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    Summary
    EudraCT Number:2018-001974-76
    Sponsor's Protocol Code Number:MK-3475-630
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2018-12-17
    Trial 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 ConcernedGermany - PEI
    A.2EudraCT number2018-001974-76
    A.3Full title of the trial
    A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Pembrolizumab Versus Placebo as Adjuvant Therapy Following Surgery and Radiation in Participants with High-risk Locally Advanced Cutaneous Squamous Cell Carcinoma (LA cSCC) (KEYNOTE-630)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Pembrolizumab as adjuvant therapy for resectable high-risk LA cSCC
    A.3.2Name or abbreviated title of the trial where available
    Pembrolizumab as adjuvant therapy for resectable high-risk LA cSCC
    A.4.1Sponsor's protocol code numberMK-3475-630
    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 LLC
    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 LLC
    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 LLC
    B.5.2Functional name of contact pointGCTO
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Avenue P.O. Box 2000
    B.5.3.2Town/ cityRahway, NJ
    B.5.3.3Post code07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+17325944093
    B.5.6E-mailjianda.yuan@merck.com
    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 No
    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.3.1Product namePEMBROLIZUMAB
    D.3.2Product code MK-3475
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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.IMP: 2
    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 KEYTRUDA (pembrolizumab, MK-3475)
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Sharp & Dohme B.V.
    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 Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPEMBROLIZUMAB
    D.3.9.1CAS number 1374853-91-4
    D.3.9.2Current sponsor codeMK-3475
    D.3.9.4EV Substance CodeSUB167136
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Resectable high-risk locally advanced cutaneous squamous cell carcinoma (LA cSCC)
    E.1.1.1Medical condition in easily understood language
    High-risk Locally Advanced cutaneous squamous cell carcinoma (non-melanoma skin cancer)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level PT
    E.1.2Classification code 10041823
    E.1.2Term Squamous cell carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the recurrence-free survival (RFS), as assessed by the investigator and confirmed by biopsy, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy
    E.2.2Secondary objectives of the trial
    1. To compare overall survival (OS) in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy
    2. To compare mean change from baseline in health-related quality of life (HRQoL) scores from the European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ)-C30, in individuals who receive pembrolizumab with individuals who receive placebo as adjuvant therapy
    3. To determine the safety and tolerability of pembrolizumab as adjuvant therapy in study participants
    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 and tissue) 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
    1. Participant must have histologically confirmed cSCC as the primary site of malignancy (metastatic skin involvement from another type of primary cancer or from an unknown primary cancer is not permitted)
    2. Participant must have undergone complete macroscopic resection of all known cSCC disease with or without microscopic positive margins. For those participants with residual microscopic positive margin
    involvement, confirmation that additional re-excision is not possible must be provided. Surgery may consist of 1 or a combination of the following:
    a. Resection of the primary lesion
    b. Any type of neck dissection(s)
    c. Any type of parotidectomy (superficial, total, partial)
    3. Participant must have histologically confirmed LA cSCC with a highrisk feature(s) as the primary site of malignancy (metastatic skin involvement from another primary cancer or from an unknown primary
    cancer is not permitted).
    High-risk features include at least 1 of the following:
    a) Histologically involved nodal disease with the following features:
    •Extracapsular extension with either at least 1 lymph node >2 cm in greatest diameter or ≥2 lymph nodes involved.
    b) Any index tumor with ≥2 of the following high-risk features:
    •Tumor ≥4 cm with a depth >6 mm or invasion beyond subcutaneous fat
    •Multifocal perineural invasion for nerves of <0.1 mm diameter (3 or more foci) or any involved nerve ≥0.1 mm diameter
    •Poor differentiation and/or sarcomatoid and/or spindle cell histology
    •Recurrent disease (any cSCC that recurs within 3 years in the previously surgically or topically treated area)
    •Satellite lesions (satellitosis) and/or in transit metastases
    •Lymphatic or vascular involvement
    c) Any gross cortical bone invasion or skull base invasion and/or skull base foramen invasion.
    4. Participant must have completed adjuvant RT for LA cSCC with last dose of RT ≥4 weeks and ≤16 weeks from randomization
    5. Participant must have completed at least 45 Gy of adjuvant RT for LA cSCC prior to study entry
    6. Participant is disease-free as assessed by the investigator with complete radiographic staging assessment ≤28 days from randomization
    7. Participant is male or female and at least 18 years of age at the time of signing the informed consent
    8. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
    • A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
    - Is not a woman of childbearing potential (WOCBP)
    OR
    - Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis),during the intervention period and for at least 120 days after the last dose of study intervention The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention
    - A WOCBP must have a negative highly sensitive pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention
    - If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
    -Abstains from breastfeeding during the study intervention period and for at least 120 days after study intervention.
    -If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
    9. Participant (or legally acceptable representative, if applicable) provides documented informed consent for the study. The participant
    may also provide consent for future biomedical research. However, the participant may participate in the main study without participating in
    future biomedical research
    10. Participant provides a tumor tissue sample adequate for PD-L1 testing as determined by central laboratory testing. This tissue sample may be obtained from either the surgical resection, or a prior archival tissue specimen not previously irradiated. FFPE tissue blocks are preferred to slides.
    11. Participant has a life expectancy of greater than 3 months.
    12. Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 performed within 10 days prior to treatment initiation.
    13. Participant has adequate organ function.Specimens must be collected within 10 days prior to the start of study treatment

    E.4Principal exclusion criteria
    1. Has macroscopic residual cSCC after surgery and/or recurrence with active cSCC disease before randomization
    2. Has any other histologic type of skin cancer other than invasive cSCC, eg, basal cell carcinoma that has not been definitively treated with surgery or radiation, Bowen’s disease, MCC, melanoma
    3. A WOCBP who has a positive urine pregnancy test within 72 hours before the first dose of study treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive
    4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another costimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
    5. Has received prior systemic anticancer therapy including investigational agents for cSCC within 4 weeks before the start of study
    intervention
    6. Participant must have recovered from all radiation-related toxicities and not have had radiation pneumonitis
    7. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study treatment. Administration of killed vaccines are
    allowed
    8. Has received an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment
    9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
    10. Known additional malignancy that is progressing or has required active treatment the past 2 years
    11. Has known active central nervous system metastases and/or carcinomatous meningitis
    12. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients
    13. Has an active autoimmune disease that has required systemic treatment in past 2 years except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid)
    14. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
    15. Has an active infection requiring systemic therapy
    16. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority
    17. Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV; defined as HCV RNA [qualitative] is detected) infection
    18. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstances that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator
    19. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study
    20. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment
    21. Has had an allogeneic tissue/solid organ transplant
    E.5 End points
    E.5.1Primary end point(s)
    Recurrence-free survival (RFS) as assessed by the investigator and confirmed by biopsy
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to approximately 60 months
    E.5.2Secondary end point(s)
    1. Overall Survival (OS)
    2. Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Score
    3.Change From Baseline in Physical Functioning Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) Items 1-5 Score
    4. Percentage of participants who experience an adverse event (AE)
    5. Percentage of participants who discontinue study treatment due to an adverse event (AE)
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Up to approximately 60 months
    2. Baseline and up to approximately 60 months
    3. Baseline and up to approximately 60 months
    4. Up to approximately 63 months
    5. Up to approximately 38 months
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    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 No
    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 Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    open-label retreatment
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA65
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Colombia
    Israel
    Mexico
    United States
    France
    Romania
    Spain
    Germany
    Greece
    Italy
    Hungary
    Norway
    Portugal
    Russian Federation
    United Kingdom
    E.8.7Trial has a data monitoring committee Yes
    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
    Receipt of the last laboratory result or LVLS, whichever comes last.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 220
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 350
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 285
    F.4.2.2In the whole clinical trial 570
    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 Decision2019-04-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-13
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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