Application for Inclusion of MILTEFOSINE on WHO Model List of Essential Medicines: Comments re Feb 2011 reviews of the v 2010 application February 23, 2011 1. The application and its review In v 2010, Paladin proposed Miltefosine (as tradename Impavido ) to be included in WHO Model list of Essential Medicines as a single agent for treatment of visceral, cutaneous, and mucosal leishmaniasis. In Feb 2011, the Miltefosine application was reviewed by Dr Alvar, Reviewer #1, and Reviewer #2. These reviews are attached. 2. Review by Dr Alvar Dr Alvar states (page 2) that miltefosine has an essential place in therapy, is effective in different manifestations of leishmaniasis (HIV, PKDL, (M)CL, combination therapy for visceral leishmaniasis), and should therefore be included in the EML. Dr Alvar references the recent, exhaustive, expert compendium of treatment recommendations WHO Technical Report Series.949 published in December 2010, which indeed supports the recommendation for miltefosine for each of visceral leishmaniasis, cutaneous leishmaniasis and mucosal leishmaniasis. -Box 1 (Alvar page 3) recommends miltefosine in combination for anthroponotic visceral leishmaniasis -Box 1 (Alvar page 3) recommends miltefosine as single-agent therapy for East African visceral leishmaniasis; -Box 1 (Alvar page 4) recommends miltefosine as single agent therapy for Indian Subcontinent post-kala-azar dermal leishmaniasis -Box 3 (Alvar page 7) recommends miltefosine as single agent therapy for L mexicana systemic cutaneous leishmaniasis -Box 3 (Alvar page 7) recommends miltefosine as single agent therapy for L guyanensis and L panamensis systemic cutaneous leishmaniasis -Box 4 (Alvar page 8) recommends miltefosine as single agent therapy for Bolivian mucosal leishmaniasis Dr Alvar further comments that Miltefosine should not be used in women of child bearing age unless contraception can be guaranteed for the duration of treatment and 3 months afterwards., as is also stated in WHO Technical Report Series.949, page 56. Comment: Paladin agrees with the review of Dr Alvar and of WHO TRS #949. Both recommend miltefosine for each of visceral leishmaniasis, cutaneous leishmaniasis and mucosal leishmaniasis, and for all populations with the restriction that women of childbearing age must use contraception. February 23, 2011 Page 1 of 3
3. Reviewer #1 Reviewer #1 comments in Section #8 Add to EMLc (with age restriction for children in non-fertile age). After review of real teratologic risk add to EML with appropriate harm reduction measures (concerning teratologic effects) if necessary And in Section #9: Current regulatory assessment by competent authorities (EMA) has assessed the risk of teratogenic effects as high enough to require women of childbearing potential to use effective contraception during and up to 3 months after treatment. This assessment can be accepted and included (in a feasible way) by placing the medicine on complementary list. Alternatively the data on teratologic could be reassessed by experts in the field (employing all available data) and appropriate harm reduction measures that are realistic to the settings where the disease is could be required. The key statements: EMLc (with age restriction for children in non fertile age) ; this assessment can be accepted and included (in a feasible way) by placing the medicine on complementary list. ; and appropriate harm reduction measures that are realistic to the settings where the disease is could be required. made by the Reviewer are not completely clear. Restriction to non-fertile children is not feasible, because adults including males with disease would be non-treated. Most importantly, female contraception is a feasible appropriate harm reduction measures that are realistic to the settings where the disease is could be required and is already in place, so there is no need to imply that future harm reduction measures could be instituted. Comment: Given the difficulty in interpreting reviewer comments in Sections #8 and #9, Paladin requests the EML Review Board to utilize the language approved by European Registrars, which is the language of WHO TRS #949 and Dr Alvar: that miltefosine can be used in all patients except women of child bearing age unless contraception can be guaranteed. 4. Reviewer #2 In Section #7, Reviewer #2 ticked that the dosage form has not been reviewed by a stringent regulatory authority. may have been a typographical error, since as Reviewer #1 noted, EMA review is competent and respected. In Sections #8 and #9, Reviewer #2 focuses on 3 issues: a) Use in combination for VL caused by L donovani. Paladin agrees with the reviewer. b) Use in fertile females only if contraception can be ensured. Paladin agrees with this reviewer, and notes again the uniformity of opinion that all patients can be treated as long as female contraception is provided. February 23, 2011 Page 2 of 3
c) Price As described by the WHO, Essential medicines are selected with due regard to disease prevalence, evidence on efficacy and safety, and comparative costeffectiveness. Paladin is acutely aware of the need for cost-effective therapies for leishmaniasis, and is committed to as open and broad an access to miltefosine as possible. Paladin is in direct dialogue with key stakeholders and Government officials to ensure any n-governmental Organization or public Government program will be able to procure miltefosine without cost being an issue. As was described in the EML application for miltefosine, even where the cost of goods for Liposomal amphotericin B has been reduced 90% via an agreement with the WHO, miltefosine treatment is the least expensive regimen with the exception of paromomycin. 5. Overall comments The statements of WHO TRS #949 and Dr Alvar are below. The statements of Reviewer #2 are in accord. Reviewer #1 seems to have raised a question about appropriate patient populations, but the final statement is appropriate harm reduction measures that are realistic to the settings where the disease is could be required. Since such measures are already present in the sense of mandatory female contraception for women of child-bearing potential, it can be said that all four authorities [WHO, Alvar, Reviewer #1, Reviewer #2] are in accord. To summarize the reviews made on the miltefosine EML application, Paladin believes the indication and precautions listed below satisfies all comments made by the reviewers: Indications: miltefosine has an essential place in therapy, is effective in different manifestations of leishmaniasis (HIV, PKDL, (M)CL, combination therapy for visceral leishmaniasis), and should therefore be included in the EML. Precautions: [Miltefosine] should not be used in women of child bearing age unless contraception can be guaranteed for the duration of treatment and 3 months afterwards. Paladin appreciates the efforts of the reviewers in advancing our application with the EML committee. Sincerely, Robert K. Vinson, Ph.D. Director, Product Development Paladin Labs Inc. February 23, 2011 Page 3 of 3
Reviewer. 1 checklist for: Miltefosine In the WHO Essential Medicines List (1) Have all important studies that you are aware of been included? (2) Is there adequate evidence of efficacy for the proposed use? (3) Is there evidence of efficacy in diverse settings and/or populations? (4) Are there adverse effects of concern? Possible teratogenicity (5) Are there special requirements or training needed for safe/effective use? Women of childbearing potential to use effective contraception during and up to 3 months after treatment (6) Is this product needed to meet the majority health needs of the population? (7) Is the proposed dosage form registered by a stringent regulatory authority? (8) What action do you propose for the Committee to take? Add to EMLc (with age restriction for children in non fertile age). After review of real teratologic risk add to EML with appropriate harm reduction measures (concerning teratologic effects) if necessary (9) Additional comment, if any. Current regulatory assessment by competent authorities (EMA) has assessed the risk of teratogenic effects as high enough to require women of childbearing potential to use effective contraception during and up to 3 months after treatment. This assessment can be accepted and included (in a feasible way) by placing the medicine on complementary list. Alternatively the data on teratologic could be reassessed by experts in the field (employing all available data) and appropriate harm reduction measures that are realistic to the settings where the disease is could be required.
Reviewer. 2 checklist for: [Miltefosine] In the WHO Essential Medicines List (1) Have all important studies that you are aware of been included? (2) Is there adequate evidence of efficacy for the proposed use? See comment (3) Is there evidence of efficacy in diverse settings and/or populations? See comment (4) Are there adverse effects of concern? (5) Are there special requirements or training needed for safe/effective use? (6) Is this product needed to meet the majority health needs of the population? (7) Is the proposed dosage form registered by a stringent regulatory authority? (8) What action do you propose for the Committee to take? Include with following specifications 1. Should be used as combination therapy with other agents in the treatment of visceral leishmaniasis caused by L. donovani 2. Miltefosine is potentially teratogenic and should not be used in pregnancy or in women of reproductive age unless contraception is ensured
(9) Additional comment, if any. Miltefosine is the only oral agent available for VL and use has shown high cure rates. However, most studies are industry sponsored, and recent data from India and Nepal has shown relapse rates of 20 30% after therapy completion. Development of resistance when used as a single agent is therefore a serious concern, and combination therapy is advisable. High quality data on what combinations would be advisable are not available at the moment but some trials are underway to evaluate this. There is one additional concern. Although miltefosine has been available to Paladin at a comparatively low cost under a temporary arrangement with the manufacturer, this price guarantee expired in 2010. A new price has not been provided and a higher price could become a barrier to inclusion in the EML.