Global Standards for Interventional Clinical Studies

1. Purpose

This policy sets forth global standards for the conduct of all Pfizer-sponsored interventional clinical studies. This policy ensures Pfizer-sponsored interventional clinical studies respect the rights and welfare of study participants (i.e., healthy volunteers, subjects, patients and others) and that those clinical studies are designed and conducted in accordance with the highest scientific and ethical standards as well as regulatory requirements.

2. Scope

This policy applies to all Pfizer colleagues and to those parties with whom Pfizer contracts (e.g., Contract Research Organizations [CROs], vendors or consultants) who are involved in Pfizer-sponsored interventional clinical studies.

This policy applies globally to all Pfizer-sponsored interventional clinical studies.

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3. Policy

All Pfizer-sponsored interventional clinical studies must be 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 Conference on Harmonisation Good Clinical Practices (ICH-GCP) Guidelines
• Ethical principles set forth in the Declaration of Helsinki (World Medical Association 2008)
• United States Belmont Report (1974)
• Pfizer Corporate Policies and Procedures including Corporate Procedure 115 International Anti-Bribery and Anti-Corruption Procedure; Corporate Policy 208 Global Policy on Interactions with Healthcare Professionals

All Pfizer-sponsored interventional clinical studies in patients 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, risk/benefit assessment, qualification of study team members, and the selection of study participants for research will conform to all CIOMS and ICH guidelines, and will be consistent with the principles set forth in the Declaration of Helsinki and the U.S. Belmont Report as well as any local legal and regulatory requirements.

3.1 Risk/Benefit Maximization

All Pfizer-sponsored interventional clinical studies must have a favorable risk/benefit ratio (e.g., the known or foreseeable risks to the study participants must be justified by the expected benefits, direct or indirect), and must be designed and conducted to maximize the benefit and minimize risks. The clinician is responsible for:

• Assessing the risk/benefit ratio before the protocol is submitted to the relevant Institutional Review Board or Independent Ethics Committee (IRB/IEC)
• Monitoring the risk/benefit ratio 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 Global Pharmacovigilance (PV) legislation and includes the collection and reporting of serious and non-serious adverse events to ascertain if the risks are determined to outweigh the benefits of continued participation and permit the clinical study to remain ongoing.

3.2 Ethical Review

A qualified Institutional Review Board or Independent Ethics Committee (IRB/IEC) must review and approve Pfizer-sponsored interventional clinical studies before the study is conducted. That review may be done by a central IRB/IEC, as well as local IRB/IECs that review proposed research for a specific research organization or clinical trial sites.

IRB/IECs enlisted to review Pfizer protocols must be independent from Pfizer and have members with appropriate medical and scientific qualifications and be knowledgeable about the community where the study will be conducted.

Subjects may not be enrolled into Pfizer-sponsored interventional clinical studies until written authorization is received from the IRB/IEC as well as the appropriate regulatory or official governmental body from the country in which the study will be conducted, as described by local regulations.

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3.3 Protocol Inclusion and Exclusion

A qualified IRB/IEC must review and approve Pfizer-sponsored interventional clinical studies before the study is conducted. The review may be conducted by a central IRB/IEC, as well as by local IRB/IECs that review proposed research for a specific research organization or for clinical study sites. In the U.S., only Association for the Accreditation of Human Research Protection Programs, Inc (AAHRPP) accredited IRBs may be used as central IRBs to review Pfizer-sponsored interventional clinical studies. According to GCP and local regulations, IRB/IECs engaged to review Pfizer studies must be independent from Pfizer 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.

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

3.4 Informed Consent

Study participants may only be enrolled after providing their voluntary informed consent. Investigators involved in Pfizer-sponsored interventional clinical studies must ensure that study subjects have adequate understanding of the study. Informed consent must be documented in writing as part of the informed consent process in accordance with CIOMS Ethical Guidelines, in accordance with the principles set forth in CT05 ý Informed Consent SOP and local legal requirements which include clear explanations of the purpose of the study, the material risks and expected benefits associated with participation in the study and the right of the study participant to refuse to participate in the study at any time.

The permission of a legally-authorized 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 subjects and other decisionally-impaired subjects). Such study participants must be afforded the opportunity to provide or withhold their assent, whenever possible.

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 may not diminish or compromise the rights of the proposed study participant. Pfizer and its representatives must work with the study investigators, ethics committees, local health authorities or community representatives, where appropriate, to ensure the appropriateness of the informed consent process is consistent with Pfizer standards.

3.5 Standard of Care and Use of Placebo Controls

Where Pfizer-sponsored interventional clinical 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 may only be used in Pfizer-sponsored interventional clinical studies where:

• 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 Trial Placement

Pfizer-sponsored clinical research in patients must be relevant to the host country's health needs. In order to be conducted in a particular country, the clinical research in patients must have the potential and be intended to benefit that country's population. Clinical studies in patients may only be placed in countries where Pfizer intends to commercialize the investigational medicine, if it is proven to be safe and effective. This restriction does not apply to studies involving healthy volunteers. Studies in healthy volunteers (those where study participants do not receive any medical treatment as part of the study) may be placed in any country that has the appropriate medical and research infrastructure to conduct the clinical study.

3.7 Study Team Responsibilities

Pfizer-sponsored clinical research must be designed, conducted, and monitored to ensure the protection of the rights and safety of study participants and the integrity of the research data, in compliance with Pfizer standards, applicable laws, regulations, and ethical standards. Pfizer may outsource the conduct of all or part of an interventional clinical study to a CRO but the sponsor responsibilities for the quality and integrity of study conduct and data residewith Pfizer.

When Pfizer contracts with a CRO, the study team must comply with the requirements for requesting, contracting and managing a CRO in accordance with the principles set forth in CT06 - Requesting Contracting, Managing and Oversight of Contract Research Organizations SOP.

When Pfizer collaborates with another sponsor on the joint development of a product or with a third-party or a CRO to conduct a study, Pfizer and the other Sponsor, third-party, or CRO must agree, in writing, which party has responsibility for each process of the clinical study, including the Good Manufacturing Practice (GMP), GCP, and PV responsibilities.

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3.8 Monitoring

Pfizer-sponsored interventional clinical studies must be monitored by trained, qualified and experienced personnel to assess the protection of study participants' rights and welfare and to ensure that the study is being conducted in accordance with ICH-GCP, local regulations, the protocol and in accordance with the principles set forth in CT08 ý Clinical Site Management and Monitoring SOP and CT33 ý Study Training SOP. In addition, a study monitoring plan 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 Pfizer and regulatory agencies, as appropriate; investigation and appropriate action must be taken to ensure study participant safety and data integrity, a return to compliance, and corrective and preventative actions, in accordance with the principles set forth in CT11 ý Reporting and Management of Suspected Significant Deviations in Clinical Research SOP.

3.9 Data Monitoring Committees

Data Monitoring Committees (DMCs) are used to monitor safety in randomized studies with mortality or major morbidity as primary or secondary endpoints, studies where study participants may be at elevated risk of such outcomes, and other studies where an independent review of study data is warranted. Establishment and conduct of DMCs must follow international and local requirements, in accordance with the principles set forth in CT22 - Use of Data Monitoring Committees and Conduct of Interim Analysis SOP.

3.10 Control of Investigational Product

All products under investigation are tracked and controlled from the time they leave Pfizer through to their use, appropriate disposal or return to Pfizer. Pfizer ensures that records documenting the control of investigational product are established for all Pfizer-sponsored interventional clinical studies, in accordance with the principles set forth in SOP CT13 ý Investigational Product.

3.11 Organ Transplantation

Pfizer supports the ethical principles articulated by the World Health Organization's Guiding Principles for Human Cell, Tissue and Organ Transplantation. Additionally, all investigators for Pfizer-sponsored interventional clinical 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 essential documents for Pfizer-sponsored interventional clinical studies must be maintained and archived in accordance with ICH GCP standards, applicable regulatory requirements, and in accordance with the principles set forth in CT01 ý Trial Master File SOP.

3.13 Post Study Care

An assessment must be made by the clinician responsible for the study, documented in the protocol prior to submission to an IRB/IEC for review, of the appropriateness, relevance, and feasibility of providing investigational product and/or alternative therapies to research participants at the conclusion of the study, or other necessary follow-up care. 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 risk/benefit ratio of the investigational product, as well as individual study participant's results.

3.14 Subject Access to Health Information From Studies

Study participants may request access or changes to health information arising from their participation in a Pfizer-sponsored interventional clinical study. Such requests are made to the physician or investigator treating them in the study. Investigators who request access to laboratory or other data about study participants must submit such requests to the study manager. Pfizer study teams must work with Research & Development (R&D) Legal and the Global Privacy Office to determine the appropriate response to such requests, taking into account local regulations and standards.

The privacy of study participants and the confidentiality of their personal information must be protected.

4. Responsibilities

The clinician responsible for the study, along with the study team, design Pfizer-sponsored interventional clinical studies and ensure they are conducted in accordance with this policy and Pfizer standards.

In addition to the formal waiver processes, according to Pfizer standards, exceptions to this policy may not be made without final approval of senior management, including the Chief Medical Officer (CMO), and R&D Compliance.

5. Appendices

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