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Home , Lactational amenorrhea, Oral contraceptive pill, Ormeloxifene, Pearl Index, Vaginal ring

Modern Methods of Contraception in India The Potential of Progestin-Only Pills and Centchroman

April 2016 Table of Contents

Executive Summary ------3 Introduction ------5 The Facts ------7 Progestin-Only Pills ------7 Centchroman ------8 Introduction of Progestin-Only Pills and Centchroman into the Basket of Choice: considerations ------9 Progestin-Only Pills ------9 ‐ Global Experiences ------9 ‐ Global Evidence ------10 ‐ Indian Scenario ------13 Centchroman ------11 ‐ Global Experiences ------11 ‐ History in India ------12 ‐ The Evidence from India ------12 ‐ The Opportunities in India ------18

Policy considerations: The Way Forward ------20 ‐ Technical Issues ------20 ‐ Building the Evidence/Operations Research ------20 ‐ Introduction of additional methods into the national program ------21 ‐ Communication Strategy ------21 ‐ Multipronged Strategy for Service Delivery ------21 ‐ Build and Leverage Public-Private Partnerships ------21 ‐ Task Shifting for Service Delivery ------21 ‐ Operational Plan for Implementation & Monitoring ------21

References ------22

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EXECUTIVE SUMMARY

A paradigm shift in India’s national policy from the “population control” approach (focused on ), to a reproductive rights-based approach that seeks to empower couples to take informed decisions about timing of and family size is evident. Under the National Health Mission (NHM), family planning is now positioned as a critical intervention for improving women’s health and reducing maternal and child mortality. The focus is on increasing access, expanding choices of available methods and improving the quality of family planning services.

International data over a period of twenty-seven years shows that expansion of the contraceptive method mix in low and middle-income countries has a positive relationship with contraceptive use. Use of contraception may be increased by extending the availability of current methods, by improving features of current methods, or by introducing new methods. A wider choice of methods also improves the ability to meet the individual needs of women and couples.

The strategic framework of the Reproductive Maternal Newborn Child + Adolescent Health (RMNCH + A) program offers a fresh paradigm for family planning interventions. The time is opportune for expanding access of women to a wider modern method-mix of contraceptives.

A significant development in the recent past has been policy decisions of the Government of India to expand the basket of choice of modern methods of contraception available in the public health system by introducing newer contraceptives such as the injectable contraceptive Depot Provera or Depot Medroxy Acetate (DMPA), the non- steroidal and non-hormonal contraceptive Centchroman, and Progestin – Only Pills (POPs).

The exponential increase in institutional deliveries to more than 80%, accords an opportunity to increase the choices on offer to women in the . In addition to postpartum sterilization and postpartum Intra Uterine Contraceptive Device, the potential of POPs as a non-invasive option for spacing births in the postpartum period, particularly for women, has been accepted. The recently revised World Health Organization’s Medical Eligibility Criteria (WHO MEC 2015) for contraceptives have endorsed POPs for use in breastfeeding women in the immediate postpartum period (< 6 weeks) as the advantages are said to outweigh the risks during this period. Availability of POPs has till now been restricted to the private sector in India.

Centchroman () is another promising option for spacing, referred to as the once-a- week non-steroidal oral contraceptive available under the brand name ‘Saheli’.This was developed indigenously in India by the Central Drug Research Institute in the 1980s, approved for marketing in 1990 and is available at a subsidized rate through the social marketing scheme of the Government of India since 1995.

This paper presents the global and national historical experience with POPs and Centchroman as credible methods of reversible contraception. It presents a summary of the scientific evidence that testifies to the safety, efficacy and acceptability of these products and is the basis of the policy initiative of the Government of India to include them in the basket of contraceptive choices for clients in the public health system. It also explores the programmatic opportunities and issues, for consideration, for taking these methods to scale in the country.

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List of Abbreviations

ARC – Advocating for Reproductive Choices ASHA – Accredited Social Health Activist AUB – Abnormal Uterine Bleeding API – Active Pharmaceutical Ingredient BMD – Mineral Density CDRI – Central Drug Research Institute COC – Combined Oral Contraceptive CSIR – Council of Scientific & Industrial Research DCGI – Drug Controller General of India DGHS – Director General of Health Services DLHS – District Level Household Survey DMPA – Depot Medroxy Progesterone Acetate DTAB – Drugs Technical Advisory Board DUB – Dysfunctional Uterine Bleeding FDA – Food and Drug Administration FP – Family Planning FOGSI – Federation of Obstetrical and Gynecological Societies of India ICMR – Indian Council of Medical Research ICT – Information Communication Technology INN – International Nonproprietary Name MEC – Medical Eligibility Criteria mCPR – Contraceptive Prevalence Rate, modern methods MF – Method Failure NGO – Non-Governmental Organisation NHM – National Health Mission OCP – PI – POP – Progestin Only Pills RMNCH+A – Reproductive Maternal Newborn Child and Adolescent Health SIDA – Swedish International Development Cooperation Agency SRS – Sample Registration system TFR – Total Fertility Rate UF – User Failure USG – Ultrasonogram

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Modern Methods of Contraception in India The Potential of Progestin - Only Pills and Centchroman

Introduction

Twenty per cent of the world’s eligible couples with an unmet need for contraception live in India. In 2007-08, the country had an unmet need of 21.3 % and only 47.1% of eligible couples were reported to be using a modern method of contraception.12

In 1952, India became the first country in the world to launch a national family planning program. One of the goals enunciated in the National Population Policy 2000, is to stabilize the population at a level consistent with the requirement of the national economy and achieve the replacement level Total Fertility Rate (TFR) of 2.1 by the year 2010.20 Several interventions have contributed to the secular decline of TFR, however it was still 2.3 per woman in the year 2013.8

The high unmet need for family planning and the still relatively high TFR have triggered strategic change over a period of time. A paradigm shift in national policy from the “population control” approach (focused on sterilization), to a reproductive, rights-based approach, that seeks to empower couples to take informed decisions about timing of births and family size, is evident. Under the National Health Mission (NHM), family planning is now positioned as a critical intervention for improving women’s health and reducing maternal and child mortality. The focus is on increasing access, expanding choices of available methods and improving the quality of family planning services.

India’s commitments made in the London Summit on Family Planning are articulated in “India’s Vision FP2020”.18 These include:  Ensuring access to family planning services to an additional 48 million women by 2020  Increasing financial commitment on family planning to more than 2 billion USD  Expanding the basket of choices and scaling up the use of the currently available methods  Ensuring availability of free commodities and providing services to all clients (including adolescents) through the integrated Reproductive Maternal Neonatal Child and Adolescent Health (RMNCH + A) strategic approach.

International data over a period of twenty-seven years (113 countries for the period 1982- 2009) shows that expansion of the contraceptive method mix in low and middle-income countries has a positive relationship with contraceptive use. The addition of one method available to at least half the population correlates with an increase of 4–8 percentage points in total use of the six modern methods, namely, male and female sterilization, pills, Intra Uterine Devices (IUDs), and injectable contraceptives. Use of contraception can be increased by extending the availability of current methods, by improving features of current methods, or by introducing new methods. A wider choice of methods also improves the ability to meet the individual needs of women and couples.24

In neighboring countries such as Bhutan, Bangladesh, Indonesia and Nepal, the public sector provides at least seven contraceptive method options to couples. These include implants and injectable contraceptives.7 Currently, the national program in India offers five modern contraceptive options: three spacing methods (combined oral contraceptive pills, condoms, and IUDs) and two limiting methods (male and female sterilization).

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The strategic framework of the RMNCH + A program offers a fresh paradigm for family planning interventions. The time is opportune for expanding access of women to a wider modern method - mix of contraceptives.

A significant development in the recent past is the policy decision of the Government of India (GoI) to introduce injectable contraceptives, notably Depot Provera or Depot Medroxy Progesterone Acetate (DMPA), in the public health delivery system. The Drugs Controller General of India (DCGI), has already accorded requisite approvals. An operational plan for rollout is ready. Resource material for skill building of providers has been developed and the process of procurement of the commodity is underway.

An important avenue for offering family planning services is the post-partum period. Contraception for women who are breastfeeding is a public health issue of global importance. Each year over 100 million women make decisions about beginning or resuming contraception after childbirth. These decisions include both the choice of contraceptive method and the time at which its use begins, both of which continue to be debated by experts. Choices of contraception may be limited for lactating women, due to concerns about hormonal effects on quality and quantity of milk; passage of hormones to the infant; and infant growth. Ideally, the contraceptive method chosen should not interfere with . Additionally, because the return of and can be unpredictable in breastfeeding women, the timing of contraception initiation is important.16, 27

In India, the exponential increase in institutional deliveries to more than 80%, accords an opportunity to increase the choices on offer to women in the postpartum period, other than postpartum sterilization and Postpartum Intra Uterine Contraceptive Device (PPIUCD). The potential of Progestin- Only Pills (POPs) as a non-invasive option for spacing births in the postpartum period particularly for breastfeeding women is well recognized. In the recently revised World Health Organization’s (WHO) Medical Eligibility Criteria (MEC) 2015 for contraceptives, POPs have been moved from Category 3 to Category 2 for < 6 weeks breastfeeding women, which means that they can generally be used in the immediate postpartum period as the advantages outweigh the risks.31

In India, POPs are currently available for distribution only in the private sector. Taking into consideration the available evidence on the safety, efficacy and acceptability of the method, the GoI has taken a policy decision to include POPs in an expanded basket of choice for the public health delivery system, which is indeed a step in the right direction.

Centchroman (Ormeloxifene) offers another promising non-hormonal option for spacing, referred to as the once-a-week non-steroidal oral contraceptive available under the brand name ‘Saheli’. This was developed by the Central Drug Research Institute, in the 1980s; approved for marketing in 1990; and is available at a subsidized rate through the social marketing scheme of the GoI since 1995. Clinical trials on women of reproductive age and market surveys have demonstrated its safety, efficacy and acceptability.2, 3, 4, 21

Leveraging program strengths to expand contraceptive options to include POPs and Centchroman in the national program, and providing them through the public health delivery system has the potential to make a meaningful difference to the health of men, women and children in the country. A policy decision has been recently taken by the GoI to introduce POPs and Centchroman in the basket of choice of contraceptives for the public health system.

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The Facts

Progestin- Only Pills 9, 13, 30

About the method  POPs are also called mini pills and progestin-only oral contraceptives.  POPs contain lower doses of progestin than Combined Oral Contraceptives (COCs)  Commercially available POPs contain , norethindrone (), ethynodiol diacetate or  POPs prevent pregnancy through : ‐ thickening the cervical mucus, making it impenetrable to sperm ‐ thinning the endometrium, which makes implantation less likely ‐ suppressing ovulation which is not consistent, and happens more likely with desogestrel  Essential to take the pill at the same time each day to maximize contraceptive efficacy, preferably from first day of menses  Back up contraception is needed at least for 2 days if the pill is started >5 days from onset of menses, or taken more than 3 hours late, or missed on any given day Effectiveness  POPs may not be as effective as COCs in preventing pregnancy due to lower dose of progestin; there is reliance on mechanisms other than ovulation inhibition; and consistent timing is important for effectiveness.  Failure rates are lower in women who are sub-fertile, as in breastfeeding women and women of older reproductive age: ‐ Less than 1 pregnancy per 100 women in the first year among feeding women ‐ 3 – 10 pregnancies per 100 women in the first year among non- breast feeding women ‐ Reported pregnancy rates in the first year of use range from zero to 13 %  Fertility returns immediately after being discontinued Safety and Advantages  POPs are safe and suitable for nearly all women  A good option, particularly for breast feeding women who have resumed menstruation and want an oral contraceptive, although less effective than in fully breastfeeding women  Can be used during postpartum period in breastfeeding women even if < 6 months postpartum. WHO MEC 2015 have categorized POPs to signify that they can be used in < 6 weeks postpartum breastfeeding women with reasonable safety  If adopted by a breastfeeding woman before 6 weeks postpartum, offer a gateway to start another method once she stops breastfeeding  Can be initiated immediately post  Good option for women in whom is contraindicated or causes additional health concerns such as migraine with aura; >35 years of age; women at high-risk of, or known, coronary artery disease; venous thromboembolic disease; hypertension  Can be initiated without blood or other routine lab tests, pelvic examination, cervical cancer screening or breast examination  Can be discontinued at any time without a provider’s help  Do not interfere with sexual activity

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 There are no known health risks but should not be given to women with current or history of breast cancer, as their impact on recurrence is unknown  Protect against  Protect against the reversible loss of bone density, which occurs in breastfeeding women  Do not cause significant weight gain and are not likely to increase frequency of headaches Disadvantages/ Side effects  POPs cause disruption of normal menstrual bleeding patterns : - Longer delay in the return of monthly bleeding for breastfeeding women (lengthened postpartum ) - Frequent, irregular, prolonged or no monthly bleeding ‐ Bleeding irregularity may not however bother postpartum women because they may be amenorrheic or expect irregular bleeding  May be associated with more functional ovarian cysts and acne flare than COCs

Centchroman (Ormeloxifene) 2, 3, 4, 21, 25, 32

About the method

 WHO has approved Ormeloxifene as the International Non-proprietary Name (INN)* for the product Centchroman, popularly known as the once-a-week oral non-steroidal contraceptive available under the brand name of ‘Saheli’ in India  Centchroman is the generic name of the product that was initially developed as a post coital emergency contraceptive pill  It is now prescribed as a once-a-week pill (30 mg) on a fixed day, following a loading dose of one pill twice a week for 3 months  Under the WHO Anatomical Therapeutic Chemical (ATC) Classification System, the ATC Code for Ormeloxifene is G03XC04  This is a Selective Modulator (SERM) and has tissue selective estrogenic or anti-estrogenic effects. It suppresses the estrogen receptors in the reproductive organs like ovaries, and , but stimulates those of other organs like the  The contraceptive effect is due to prevention of implantation of the fertilized ovum through local action on the uterine environment, the hypothalamic-pituitary-ovarian axis remaining unaffected  Non-contraceptive effects include prevention of breast cancer, endometrial cancer and stimulating the formation of new bone; also used in treatment of Dysfunctional Uterine Bleeding (DUB)/Abnormal Uterine Bleeding (AUB), breast, mastalgia.

Efficacy /Effectiveness  Safe and effective and can be used by almost all women opting for a spacing method

* International Non‐Proprietary Name (INN): A single name of worldwide acceptability for an active substance to be marketed as a pharmaceutical. The selection of this name is the mandate of WHO.

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 Failure rates are similar to combined hormonal pills:  A Pearl Index† of 1.14 has been estimated through Post Marketing Surveillance data  Pearl Index varied from 1.83 to 3.42 in various clinical trials  Contraceptive effect is easily reversible, majority of women conceiving within 6 months among those who withdrew from clinical trials

Advantages  It is a non-steroidal contraceptive and thus free from hormonal side effects like menstrual disturbances  Readily reversible contraceptive effect with no adverse effect on the foetal outcomes  Acceptability and user compliance is very good due to simple and less frequent dose regimen  No adverse health outcomes reported; in fact, it prevents breast cancer and is associated with a decline in incidence of ovarian and endometrial malignancy, pelvic inflammatory disease, ectopic pregnancy, benign breast disease, iron deficiency anaemia and formation of functional ovarian cysts Disadvantages /Side effects Prolonged menstrual cycles have been reported by users (8%) in clinical trials

Introduction of Progestin – Only Pills and Centchroman into the Basket of Choice: considerations

A. Progestin - Only Pills

Global Experiences

Historical perspective 17

Years Milestones 1955  First trials of Progesterone as a contraceptive conducted on female volunteers in the United States of America (USA) and Puerto Rico 1960  US Food and Drug Administration (US FDA) approved the sale of Enovid as a ‘ control pill’, a combination of estrogen and progestin, with 10 times the progestin and 4 times the estrogen contained in today’s pills 1961  Oral Contraceptives entered the markets of New Zealand, Britain, Europe onwards and Australia in 1961 and became the leading contraceptive in the US by 1965  Appeared in the markets of developing countries in mid 60s,but were beyond reach of most women due to high prices  Donor agencies led by US Agency for International Development (USAID) and Swedish International Development Cooperation Agency (SIDA) supported developing country governments in supplying OCPs to women  Estimated 20-30 m. women were using OCPs in early 70s in developing countries

† Pearl Index = Total no. of failures x 12 x 100 Total women months of use

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1973  Progestin-only ‘mini pill’ introduced in response to research which linked the estrogen content of early OCPs with risk of thromboembolic disorders 1984-2009  An estimated 50- 80 million women users of OCPs increased to 100 million worldwide

The first ever POP developed used , a progesterone derivative, which was first synthesized in 1961. It was used alone for contraception in arterial risk patients for more than 20 years. It was used in combination with ethinyl as an oral contraceptive since 1999.5 Over the decades, however, various newer progestins were used to improve the safety and efficacy of the method.

Commercially available POPs contain low doses of levonorgestrel, norethindrone (norethisterone), ethynodiol diacetate or desogestrel. The current desogestrel POP combines safety with high levels of effectiveness and was first approved for manufacture and marketing in the year 2003.

The Global Evidence

Literature review reveals an abundance of research studies worldwide on different aspects of Progestin-only contraceptives, including POPs. The focus of research includes measurement of parameters like safety, efficacy, acceptability and continuation rates. Other outcomes include effects on breastfeeding performance, in terms of amount and duration; effects on infant growth and development; health effects including on Bone Mineral Density (BMD), cardiovascular system, and others. The available evidence clearly demonstrates positive outcomes with respect to these parameters. Some of the key evidence is summarized below:

Summary of Global Evidence

1. Cochrane Review on Progestin only pills for contraception : Grimes et al (Cochrane Collaboration 2013) 9

Objective: Examine randomized controlled trials of progestin only pills for differences in efficacy, acceptability, and continuation rates

Summary of Review:  No significant increase in the risk of stroke, myocardial infarction, and venous thromboembolism among users of POPs, compared with non-users  The literature is equivocal concerning the potential impact of combined oral contraceptives on lactation, but no concerns exist for POPs  No data is available concerning a potential effect on infant brain or liver  Overall, POPs are associated with more days of bleeding and spotting, than are combined oral contraceptives  Any potential benefit of better contraceptive efficacy with desogestrel 75 µg versus levonorgestrel 30 µg may be offset by worse bleeding patterns and higher discontinuation rates, which however reflects the better suppression of ovulation with the desogestrel POP than with the levonorgestrel POP  Nuisance bleeding with POPs remains an obstacle to wider use

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 A POP may be preferred for safety reasons in older women with lower fertility who wish to continue oral contraception  Inconclusive on the comparative efficacy of POPs with each other or their effectiveness in comparison to combined oral contraceptives 2. Effect of Progestin Compared with Combined Oral Contraceptive Pills on Lactation- A Randomized Controlled Trial: Espey et al (2012) 6

Objective: To estimate the effect of progestin-only compared with combined hormonal contraceptive pills on outcomes such as, rates of breastfeeding continuation in postpartum women, infant growth parameters, contraceptive method continuation, and patient satisfaction with breastfeeding and contraceptive method

Summary of Review:  Breastfeeding continuation rates at 8 weeks (progestin-only 63.5%; combined hormonal 64.1%), contraceptive continuation, and infant growth parameters did not differ between users of progestin-only and combined hormonal contraceptive pills  Reasons cited for discontinuing breastfeeding did not differ between groups; maternal perception of inadequate milk supply was the most common reason cited. Introduction of supplementation with formula or a perceived lack of milk supply correlated with breastfeeding discontinuation, whereas type of OCP used had no effect 3. Contraception and Lactation : King et al (Journal of Midwifery and Women’s Health, 2007) 14

Objective: Review of research on effect of contraceptives, including hormonal contraceptives, on lactation

Summary of Review:  A study at two public hospitals in Chile evaluated four methods of contraception: a progesterone ; progestin-only pills; Norplant implants and copper T 380 A in lactating women for their effects on contraceptive performance, duration of lactation, infant growth, duration of , and menstrual patterns during the first year of use  All methods were found to be highly effective; duration of lactation was similar in users of all the methods, as were measurements of infant growth; prolonged or frequent bleeding occurred infrequently with all the methods, and very few women discontinued their contraceptive method because of bleeding problems  Several other studies that evaluated early administration of progestin-only methods, POPs at 1 week postpartum and DMPA injected at 2 days and 7 days, found no differences in infant growth or breastfeeding practices, such as duration of breastfeeding or supplementation, between users of the different progestin-only contraceptives; furthermore, these studies support that there are no adverse effects on breastfeeding practices or infant growth with these methods 4. Impact of early postpartum administration of progestin-only hormonal contraceptives compared with non-hormonal contraceptives on short-term breast-feeding patterns: Halderman et al (2002) 11

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Objective: To identify the impact on breast-feeding patterns of early postpartum initiation of progestin-only methods compared with non-hormonal methods

Summary of Review  There was no significant difference in the continuation rates of breastfeeding in women using progestin-only methods of contraception that were initiated before hospital discharge with those who used non hormonal methods  Supplementation because of the perception of insufficient milk production also did not differ between the two groups, supporting the earlier findings that early initiation of progestin-only methods of contraception has no adverse impact on breastfeeding practices 5. Comparison between desogestrel and use among postpartum Thai women: Thamkhantho et al (2012) 26

Objective: A prospective, open-label, randomized controlled trial to evaluate the vaginal bleeding patterns, side effects, safety and acceptability of the 2 types of POPs

Summary of Review:  Breastfeeding postpartum women can safely and successfully use both types of POPs  Frequent, irregular bleeding was observed in a majority of patients during the first three months of use; thereafter, amenorrhea developed over time  Proper counselling is highly recommended for achieving continuation of use; this in turn was associated with a high satisfaction rate about the method  The minimal side effects of the progestin-only contraceptive pills allow modern women of reproductive age to consider use of this contraceptive method. 6. Progestin–only contraception prevents bone loss in postpartum breastfeeding women: Costa et al (2012) 1

Objective: To evaluate the effect of contraceptive use on BMD for breastfeeding women until 6 months postpartum, those using non-hormonal and progestin-only contraceptive methods. This period was chosen because the bone loss is maximum, the prevalence of breastfeeding is very high and majority of women are still using the same contraceptive method that was initiated around the 42nd postpartum day.

Summary of Review: The comparison showed a protective effect towards bone loss with the progestin-only methods. 7. The WHO Medical Eligibility Criteria (MEC) 2015 31

Objective: This document is part of the process for improving the quality of care in family planning. MEC criteria for contraceptive use, the first edition of which was published in 1996, presents current WHO guidance on the safety of various contraceptive methods for use in the context of specific health conditions and characteristics. These were developed through an exhaustive, transparent and evidence based process.

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Summary of Review  Direct evidence from clinical studies demonstrates no effects of POPs on the breastfeeding performance and generally demonstrates no harmful effects from exposure through in infants less than 6 weeks of age.  The document has clearly defined who can safely take POPs-  Breastfeeding women who are >6 weeks to <6 months postpartum can use POPs, without restriction (MEC Category 1).  For breastfeeding women less than 6 weeks postpartum, POPs were moved from MEC Category 3 to Category 2, which means that the advantages of using the method generally outweigh the theoretical or proven risks.

Indian Scenario:

In India, the first desogestrel POP was launched in 2005. Currently two brands of desogestrel POPs, Cerazette and Zerogen, are available in the Indian commercial market. The total market is estimated at around 180,000 cycles per year. Cerazette is the market leader with annual sales of approximately 145,000 cycles, growing at a compound annual growth rate of over 15%.23 Cerazette is manufactured and marketed by Organon (India) Ltd., a legal entity of MSD Pharmaceuticals; and Zerogen by Glaxo Smith Kline Pharmaceuticals. Current market prices are between Rs.220 to 230 per pack of 28 tablets. There is a dearth of evidence, in the form of clinical trials or operations research from India.

B. Centchroman

Global Experiences

Historical Perspective

Research to develop a safer alternative to hormonal oral contraceptives was a felt-need since the 1960s. Researchers worldwide were attempting to develop and synthesize a non- steroidal estrogen antagonist agent that would prevent pregnancy by interfering with implantation of the fertilized ovum at the uterine level, without disturbing the hypothalamic- pituitary-ovarian axis and the blood levels of estrogen and progesterone. The Central Drug Research Institute (CDRI), Lucknow (Uttar Pradesh, India), under the Council of Scientific and Industrial Research (CSIR) took the lead in this and successfully developed the first non-steroidal once-a-week pill, Centchroman. This is the only anti-implantation agent approved for clinical use globally and was included in the US Pharmacoepia in 2010.2, 3, 4

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History in India 2, 3, 4, 21

A Summary

Years Milestones 1960s,1970s, Extensive research by CSIR- CDRI and ICMR: 1980s,1990s  Pharmacological studies in animals  Clinical Trials 1990  Approved by DCGI 1991-92  Licensed to Hindustan Latex Ltd. (now HLL Lifecare Ltd.) for marketing as a contraceptive under the trade name Saheli and to Torrent India Ltd. under the name Centron (discontinued subsequently by Torrent) 1995  Subsidized under Social Marketing Scheme of Govt. of India, MOHFW 2005  Launch of Novex DS for DUB 2010  Included in the United States Pharmacopoeia as “Ormeloxifene hydrochloride USP compendium” 2012  Launch of ‘TATKAL’ as Emergency Contraceptive

2013  Launch of Novex for mastalgia and fibro adenoma of breast 2016  Launch under the brand name “Chhaya” for public health sector

The Evidence from India

Summary of Clinical Trials 2, 10, 15, 25

Year Title Results 1970s Phase I: Well tolerated, with no side effects or Single and multiple dose abnormality in laboratory parameters, except for double blind non a few menstrual disturbances in 4 volunteers crossover studies 1980s – Phase II:  Acceptable pregnancy protection Upto 1982 Post coital schedule and  Some cases of prolonged menstrual cycles Once a week schedule  No other side effects  Babies born to women who became pregnant due to User Failure (UF) or Method Failure (MF) showed normal growth and development when followed up for 5 years 1980s – Phase III multi-centric:  Acceptable pregnancy protection (Pearl Upto 1986 30 mg once-a-week Index (PI): 3.76) schedule at 10 FW  About 50 % volunteers had normal cycles, Centres and the remaining had one, two or more prolonged cycles, but none had all cycles delayed  Children born to 28 women of MF and UF pregnancies followed up periodically showed

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normal physical, mental and social development and no congenital anomaly. 1980s – Extended Phase III and  Good pregnancy protection (PI: 1.20) 1987 to 1989 re-extended Phase III:  10 % had prolonged cycles > 45 days in 30 mg once-a-week Extended Phase III and 5.8% in re-extended schedule at 5 FW Phase III Centres  Haematological and biochemical investigations were within normal range and USG in re-extended Phase III showed normal ovarian size and volume  No significant difference in body weight was observed before and after Centchroman use  Compliance was good and there was not a single drop out 1990s New Extended Phase III:  The bi-weekly regimen showed a lower Simultaneous trials to pregnancy rate (PI: 1.83) evaluate contraceptive  Other findings were similar to the previous efficacy and safety of 30 studies mg weekly vs. 30 mg bi-  Return to fertility within 6 months was the weekly dose schedules case with the majority of women who opted at 4 and 5 FW Centres out of the multi-centric Phase III trials respectively 1990s Other independent  Corroborated the absence of an effect of studies Centchroman on ovulation  Minor side effects such as mid cycle pain, prolonged cycle length upto <45 days and backache were observed  Delayed cycles were seen in 16% cases in one study which corrected by the 4th month, which supported the use of Centchroman in regulation of menstrual cycles  There was no MF or UF pregnancy  Clinical trials, which assessed the clinical pharmacokinetics of Centchroman in nursing women volunteers, concluded that the amount of Centchroman secreted in breast milk is unlikely to be of physiological consequence to suckling babies.

Non-contraceptive uses of Centchroman in management of hormone-related clinical disorders: 25

The potential of Centchroman, other than as a contraceptive, has been demonstrated through a number of studies by researchers worldwide. These are notably the areas of management of hormone-related clinical disorders – induction of ovulation, Breast Cancer, Abnormal/Dysfunctional Uterine Bleeding (AUB/DUB), and Osteoporosis and Male infertility.

Centchroman- other attributes: 25 Regulatory studies, including animal studies and clinical trials on women, have demonstrated the following properties of Centchroman:

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 Pharmacological Effects: There is no effect on gross behavior or central nervous system.  Toxicological Effects: Centchroman has an excellent therapeutic index and is well tolerated. There is no haematological, biochemical or histopathological evidence of toxicity, when administered at many times the contraceptive dose in rats or rhesus monkeys. Oral administration to mice and rabbits during organogenesis does not cause or congenital anomalies in the foetus.This is substantiated by the normal physical, mental and social development, and absence of congenital anomalies, in children born from UF and MF pregnancies during Phase III multi-centric trials.  Drug Interaction: Contraceptive efficacy of Centchroman has not shown to be affected by simultaneous administration of oral non-steroidal anti- inflammatory agent Ibuprofen, anti-tubercular drug or Paracetamol.  Safety after prolonged use: Follow-up assessments of women on Centchroman for >4 years; results of USG studies on women during multi-centric clinical trials; and follow up of children born to women using Centchroman have demonstrated: ‐ No derangement in haemotological and biochemical parameters ‐ Size of uterus and utero: ovarian ratio within normal range and unilateral ovarian enlargement observed in 15% of both control and Centchroman treated cases disappeared in subsequent cycles. This allays fears of ovarian enlargement in Centchroman users ‐ No evidence of congenital anomalies at birth, normal milestones and normal physical, mental and social development through childhood ‐ No side effects such as nausea, headache, vomiting, dizziness, depression, mood changes, acne, , hypertension, coagulation disorders; or metabolic disturbances such as weight gain, hyperglycemia and abnormal lipid profile; ‐ Well tolerated by lactating mothers and suckling infants.  Contraindications: Women with recent history of hepatitis or other liver disorders, polycystic ovarian disease, chronic cervicitis or cervical hyperplasia

Market Behavior 19, 21

Centchroman as a once –a – week contraceptive is marketed under the popular brand name ‘Saheli’ at a reasonable price (Rs. 25 for a pack of 8 tablets) over- the- counter. It is manufactured by HLL Lifecare Ltd. Launched in the commercial market in 1991 at a price of Rs.3.50 per tablet, it was subsidized under the Social Marketing Scheme of the GoI, Ministry of Health and Family Welfare (MoHFW) in 1995, the company receiving a subsidy for meeting production and promotional costs.

Although Centchroman is not yet available at the public health facilities, sales data from the MoHFW, GoI and from HLL Lifecare indicates rising annual sales trends over the last decade; sales having almost doubled from 17 million tablets in 2005 -06 to 32 million tables in 2014 -15.

The GoI has recently announced the launch of Centchroman for the public health sector under the brand name “Chhaya”.

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Annual costs incurred by the GoI on subsidy show a steady rise from Rs.607 lakhs in 2010- 11 to Rs.781 lakhs in 2014-15.

The demand for the product is also reflected in the quantity of Ormeloxifene (international nonproprietary nomenclature) synthesized at the Belgaum factory of HLL in a period of 8 years from 2007-08 to 2014-15, reaching a total quantity of approximately 7500 KG.

A Market Research Report, based on a Client Survey of 200 women over 3 months from November 2014 to January 2015 in the cities of Lucknow and Kanpur, demonstrated average satisfaction levels > 8 on a scale of 1- 10 applied to parameters such as effectiveness, side-effects, ease of consumption and packaging.

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Promotional activities for this contraceptive are mainly limited to communication campaigns on mass media. Current market reach is limited to the states of Uttar Pradesh, Delhi, Rajasthan, Haryana, Punjab and Jammu & Kashmir. The reach in Western, Southern and Eastern India is negligible.

Although Ormeloxifene is included in the US Pharmacoepia, USFDA has not approved it for marketing in the US. The patent for the product is with the Indian company. Marketing it globally may not be lucrative for any multinational pharmaceutical company, considering the low pricing and low profit margins associated with the product and the processes that are required for approval by FDAs outside India. Notwithstanding this, it appears that globally a demand does exist a for the contraceptive product, as a number of clients are accessing it through online pharmacies.

The product is also marketed under other brand names e.g. Novex, Novex-DS, Sevista for its non-contraceptive uses.

The Opportunities in India

1. Policy environment and India’s commitments:  The policy environment is conducive to expanding the basket of choice of contraceptives that the national family planning program offers.  A key objective of the National Population Policy 2000 was to achieve replacement level fertility, in other words a TFR of 2.1 by the year 2010.20 Although the TFR has witnessed a steady secular decline, it was still 2.3 children per woman in 2013.8  A paradigm shift in the GoI’s policy from a sterilization-centric approach is evident. The government’s commitment to ensure access to an expanded choice of safe and effective contraceptive methods is being translated into action to fulfil visions and goals enunciated in the NHM and under FP 2020.  Key indicators to track progress under FP 2020 include: Contraceptive Prevalence Rate (CPR) of modern methods (mCPR); percentage distribution of users by modern methods of contraception; number of additional users of modern methods of contraception; percentage of women with an unmet need for modern methods of contraception; number

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of maternal deaths averted due to modern contraceptive use; and number of unintended pregnancies averted due to modern contraceptive use. Expanding the method mix to include newer methods, which are safe and effective, and correcting “method skew” is imperative to achieve satisfactory progress in these indicators.7, 28 The recent policy decision by Government of India to expand the basket of choice of newer contraceptives in the public health delivery system is a step in the right direction. The GoI has initiated procurement of the injectable contraceptive DMPA under the brand name of “Antara. It has also taken policy decisions to include other oral contraceptives, such as POPs and Centchroman, for supply through the public health system.  Under the NHM, there has been a significant growth in human resources, financial investment, geographic reach and quality of services. This has resulted in improved access to family planning services. The catalytic support provided by development partners and affiliated agencies, particularly in the high priority districts, where the most vulnerable and marginalized populations live, plays a key role in implementing the delivery of high impact interventions.  The framework of the RMNCH+A strategic approach recognizes the primacy of high impact family planning interventions as a critical input for improving women’s health and for reducing maternal and child mortality. Thus, there is a window of opportunity for introduction of additional modern methods of contraception such as injectable contraceptives, POPs and Centchroman. Contraceptive implants and the Progesterone Contraceptive Vaginal Ring (PCVR) are the other newer contraceptives with a potential in India.

2. Postpartum Family Planning (PPFP) strategy:  A USAID study (2008) which summarized key findings related to and postpartum family planning from National Family Health Survey 3 (NFHS 3) data for Uttar Pradesh reveals a high unmet need for family planning in women (3 out of every 4 women) in the extended postpartum period (one year). A reduction in exclusive breastfeeding, return of fertility and resumption of sexual activity at 3-6 months after delivery, resulted in an increased vulnerability of these women to pregnancy during this period. Another significant finding was that women, who had regular and adequate number of antenatal care contacts with the health system and the health provider during pregnancy, were more likely to adopt a modern method, postpartum.29  In addition to postpartum sterilization and PPIUCD, currently available under the national program, the exponential increase in institutional deliveries in India to more than 80% provides an opportunity to increase the choices on offer to women in the postpartum period in the health facility setting.  The scale-up of services for PPIUCD in the country and their increasing acceptance by women after delivery is an added opportunity. 17 lakh PPIUCD insertions have been reported country-wide since inception of the scheme, with high acceptance rates in states such as Haryana,Tamil Nadu, Madhya Pradesh, Rajasthan, Uttarakhand and Odisha.22 This has created an effective platform for facility-based counselling of women in antenatal period, in early labor and immediately after childbirth, to help them in making an informed choice of a contraceptive method.  Centchroman is a non-hormonal contraceptive, which despite being approved by the GoI for subsidy under their Social Marketing Scheme, and available for more than two decades, has not realized its full potential. It is safe, effective and acceptable with minimal side effects or health effects on the woman, the suckling infant or the progeny conceived in case of failure. The amount secreted in breast milk in nursing mothers ostensibly does not have any physiological effect on the infant. It could thus potentially be a good option for breastfeeding women.

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 As many women prefer a non-invasive method of contraception after delivery, the time is opportune for introducing additional oral contraceptives, such as POPs and Centchroman, into the basket of choice, which are approved and certified for use in the country; and further promote them for breastfeeding women in the postpartum period. 3. Market Realities:  The patent for Centchroman lies with Indian companies, and it is available at a low price of Rs.25 for a pack of 8 tablets under the brand name of “Saheli”. The GoI has subsidized the production and promotional costs of the product under its Social Marketing Scheme. POPs are free from patent issues. Costs of POPs, once introduced in the public health delivery system, are likely to reduce due to economies of scale resulting from government procurements, and help enhance access for the poor women from marginalized communities, especially in rural remote areas.  The trends in sales over the years; the findings of market research; and, the wealth of other evidence that indicates the safety, effectiveness and acceptability of these methods has strengthened the case for making them widely accessible and available through the public health delivery system.

4. Potential of Partnerships:  The strong capacity, commitment and support for public health programs extended by professional bodies such as Federation of Obstetrical and Gynecological Societies of India (FOGSI), technical agencies and the Non-Governmental Organizations (NGOs) can be capitalized upon for promoting the use and acceptability of these methods in the public sector.  Institutional capacities of technical agencies and other organisations for conducting operations research such as feasibility studies on POPs and Centchroman are ready to be harnessed to build evidence on these methods.

Policy Considerations: The Way Forward

The MoHFW, GoI, has recently taken landmark policy decisions on the introduction of additional modern methods of contraception, injectable contraceptives (DMPA), POPs and Centchroman, into the basket of choice available in the public health delivery system.

Issues for consideration are: 1. Technical and Regulatory issues: DCGI has already approved manufacture and marketing of POPs and Centchroman in India and they are commercially available. Centchroman is available at a low subsidized price under the Social Marketing Scheme of the MoHFW, GoI, under the brand name “Saheli”. The GoI has to move forward on the policy decisions for offering POPs and Centchroman as additional methods in the basket of contraceptive choice. Centchroman is proposed to be offered as a choice in the public health sector under the brand name “Chhaya”.

2. Building the Evidence / Operations Research: For introduction of any new method to scale in the public health service delivery system, it is important to conduct operations research at select health facilities to assess outcomes and build evidence for feasibility of the proposed interventions. Some of the suggested study objectives and outcomes could be on assessment of operational feasibility, acceptability to clients, method specific continuation rates, and clients’ perspectives on accessibility and availability. It would be ideal if the research were to be mounted at the initial stage itself to enable evidence generation for considering program changes as the interventions roll out.

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3. Introduction of additional methods into the national program: The following policy questions are for consideration – a) Whether the new contraceptive options are added to the existing basket of contraceptive choice at public health facilities throughout the country to ensure maximum coverage; or they are introduced in phases, initially at select public health facilities which are already providing efficient postpartum family planning services for PPIUCD and postpartum sterilization. b) Whether the introduction is linked to the doorstep delivery of other contraceptives such as Emergency Contraceptive Pills (ECPs) and Combined OCPs by ASHA workers.

Irrespective of the entry point, the introduction of the additional contraceptives would imply systems strengthening including robust procurement- supply chain mechanisms to prevent shortages as well as wastages.

4. Communication Strategy: A focused and comprehensive communication campaign needs to be developed at national/subnational level for advocacy and raising awareness about these modern methods of contraception. This may be done through partnerships between relevant stakeholders- Government of India, State Governments, FOGSI, ARC, development partners and technical agencies. It may be prudent to conduct a communications needs-assessment before designing and implementing the communication campaign. 5. Multipronged strategy for service delivery: It is imperative to deliver services for these methods at no cost or low cost through the public health delivery system, as well as bring these under the fold of the private /NGO sector using appropriate mechanisms, including social marketing and social franchising. 6. Build and leverage public-private partnerships: Existing partnerships need to be capitalized and new ones forged with NGOs, development partners, international technical agencies, professional bodies, corporates, marketers and manufacturers and private sector service providers to increase the reach and ensure quality services for the new methods. 7. Task shifting for service delivery: Expanding health workers’ roles and empowering them to deliver the range of new contraceptive options after suitable skills-building will increase access to these contraceptive options for poor, marginalized women in underserved urban pockets and remote rural areas. 8. Operational Plan for Implementation and Monitoring, and Technical Guidelines and Resource material for training: An Operational Plan for national and state program managers for introduction of the new methods would include mechanisms and tools for monitoring and supportive supervision. In addition, an efficient system for data collection and analysis and use of information, communication and technology for follow-up of clients will be required. Technical guidelines and other resource material for skills- development would also be needed. In addition, roles and responsibilities to be undertaken by different stakeholders in implementation and monitoring will have to be assigned.

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References

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