Analyzing case studies of conducting trials outside the USA: the MENA region and the specific challenges involved. Oct 7, 2014

Transcription

1 Analyzing case studies of conducting trials outside the USA: the MENA region and the specific challenges involved Oct 7, 2014 Steven A. Kates, Ph.D. Adjunct Professor, Northeastern University - Boston

2 Contents of the Presentation Introducing the region Differences specific to the region Modifications to study design? Needed? Or not? Regulatory differences How you adapt and making it work Working with local vendors 2

3 MENA the Final Frontier Source: Applied Clinical Trials. Vol 20, N April

4 Potential Growth in MENA s Market MENA s clinical trial revenues should increase almost 10-fold over the next decade, which will build an annual market of about $1 billion (based on a 20% annual growth from actual level) First likely countries to grow: S. Arabia and Egypt then; Algeria, Jordan, Lebanon, Morocco, Tunisia and the Gulf cluster/region (Kuwait, Qatar, and UAE) CROs will capture 60 to 80% of the market, possibly more in some countries (equivalent to $ M in annual revenues 10 years from now) Vladimir Misik, Ph.D., Senior Regional Director, Clinical Operations, EMEA, Quintiles 4

5 Israel 5

6 MENA s Close Proximity to the West 6

7 Landscape of the Region (North Africa) Modern infrastructure and history 7

8 Landscape of the Region (Middle East) Modern infrastructure and history 8

9 Population of MENA Country Population in MM (2012) Number of clinical trials Morocco /73 Algeria /55** Tunisia /140 Libya 6.5 4/0 Egypt /549 Jordan /508 Israel /6497 Lebanon /1485 UAE /85 S. Arabia /103 Yemen /3 Oman /18 Qatar /47 Turkey /1487 Total* /11050 MENA is ~4% of the world population *< 1% of global CTs **Local CT numbers much higher 9

10 MENA Possesses Several Desirable Features for Clinical Research Highly centralized healthcare systems Many world-class healthcare facilities Hospitals and physicians interested in participating in clinical trials Governments and institutions focused on attracting clinical research Western-trained investigators with excellent command of English Hospital source documents in English or French (except for Syria) 10

11 MENA - Home for Highly Solicited Patient Profiles Six of the world s top 10 countries with diabetes are in the Middle East United Arab Emirates, Kuwait, Qatar, Saudi Arabia, Bahrain, and Lebanon Cardiovascular: 80% of disease related deaths occur in Arab countries Egypt has highest prevalence of hepatitis C virus (HCV) in the world, estimated nationally at 14.7% (8 to 10 million people) Wealth of pulmonary pathologies encountered in the Middle East probably surpasses all other regions of the world Classic infectious disorders: TB, malaria, trachoma etc. 11

12 Leading Causes of Death Africa, Sub-Saharan Africa and North Africa (2004*) Diseases Africa Rank Deaths % Sub-S. Africa** Rank Deaths % N. Africa** Rank Deaths % Worldwide Rank Deaths % HIV/AIDs 1 1, , , Lower respiratory infections 2 1, , , Diarrheal diseases 3 1, , , Perinatal conditions 4 1, , , Malaria Heart diseases , Malignant neoplasms , Cerebrovascular diseases , Chronic obstructive pulmonary disease , Tuberculosis , Road traffic accidents , Diabetes mellitus , Nephritis and nephrosis Cirrohsis of the liver Suicide All Causes 12, , , *: in thousands **: countries groped according to UN grouping Source: Global Cancer Facts and Figures, 2 nd edition,

13 Cancer Increase by 75% in % in low to middle level of human development index vs. 69% in high to very high human development index (HDI) In 2008 Most prevalent cancer in women was breast Most prevalent cancer in men was bladder for Algeria and colorectal for Tunisia North America North Africa South Africa Lung 15% Breast 17% Breast 11% Prostate 13% Lung 7% Prostate 10% Breast 13% Bladder 7% Esophagus 9% CRC 11% NHL 7% Cervix 8% Source: 13

14 Recent Challenges in the Clinical Landscape Changes in the regulatory landscape and enroller countries India E. Europe S. Africa Increase in medical costs and study conduct Tough competition Challenges in recruitment Changes in standard of care Increase in the buying power of some of these countries (KSA, Algeria and UAEs) 14

15 Selecting a New Region Right patient population with good recruitment potential Reasonable regulatory timelines Good infrastructure Adequate standard of care Investigator compliance to study protocol and procedures Respect of patients and compliance with ICH, FDA and local ethical guidelines 15

16 MENA the Final Frontier Source: Applied Clinical Trials. Vol 20, N April

17 MENA Advantages Population Sizeable, Caucasian, genetically diverse populations mainly located in urban areas Access to treatment naïve patients Rapid recruitment, highly populated clinical practices and better patient retention Investigators/Sites Proficient French and English speakers; postdoctoral training in Europe Well equipped medical facilities All source documents and communications in English Closer to Europe and US 17

18 Regulatory Environment in MENA Notable efforts to establish national research ethics guidelines have been made in many countries in MENA region ICH compliant EC available in large university institutions Increasing governmental awareness on bioethics, patient rights, drug safety and pharmacovigilance Emerging awareness and support of a new knowledge economy that supports research 18

19 Types of Trials You Can Conduct in MENA Middle East: Phase II and IIIs Phase I in Israel and Lebanon Bioequivalence Observational North Africa Phase II and IIIs Bioequivalence Observational Note: Some of these countries are considering to allow for Phase I trials 19

20 Regulatory Processes in Timelines in MENA Country Time to IEC Approval Time to MOH Approval MOH / EC submissions Time to Import license EC local / central Algeria 1 month 2 months Sequential 3-4 days Central Tunisia 1 to 3 months 2 weeks Sequential 3 to 4 weeks Local Egypt 2-3 months 2 months Sequential 3-4 weeks Local Jordan 2-3 months 2 months Sequential Included in MOH approval Local UAE 4 6 weeks 2-3 months Sequential 2 weeks Local KSA 2-3 months 3 months Sequential 3 weeks Local Bahrain Not needed 6-8 weeks NA 3 weeks Local Qatar 1 month Not needed NA 3 weeks Local Oman 1 month Not needed NA 3 weeks Local 20

21 Examples of Regulatory Submissions (N. Africa) Regulatory Body Approval Time (Approval/Review) Ethics Committees Ministry of Health (MoH) Direction de la Pharmacie et du Medicament (DPM) MoH and DMP Must be available prior to submission to MoH (Algeria), DPM (Tunisia) Provide review and approval for studies and import/export licenses License for importation and exportation of study supplies Algeria: 1 month Tunisia: 1 to 3 months Algeria: 2 months Tunisia: 1 month Algeria: same time as approval Tunisia: with each shipment Total (parallel processing) N.A. Algeria: 3 months Tunisia: 3 to 4 months Notes: 1. CRO must provide letter of delegation to the MoH and/or DPM 2. Post registration studies may not require EC approval at the site level 21

22 Regulatory Approval Times Some Examples: USA 30 days North Africa (Algeria and Tunisia) 90 to 120 days Middle East: 30 to 180 days South Africa 120 to 210 days E. Europe: varies from 90 days to over 180 days India days China up to 270 days Central/South America days 22

23 The Regulatory Application Package for MoH Similar to most submitted information for a clinical trial application Some differences related to the region: Application Form (in French for N. Africa) Final Protocol, plus synopsis to be provided in French (N. Africa) Investigator Brochure Case Report Forms (in French for N. Africa) List of sites already participating and enrolling patients or sites to participate in the study Approvals from other agencies ICF (to be formatted to meet regulatory requirements and translated in all relevant languages, French and Arabic based on the countries) Letter of delegation Proof of insurance Investigator agreement (in French for N. Africa) 23

24 The Regulatory Application Package For EC For EC submission: Protocol (French for N. Africa) Case Report Form (CRF) complete set (French for N. Africa) Investigator Brochure All relevant regulatory documents Informed consent (IC) including translated IC (Arabic and French for N. Africa) Earlier clinical phase data when available (Interventional studies) List of centers participating in the study Proposed financial agreement (French for N. Africa) Indemnity insurance CV of the investigators (Principal and sub-investigators) Clear research objectives for undertaking the trial in human subjects in light of existing knowledge 24

25 Translations Informed Consent Forms need to be translated French and Arabic Contracts and legal documents, review may vary from site to site. They will be reviewed and signed in French by institution and investigators (N. Africa), English for ME. Can be signed by investigator and/or institution. Phase IV: contract with investigators Phase II and III: may be with the institutions too Drug label are accepted in English at this time but may require translation Translation of basic study material: synopsis, CRF pages as guidelines etc 25

26 Managing Regulatory Expectations - How to Optimize Results? Local expertise essential to ensure smooth regulatory setup and up-to-date knowledge of regulations Local legal entity of representative scientific office or CRO mandatory in many countries Face to face meetings, personal interaction, and close follow-ups are highly influential in boosting processes With regulatory agencies With Investigators 26

27 Challenges Related to Global Studies There are basic challenges related to conducting global studies; these are present no matter the disease or indication: Cultural differences Differences in standard of care Differences in diseases, in some cases Experience in clinical trials Compliance and understanding of roles and responsibilities of research team Language barrier Translations Patient consents Regulatory constraints Operational limitation based on the country Recruitment strategies Safety and SAE reporting 27

28 Managing naïve Investigators Management of Investigators Majority of investigators in MENA are naïve with respect to clinical trials Provide basic GCP training Provide extensive training related to the study and study related activities Provide continued support to the investigator and site staff Establish a trust relationship, working as a team and encourage transparence CRO must be available as often as needed to help and support the sites For tough indications, may consider via CRO, providing study site coordinators for the duration of your study 28

29 Issues Specific to the Region Feasibility studies: Sites are not used to clinical trials, and for interventional studies you physically need to go to the sites, in general For observational studies, not that different (clients talk about site qualifications via phone, does not really work) Document collection: Investigators very busy, often don t have SSC, so the CRO/CRA has to do the work Prepare CV or help them develop their CVs particularly for the naïve sites, unexperienced sites Prepare all the forms so they only have to sign Be prepare to train the sites GCPs Study specific procedures, recommend mock patient Consenting and safety reporting 29

30 Choosing a Partner for the Region Local presence and local knowledge is paramount Full integration with ICH/FDA/regional regulatory requirements Team accustomed to Western work style Local CRAs in countries Operational team speaking the key languages English, French and native language (Arabic!) Experienced team with global clinical trial expertise in multiple therapeutic areas Established relationships with MoH and clinical sites 30

31 Clinical Trials in New Emerging and Developing Economies Pros Sizeable patient populations with diseases of both developed and developing world Fewer competitor trials Keen investigators Competitive timelines and cost savings High data quality Cons Nascent clinical development environments Relatively poor commercialisation potential Ethical dilemmas Concerns regarding Intellectual Property protection 31

32 MENA vs NEEs MENA Access to large Caucasian population, European decent for a large part Limited exposure to CTs Untapped population Attractive healthcare system/ Reimbursement IP Protection enforced Peripheral activities nascent but not absent (DM, BS, central labs) Positive selling points: Closeness to the West Reasonable regulatory timelines Languages (restricted to 3) NEEs Mix populations, Caucasians etc. Have been conducting studies for over a decade Populations more exposed to CTs Not all equal IP protection questionable Drug Depots, Local DM etc. available Negative selling points: Regulatory timeline Big cultural differences Multitude of languages 32

33 Take Home Message New region worth considering Great recruitment for challenging indications including rare and ultra rare disorders Has reasonable regulatory timelines Has the right infrastructures for study conduct May require a little more hand holding of investigators Choice of CRO critical 33

34 Thank you Merci شكرا teşekkür ederim תודה Steven Kates, Ph.D. Cell: