( previously known as Du Pont Merck)


They also updated that patent in 1994 per the FDA website.

Bihari is treating 395 MS patients with low dose naltrexone. He said a survey of around 100 pharmacies across North America showed almost 16,000 prescriptions for low dose naltrexone being used to treat the disease. He said unscientific research shows a 98 percent rate of stabilization in MS patient.


Amazing numbers but until someone does some scientific studies with LDN, I'm afraid the stats are unfortunately meaningless in the world of medicine. You would think that "someone" out there would get ahold of this anecdotal info and run with it.

As for the origin of Naltrexone I am still searching..


Thanks...please let us know if you come up with anything.

BTW, this is the email I got back from Teva when I asked them to give me a rough idea of the cost to get Copaxone approved...

_____________________
Dear Mr. Zanin,
Thank you for contacting us through our website and for your interest.
Kindly be advised that I could not supply you with the requested
information as for the Copaxone, however, the amount for a new drug
development is estimated in hundreds of millions of dollars.
Should you require any further information, please do not hesitate to
contact me again.


Sincerely,
Teva PR

_____________________

I looked extensively at their website which gives all kinds of financial information but nowhere did I see anything about the cost of getting Copaxone FDA approved. It isn't surprising that they wouldn't give out detailed info on Copaxone....pharmas are usually quite tight lipped about this kind of information.

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does this help?

Postby dignan » Wed Sep 08, 2004 11:44 am

I didn't find out who did the original clinical trials, but this company, Alkermes, is working on a new formulation of naltrexone and must know the history / status of it (I assume). It's not an answer, but if nothing better pops up, it's a lead anyway.


"Alkermes, Inc. is a pharmaceutical company that develops products based on sophisticated drug delivery technologies to enhance therapeutic outcomes in major diseases.

The Company's lead proprietary product candidate, Vivitrex(R) ((naltrexone long-acting injection), is a once-a-month injection for the treatment of alcohol dependence.

Alkermes' product development strategy is twofold: the Company partners its proprietary technology systems and drug delivery expertise with several of the world's finest pharmaceutical companies and it also develops novel, proprietary drug candidates for its own account. The Company's headquarters are in Cambridge, Massachusetts, and it operates research and manufacturing facilities in Massachusetts and Ohio."

Alkermes' website: www.alkermes.com
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Postby finn » Wed Sep 08, 2004 12:19 pm

Sorry, time to leave the board.

-finn
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Postby HarryZ » Wed Sep 08, 2004 12:57 pm

Finn,


"Washington Post"]James Love, director of the Consumer Project on Technology, said it is difficult to get an accurate accounting of the industry's finances. Tax returns filed by drug manufacturers showed that the companies spent $8 million on clinical trials for each new drug to treat rare diseases, he said.


The term "rare diseases" caught my attention. In many instances, drug companies apply for and usually receive orphan drug status from the FDA when they are developing drugs for rare diseases or diseases that don't effect more than 300,000 people in the US. This is granted because the possibility of returns on the initial investment is not very good in producing drugs of this nature. So the $ 8 million figure could very well apply in this case but certainly not for the standard FDA drug approval process.

You probably read the email I got back from Teva who stated their development costs for new drugs run into the hundreds of millions of dollars. I'm not sure just how true that is but like the Washington Post stated, it's very difficult to get accurate info from these guys!

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Postby finn » Wed Sep 08, 2004 1:11 pm

Sorry, time to leave the board.

-finn
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Postby mscaregiver » Wed Sep 08, 2004 3:30 pm

As the origin of Naltrexone has somewhat occupied my day, I finnally came across this article, It is a historical document on the facts relating to Natrexone in regards to its anti addiction properties..

I did not read all of this article as I am so tired my eyes are heavy, but I read enough to see Naltrexone mentioned in 1967. And I still did not see the actual maker of the compound , yet this article is very interesting and informative and hopefully when I wake up tommorrow and read it all, more clues as to the actual makers will be there..

I would also like to say that in my many adventures today in search of the origin, I have discovered that Naltrexone has been considered for about every medical condition one could think of, It was truely amazing to me as to the number of medical conditions that this drug has been researched and thought to be beneficial in the treatment of..

The below link is to the historical document, it is in PDF format..

http://www.nida.nih.gov/pdf/monographs/09.pdf

I am going to bed now, goodnight :-)

Philip
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Postby HarryZ » Wed Sep 08, 2004 5:50 pm

Finn,

From a statistical point of view, the number of patients determined to make a clinical trial valid is calculated from something they call the "power effect". When a drug company decides to do a trial, they hire statisticians and one of the big questions asked to the drug company is what effect they expect the drug to have on the patient. The higher the expected effect, the fewer the number of patients needed.

The standard that is generally used is a 40% effect. If a drug is expected to have a lower effect than this (as was the case with the CRABs) then the numbers in a particular trial will be elevated to ensure a better result.

Again, this is from a statistical point of view and not necessarily what a drug company may want for FDA approval.

That web site you mentioned sure has some interesting info about trials and the related costs. I've been told some stories about drug trials and how big pharma operates and I can only shake my head in sadness.

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Drug Trials

Postby Ptwo » Fri Sep 10, 2004 4:22 am

I went to a seminar at our local ms center at Dartmouth Hitchcock on clinical trials last spring. (or was it last fall?) The speaker was Dr. Lloyd Kasper the head of the center.

He mentioned that the majority of all phase I and phase II trials were financed by the NIH and that the drug companies usually *just* cover the phase III.

He described the cost's as being single digit millions for phase I, tens of millions for phase II, and up to 100 million for phase III.

I would think that if an interested researcher wrote a good proposal to the NIH they could get funding for a trial of LDN.

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Re: Drug Trials

Postby HarryZ » Fri Sep 10, 2004 6:35 am

Peter,

Those trial costs more or less reflect what I have been told in the past although perhaps higher in the Phase II than I thought.

I would think that it would take a bit more than one researcher outlining a LDN trial protocol to the NIH to get the ball rolling. I'm guessing that there would have to be some long term plan of eventual FDA approval with a large pharma involved before this might be done. Then again, perhaps there are some scientists out there who might want to do this simply for the sake of science and not with $$$ signs being the main motivator.

Apparently a neurologist at the University of Texas has started some initial work on a LDN trial and The Consortium, a group of MS docs, nurses and MS institutions is talking about doing some small trial work.
I guess we'll just have to wait and see what happens.

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Postby HarryZ » Fri Sep 10, 2004 7:28 pm

Finn,

I had an interesting phone conversation today with the moderator of the MS Foundation Forum which is located in Fort Lauderdale FL. We got to talking about clinical trials and she told me something very interesting that is hopefully going to happen in the near future.

The main journals that publish MS clinical trials (Annals of Neurology, Lancet and The MS Journal to name a few that she mentioned) are going to demand that anyone who wants a clinical trial published must also publish ALL their trials, regardless if they have been failures. Otherwise these journals will not publish anything from the company that fails to follow this guideline. How they are going to administer this rule I don't know but it is something that hopefully will happen. I guess there have been numerous trials done that have been failures but the pharmas conveniently forget these and only publish what they want the FDA to see.

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