Fertility Research Policy

Transcription

1 Fertility Research Policy Rationale and Objective Merck Serono has a strong commitment to deliver innovations in Fertility treatments to help infertile couples achieve their desire to have a baby. Innovations beyond gonadotrophins are required to improve in vitro fertilization (IVF) success rates. Merck Serono is conducting research to identify biochemical markers of oocyte and embryo viability that enable development of new technologies and therapies that may be used to improve implantation rates of healthy embryos, and increase the take-home baby rate. International policies for embryo research differ, and the purpose of this document is to establish clear guidelines that can be followed in all jurisdictions where Merck Group conducts business. This corporate responsibility statement can be used for internal and external communication of our activity in this sensitive area of research. The application of technologies and therapies to improve fertility treatment outcomes undergoes regular internal review, and an external review is performed by the Merck Bioethics Advisory Panel (MBAP). A recent amendment of the German embryo protection act (EPA) was accepted by the Bundesrat, and this policy has been updated according to the revised guidelines. Executive Summary A wide variety of technological advances exist that can be applied to evaluation of embryos in the context of human IVF. The Merck Bioethics Advisory Panel evaluated the legal and ethical guidelines surrounding embryo technologies in 2009 and in 2011 the panel reviewed this policy. The consensus opinion of bioethics experts was that a non-invasive* technology applied to human embryo evaluation was a desirable objective with the wellbeing of the child in mind without discrimination according to gender or genetic traits. Secondly, the development and promotion of technologies for evaluation of embryos need to be supported by adequately powered clinical studies...

2 FERTILITY RESEARCH POLICY 2 conducted with patient consent. Beyond the ethical guidelines of this research, legal boundaries limit the scope of research on human embryos. This policy has been developed to adhere to the German Embryo Protection Act (1990) which prohibits invasive* research that consumes any portion of the embryo. Regardless of the international location of Merck Serono facilities that conducts non-invasive embryo research, this policy is intended to guide planning and execution of all research and development activities conducted by or on behalf of Merck Serono. The key modifications to the German embryo protection act in 2011 are: invasive biopsy of trophoblast layer is permitted for clinical evaluation of a) inherited genetic disorders and b) risk of miscarriage or stillbirth. As a result of this amendment, a decision to perform trophoblast biopsy can be made by the physician in Germany based on medical need of the patient. Accordingly, Merck Serono can sponsor clinical studies in which the invasive biopsy of trophoblast is evaluated for genetic or chromosomal analysis as an observational endpoint. However, Merck Serono cannot sponsor randomized clinical trials with invasive trophoblast biopsy as a variable of the trial design. Any randomization supported or endorsed by Merck Serono of patients to biopsy any portion of the embryo is considered to be invasive embryo research. For Merck Serono CMGs, support of biopsy of any portion of the embryo in a research protocol remains prohibited by the German embryo protection act (1990, 2011). A parallel principle exists to describe guidelines for research conducted with stem cells. There is an obvious link between research conducted with embryonic stem cells, trophoblast stem cells, and this embryo research policy. The critical connection between these two documents is that Merck Serono will not sponsor or support derivation of totipotent or pluripotent stem cells that require consumption of a portion or the entirety of a human embryo. - Page 2 of 10 -

3 FERTILITY RESEARCH POLICY 3 Table of Contents 1 Merck Serono is a Leader in Infertility Care. 4 2 Merck s Position for Embryo Technology Research Merck Current Engagement in Embryo Research Merck adherence to this policy Glossary / Definition References Page 3 of 10 -

4 FERTILITY RESEARCH POLICY 4 1. Merck Serono is a Leader in Infertility Care Merck Serono is the world leader in fertility treatment. We respect the strong wish of people to have children and want to aid the estimated one in 10 couples of childbearing age who seek medical help for infertility. The right of infertile couples to realize their dream of having a child is of high importance to us. For this reason, Merck has developed a comprehensive range of treatments relating to In Vitro Fertilization (IVF). During the different steps of IVF, our products support the production of oocytes and help to maintain the pregnancy when the embryo is introduced into the uterus. According to expert opinions, the optimization of this process through additional modifications of existing gondotropins is unlikely to produce clinically significant increases in pregnancy rate or take-home baby rate. To further improve the efficiency and success rate of IVF, Merck is conducting research to identify biochemical markers of oocyte and embryo viability that may be used to improve implantation rates of viable embryos, and increase the take-home baby rate. Once successful in validating biomarkers of oocyte and embryo viability, Merck may perform research to identify potential therapies to improve the viability of oocytes and/or preimplantation embryos prior to or coincident with transfer into the uterus. In addition, Merck may perform research to improve the receptive status of the endometrium to increase the probability of a viable embryo to implant. In this context Merck is actively engaged in non-invasive research in the field of embryo biology and in endometrial receptivity. Current technologies used for embryo screening are insufficiently validated to demonstrate a clinical benefit A consensus was derived from the Merck-Serono Bioethics Advisory Board, 2009 that is consistent with statements of professional organizations relevant for this field. The American Society for Reproductive Medicine (ASRM; and the European Society for Human Reproduction and Embryology (ESHRE; both have issued press releases in 2008 that current evidence does not support the use of preimplantation genetic screening (PGS) for chromosomal imbalance (aneuploidy) as a means to increase pregnancy rates. Both organizations additionally reference the development of newer technologies and embryological protocols that may improve the accuracy of either invasive or non-invasive assessments of chromosomal ploidy of embryos. Recent methods that perform comprehensive chromosomal screening (CCS) for ploidy status by microarrays containing single nucleotide polymorphisms (SNP) or polymerase chain reaction analysis of these SNPs have shown significant accuracy in aneuploidy diagnosis (>99%) and increases in pregnancy rates in women with previous pregnancy failures in IVF (71% live birth rate with CCS; Schoolcraft et al., 2011). Methods such as those described above must be reviewed, approved, and licensed by a German parliamentary ethics committee that has recently been proposed (2011) to the German embryo protection act (1990), if the technologies are to be used in German fertility centers. What has changed in the German embryo protection act? On 7 July 2011, an amendment to the German embryo protection act was adopted by the German parliament and Bundesrat. The amendment permits the clinical evaluation of genetic disorders and risk of miscarriage or stillbirth of blastocyst stage embryos by - Page 4 of 10 -

5 FERTILITY RESEARCH POLICY 5 analysis of trophoblast cells that eventually give rise to the placenta. This analysis of blastocyst by the responsible medical health professional is permitted in Germany: a. after consultation with the woman on the medical, psychological, and sociological outcomes of genetic and chromosomal examination, and after obtaining informed consent of the woman before the analysis is performed; b. after an interdisciplinary ethical commission verifies compliance of a licensed center for preimplantation genetic diagnosis (including aneuploidy screening) with the new guidelines of the Bundesrat; c. by a medical health professional in a licensed center for preimplantation genetic diagnosis, equipped with diagnostic, medical, and technical capabilities needed for this procedure. d. according to guidelines and regulations yet to be defined by the German interdisciplinary ethics commission. In regions outside Germany, the responsibility for obtaining regionally relevant licenses and certification are the responsibility of the physician and clinic. Incorporation of invasive trophoblast biopsies for analysis of embryo viability in the fertility treatment protocol is determined by the IVF center, the physician, and patient. Most importantly for Merck, the sponsorship of genetic or chromosomal research on embryos remains prohibited as described in the original embryo protection act (1990). Sufficiently powered clinical studies are required to demonstrate a clinical benefit of embryo technologies in IVF Non-invasive technologies are emerging from human embryo research that are preferred over invasive technologies for two basic reasons; first, there is no harm to the embryo during the sample collection; and second, patient populations without risk of inherited diseases or previous IVF failures are not expected to benefit from invasive blastocyst analyses. Several research groups have made recent scientific progress in identifying non-invasive markers of embryo viability. In view of the more favourable legal position for non-invasive technologies, Merck has engaged in research to identify non-invasive markers of embryo viability that can lead to improved pregnancy rates in IVF. 2. Merck s Position for Embryo Technology Research A summary of the 2009 and 2011 Merck Bioethics Advisory Panel (MBAP) meetings are indicated in the references (6). Also through the references (7), the English translation of the original embryo protection act (1990) and the recent amendment (7 July 2011; [translation from Prof Taupitz]) to the embryo protection act are available. Based on the instruction provided by these ethical and legal sources, Merck follows 7 guiding principles to insure we follow ethical principles in our fertility research program. We recognize the wish of a person / couple to have a child; We are committed to protect the welfare (wellbeing) of a child; - Page 5 of 10 -

6 FERTILITY RESEARCH POLICY 6 We intend to demonstrate the safety and clinical benefit of any technologies we develop; We intend to validate non-invasive embryo technologies with high-quality data before adoption of a technology into clinical practice; We adhere to responsible integration of technology that prevents misuse of technologies for phenotypic or social gender selection, or for negative effects on people with disabilities or other traits that may lead to discrimination of societal groups. Irrespective of national legislation, Merck opposes the production of human embryos solely for research purposes. Merck opposes collection of embryo culture medium after the seventh day of embryo development, which represents the current maximum duration of embryo culture prior to embryo transfer for in vitro fertilization procedures. In line with the German Embryo Protection Act (1990, 2011), Merck will not support invasive embryo research that requires destruction of a portion or the entirety of a human embryo as part of an experimental program. Merck may support clinical trials that include invasive embryo technologies recommended by the physician and accepted by the patient as observational endpoints under regionally appropriate guidelines (2011). Guidelines for stem cell research are outlined in a separate Merck document (Principle on Stem Cells and Human Cloning). 3. Merck s Current Engagement in Embryo Research Our Fertility Research intends to develop non-invasive technologies for oocyte and embryo evaluation that follow the legal guidelines of the German Embryo Protection Act of Non-invasive methods analyze the embryonic environment (rather than the embryo per se) or products of the oocyte retrieval that are not incorporated into the embryo (somatic cells and polar bodies). Non-invasive analysis is anticipated to provide more objective (and therefore reproducible) evaluation of oocytes and embryos than does current morphological evaluation. Although invasive methods for trophoblast evaluation are now permitted for clinical diagnosis under the amended German Embryo Protection Act, only non-invasive methods are options for Merck Serono Research & Development or external research sponsored by Merck Serono. The following guidelines are followed by Merck Fertility Research for collecting clinical samples of discarded material. 1. Merck is conducting observational clinical research under clinical protocols. Merck Fertility Research and Development will prepare clinical protocols and informed consent forms for collection of clinical material for review and approval by an internal safety and ethics committee. A patient information sheet will be prepared and shared with subjects prior to the start of down-regulation that describes the study and it s implications on their current treatment cycle. Merck will obtain Institutional Review Board (IRB) approvals for this that can be used by clinics participating with Merck Fertility Research in the embryo technology projects. 2. No investigational drug or procedure will be tested in the non-invasive embryo technology projects. No additional interventions other than the ones that - Page 6 of 10 -

7 FERTILITY RESEARCH POLICY 7 will be part of the centre s routine clinical practice for an ART cycle will be performed. Therefore there are no additional medical risks for the participants in this study. 3. Merck is collecting clinical samples that are discarded products of IVF procedures. Merck Fertility Research receives human biological materials from collaborating IVF clinics in the course of this research. These materials include follicular contents (somatic cells and fluids associated with unfertilized oocyte) as well as conditioned culture medium from day 3 (8-cell stage) and day 5-6 (blastocyst stage) embryos. The follicular fluid and discarded embryo culture medium samples are used to carry out biochemical assessments of developing embryos. In addition, genomic assessments are conducted with somatic cells surrounding unfertilized oocyte. The collection of embryo conditioned culture medium occurs after the embryo has been removed to a separate culture environment. Merck does not receive any embryos or portions of embryos. 4. Merck anticipates that non-invasive embryo biomarkers that measure aneuploidy may become a component of viability assessments in the future. For these anticipated clinical trials, Merck is limited to use of observational endpoints that require invasive procedures according to recent amendments (2011). Collection and analysis of polar bodies by biopsy from 2PN zygotes, remains compatible with the German Embryo Protection Act (1990). Association of non-invasive biomarkers with implantation of a sibling embryo can be accomplished through genetic fingerprinting of first polar bodies (Treff et al., 2009) This can be used in cases where 2 or 3 embryos are transferred. 5. Merck adheres to the guidelines established by the German Embryo Protection Act (1990, 2011). As an alternative to human embryo research, Merck may utilize existing human embryonic and trophoblast stem cell lines that are obtained according to principles defined in the Merck Stem Cell principle. Candidate biomarkers identified using stem cells obtained from external sources can be later confirmed in samples obtained by non-invasive methods described above. Merck is also conducting research to discover novel therapeutics that promotes implantation of the embryo into the uterine endometrial lining of the trophoblast. For this research, Merck uses trophoblast stem cells to mimic the process of embryo attachment and invasion. The policies that govern use of stem cells in research differ across international boundaries. Local or regional laws govern the policies to be followed for this research activity (please refer to Merck Stem Cell Principle). 6. Merck is acquiring access to existing human trophoblast stem cells to act as surrogates of human embryos for implantation research. Trophoblast stem cells used in this research have been derived from human chorion of elective pregnancy terminations, from existing embryonic stem cell lines, or from human embryos in countries where embryo research is allowed. In none of these circumstances has Merck sponsored the research to derive the trophoblast stem cells. - Page 7 of 10 -

8 FERTILITY RESEARCH POLICY 8 4. Merck adherence to this policy Merck recognizes the sensitive nature of human embryo technology research. Furthermore, Merck recognizes as of November, 2009, that the German Embryo Protection Act (1990) is the guiding document for this policy statement and for further sponsored research in this field. Merck also acknowledges the recent amendment of this embryo protection act, and is diligently working to maintain compliance of all Fertility Research within the guidelines of the Bundesrat. In light of prior research activity on embryo technologies, and to insure consistency of future research activity with the guidelines of the German Embryo Protection Act, Merck has elevated the corporate review of this endeavor to include global safety and ethics committee, and the chief medical officer. In addition, technologies intended for commercial use in IVF clinics will be reviewed by an external Merck Bioethics Advisory Panel (MBAP) to insure that these technologies deliver a clinical benefit for our IVF patients and their babies. - Page 8 of 10 -

9 FERTILITY RESEARCH POLICY 9 5. Glossary / Definition Oocyte: Female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. Follicular Fluid: liquid which fills the follicular antrum and surrounds the ovum in an ovarian follicle. Granulosa Cell: Somatic cell closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Polar Body: A cell structure found between the oocyte and the zona pellucid. Zona Pellucida: a glycoprotein membrane surrounding the plasma membrane of an oocyte. Embryonic Stem Cells (ESC): pluripotent stem cells derived from the inner cell mass of the blastocyst, an early-stage embryo. Blastocyst: An embryo stage formed in the early embryogenesis of mammals, after the formation of the morula, but before implantation. Gonadotrophins: Protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. non-invasive technology: collection of biological sample at IVF center does not involve removal of any portion of the embryo (after syngamy) analysis of sample restricted to viability, rather than chromosomal analysis. invasive research: collection of biological sample requires removal of some or all cells of the embryo (after syngamy). The discarded products of meiosis (polar bodies) are not considered a portion of the embryo proper. trophoblast: outer layer of embryo visible by day 5 of embryo culture that develops into the placenta after implantation. - Page 9 of 10 -

10 FERTILITY RESEARCH POLICY References 1. The General Assembly of the United Nations Universal Declaration of Human Rights. Available from: accessed 3 December Health Insurance Portability and Accountability Act (1996), Privacy Rule. 3. Meister U, Finck C, Stöbel-Richter Y, Schmutzer G, Brähler E. Knowledge and attitudes towards preimplantation genetic diagnosis in Germany. Hum Reprod 2005; 20(1): Treff NR, Su J, Kasabwala N, Tao X, Miller KA, Scott RT Jr. Robust embryo identification using first polar body single nucleotide polymorphism microarraybased DNA fingerprinting. Fertil Steril. 2010, 93: Schoolcraft WB, Treff NR, Stevens JM, Ferry K, Katz-Jaffe M, Scott RT Jr. Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and singlenucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients. Fertil Steril 2011, July Meeting report from the Ad-hoc Bioethics Advisory Board on Fertility research, Meeting report from the the first Merck Bioethics Advisory Panel, Page 10 of 10 -