Tuesday, September 22, 2009

Ormeloxifene in Osteoporosis Management

These are the two studies which deal with the Anti-resorptive properties of Ormeloxifene. These are animal studies which can further help us to progress in this indication

..download trial


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Saturday, September 19, 2009

Multicentric Trial on Ormeloxifene (Biweekly cum Weekly schedule))

This work of CDRI carries entire data from Pre clinical to Phase III trials along with the pharmacokinetic profile of Ormeloxifene. Apart from the Biweekly cum weekly dosage schedule of Ormeloxifene various modified dosage regimens were discussed.

..download Multi centric Trial


Multicentric Trial (3)




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Effect of Ormeloxifene on Fertility

This is the latest Prospective study yet to be published. It is expected to be out by Dec 2009. This study was done by Dr. MM Singh from CDRI. The trial discusses about the long term (2-3 years usage) efficacy of Ormeloxifene as contraceptive.
During our meeting with Dr. Singh he has appraised us about the impairment in development of Pinopodes by Ormeloxifene, which makes it a efficacies contraceptive in long term.
.download trial
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DUB Clinical Trial

This is the only published trial available on Ormeloxifene in DUB management. Since it is not a comparative study it carries less weightage.


download trial..

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DUB trial done by Dr. Alokendu Chatterjee

This trial was done on 2004 by Dr. Alokendu with the funding from HLL. Currently the piece of information available with us are the three PPTs(Linked below). According to Dr. Alokendu the trial is a guidance for taking Ormeloxifene as a molecule that will fit perfectly in DUB(Dysfunctional Uterine) management.

WHD is seriously searching for the clinical trial papers for publishing. A humble appeal is that any body directly or indirectly involved in this trail shall share the information with us.

download PPT

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Friday, September 18, 2009

Centchroman: An Overview

This a master document about Ormeloxifene from CDRI. This document covers the Phase I, Phase II and Phase III trials and Toxicological studies.

Download the document:


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Thursday, September 17, 2009

Minutes of Technical Advisory Committee Meeting on Ormeloxifene as a Contraceptive

July 22, 2009

shagri-la hotel
19 Ashoka Road
Connaught Place
New Delhi 110 001

Advisory Committee Members

External Members

1. Dr. Nithyanand. CDRI

2. Dr. T. K. Chakraborthy. CDRI (D)

3. Dr. Kunjamma Roy. Kottayam Med College

4. Dr. Sunitha Mittal. AIIMS

Internal Members

1. Shri. M. Ayyappan CMD

2. Shri. K.K. Suresh Kumar D(M)

3. Dr. K.R.S Krishnan ED (SP)

4. Dr. M. D. Nair

The meeting started with a formal address by C&MD Shri M. Ayyappan followed by the Welcome note by Dr. K. R. S. Krishnan ED(SP). A presentation was made by Mr. T.Rajsekar DGM(WHD) covering a brief introduction about Women Healthcare Division followed by the marketing experience on Ormeloxifene as a Contraceptive both in ethical and OTC route.

Following this, there was a group discussion by the committee members on the newer 30mg thrice a week dosage regimen of Ormeloxifene as a contraceptive and on new therapeutic indications for the drug.

Contraceptive

The committee discussed about the effectiveness of various dosage regimens available for ormeloxifene as a contraceptive and finally suggested to go ahead with a Clinical trial with the following dosage regimens.

Dosage Regimen 1.

30mg Thrice a week Ormeloxifene for first three months followed by once a week dose.

Currently WHD marketing team is facing pregnancy failures with Ormeloxifene in the first three months of usage and another marketing challenge which has to be addressed by the team is the usage of Condoms in the first three months where in the drug need the time to start it’s contraceptive action.

Hence the Marketing team of WHD expected the Advisory committee to address these two issues (1. Pregnancy failures in the first three months of Ormeloxifene usage. & 2.Usage of another contraceptive along Oremeloxifene which is again a contraceptive)

WHD marketing team shared their experience with the committee about a new dosage regimen followed by Kottayam medical college which is thrice a week Ormeloxifene 30mg dose in the first three months followed by once a week 30mg ormeloxifene. With this dosage regimen it was found that the pregnancy failures in the first three months was relatively low and there is no need for a barrier method usage in this initial phase.

Dr. Kunjamma Roy from Kottayam Medical shared her experience about the thrice a week ormeloxifene 30mg dose which she has followed in her practice. She had the opinion that this dosage regimen is far better in preventing pregnancies in comparison with the conventional twice a week initial dosage regimen. She also shared with the committee that there were not only pregnancy failures with the conventional dose but also multiple pregnancies which are caused by the ovarian stimulation by Ormeloxifene.

But Dr. Nithyanand had the opinion that the experience of thrice a week dosage regimen requires more data to take forward. He also suggested the pregnancy failures reported may be false pregnancies that has to be further evaluated.

Dr. M. D. Nair also supported Dr. Nithyanand’s view to rule out such false positives which may be due pregnancy test failures.

Dr. Kunjamma Roy agreed about the chance of false positives but she was very strong in her point about the pregnancy failures caused by the conventional Ormeloxifene 30mg dosage regimen because she and her team either gave an option of continuing the pregnancy or did MTP on the patients who reported the pregnancy failure.

The experience of Ormeloxifene 30mg thrice a week dosage regimen from Kottayam medical college was finally supported by Dr. T. K. Chakraborty CDRI Director and other members too.

The Advisory committee suggested HLL Lifecare to initiate a clinical trail on this new dosage regimen and document the results for submission to DCGI for approvals.

Dosage Regimen 2.

60mg Ormeloxifene Loading dose followed by 30mg once a week.

Dr. Nithyanand put forth this dosage regimen to the committee and the committee discussed about the patient compliance which this dosage regimen offered. Further the committee opinioned about the pregnancy failures with this dose in the first three months.

At this juncture Dr. K. R. S. Krishnan raised the point of Ormeloxifene being published in international journals like Lancet which will raise the image of the molecule among the medical fraternity. This opinion was strongly supported by Dr. Nithyanand.

Dosage Regimen 3.

15mg Ormeloxifene alternate day dose for the first three months.

To improve the patient compliance the committee suggested the evaluation of lower alternative day dose of ormeloxifene. CBD PMG team wanted to take up this dosage since it can ensure a patient compliance particularly in the OTC route.

Dr. T. K Chakraboty and Dr. M. D. Nair suggested to try the various alternative day doses of 25mg, 20mg and 15mg of Ormeloxifene to arrive at an optimal dose.

Finally the committee advised that the protocols for the above suggested doses to be designed by HLL Lifecare and to be discussed with CDRI for giving final shape to the study design.

Emergency Contraceptive

Since statutory approvals are available for Ormeloxifne as an Emergency Contraceptive, the committee recommended HLL to start the marketing process. Whether the promotion has to be done through Ethical route or OTC route has to be decided internally by HLL.

Dr. Sunita Mittal from AIIMS shared her experience with Ormeloxifene as a Emergency Contraceptive with the advisory committee. She told the committee that Ormeloxifene works well as a emergency contraceptive and Dr. Sunita Mittal is the person who has basically done all the clinical trails on Ormeloxifene pertaining to this indication at AIIMS hospital Delhi.

The committee suggested that more recent data pertaining to Emergency Contraceptive will be of meaningful help to market the product.

Dr. M. D. Nair and Dr. Sunita Mittal put forth the point that patient recruitment for conducting a clinical trail for Emergency contraceptive will be very difficult as rarely patients come to a doctor or hospital for this purpose.

Osteoporosis

The development of Osteoporotic drugs mainly depends upon the Risk Benefit profile of the drug and even if small side effects are seen, the pharma companies avoid taking risk. Hence it was suggested by the committee not to outsource the clinical trials to third party, instead it is recommended that HLL and CDRI work in unison to develop the clinical data for Ormeloxifene in Osteoporosis.

Dr. M. D. Nair shared the work done by Nova Nordisk with Levo ormeloxifene for osteoporosis and he also informed the committee that Nova has dropped the trail because of the skin pigmentation that appeared in the patients during trial. He insisted the point of taking Risk benefit ratio into consideration in such situations.

Breast Cancer

The committee discussed and debated about the usage of Ormeloxifene in this therapeutic indication and the members have agreed that the recruitment of patients for the study of Ormeloxifene in Breast Cancer is a difficult task. Hence CDRI and HLL will get in touch with the various Cancer Research Institutes in the country to analyze the feasibility to proceed further.

Dr. M. D. Nair threw light on the genetic factors which can be considered to recruit patients for studying the effect of Ormeloxifene in treating breast cancer.

Dr. T. K Chakraboty also expressed his interest to extend CDRI’s support to HLL for taking up trials on this indication.

The meeting concluded with the consent of all the members to work at their ends on the above discussed topics and meet again at CDRI to proceed further.

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Meeting with Dr. MM Singh. (Report submitted to DGM(WHD)))

Dear Sir,

It was a little bit of wallowing yesterday with Dr.Singh a veteran who lives with Ormeloxifene on one side and a novice on the subject who is me on the other side. End of the day Dr. Singh has explained every detail in depth about ormeloxifene and it is as follows to summarize

1. The extensive review published by Dr. Singh on Ormeloxifene is quoting more than 200 references and Elsevier, willy has given a impact factor of 7.4 for the citation, which is rare and is given to standard reference text only. So the new dosage mentioned in the study can to promoted to medical fraternity with confidence and other approvals are not required.

2.To have undoubted confidence on the molecule as contraceptive, the objective of yesterday's meeting was to learn the effects of Ormeloxifene on the embryo and the endometrium and decidual reaction. According to Dr. Singh the embryo is a small creature with only 40-50 cells, but is powerful enough to do any damm thing right from production of progesterones, leukotrienes , prostaglandins to metabolising carbohydrates, to triggering powerful signals to make endometrium receptive to it. To prove Ormeloxifene is effective in preventing implantation, Dr. Singh has taken endometrium teated with ormeloxifene and a normal one. First he has introduced a live embryo on the ormeloxifene treated endometrium and observed that it has not implanted and then he has taken the same embryo out and introduced it into a normal endometrium where there is normal implantation and growth.The reverse of the experiment was also done with an implanted embryo from a normal endometrium when introduced into ormeloxifene treated endometrium, implantation failed but not ormeloxifene.

3.The various reasons for the above as quoted by Dr. Singh in his study is pasted below
/Ultrastructurally, inhibition in endometrial receptivity by centchroman is characterized by
reduced surface undulations, absence of pinopods, ¯attening and clumping of electron transparent
vesicles in the apical portion of luminal epithelial cells and highly distended uterine lumen on day of
maximal receptivity, suggesting inhibition of endocytosis/pinocytosis of luminal ¯uid, luminal
closure, apposition of blastocyst trophoblast to luminal epithelium, and secretory activity of glandular
epithelium, effecting inhibition of implantation.96 This might be related to altered permeability
characteristics of epithelial cells as evidenced by complete and selective inhibition in alkaline
phosphatase in uterine luminal and glandular epithelium on days 4 and 5, coinciding, respectively,
with the time of entry of pre-implantation embryos into uterus and maximal receptivity.120

/4.Coming to minimal endometrial thickness for implantation, Dr. Sing has observed some long term users of Ormeloxifene and subsequent to the observation a article is in press to be published in "Fertility and Sterility" International journal which is quoting the endometrial thickness after ormeloxifene treatment and that is required for normal fertility. This is a good proof that Ormeloxifene is an effective contraceptive. The tabulation from the abstract is as below

/
/5. To take advantage of the above points we should have a dosage regimen which ensures patient compliance and the pharmacokinetic aspects of the molecule in the first three months where most of the failures happen. To do this our field force has to equipped, KOLs has to be developed and might be a tinge of Dr.Rajan is required to derive the message effectively in the starting.

6. Above all in my subsequent meeting with Dr. Nithyanand yesterday evening, he gave the good news that our Ormeloxifene is getting entry into US Pharmacopoeia in a couple of weeks time. Subsequently as a Charmain of Indian Pharmacopoeia he is trying for a USFDA approval also for the molecule.

With this I feel we can build a powerful Brand Novex and Delivery before Top Management as Team WHD PMG. Open for Discussion.

Novexly
A. M. Kadar
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