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    Summary
    EudraCT Number:2015-005093-38
    Sponsor's Protocol Code Number:V503-004
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-05-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-005093-38
    A.3Full title of the trial
    An Open-Label Phase III Clinical Trial to Study the Immunogenicity and Tolerability of GARDASIL®9 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Adult Women (27- to 45-Year-Olds) Compared to Young Adult Women (16-to-26 Year-Olds)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial to study the antibody response and tolerability of GARDASIL®9 in women aged 27 to 45 years old compared to women aged 16 to 26 years old.
    A.4.1Sponsor's protocol code numberV503-004
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck Co., Inc
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMerck Sharp & Dohme Corp., a subsidiary of Merck Co., Inc
    B.5.2Functional name of contact pointGlobal Clinical Trials Operations
    B.5.3 Address:
    B.5.3.1Street AddressOne Merck Drive, PO Box 100
    B.5.3.2Town/ cityWhitehouse Station, NJ
    B.5.3.3Post code08889-0100
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17325947598
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name GARDASIL®9
    D.2.1.1.2Name of the Marketing Authorisation holderMSD VACCINS
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntramuscular use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 6 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 6 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB22591
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number30
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 11 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 11 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB22592
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 16 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 16 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB22593
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 18 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 18 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB22594
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 31 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 31 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB91674
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 33 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 33 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB91675
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 45 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 45 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB91676
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHuman Papillomavirus Type 52 L1 protein
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 52 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB91677
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNHUMAN PAPILLOMAVIRUS TYPE 58 L1 PROTEIN
    D.3.9.3Other descriptive nameHUMAN PAPILLOMAVIRUS TYPE 58 L1 PROTEIN
    D.3.9.4EV Substance CodeSUB91678
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Prevention of cervical,vulvar,vaginal, and anal cancers and related precancers, external genital lesions, Pap test abnormalities, and persistent infection caused by HPV Types 6,11,16,18,31,33,45,52,58
    E.1.1.1Medical condition in easily understood language
    Prevention of cervical,vulvar,vaginal, and anal cancers and related precancers, external genital lesions, Pap test abnormalities, and persistent infection caused by Human Papillomavirus
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10061331
    E.1.2Term Papilloma viral infection
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To demonstrate that the administration of GARDASIL®9 in 27- to 45 year old women induces non inferior geometric mean titres (GMTs) for serum anti-HPV 16, 18, 31, 33, 45, 52, and 58 compared with 16- to 26-year-old women.
    E.2.2Secondary objectives of the trial
    To evaluate the safety/tolerability of GARDASIL®9 in 27- to 45-year-old women compared with 16 to 26-year-old women.

    To demonstrate that GARDASIL®9 is immunogenic with respect to HPV types 16, 18, 31, 33, 45, 52, and 58 in 27- to 45-year-old women.

    To summarize humoral immune responses (including anti-HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 GMTs and seroconversion rates at Day 1 and 4 weeks after Dose 3) in 16- to 26-year-old and 27- to 45-year-old women who received GARDASIL®9.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for
    biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be
    conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time.
    E.3Principal inclusion criteria
    To be included in the study and to receive the first study vaccination, subjects must meet all inclusion criteria. For items with an asterisk (*), if the subject does not meet these inclusion criteria, the Day 1 visit may be rescheduled for a time when these criteria can be met.
    1. Independent Ethics Committee (IEC)-approved written informed consent form (ICF) and privacy language as per national regulations must be obtained from the subject and/or from the subject’s parent(s) or legal guardian(s) prior to any study-related procedures (including discontinuation of prohibited medication, if applicable); assent (for minor subjects) by the subject is given as required by local law. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
    2. Subject is a woman between the ages 16 years and 0 days and 45 years and 364 days as of first vaccination.
    3. Subject is judged to be in good physical health on the basis of medical history, physical examination (if deemed necessary), and laboratory testing.
    4. Subject, or subject's parent or guardian, is able to understand and adhere to the study procedures (e.g., is not planning to relocate far from the investigational centre during the study period); is able to read, understand, and complete the electronic vaccination report card (eVRC); is able to understand the risks involved with the study; and voluntarily agrees to participate in the study by giving written informed consent.
    5. *Since the first day of the subject’s last menstrual period through Day 1, the subject has not had sex with males or has had sex with males and used effective contraception with no failures (an example of a failure is a male condom that ruptures during sexual intercourse). Effective contraception is defined as a marketed, approved contraceptive product that the subject has used per the manufacturer’s instructions with every act of sexual intercourse. The subject understands and agrees that during the Day 1 through Month 7 period, she should not have sexual intercourse with males without effective contraception, and the uses of the rhythm method alone, withdrawal alone, and emergency contraception, are not acceptable methods per the protocol. Subjects who have reached menopause, undergone hysterectomy, bilateral oophorectomy, or bilateral tubal ligation are eligible without the use of contraceptives. Postmenopausal status is defined as: (1) No menses for >1 year but <3 years and confirmed by follicle stimulating hormone (FSH) levels elevated into the postmenopausal range, or (2) no menses for at least 3 years.
    6.* Subject has had no temperature ≥37.8°C or 100.0°F (oral) within 24 hours prior to the first injection.
    7. Subject agrees to provide study personnel with a primary telephone number as well as an alternate telephone number for follow-up purposes.
    E.4Principal exclusion criteria
    To be included and receive the first study vaccination, subjects should not have any exclusion criteria. For items with an asterisk (*), if the subject meets these exclusion criteria, the Day 1 visit may be rescheduled for a time when these criteria are not met.
    1. Subject has a history of an abnormal Pap test or abnormal cervical biopsy results (showing cervical intraepithelial neoplasia or worse) or cervical disease (i.e., surgical treatment for cervical lesions).
    2. Subject has history of genital warts, Vulvar Intraepithelial Neoplasia or Vaginal Intraepithelial Neoplasia.
    3. Subject has a history of a positive test for HPV.
    4. Subject has a history of known prior vaccination with an HPV vaccine, i.e., received a marketed HPV vaccine, or has participated in an HPV vaccine clinical study and has received either active agent or placebo.
    5. Subject is pregnant (as determined by serum or urine pregnancy test).
    6. Subject is, at the time of signing ICF, a user of recreational or illicit drugs or has had a recent history (within the last year) of drug or alcohol abuse or dependence. Alcohol abusers are defined as those who drink despite recurrent social, interpersonal, and/or legal problems as a result of alcohol use.
    7. Subject has a history of severe allergic reaction, including known allergy to any vaccine component, including aluminum, yeast, or BENZONASE® (nuclease, Nycomed [used to remove residual nucleic acids from this and other vaccines]) (e.g., swelling of the mouth and throat, difficulty breathing, hypotension or shock) that met the criteria for serious adverse experiences defined in this protocol.
    8. Subject has had a splenectomy, or is currently immunocompromised or has been diagnosed as having a congenital or acquired immunodeficiency, HIV infection, lymphoma, leukaemia, systemic lupus erythematosus, rheumatoid arthritis, juvenile rheumatoid arthritis, inflammatory bowel disease, or other autoimmune or immunosuppressive condition, or has a history of any disease, which, in the investigator’s opinion, may confound the results of the study or pose an additional risk to the subject.
    9. Subject is receiving or has received in the year prior to enrolment the following immunosuppressive therapies: radiation therapy, cyclophosphamide, azathioprine, methotrexate, any chemotherapy, cyclosporin, leflunomide (tumour necrosis factor-α antagonists, monoclonal antibody therapies (including rituximab [Rituxan]), intravenous gamma globulin, antilymphocyte sera, or other therapy known to interfere with the immune response. With regard to systemic corticosteroids, a subject will be excluded if she is currently receiving steroid therapy, has recently (defined as within 2 weeks of enrolment) received such therapy, or has received 2 or more courses of high dose corticosteroids (≥20mg/day of prednisone [or equivalent] orally or parenterally) lasting at least 1 week in duration in the year prior to enrolment. Subjects using inhaled, nasal, or topical corticosteroids are considered eligible for the study.
    10. Subject has received any immune globulin or blood-derived product within the 3 months prior to the Day 1 vaccination, or plans to receive any such product during Day 1 through Month 7 of the study.
    11. * Subject has received non-replicating (inactivated) vaccines within 14 days prior to the Day 1 vaccination or has received replicating (live) vaccines within 21 days prior to the Day 1 vaccination.
    12. Subject has thrombocytopenia or other coagulation disorder that would contraindicate intramuscular injections.
    13. Subject is concurrently enrolled in a clinical study of investigational agent.
    14. Subject has a history or current evidence of any condition, therapy, lab abnormality or other circumstance that might confound the results of the study, or interfere with the subject’s participation for the full duration of the study, such that it is not in the best interest of the subject to participate.
    15. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or Sponsor staff directly involved with this trial.
    E.5 End points
    E.5.1Primary end point(s)
    The primary immunogenicity endpoints are the cLIA GMTs to HPV 16, 18, 31, 33, 45, 52 and 58.
    E.5.1.1Timepoint(s) of evaluation of this end point
    at 4 weeks after Dose 3.
    E.5.2Secondary end point(s)
    The secondary immunogenicity endpoints are:

    the cLIA seroconversion percentages to HPV 16, 18, 31, 33, 45, 52 and 58 in 27- to 45-year-old women.

    the cLIA GMTs and the cLIA seroconversion percentages to each of HPV 6,11,16,18,31,33,45,52, and 58 in 16- to 26-year-old women and 27- to 45 year-old women.

    The Safety assessment will focus on injection site adverse reactions and elevated temperatures reported on the electronic VRC. SAEs, pregnancy, and pregnancy-related events will be collected.

    E.5.2.1Timepoint(s) of evaluation of this end point
    Immunogenicity: by 4 weeks after Dose 3.
    Safety: for injection Day 1 to Day 5 post-vaccination and systemic AEs Day 1 to Day 15 post-vaccination. For SAEs, pregnancy, and pregnancy-related events , from the time the ICF is signed through 1 month following the last vaccination
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    tolerability
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    different age group
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the study will be defined as when final report of study results is available.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months14
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 150
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 150
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1050
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state250
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 1200
    F.4.2.2In the whole clinical trial 1200
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-11-13
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-21
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