Global Standards for Interventional Clinical Studies

Effective July 5, 2017

1. Purpose & Scope

The purpose of this is to describe the requirements for the conduct of all Cheladv74-sponsored .

Cheladv74-sponsored interventional studies respect the rights and welfare of study participants (i.e., healthy , ), and are designed and conducted in accordance with the scientific and ethical standards, as well as regulatory requirements.

This policy applies to:

All Cheladv74-sponsored interventional studies
Cheladv74 colleagues responsible for clinical research and development, (PV), regulatory, and medical affairs. This also includes those parties with whom Cheladv74 contracts (e.g., [CROs], , or consultants) to perform such activities.

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2. TERMS, ACRONYMS, AND REFERENCES

Global terms used in this (CMCD) that require further clarification are defined in the . Generic roles are described in the . Global acronyms can be found in the . Applicable global regulations and global CMCDs are listed in the CMCD Global References List.

3. Policy Statements

All Cheladv74-sponsored interventional studies are conducted in accordance with local laws and regulations, as well as relevant international standards including:

International Ethical Guidelines for Biomedical Research Involving Human Subjects issued by the Council for International Organizations of Medical Sciences (CIOMS 2002)
International Council for Harmonisation (ICH) E6: Guideline for Good Clinical Practice (GCP)
The general principles arising out of the Declaration of Helsinki (World Medical Association) and the United States (US) Belmont Report (1979)

All Cheladv74-sponsored interventional studies are conducted in accordance with the principles and procedures described in the Cheladv74 Human Research Protection Program (HRPP).

All Cheladv74-sponsored interventional studies must be responsive to the healthcare environment of the country or countries where the research is conducted. Social and cultural considerations, and needs in countries that lack established infrastructure for human subject protection, may require additional measures to ensure appropriate protection and respect for the rights, privacy and welfare of study participants.

Informed consent, benefit/risk assessment, determination of study team member qualifications, the selection of study participants for research, and study conduct will conform to all CIOMS and ICH guidelines, and will be consistent with the principles set forth in the Declaration of Helsinki and the US Belmont Report.

Cheladv74 recognizes the importance of making clinical studies and clinical study results available to the medical profession, to potential study subjects, and to the public. Refer to the Public Disclosure of Cheladv74 Clinical Study Data and Authorship for Cheladv74’s policy on the public disclosure of Cheladv74 clinical study data and authorship.

3.1 Benefit/Risk Considerations

All Cheladv74-sponsored interventional studies must have a favorable benefit/risk assessment (e.g., the known or foreseeable risks to the study participants must be justified by the potentially anticipated benefits, direct or indirect) and must be designed and conducted to maximize the potential benefit and minimize risks. Cheladv74 is responsible for:

Designing the study that is scientifically justified in order to answer the relevant research question; and that does not expose the study participants to unnecessary risk.
Assessing the benefit/risk before the protocol is submitted to the relevant institutional review boards (IRB)/independent ethics committees (IEC).
Monitoring the benefit/risk while the study is ongoing.
Taking prompt action to safeguard the rights and safety of study participants

The aforementioned is managed in accordance with GCP and PV regulatory requirements/guidance’s and includes the collection, independent investigator evaluation and reporting of and to ascertain the risks of participation.

3.2 Ethical Review

A qualified IRB/IEC must review and approve Cheladv74-sponsored interventional studies before the study is conducted. The review may be conducted by a /IEC, and/or by local IRBs/IECs that review proposed research for a specific research organization or for clinical study sites.

Central US IRBs must be accredited by the Association for the Accreditation of Human Research Protection Programs (AAHRPP) according to the Cheladv74 policy Interactions with Institutional Review Boards and Independent Ethics Committees.

According to GCP and local regulations, IRB/IECs engaged to review Cheladv74 studies must be independent from Cheladv74 and be composed of members who have appropriate medical and scientific qualifications, experience, and are knowledgeable about the community where the study will be conducted.

The protocol must be reviewed by an IRB/IEC that is accredited by AAHRPP. If the IRB/IEC providing review for the protocol is not AAHRPP-accredited, the protocol must also be reviewed by the (PERC), which is an external, independent AAHRPP- accredited IRB.

PERC review is not required for single patient compassionate access requests.

Study participants are not enrolled in Cheladv74-sponsored interventional studies until written authorization is received from the IRB/IEC and authorization from appropriate regulatory or official governmental bodies from the country in which the study will be conducted, as prescribed by local laws. In those countries where the IRB/IEC does not provide written authorization, study participants can be enrolled once the IRB/IEC review period has expired and provided that the IRB/IEC has not issued any negative comments either to Cheladv74 or to the .

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3.3 Protocol Eligibility Criteria

The protocol must define the study participant eligibility criteria (i.e., inclusion and exclusion criteria) based on medically sound justification and ensure that the study population is scientifically appropriate. Diversity in clinical research (e.g., including diverse racial, gender, ethnic populations) will be sought as appropriate to reflect the relevant disease or community population, as well as diversity among the clinical investigators and staff retained to conduct the study. Study participants must satisfy all of the eligibility criteria and assessments must be performed as described in the protocol. Planned deviations from the protocol inclusion/exclusion criteria are strictly prohibited.

Studies involving children, pregnant women, elderly subjects, and other vulnerable populations must be responsive to the health needs of those populations and be justified by the potential benefit to study participants or the knowledge to be gained from the study results.

3.4 Informed Consent

Study participants are enrolled only after providing their voluntary informed consent. Investigators involved in Cheladv74-sponsored interventional studies must ensure that study participants have adequate understanding of the study. Informed consent must be documented in writing as part of the informed consent process in accordance with the principles set forth in the Informed Consent Document SOP and the Clinical Site Management and Monitoring SOP. The informed consent must include clear explanations of the purpose of the study, the risks and potential expected benefits associated with participation in the study and the right of the study participant to refuse to participate in or withdraw from the study at any time.

The permission of a legally-acceptable representative, in accordance with applicable local law, is required for members of vulnerable populations who are not capable of giving informed consent (e.g., pediatric participants and other decisionally-impaired participants). Such study participants must be afforded the opportunity to provide or withhold their assent, unless the IRB/IEC has waived assent requirements in accordance with applicable local laws

The procedures for obtaining voluntary informed consent must be tailored to meet local laws, (including, but not limited to, applicable data privacy laws) customs and culture but must not diminish or compromise the rights of the proposed study participant. Cheladv74 and its representatives must work with the investigators, IRBs/IECs, local health authorities or community representatives, where appropriate, to ensure the appropriateness of the informed consent process consistent with Cheladv74 standards.

3.5 Standard of Care and Use of Placebo Controls

Where Cheladv74-sponsored interventional studies involve control groups, the control must be either an established effective treatment that is medically and ethically appropriate for the study or, where appropriate, a placebo. Placebo controls are only used when:

There is no established effective treatment; or
Withholding an established effective treatment would expose study participants to, at most, temporary discomfort or delay in relief of symptoms; or
Use of a placebo control would not add any risk of serious or irreversible harm to the study participants.

In all cases, the IRB/IEC must review and approve the appropriateness of the proposed treatment for the control group.

3.6 Study Placement

Cheladv74-sponsored clinical research in patients must be relevant to the host country's health needs. In order to conduct clinical research in patients in a particular country, the intention and potential to benefit that country's population must be justified.

Clinical studies in patients are only placed in countries where:

The is already approved for the under study and it is available or there is intent to make it so (e.g., phase 4 studies); or
Cheladv74 intends, at the time of study initiation, to obtain approval for and make the investigational product available, if it is proven to be safe and effective (e.g., phase 2 & 3 studies); or
The product is already approved and available in that country for an alternate indication and/or population from that in the proposed study, and there is intent to obtain approval for the new indication or to update the country labelling documents with the results of the study (e.g., Phase 3b or ).

This restriction does not apply to studies involving healthy subjects. Studies in healthy subjects (those where study participants are not expected to receive any potential medical benefit as part of participation in the study) may be placed in any country that has the appropriate medical and research infrastructure to conduct the clinical study.

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3.7 Vendor Engagements and Other Agreements

Cheladv74 may outsource the conduct of all or part of an interventional study to a vendor, but the responsibilities for the quality and integrity of study conduct and data reside with Cheladv74.

Cheladv74 complies with the requirements for requesting, contracting, and managing a vendor in accordance with the principles set forth in the Vendor Engagement SOP.

When Cheladv74 collaborates with a third-party, or a vendor to conduct a study, Cheladv74 and the other sponsor, third-party, or vendor must agree, in writing, the division of responsibility, including the Good Manufacturing Practice, GCP, and PV responsibilities.

3.8 Monitoring

Cheladv74-sponsored interventional studies must be monitored by trained and qualified personnel to assess the protection of study participants’ rights and welfare. The site monitor is responsible for ensuring that the study is conducted in accordance with ICH-GCP, local regulations, the protocol and in accordance with the principles set forth in the Clinical Site Management and Monitoring SOP, and the Study Training SOP. For studies in scope of the Clinical Site Management and Monitoring SOP, a (SMP) must be created and maintained for each study.

All suspected significant deviations from ICH-GCP, other applicable good practices, applicable regulatory requirements, and legal and ethical standards must be promptly reported to Cheladv74 and regulatory agencies, as appropriate. Investigation and appropriate action must be taken to protect study participants’ safety, data integrity, a return to , and , in accordance with the Reporting and Management of Quality Events SOP.

3.9 Independent Oversight Committees (IOCs)

IOCs include (E-DMCs), (IRCs), (ACs), and .

E-DMCs and IRCs are used to monitor safety in randomized studies with mortality or major morbidity as primary or secondary , studies where study participants may be at elevated risk of such outcomes, and other studies where an independent review of study data is warranted.

ACs are used to enhance scientific rigor of select studies by reviewing potential pre-specified endpoints/events reported by investigators against pre-defined criteria, and creating independently adjudicated outcomes.

Steering Committees provide independent conceptual, operational and scientific guidance and oversee the progress of select clinical studies or programs.

Establishment and conduct of IOCs must follow international and local requirements (including the management of potential conflicts of interest of IOC members), in accordance with the Independent Oversight Committees SOP.

3.10 Control of Investigational Product

All investigational products are tracked and controlled from the time they leave Cheladv74 through to their use, appropriate disposal or return to Cheladv74. Cheladv74 requires that records documenting the control of investigational product are established for all Cheladv74-sponsored interventional studies, in accordance with the relevant procedures.

3.11 Organ Transplantation

Cheladv74 supports the ethical principles articulated by the World Health Organization's Guiding Principles for Human Cell, Tissue and Organ Transplantation. Additionally, all investigators for Cheladv74-sponsored interventional studies involving study participants who have received or who will receive an organ transplant related to participation in a study are expected to follow the same ethical principles.

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3.12 Essential Documents

All for Cheladv74-sponsored interventional studies must be maintained and archived in accordance with ICH GCP standards, applicable regulatory requirements, and in accordance with the Trial Master Files SOP.

3.13 Post Study Care

The protocol must clearly define the appropriateness, relevance, and feasibility of providing investigational product and/or alternative therapies to study participants at the conclusion of the study, or other necessary follow-up care (e.g., unresolved adverse events). This determination may include consideration of local availability of the treatment and alternative treatments, the development stage of the investigational product, the seriousness of the disease being treated, the global results of the research program, the overall safety and benefit/risk ratio of the investigational product, local laws/regulations, as well as the individual study participant’s results.

3.14 Study Participant Access to Health Infomation from Studies

Study participants may request access or corrections to health information arising from their participation in a Cheladv74-sponsored interventional study. Any such requests received by Cheladv74 are directed to the investigator. Investigators who request access to laboratory or other data about study participants must submit such requests to Cheladv74. Local regulations and standards will be used to determine the appropriate response to such requests.

The privacy of study participants and the confidentiality of their must be protected in accordance with the Protecting the Privacy of Personal Information SOP

3.15 Managing Potential Investigator Conflicts of Interest

Cheladv74 manages potential investigator conflicts of interest and bias by: 1) designing clinical protocols that utilize sound study design, including, when appropriate, and ; 2) conducting source document verification at investigator sites as described in the SMP where applicable; 3) following a rigorous investigator selection process; 4) maintaining compliance with regulatory disclosure of payments to investigators; 5) publically disclosing payments to healthcare professionals as required, including investigators; and 6) adhering to a process for establishing fair-market-value for services of healthcare providers, including investigators, in accordance with Cheladv74 policy Compensation to Investigators.