Global Health Trials/DNDi: 19 Aug 2011 Clinical Trials in Kenya One Day Skills Sharing Workshop

Presentation 1: Clinical Trial Regulations and Guidelines by Dr. Jayesh M. Pandit from Pharmacy and Poisons Board of Kenya

The Pharmacy and Poisons Board [PPB] is the Drug Regulatory Authority of the Ministry of Health, Kenya with one of it’s core mandate: “to make better provision for the practice and profession of pharmacy and the trade in pharmaceutical products.”

Aim of clinical trials

The aim of most clinical trials is to test in humans, the safety and efficacy of new drugs and medical devices under development. It is mandatory for any trial that includes the testing of drugs and medical devices in humans to obtain the necessary regulatory clearances and approvals from the Pharmacy and Poisons Board. In recent years, the number of clinical trials being conducted in Kenya especially in the major diseases of HIV/AIDS, Malaria and TB has increased.

The ECCT [The Expert Committee on Clinical Trials]

No clinical trial can commence without receiving a final approval from the PPB.

License to import investigational product and/or medical device is permitted only after ECCT approval.
ECCT reviews all clinical trial protocols on investigational products (pharmaceuticals) and medical devices to be conducted in Kenya and provides recommendations and advice to the Board. Protocol flow

The procedural protocol is as outlined below:
Investigator (study protocol submission),
Scientific Peer Review(Intramural and Extramural),
Institutional Review Boards / Ethical Review Committees,
Pharmacy and Poisons Board's Expert Committee on Clinical Trials,
Final Approval,
Issuance of licenses to import / manufacture investigational product

Since its inception, the ECCT has developed:
Terms of References (TORs)
Check list for submission of clinical trial protocols.
Developed a brochure to assist in disseminating information and create awareness of the existence of the ECCT and the role of the Pharmacy and Poisons Board in clinical trial authorization.
Inventory on the nationally accredited IRBs/IECs in collaboration with NCST.
Developed a National Guidelines for Applicants Seeking Approval for Clinical Trials in Kenya.

Challenges and limitations
Staffing, expansion of clinical trials registry, funding, increase awareness and advocacy of ECCT
Difficulties faced when receiving protocols

Protocols submitted to ECCT prior to Ethics favourable opinion: NOT ACCEPTED
Checklist for submission of protocols and documents not followed: NOT ACCEPTED
Parallel submission to PPB and ERCs: NOT ACCEPTED
Assumption by applicants that ECCT will approve “in a day”: SERVICE CHARTER = 1 MONTH
The Way forward for ECCT

Gap: Network locally so the various bodies working in isolation come together
Enhance links with stakeholders, institutions and other regulators: in Kenya, within EAC and internationally
In-line with the FDA responsibilities
Regular site visits, audits and inspections
Joint inspections of sites with ERCs
Ensure appropriate implementation of GCP principles at trial sites and strengthen them
Participate in FDA –Kenya audits
Joint Clinical Trial Application reviews e.g. WHO-AVAREF
Annual joint meeting of IRBs / ERCs / Regulators

Phamacovigilance

Definition: Pharmacovigilance is the science of collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medicines, biological products, herbals and traditional medicines, with the view to: [Identifying new information about hazards, and Preventing harm to patients.]
Widening scope of Pharmacovigilance
1. Substandard and counterfeit medicines
2. Product development
3. Medication error reporting
4. Adverse interactions of medicines with chemicals, other medicines, and food reports
5. Assessment of drug-related mortality
6. Abuse and misuse of medicines reports
7. Efficacy monitoring
8. Off-label use of medicines
9. Case reports of acute and chronic poisoning

Post market surveillance: Post market surveillance ensures that, even after registration, drugs continue to meet there required standards whilst in the market.

Medication errors: Any preventable event that may cause or lead to inappropriate medication use or patient harm while the medication is in control of the health care worker

Contacts

Website: www.pharmacyboardkenya.org

Presentation 2: Informed Consent by Allan Maleche and Ambrose Rachier from Kenya Ethical

Definition of Informed Consent

In any research on human beings, each potential subject must be adequately informed of the aims, methods, anticipated benefits and potential hazards of the study and are free to withdraw consent to participation at anytime. The physician should then obtain the subject’s freely given informed consent preferably in writing. (Article 1.9 of the Declaration of Helsinki World Medical Association 1996)

History of informed consent

This developed as a result of the reaction of the International Community towards:
a. World War I and II atrocities ( Universal Declaration of Human Rights )
b. Nazi Physicians (Nuremberg Code)
c. Tuskegee Syphilis Experiment (The Belmont Report, CFR 45+46)
d. Japanese Vivisection Experiments
e. Thalidomide Babies
f. The Willow brook Hepatitis Study (Helsinki Declaration and CIOMS)#

Process of Informed Consent

It is a process that involves conveying accurate and relevant information about the study, its purpose, disclosing known benefits, risks alternatives and procedures, in a language which the participant best understands.

It also involves answering questions and enabling the potential participant to make an informed decision whether or not to participate in a given research study.

Legal capacity

Generally consent should only be given by adults of sound mind without compulsion inducement or deception.

There are however exceptions where minors and mentally challenged persons/participants may be used as subjects of research.

The consent should where appropriate be express and may be withdrawn at any time and for any reason without disadvantage or prejudice.

Exceptions can only be by law enacted with interests of public safety for the investigation, deletion and prosecution criminal offenders, for the protection of public health and of the rights and freedoms of others.

Basis of Informed Consent

It is derived from the principle of autonomy/ respect of persons.
It places emphasis on the fact that an investigator should respect each research participant as a person capable of making an informed decision regarding participation in the research study.

Principle of Autonomy
It also creates two ethical obligations which are:
a. That individuals should be treated as autonomous agents.
b. That persons with diminished or impaired autonomy are entitled to protection

Requirements of Informed Consent

For consent to be valid , the researcher must:

i. Communicate to the prospective subject all the information necessary for adequately informed consent

ii. Give the prospective subject full opportunity and encouragement to ask questions

iii. Exclude the possibility of unjustified deception, undue influence and intimidation

iv. Seek consent only after the prospective participant has adequate knowledge of the relevant facts and of the consequences of participation, and has sufficient opportunity to consider whether to participate

v. Obtain from each prospective subject a signed form as evidence of informed consent

Basic Elements of Informed Consent

An informed consent sheet should contain the following information:

- A statement that research is being conducted, its purposes, duration and a description of the experimental procedures to be employed

- Description of foreseeable risks and discomfort to the subject

- Potential benefits to subjects or to others

- Description of alternative treatments available

- Statement regarding the extent to which research records will be kept confidential

- Arrangement for compensation should the subject be harmed

- Contacts for further information or redress

- Statement that participation is voluntary and that the participant will not lose any treatment benefit should he or she refuse to participate or withdraw

Difficult Circumstances of informed consent

Obtaining informed consent from participants can be challenging when dealing with the following category of people:

- Children

- Patients with learning disability, serious psychiatric problems and all forms of dementia

- Illegal populations ( Commercial Sex Workers, Men Who have Sex with men, Intravenous Drug Users)

- Seriously ill Patients

- Convenient and Captive Populations (Soldiers, Prisoners and Students).

Community Consultations and Consent

Community consultation should not be mistaken for community consent, although the 2 are not mutually exclusive. (To consult is “to seek advice or information.)

Consulting with a community includes eliciting feedback, criticism, and suggestions; it does not include asking for approval or permission.

Community consultation is designed to recognize and accommodate the relevant particularities of a given community for a specific project. E.g. speaking to advocacy groups, persons living with HIV in cases of HIV related trials

Rather than soliciting input, community consent involves soliciting approval or permission to conduct a study within a community.

Community consent may occur after community consultation and does not obviate the need for individual consent.

Rather, the community decides whether to permit investigators to solicit participation from community members.

For community consent to be valid, there must be a legitimate political system in place, with representatives properly empowered to make such decisions on behalf of the community.( Area elders)

Challenges of Informed Consent in Developing Countries

Is it achievable and practicable in the context of a developing country in light of these factors:

- Illiteracy;

- Poverty;

- Inducement;

- Gender inequity and inequality;

- Culture; Community Consent

- Language Barrier;

- Therapeutic Misconception;

Contacts of presenters

amaleche@kelinkenya.org & lawtechs@rachieradvs.co.ke

Presentation 3: CLINICAL TRIALS LABORATORIES by Bashir Farah from Kenya AIDS Vaccine Initiative (KAVI)

· GCLP should be adopted by any organisation that analyses samples generated during the conduct of a clinical trial so as to provide a unified guidance that can be applied globally to clinical sample analysis to facilitate patient safety, confidence in the data generated.

· The Key elements discussed were:

a. Organisation and personnel:

- Qualified personnel are critical in ensuring good quality of outcomes and service provision.

- An establish working structure ensures sufficiency at all parts in the laboratory work flow.

- Proper designate of responsibilities and roles is of importance and development of an organization chart.

- Personnel management can be assessed by checking the following: Job qualifications, Job descriptions, Orientation, Training, competence assessment, continuing education, performance appraisal, and staff equals workload

b. Facility

- When choosing a facility put to consideration: Space and size; design and fabrics; archive facility;

c. Equipment

- When choosing an equipment put to consideration: Installation, calibration/performance evaluation, maintenance, trouble-shooting, service and repair, and retiring requirement/disposition.

- Equipment management ensures: high performance levels, lowers repair costs, lengthens lifespan, increases safety, reduces interruption of service and ensures greater customer satisfaction.

d. Sample management

- Essential to accurate laboratory diagnosis, influences therapeutic decisions, directly affects patient care and outcome and influences laboratory efficiency.

e. Standard operating procedures [SOPs]

- Standard Operating Procedures are documents which describe how to perform tests or other activities

- Must be approved by the laboratory management to assure clients of the quality and integrity of the data

- Defines management’s requirements and confirms that appropriate staff, equipment, reagents etc have been made available for the procedure to be performed

f. Testing analysis

- The following should be put to consideration when testing an analysis:

- Analysis 1: Requirements, Plan, method[choice, suitability, validation], automated/manual, sample handling[type, volume,ID-barcode]

- Analysis 2: Calibration, Controls[ IQC and EQA], Result validation [Maybe linked with competency level], Repeat analysis [Criteria and procedure if non-correlation], HIV test Algorithm (Important HIV Vaccine Trials), Data entry [Manual, Interfaced], Reporting [Format/timeliness/method], Alert values, Reference Ranges

g. Audits

- Quality Audit: Independent monitoring of the trial facility and its operation to assure compliance with the trial protocol, analytical plan, Standard Operating Procedures and with defined standards.

- Reason for auditing:

1. Learn “where we are” in terms of quality management

2. measure gaps

3. Need information for: Planning and implementation; monitoring and continuous improvement

- Auditing could be:

1. Internal auditing of the laboratory

2. External auditing by: Health authorities, Accreditation bodies, Funding program, public health program.

h. Occurrence management:

- Definition: Any event that has a negative impact on an organization, which includes personnel, product, equipment, or the environment.

- Common causes of error: Equipment not properly maintained, Individual responsibility unclear, No written procedures, No training, Transcription errors, Test kits not stored properly, QC, EQA not performed

- Courier Companies [DHL, World courier]

i. Consequences of laboratory error: Inadequate or inappropriate patient care, inappropriate public health action, wasteful resources undetected communicable disease outbreaks and even death.

j. Establish a process to detect problems i.e. log findings and actions, investigate causes, analyse information, take appropriate action, monitor for reoccurring problems, provide information to all needing it.

Presentation 4: DATA MANAGEMENT FOR CLINICAL TRIALS by Truphosa Omollo [DNDi data centre-Kenya]

a. Data Management

Major processes in Data Management include Entry: Validation, Query management
The Data management process begins with CRF design and ends with having a clean data set for analysis
SOPs for DM are used to ensure consistency during the DM process

b. GCP for DM

Provides minimum standards and best practises for clinical data management

Minimum standards [Ensures data are complete, reliable and processed correctly]

Best practices [Offer higher efficiency, quality and function and lower risk in addition to assuring data integrity]

Data Management tasks are often technical and specialized

Crucial that DM professionals take a proactive role in setting [appropriate expectations and standards for data quality, Methodology for quantifying data quality, and Auditing practises to assure data quality]

Understand basic data privacy issues and follow principles established by the organization to ensure the privacy of research subjects and compliance with GCP

c. Resources & Skills Sharing

Resources are generally limited and It is important to effectively utilise what is available so as to improve efficiency, effectiveness and timeliness of a study

d. What to share?

Codes for data validation, cleaning & reporting

Electronic Case Report Forms (CRF’s)

Software's for automation e.gQuery Management System

Community websites with valuable resources e.g the global health trials

e. Open Source Solutions for DM

Open source: freely available,

benefit from sharing source codes,

improve on existing systems

Examples include OpenClinica as a database system

Presentation 5: Community Engagement in KEMRI‐WellcomeTrust Research Programme (KEMRI Kilifi) BY Dorcas Kamuya

Why engage the community to biomedical research?

To address numerous research ethics challenges,

Protection of vulnerable communities,

Respect for community’s culture, value and customs,

Empowering communities and building partnerships,

Strengthening research feasibility and quality

Engaging the community depends on goals and greater involvement through:

Information giving
Consultation
Shared decision making

Greater power sharing

Community engagement in KEMRI‐Kilifi
Wide range multi‐disciplinary studies have been carried out in Kilifi e.g. lab based, wards, clinical trials, community‐based studies etc

Health and Demographic Surveillance System (HDSS) ‐covers 15 locations, over 250,000 people.

Over 700 staff, nearly half are field workers and data entry clerks.

Formal community engagement process, coordinated by the Community liaison group.

KEMRI Community Representatives [Training & consultation]

CAB for consultation on HIV research

Key SH groups Civil service; MOH and others [Consultation/ sensitization]

KEMRI Kilifi Interface staff ‐Training, supervision; CCC ‐Informed consent,

Community Outreach: Public meetings, Small groups

School engagement programme (pilot)

Summary: Key issues based on experiences…

Community engagement an on‐going process, uses a wide range of approaches
Engaging with multiple “communities” may be important: identify through consultation.
Social science is key: understanding gaps between researchers and “communities”.
Beyond information giving, effective community engagement draws on interpersonal interactivity and adequate policy support to build trust
Right mix of skills for consultation ‐include negotiation and facilitation

Presentation 6: Setting Up a Clinical Trial by Bernhards Ogutu from CCR‐KEMRI/CREATES/INDEPTH

What’s a clinical trial?
The International Committee of Medical Journal Editors (ICMJE) defines a clinical trial as: "Any research project that prospectively assigns human subjects to intervention and comparison groups to study the cause‐and‐effect relationship between a medical intervention and a health outcome. [This definition includes drugs, surgical procedures, devices, behavioural treatments, process‐of‐care changes]
Reasons for conducting a clinical trial
Evaluate a product in development,
Redefine a product, and
Monitor the continued performance of a product.
Insights during formulation of a clinical trial
Time frame [setting up and execution phase];
Phase of trial [preclinical and clinical-I-IV];
Outcomes [data collection , capacity development, sustainable platform];

Concept of conducting a clinical trial

Does my research meet a clinical trial?

Does it offer a solution?

Can it get survive the development pipeline evaluation?

Factors worth consideration when developing a clinical trial

Human capacity [GCP, GCLP & Data management Team];

Physical infrastructure [Equipment, buildings];

Institutional support [Science management, Financial management];

Appropriate population [Disease and Disease dynamics]

Considerations when planning for a Clinical trial

Protocol Development,
Sponsorship,

Trial Master File,

Partner Consultation,

Risk Assessment,

Apply for Funding,

Develop Trial Documentation,

Finalise Contracts,

SOP preparation and approval,

Accreditation,

Trial registration,

Approvals [e.g. Ethics Approval, Clinical Trial Authorisation, Host Organisation Approval and Sponsor Initiation Visit],

Monitoring plan and oversight plans-IDSMB

Partner Consultation

Does the centre sufficient infrastructure

Does the centre have appropriate experience

Can the external funding be secured

Are leverage funds

Trial management teams required

Does the host institution have required support

Management of test article

Clinical care availability

Risk Management

Map out the profile of the drug

Determine appropriate oversight plan [Monitoring plan, IDSMB requirement and Need for interim analysis]

Cost effectiveness

The Study Team

Developing SOPs [for clinical and laboratory activities; data collection and management];

Completion and tracking of study forms;

Staff training and Research management

How to Develop SOPs

SOPs and data forms should be drafted by a multidisciplinary team of primarily senior staff, further refined with input from junior staff and tested before study initiation.

Staff training should be based on written SOPs. Role‐playing, workshops, quizzes and repetition are successful training tools with research‐inexperienced junior staff.

All staff should be trained in GCP standards and research ethics.

Laboratory personnel should be trained in good laboratory practices (GLP) standards.

Key Landmines

Ensure sustained capacity development

Ensure the system maintenance and growth

A vision of Next steps

Presentation 7: Prof. Gilbert Kokwaro, Director Consortium for national Health Research [CNHR]

The presentation by Prof. G. Kokwaro was quite enriching and empowering that I have no better words to express the precision of his words but in a net shell the following were elaborately covered:

Clinical trials as a platform of diverse opportunities
IRBs, equalisation and partnership in promoting clinical trials
Capacity strengthening and training [by providing an attractive career path]

Fragmentation of effort [by supporting different centres ]

Research

Research is not a job is passion

Opportunity [making right decisions]

In research is it best to Mentor or supervise?

Opportunities in the area of clinical trials

Dosage formulation for pediatrics
Ethics and research
Community and research

Presentation 8: Global Health Trials by Dr. Trudie Lang

Global Health Trials is a collaborative web platform aiming to support and encourage clinical research in the field of global health. It is a free and open-access platform where anyone working in clinical research can access guidance, tools and response, and share their knowledge, views and experience. The membership of global health Trials is rapidly growing and attracting all types of clinical research staff from over 60 countries and across highly varied research settings.

Global Health Trials has been set up by groups running trials in Africa, Asia and Latin America. It is for all types of clinical research and all disease areas. The aim is to support researchers in running their own projects, as well as studies in partnership with others. There are guidance articles, templates, example documents and discussion areas, as well as free e-learning courses to take researches through all of the steps and processes of a study. Furthermore, we have a free and highly respected online Professional Membership Scheme for research staff to gain professional recognition and to track career development.

The website is overseen by a steering committee and six expert comittes. All content is regularly reviewed so that researchers can trust the information provided. All content is designed to be gkobally applicable and, in particular, to support clnical research in developing countries.

The ethos is to create a professional community for all clinical research staff, where knowledge and methods are exchanged and hsared. We welcome your oinvolvememnt and urge you to have a look and share your experience in designing, operating and reporting clinical research.

Many thanks and welcome more to the website and share the expounding knowledge.

Contacts

www.globalhealthtrials.org or info@glabalhealthtrials.org

Panels discussion

This was a participatory session in which various topics relevant to the subject of discussion were expounded both from the panellist and the members present. Some of the intellectual and resourceful discussions held concerned:

Translating research into policy
Contribution of community involvement in clinical trials research
Extent of impact assessment and its interplay to clinical trials reasearch
Research from the community perspective
Does all research amount to change of policy?
Inclusion of pictorials into the informed consent documents/process
The concept of emancipated minors participation in clinical trials

I welcome any comments, additions, corrections and contributions to the above document. Lots of gratitude to all the presenters and all the experts from every field of knowledge who attended. Above all I cannot forget to tender utmost appreciation to CCR-KEMRI-DNDi, Global Health Trials staff and all the partners involved that made the workshop a success. God bless you all.

Dear reader, thank you for taking your time to go through the document and I hope it has enriched you enormously in the arena of clinical trials research…I look forward to your comments and contributions.

Best regards

Kelvin M.N

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