What's up with Thiola?

[Kusuno-san]

Hello! I've watched the group here for a while, and just decided to join.
I have a question for you...

...does anyone know what the deal is with Mission Pharmisutical and Thiola? Why is it taking so long to resolve the "issues" they're having with getting the drug out there, and what are those issues in the 1st place? I followed the links from the www.cystinuria.org main page and found that, in the "Reason For Shortage" column, "Mission and FDA continuing to work to resolve this shortage ".

I noticed that this was not filed under "Capacity Constraints", "Manufacturing Issues ", "Supply problems", or "Previous Production Problems " etc. as many of the other drugs in shortage have been. I've heard that it was because of manufacturing issues, but apparently this problem goes beyond that or else they would have listed that as the reason for the shortage.

Anyone have any ideas about why it has been in shortage and such a pain to get for so LONG??

Thanks in advance,
Kusuno

p.s. The site and forums are great!!

[Matt Lewis]

Kusuno-san,

I've heard many conflicting stories regarding the Thiola situation. Unfortunately, i can't verify any one of them. :( Here's what i *can* tell you about Thiola, in a historical context that may shed some light on recent developments:

In 1988, the FDA approved Thiola for treatment of severe homozygous cystinuria. The drug was developed, according to the FDA, by Dr. Charles Y.C. Pak of the University of Texas Southwestern Medical Center at Dallas, Texas. (The same person who developed potassium citrate, approved in 1984). The drug was originally to be marketed as "Thiola" by Mission Pharmacal (who we've all come to know so well!), but it was, in fact, a product of Santen Pharmaceutical Co., Ltd. in Osaka, Japan.

An interesting note: Santen first introduced a drug called "Thiola" in Japan in 1963 as "an original antidote for liver treatment", which to the best of my knowledge was the same chemical compound that is used in today's "Thiola". In fact, Thiola is documented as far back as 1963 in scientific literature as being used to treat a number of problems. The first mention i see of it as used to treat cystinuria comes in 1975 from a study (started in 1971) conducted by A. Remien, B. Kallistratos, and P. Burchardt and another study from a German group, also published in 1975. Neither of those groups involve Dr. Charles Y.C. Pak, so i'm not sure how he is credited with developing the drug. In fact, i can only find two publications from him on the topic: one in 1984 and another in 1986. However, i might be missing key information or perhaps i am misunderstanding the meaning of "developed", and i certainly do not wish to misdirect credit from where it is due. All of these researchers, including Dr. Pak, deserve our highest praise for their dedication to this "orphan" disease and for pioneering this treatment which has arguably become the best option for so many cystinurics!!

Anyhow, back to the story. Surely enough, Santen Pharmaceutical Co., Ltd. seems to hold the trademark for the name "Thiola", filed once in 1967 and again in 1988.
I briefly talked with Dr. Hiroshi Suda, the Manager of International Regulatory Affairs for Santen Pharmaceutical Co., Ltd. He told me that Santen did manufacture Thiola and had distributed to Mission Pharmacal. However, Mission then manufactured Thiola by themselves for US distribution, and Santen no longer supplies to the US. According to Dr. Suda, Santen no longer has any involvement with Thiola or Mission Pharmacal.

Old Santen news releases state that marketing of Thiola in Japan would be transferred to Merck-Hoei Co., Ltd. as of Aug. 1, 2002. To my knowledge, Santen was still contract manufacturing the drug at the time of the marketing changeover, and continued to do so through 2003. Hitomi Iwai, Mereck Hoei Ltd.'s Production Dept. Manager informed me that Mereck took over the "business" of Thiola (which i assume means everything, including manufacturing since Santen no longer is involved with Thiola) in October 2003. They are not involved with Mission Pharmacal, and have no future plans of distributing the drug in the U.S.

So where does that leave us? Thiola used to be manufactured by Santen, and distributed in the U.S. by Mission. Somewhere along the line, Mission began to manufacture it for themselves, and eventually gained independence from Santen. Santen, meanwhile, gradually transferred the entire Japanese business to Mereck, who is not connected with Mission in any way. Other than perhaps Santen collecting royalties from the name trademark, it sounds like Mission is on it's own. Which, my guess tells me, is where the problem lies. I have yet to really get a hold of the people at Mission and the FDA and really hash it out with them. In my opinion, their disclosure, as you have pointed out, has been unsatisfactory. Both Mr. Hitomi Iwai and Dr. Hiroshi Suda as well as everyone at Santen and Mereck have been so helpful in discussing a problem that they really have nothing to do with, and i thank all of them. I suppose it's time to really get on Mission and perhaps implore the wisdom of the good people at the FDA to find out what's really going on, and just how long this shortage is going to last.

I hope this sheds some light on the topic Kusuno-san. I sincerely wish i had actual answers. If anyone has any further information, i would greatly appreciate hearing from you.
Sorry so long winded, as usual. :rolleyes: :)
Kind Regards,
matt lewis

[Kusuno-san]

Wow, thank you for the reply! Another sleepless night here (kidney pain, as usual), and I just saw that you had responsed to my post. That is a very interesting history that i did not know. It certainly puts a story behind all of this. I wonder if Mission has *ever* been able to manufacture the drug correctly, or if the problems began when the company in Japan gave the busisness over to Mission?

Does anyone have further input?
thanks,
Kusuno