acpu guidance and recommendations for the operation of clinical pharmacology · pdf...

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ACPU GUIDANCE AND RECOMMENDATIONS

FOR THE OPERATION OF

CLINICAL PHARMACOLOGY UNITS

Authors: Donna W. Dorozinsky, RN, MSN, CCRC – President, DWD & Assoc., Inc. Michael A. Turik, MD - Exploratory and Program Phase Medical, LRL, Eli Lily and Company Cathy Lavin, RN, MSN -- Director of Operations, Duke Clinical Research Unit, Duke University School of Medicine Charles H Pierce, MD, PhD, CPI, -- President, Pierce One, Consulting Howard E. Greenberg, MD, MSE, MBA, FCP -- Senior Medical Director, Clinical Pharmacology Unit, Clinilabs, Inc.

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Table of Contents

Authors: ______________________________________________________________ 1

ADMINISTRATION ______________________________________________________ 7

History, Mission, and Values ___________________________________________________ 7

Host Institution _____________________________________________________________ 7

CPU Capability, Capacity, and Scope of Services ___________________________________ 7

Management Structure _______________________________________________________ 8

Other Services ______________________________________________________________ 8

Record Keeping _____________________________________________________________ 8

Confidentiality ______________________________________________________________ 9

Risk Management ___________________________________________________________ 9

QUALITY ASSURANCE ____________________________________________________ 9

QA Program ________________________________________________________________ 9

Standard Operating Procedures ________________________________________________ 9

SITE SAFETY ___________________________________________________________ 10

STAFFING ____________________________________________________________ 11

Personnel _________________________________________________________________ 11

Training __________________________________________________________________ 11

Professional Development ___________________________________________________ 12

FACILITIES ____________________________________________________________ 12

Premises __________________________________________________________________ 12

Location __________________________________________________________________ 12

Maintenance and Validation __________________________________________________ 13

Information Technology (IT) Services ___________________________________________ 13

Facilities Emergency Plan ____________________________________________________ 13

HUMAN SUBJECTS _____________________________________________________ 14

Independent Ethical Review __________________________________________________ 14

Informed Consent __________________________________________________________ 14

Vulnerable Groups __________________________________________________________ 15

Subject Safety and Well-Being ________________________________________________ 15

Standards of Care __________________________________________________________ 15

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Early Phase I and Biologics __________________________________________________________ 15 Late Phase I – IIa __________________________________________________________________ 16 Emergency Response ______________________________________________________________ 16

Emergency and mock drills ___________________________________________________ 16

Adverse Events or Injuries ____________________________________________________ 16

Subject Compensation ______________________________________________________ 16

CONDUCT OF CLINICAL STUDIES __________________________________________ 17

Evaluation and Acceptance ___________________________________________________ 17

Protocol and Agreements ____________________________________________________ 17

Key Study Personnel ________________________________________________________ 17

Pre-study Planning and Preparation ____________________________________________ 18

Study Administration and Documentation ______________________________________ 18

Recruitment _______________________________________________________________ 18

Screening _________________________________________________________________ 19

Study Execution ____________________________________________________________ 19

Coverage _________________________________________________________________ 20

PHARMACY SERVICES ___________________________________________________ 20

Drug Storage and Handling ___________________________________________________ 20

Drug Accountability _________________________________________________________ 21

Emergency Drugs ___________________________________________________________ 21

LABORATORY _________________________________________________________ 21

Clinical Laboratory Services __________________________________________________ 21

Data Management __________________________________________________________ 22

REFERENCES __________________________________________________________ 24

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INTRODUCTION

The Association of Clinical Pharmacology Units (ACPU) was organized and founded by a dedicated group of clinical researchers who held leadership positions in Clinical Pharmacology units owned and operated by the leading Pharmaceutical companies of that era. The first two unofficial meetings in 1989 and 1990 were hosted by the Roche CPU in Newark, NJ and the Wyeth CPU in Philadelphia, PA, respectively; with its first official meeting in 1991 in Kalamazoo, MI hosted by the Upjohn CPU. The Mission of the ACPU was, and remains, to provide a forum facilitating cooperation and the exchange of information and ideas among Clinical Pharmacology Units. The Objectives of the ACPU include among other items to promote the establishment of voluntary minimum standards of practice and guidelines for clinical pharmacology units. Two of the key Values of the ACPU include the highest ethical conduct in human subject research, endorsing full adherence to the Declaration of Helsinki, and applicable research guidelines of the local regulatory authorities; and it recognizes the importance of confidentiality regarding drugs under investigation, their properties and plans for their use. In October 1992, ACPU’s Standards Committee initiated a project to draft a set of principles which would guide CPUs in the development of local

standards and procedures. The product of this work was adopted by the membership in October 1994 after several review and revision cycles; and these standards were published in Volume 31 of the DIA Journal in 1997. Since that time, the business if not the practice of CPUs has undergone a significant metamorphosis. The vast majority of pharma owned and operated CPUs have closed and the growth of CROs, small and large, has taken on the primary role of early phase clinical research study execution. ACPU has shifted from a rather homogeneous group of similar units with similar composition, mission, structure, and organization to quite a diverse array of a few remaining pharma units, many CRO-owned units of a few dozen to several hundred bed capacity, and some academic units. During the revision of this set of “Standards” it was decided after some deliberations that a “Guidance” nomenclature would be more appropriate; with the object to provide policies or principles, rather than specific procedures. Some of the previous Standards are still held immutable, such as the protection of human subjects, and the confidentiality of their records and the intellectual property of the drugs under study, as described above. Others now seem more flexible based on the type of unit, hence more of guidelines or recommendations or ‘best practices’ to provide quality operations of early phase clinical research studies. A further document is contemplated outlining more specific procedures, and

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case studies with lessons learned, which are frequently what are discussed at the ACPU Annual meeting ‘break-out’ sessions. As an example of the latter, pharmacy services can be provided by a part-time contracted yet experienced and qualified research pharmacist in a small CRO or even outsourced in a local pharmacy; or by the Investigational Drug Services (IDS) of a large academic medical center; or by the FT pharmacy group in a CRU operated in-house compounding Pharmacy. Clearly, individual situations where there is a convincing, explicit, context-specific, evidenced-based and articulated rationale may take precedence, though these best-practice guidelines can then serve as a point of reference. Consequently, these guidelines are written in such a way as to provide a reference point for the reader to interpret as appropriate for their own situation. It should be very clear that this is not a regulatory mandate. This is not a perfect document. It took almost two years from first revision through publication, with several revisions by the authors, then circulation and comments by the ACPU Board of Trustees, followed by presentation and discussion at the June

2010 DIA Annual Meeting. It was also circulated to key opinion leaders in various CRU environments including large pharma, small biotech, CROs of multinational and small size, and academic units; including all of the original authors of the original 1994 version of the “Standards” document. Through this lengthy process, the object was not to prevent the publication of the mere excellent while yet pursuing perfection. It is anticipated that the content, if not the intentions, of this document may be revised in the future. It is hoped that feedback from other venues and other research professionals contribute to the next version of this document. These guidelines are not meant to replace but complement and enhance the various regulatory codes, GCPs and other more general references listed at the end of this text, and apply them to the CPU setting. Within the text, “subject” is used to refer to other nomenclature commonly used, such as: volunteer, patient, research participant and study participant. Finally, several reviewers are acknowledged for generously contributing their time and attention, and thanked for their helpful suggestions and insights.

Recognition is given to our reviewers: Harry Alcorn Jr., Pharm.D. - Chief Scientific Officer, DaVita Clinical Research Colleen Hoke - General Manager, Clinical Services-Northwest, Charles River

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Diane K. Jorkasky, MD - Chief Medical Officer & SVP, Head of Development, Aileron Therapeutics, Inc. Walter K. Kraft, MD, MS, FACP -- Director, Clinical Research Unit; Associate Professor, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University Barry Mangum, PharmD, FCP - Associate Professor Clinical Pharmacology, Duke University Medical Center; Director, Clinical Pharmacology, Duke Clinical Research Unit, Duke Clinical Research Institute Royce Morrison, MD, CPI - Director of Clinical Strategy, Charles River Linda C. Owens - Senior Director, Phase I Services, Quintiles Alicia (Ali) Craig-Rodriguez – President, Comprehensive NeuroScience, Inc. Dr. Daniel S. Sitar - Editor in Chief, Journal of Clinical Pharmacology, Professor Emeritus, Dept of Internal Medicine (Clinical Pharmacology), Dept of Pharmacology and Therapeutics Dr. Tim Tasker, MBBS, FRCP, FFPM -- Pharmabioquintet Pty Ltd, (former VP Global Clinical Units GlaxoSmithKline) Howard Uderman, MD --Medical Director, Pfizer-New Haven Clinical Research Unit Scott A.Waldman, MD, PhD, - Chair, Department of Pharmacology and Experimental Therapeutics; Samuel MV Hamilton Endowed Professor and Director, Division of Clinical Pharmacology

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ADMINISTRATION History, Mission, and Values The CPU history, mission, values and code of ethics of each CPU should be documented clearly, reviewed periodically, and communicated regularly to staff and sponsors to assure understanding and perspective concerning unit purpose, capabilities, and standards. Host Institution Some CPUs are independent organizations, but many CPUs are part of a host organization that includes a diversity of services that support the Clinical Research community. The Principal Investigator (PI) has overall responsibility for all aspects of the clinical conduct of the study at the investigator site. In instances where a CPUs host organization also sponsors the CPUs studies, there should be a clear separation of Sponsor, Host and Investigator site responsibilities to ensure that this responsibility is not compromised. There should be an organizational structure that removes conflict of interest within the host organization which could potentially jeopardize this responsibility. The relationship of a CPU to its host or sponsoring institution should be defined and documented clearly, including administrative, medical, and scientific reporting lines. Host institutional policies should be compatible with and supportive of the CPU mission and should provide:

1. Sufficient unit autonomy to permit accomplishment of mission and compliance with applicable standards, and

2. Effective agreements and procedures to assure the availability, reliability, and quality of host-provided services on which CPU operations depends.

CPU Capability, Capacity, and Scope of

Services The scope of services offered by a CPU should be appropriate to its capability and capacity, and consistent with the needs of the current drug development, Good Clinical Practice (GCP), and the current regulatory environment. CPU capability, capacity and scope of services should be well-defined and clearly documented. These requirements extend to include organizations on which the CPU relies to expand and/or enhance its capability and capacity. CPUs should only conduct studies which are in alignment with their training and expertise. Procedures, facilities and equipment should support these capabilities. Ancillary research, clinical services, and educational activities should not be permitted to compromise or interfere with CPU operations. Especially in settings where multiple educational and research missions are undertaken, extreme care should be taken to assure the integrity and validity of all research conduct.

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CPUs should not provide nor become obligated to provide for routine medical care of subjects, however, investigators should assist in the transition of care until the subject is back to baseline health. A CPU should have an emergency medical plan in place to assure the safety of their research subjects including evaluation in crisis situations, and a plan for immediate access to interventional care. This plan should be tested on a regular basis. CPU staff should be thoroughly knowledgeable concerning the facilities and capabilities of the local medical community in order to facilitate referral of subjects for appropriate follow-up medical care. Management Structure Each CPU should have a well-defined and clearly documented executive management structure which clearly identifies primary responsibility for CPU medical, scientific, operational, and administrative affairs. Each CPU should employ or retain appropriately qualified management personnel to include without limitation:

1. A licensed physician, who may or may not be the Principal Investigator (PI), to direct and supervise medical affairs.

2. A Principal Investigator who is ideally a certified investigator, and should be qualified by education, training, and experience to carry out the PI role. If the PI is not a physician, then a physician should be responsible for the medical management of the research subject.

3. A management professional, ideally a trained research professional (RN, NP, PA, PharmD). To direct and supervise clinical operational and administrative and regulatory affairs,

4. The Laboratory should be supervised by a credentialed M.L.T. (A.S.C.P.). At a minimum, the laboratory should have access to a credentials M.L.T. for assistance in resolving complex laboratory issues.

Other Services Ideally, there is a pharmaceutical scientist to direct and supervise scientific affairs. For CPUs conducting studies requiring drug preparation a licensed pharmacist should supervise these activities. Various reporting structures among CPU leadership are satisfactory provided each leader is adequately empowered to carry out his/her functional area of responsibilities effectively. An appropriately qualified individual may serve in more than one executive capacity provided he/she can devote sufficient time and attention to each area of responsibility. Record Keeping Each CPU should maintain and manage records of its operations and studies in a manner which ensures that the records are up-to-date, secure, retained, or destroyed as appropriate, and readily accessible for use or inspection as required.

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Electronic record keeping should be done in a manner that is in consistent with local and national regulatory requirements, including a system and infrastructure validated for the specific environment in which it is used. Confidentiality The CPU should be a controlled environment to provide confidentiality of records, intellectual property of sponsors, and safety and confidentiality of the study subjects. Each CPU should have adequate and enforceable policies, systems, and procedures in place and should require all staff (including part-time and per diem staff) with access to confidential information, to comply with these principles of confidentiality. (See “Training” below). Risk Management Each CPU should be adequately insured, or should have provisions for reliable external indemnification, to be able to satisfy legitimate injury claims relating to study drug or procedures, premises liabilities, professional error, negligence, or malpractice. Investigators should ideally be protected independently from host organization and institution. The CPU should give consideration to risk mitigation strategies when evaluating a potential protocol. Consideration should be given to the compound and the study requirements to ensure the safety of the subject at all times during the study.

QUALITY ASSURANCE QA Program Each CPU should have a formal quality assurance (QA) program independent of its operational management to ensure the unit, its operations, and the conduct of each of its studies are in conformance with applicable standards and requirements. The QA program should include quality controls and retrospective review processes, and it should encourage and utilize external feedback concerning CPU performance from subjects and sponsors. This program should include the evaluation of all areas that provide services critical to the study including but not limited to: Recruitment, Screening, Pharmacy, Laboratory, Data Management, Data Collection and Study Operations. The QA department should report directly to senior leadership and not be built within the other departments. This is critical to achieve an effective and independent QA program. Additionally, the QA program should have prospectively identified targets for quality measures which are reviewed and agreed to by senior management at least yearly. Regular review (e.g., quarterly) of the CPU’s performance to these targets, as well as other relevant operational metrics, should be conducted. QA personnel is usually integral to any site audits by sponsors or regulatory agencies, and should be well versed in this arena. Standard Operating Procedures Each CPU should establish and maintain documentation of its standard operating procedures (SOPs), including evidence that the SOPs are reviewed and updated

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periodically by appropriate personnel. All staff functioning in the CPU should have documented evidence of training on all SOPs and supporting documents (policies, procedures, work instructions, etc) relevant to their job functions. SOPs should conform to applicable external standards and requirements and should provide a process for use of alternate or special study-specific procedures where appropriate. The span of SOP coverage at a minimum should include not only all clinical and study procedures from study acceptance and preparation to reporting and publication, but also all other matters addressed by ACPU standards and applicable regulatory requirements.

SITE SAFETY

It is strongly recommended that each CPU should have appropriate equipment, systems, programs, resources, and procedures:

1. To provide access to emergency care in the event of emergencies.

2. To minimize and safely manage biological, chemical, radiation, and other clinical research facility hazards in accordance with applicable requirements.

3. To enhance safety and security of premises and to minimize workplace hazards by maintaining a controlled environment.

4. To prepare for and respond to premises and community emergencies and disasters.

5. To have a disaster management plan in place to ensure the integrity of the facilities and the safety of the research subjects in the event of a disaster.

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STAFFING Personnel Each CPU should be staffed by personnel in adequate numbers and with appropriate qualifications and expertise to properly perform the scope and quantity of services offered. The following documentation should be maintained for each staff member of CPU:

1. Job descriptions that are in alignment with current job responsibilities.

2. Evidence or verification of competencies for individuals that are in alignment with the job description.

3. Evidence of orientation and training to the CPU specific processes and knowledge of the associated SOPs / Work Instructions.

4. Current licensure/certification, training, and experience.

Internal policies and controls should be established and maintained to ensure adequacy of on-site and on-call physician, nursing and other ancillary clinical staff, and administrative coverage during the course of each study depending on study nature, circumstances, activities, and risks. Work schedules should be maintained to document coverage levels over the course of each study. Training All staff active in the conduct of clinical studies should receive regular training in CPU policies and procedures and Basic Life Support (everyone involved in care

of the subjects) and Advanced Cardiac Life Support (ACLS) (licensed care givers) Pediatric Advanced Life Support (PALS) for sites conducting Pediatric studies, the proper handling of biological and radiation hazards, infection control, and other special research-related knowledge and skills. In addition, as required by local and international standards, all individuals involved in clinical research must have training in principles of GCP with annual updates that include any relevant regulatory changes. All individuals working in clinical research should have training in human subject protection. All study related training is the explicit responsibility of the Principal Investigator. The actual training itself may be delegated to other qualified individuals as long as this delegation is properly documented. There should be documented evidence that each staff member has received appropriate training regarding job responsibilities and documented evidence that they have received protocol-specific training prior to participation in study activities.

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Professional Development CPUs should permit, encourage, and support the professional development of all staff for the purpose of maintaining current training in their fields and pursuing opportunities for advancement. Individuals are encouraged to obtain certification in one’s area of specialty. There are various types of certification, and individuals should choose the certification which is in alignment with his/her job responsibilities and developmental aspirations. For example, Investigators are encouraged to become Certified Physician Investigators (CPI). Study Coordinators are encouraged to become certified as a coordinator from one of the representative organizations as Certified Clinical Research Coordinators (CCRC) or Certified Research Associates (CRA), i.e. ACRP Certified Clinical Research Professional (CCRP), i.e. SoCRA.

FACILITIES Premises CPU facilities utilized to conduct or support studies should be under the supervision of the CPU management. The CPU shall be appropriately equipped and with adequate space, layout and infrastructure to properly perform the scope and quantity of services offered and to provide subjects with reasonable privacy, comfort, and amenities. The facility should be secured at all times to ensure the protection of the privacy of the research participant, their records, and study sponsors.

Sites should have adequate facilities for the handling and storage of specimens according to laboratory standards. Additionally, there should be adequate space for secure storage of study documents. For prolonged confinement studies, there should be adequate area for subject recreation that includes access to entertainment and current technology. This may include access to such items as internet service, video games, board games and reading material. It is not recommended that CPUs have exercise equipment unless a specific protocol requires the provision of this equipment. CPU should have adequate ingress and egress security to ensure subject safety and study integrity within the confines of the unit, limiting access to the CPU to qualified study personnel and sponsor representatives as needed. Appropriate relevant protective procedures should be implemented in CPUs that work with radioactive agents. Location Clinical CPU space should be as contiguous and integrated as possible with convenient access to services and facilities upon which the CPU is dependent. The unit should be easy for subjects to find based on its location, directions provided, and signage. In order to mitigate risk, emergency care access must be available with response times relative to the types of compounds and studies conducted by the CPU. Certain jurisdictions may have specific requirements to the location of

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the CPU when conducting first time in human studies. The CPU should understand and comply with local regulatory requirements. CPU organizers should encourage location in close proximity to public transportation and at sites with adequate parking and accessible for subjects with special needs as appropriate and within federal and local guidelines. Maintenance and Validation Each CPU should have a formal and documented program for the routine and preventive maintenance. A plan should be in place to ensure that maintenance activities are in alignment with equipment manufacturers’ recommendations. Building maintenance records should be maintained for emergency evacuation procedures, fire drill testing, infrastructure repairs and operations. In addition, there should be a system in place for monitoring and documenting freezer and refrigerator temperatures where sample or drug supply are stored. Temperatures should be monitored at a minimum daily, to ensure that sample integrity is maintained. There should be a plan in place for immediately responding to and documenting out of range temperatures. CPUs should consider installing a validated central monitoring and notification system for freezers and refrigerators where laboratory samples or drug supply are stored.

If third party vendors are contracted for study services, i.e. data processing, clinical (x-rays, laboratory), it is advisable to inspect and audit these facilities on a period basis. It is strongly recommended that a back-up generator be available to power all critical systems such as freezers and centrifuges in the event of an outage. The integrity of back-up power is not available, there should be a specific plan in place for maintaining and dealing with critical systems in the event of a power failure in areas with risk of electrical failure due to storms or other reasons. Information Technology (IT) Services IT services must be compliant with local regulatory requirements around electronic data systems, which include compliance with 21 CFR, Part 11. Systems used for data collection must be in alignment with these requirements. Any computer system or programs used in data collection must be operating in a validated state. This includes the availability of controlled access, an accessible audit trail, unique user identification, and human readability within the system. For CPUs using electronic data collection, there should be a contingency plan for continuing data collection in the event of system failure. Facilities Emergency Plan The CPU should have in place a disaster recovery plan and a designated emergency preparedness team that provides for continuity of care for the subject during a disaster as well as

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continuity of the study in general. In addition, the site should have an evacuation plan that supports its overall emergency plans and is tested on a regular basis, at least annually.

HUMAN SUBJECTS Independent Ethical Review CPUs should only perform studies reviewed and approved by the properly constituted independent ethical review committee. These include Institutional Review Board (IRB), Independent Ethics Committee (IEC) or Research Ethics Board (REB). These independent committees are composed and working to the standards imposed by the local regulatory agencies and have ethical oversight responsibilities over research conducted at the site. Ethics approval must be obtained before subjects are solicited, recruited, or screened for a specific study. The CPU must maintain current documentation of ethics committee compliance with local regulatory standards and of the submissions, review, approval, and reporting of its studies in accordance with ethics committee requirements. Certain protocols (i.e. ADME studies, PET studies) also require the review of Radiation safety boards. Informed Consent Informed consent must be obtained from subjects without coercion or deception before they are screened or studied, using:

1. Informed consent process that fully describes the nature and scope of the research in a manner the subjects can and do understand; and that clearly define any limitations on the extent to which information concerning the subject can be maintained, and

2. Procedures that include an explanation of the risks, benefits, and subject’s rights as a study participant, including the use of personal and confidential medical information, and

3. Procedures that provide adequate opportunities for subjects to ask questions privately and have their concerns clarified.

Informed consent requirements vary within local regulatory areas. The site should have a documented process for obtaining informed consent and ensuring that the subject is literate to the language the consent is written in and demonstrates understanding of potential risks, study procedures and time commitment from the study. Consenting can be done in an individual or group setting, as long as there is a private conversation with each individual to allow for discussion of information that the subject may not be comfortable discussing in a group setting. Consenting should be conducted by individuals who are trained in principles of human subject protection, have received study specific training relative to the consenting process and have access to the Investigator’s Brochure. The individual

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conducting the informed consent process should assess the subject’s understanding by asking open-ended questions to verify understanding of the procedures and requirements of the study. The Principal Investigator or a medically qualified Sub-Investigator should be available to answer any questions that may occur during the consent discussion. A copy of the informed consent document should be given to the subject to take with him/her as a reference. Vulnerable Groups CPU staff should be aware of the various classes of populations and it is recommended that each CPU have specific guidelines for dealing with any of the following populations:

Cognitively impaired – Studies should be conducted in an environment with staff who are experienced with this population.

Economically challenged – Recruitment efforts should not be targeted to this group, nor should this group be avoided.

Prisoners – Statutory regulations severely limit phase I research in prisoners, unless the research is specific only to this population. This includes subjects who become incarcerated during the conduct of the study, and sites should consult their IRB should this arise.

Children – Studies should be conducted in an environment that has experience with the pediatric population, and consideration should be given to the issue of assent. Co-mingling

housing of pediatric and adult subjects should be avoided.

Employees or family members of CPU staff or sponsoring institution – It is not recommended that employees or their families participate in research studies conducted at the site.

Students – Students of investigators or staff members should not be enrolled. Students of an institution sponsoring a CPU, but not directly overseen by CPU staff in an educational role, can participate.

Subject Safety and Well-Being Subject safety and well-being are of prime concern. It is highly recommended that the CPU take all precautions at all times to ensure each subject’s safety and well-being. No CPU policy, procedure, or practice may be established which conflicts with this principle. Each unit should have an established and practiced internal emergency medical response system (EMS) that assures the safety of the subjects in the CPU. Emergency procedures should be consistent with the level of risk of the studies being conducted. It is suggested that the CPU establish a direct relationship with the local emergency facility based on the types of studies being conducted. Standards of Care Early Phase I and Biologics Sites conducting early phase studies such as first time in humans/single ascending dose, multiple ascending dose studies, studies with biologics and certain other studies including drug

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interactions should have well-defined processes that provide immediate interventional response to acute medical situations. Late Phase I – IIa Sites conducting studies that support drug labeling such as bioequivalence and bioavailability studies should have well defined process for ensuring rapid response to medical emergencies. Emergency Response Provisions should be made for the following types of emergency situations including an operational process for responding to medical emergencies, cardiac arrest, respiratory arrest, anaphylaxis and other serious or life threatening situations. When establishing these standards, considerations should be given to the types of compounds being studied in the CPU and the local emergency health systems. Note that consideration of Medicines and Healthcare products Regulatory Agency (MHRA) standards for establishing risk should be taken into consideration when considering standardization of emergency care in the CPU. Emergency and mock drills It is advisable to have periodic unannounced emergency drills to evaluate the preparedness of staff, and correct any deficiencies. Establishing and testing a good working relationship with the local Emergency facilities in advance of executing the clinical trials, especially those particularly risky studies, is also advisable. This may

include lists of key contact at both facilities and having mock drills of emergency events and transfers of research subjects. Adverse Events or Injuries In the event a subject experiences an adverse event or is injured during the course of a study, the CPU should make every effort to provide timely and appropriate treatment, to manage its relationship with the subject in an affirmative manner, and to settle all legitimate claims promptly and fairly. CPU policies, procedures, and practices should minimize the possibility of fraudulent or abusive claims and discourage inappropriate litigation. Subject Compensation CPUs may pay subjects for their participation in studies in compensation for their time and inconvenience. Subject compensation should be limited to amounts that will not coerce subjects to accept risks that they would not accept without financial inducement. Subject fees should be in alignment with local regulatory agency guidance and standards. In the United States, the FDA requires that both the amount of payment and the proposed method and timing of disbursement should be reviewed by the IRB to assure that neither are coercive or present undue influence [21 CFR 50.20]. Fees should take into consideration the local economy and cost of living in the region where the study is being conducted. There should not be different fees within a site for a specific study that are not based on different study requirements.

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CONDUCT OF CLINICAL STUDIES

Evaluation and Acceptance Each study should be evaluated prospectively and performed only if it is:

1. Ethically and scientifically justified.

2. Designed to minimize risk to subjects.

3. Reviewed and approved by an independent, qualified Institutional Review Board / IEC.

4. Within the CPU’s capability and capacity to perform within the scope of these standards.

Protocol and Agreements Each study should be described by a formal, written protocol agreed upon by the sponsor, CPU management, and the Principal Investigator. Once established, the protocol may be revised or amended only by the mutual agreement among the sponsor, CPU, and Principal Investigator and with the approval of the IRB. Each study also should be subject to further understanding and written agreement between the sponsor and CPU concerning key non-protocol matters such as:

allocation of sponsor and investigator obligations

allocation of logistical responsibilities

study operational plan including agreed-upon timelines

drug or device supply, preparation, and disposition

planned monitoring schedules and expectations

non-safety reporting requirements

conflict of interest

intellectual property

confidentiality requirements Key Study Personnel As defined by standards of GCP, a Principal Investigator qualified by appropriate training, education and experience is responsible for the direct supervision for the study. If the PI is not a physician, then a physician should be responsible for the medical management of the research subjects. The organizational design should include consideration for the following key responsibilities: Principal Investigator for medical, scientific, and administrative accountability; recruitment; project management; study operations, including data management; clinical staff; pharmacy; laboratory; and regulatory. The responsibility for study quality assurance (QA) should be undertaken by someone who has no other responsibilities in connection with the study. When staffing patterns preclude total independence, every effort should be made to assign this role to the qualified person who has the least responsibility in connection with conduct of the study. An appropriately qualified individual can be responsible for more than one of these roles, except quality assurance, provided s/he can devote sufficient time and attention to each area of

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responsibility. Also, various approaches to allocating specific responsibilities to each of those roles are acceptable provided that all the responsibilities comprising these roles are covered. The Principal Investigator retains accountability for all study activities. The delegation of study responsibilities must be documented and kept current. Key study personnel and their supervisors in the CPU should disclose any potential conflicts of interest they might have in relation to a study prior to its performance. Pre-study Planning and Preparation Pre-study planning and preparation should include: Initiation meeting between sponsor and key study personnel; orientation and initial briefing of staff participating in study; project management work-up including master schedules; commitment of necessary personnel and facilities and contingency planning; set-up of study administration and documentation framework; establishment of special procedures; and compliance with applicable regulatory requirements, including approval of protocol, amendments, informed consent document, advertisements, and any written information that will be provided to study subjects. Study Administration and Documentation Study documentation should be collected and retained in an organized and verifiable manner that is human readable. Studies should be conducted in alliance with local regulatory requirements. Study communications

relative to conduct of the study or subject safety should be documented as part of the study records, whether electronic or paper. Essential study documents, as described by ICH Document E6 Consolidated Guidance for Industry, should be maintained in a secure location and archived at the conclusion of the study in such a way that they are easily retrieved. A back-up version of all electronic data should be maintained by the site. Study data documentation should reflect the identity of the individual collecting the data. Modifications to the data are acceptable, but must take place in such a way that prior data is not destroyed. Any changes cannot obliterate past information and the reason for the change should also be evident. The site should have an established standard process for making changes to source data. Recruitment Recruitment is an integral and critical part of the operation of a CPU. It is important that the individual performing this job responsibility is adequately trained in human subject protection and confidentiality. A site may maintain a local database to manage recruitment. Subject information may be entered into the database once permission has been received from the subject. Advertising and communications with the potential research subject must comply with local regulatory requirements and be approved by an independent ethics committee/IRB.

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Recruitment should be without coercion or deception and incorporate the objectives of fully informing potential subjects about the study and dropping ineligible individuals from consideration as early in the recruitment process as possible. To this end, phone pre-screening of individuals by interview prior to informed consent is permissible; however this phone script must be approved by an independent ethics committee/IRB. Screening An independent ethics committee-approved, general screening protocol and consent is an acceptable means of developing a pool of potential subjects for participating in studies. It is acceptable to use the results of this screening as part of a study screen if the data is collected within the time period allowed by the protocol. It is unacceptable to add tests to the general screening with the direct intent of using data for an upcoming study. Different independent ethics committees and sponsors employ different requirements regarding frequency of study participation and volume of blood donation. Today’s drug development environment requires that multiple factors be considered when establishing frequency of participation guidelines. Type of molecule, pharmacokinetics and prior exposure to the compound should all be taken into consideration when evaluating a subject’s capacity to participate. A CPU should establish minimum standards for limits to frequency of subject study participation and take precautionary measures during the screening process to ensure subjects

have met the minimum washout period requirement CPUs should have a standard policy in place for follow-up of subjects with screening abnormalities. It is expected that subjects with potentially clinically significant abnormal findings on screening will be referred to a clinic for follow-up. This follow-up should be documented as part of the study file. Each subject should receive and sign documents that delineate the rights of research subjects (Subject Bill of Rights), the standards of conduct (rules and regulations) with which they should comply during their research participation, and any penalties associated with failure to comply. Study Execution Each study should be conducted in strict compliance with its approved protocol, applicable SOPs, GCP guidelines and the highest standards of scientific integrity. The facilities, staff experience and resources shall be appropriate to the procedures being undertaken. The protocol is designed in such a way as to mitigate risk to the subject, and the timing of events is a critical consideration. A site should have an established process of following the protocol as it is written. Deviations from the protocol should only occur in an effort to preserve the safety of the subject. All deviations should be promptly reported to the sponsor and IRB (as required). Mechanisms should be in place to ensure that adverse effects are properly documented and reported and that

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study subjects, staff, sponsor and IRB are informed, as appropriate, concerning any new information which becomes available concerning the study drug and its possible effects. This includes unanticipated events/problems. The site should have a process in place for routinely assessing and documenting the presence of any adverse events, and evaluating its relation to investigational agent. This should be done in a consistent manor by asking an open ended question such as “How do you feel?” Subjects should also be assessed at each outpatient visit for any changes in their health since the previous visit. It is suggested that there is a defined mechanism for assigning severity of the event based on the subject’s ability to perform activities of daily living. Quality Control (QC) is a critical component to ensuring quality data. Each step of the study should have a quality control component built into it that ensures data integrity and completeness. The individual performing the QC activity should not be the individual that collected the data or performed the task. Coverage The CPU should establish standards for medical coverage based on the types of studies conducted and the site’s direct access to interventional emergency care. Care should be taken when delegating responsibility to trained individuals, ensuring that assigned responsibilities are within the scope of practice of the individual. Each study should have an individual assigned who is a qualified and licensed physician and

is responsible for the safety of the subject. This does not negate the responsibility of other staff to ensure the safety of the subject at all times. Clinical coverage should be provided during the course of a study which at all times is adequate to perform required procedures, monitor subject status, and respond properly to medical emergencies. Administrative coverage should be provided by CPU management during the course of each study which at all times is adequate to respond to foreseeable non-medical problems and emergencies that could compromise study conduct or timely completion. There must be a medically qualified individual to handle reports of adverse experiences during non-business hours. The subject should be given instructions for how to contact this individual.

PHARMACY SERVICES

It is recommended that the PI delegate accountability for clinical supplies, including study drug, placebo and devices to an individual who is experienced in the handling of clinical supplies and familiar with the requirements of Good Clinical Practice (GCP). Drug preparation and accountability may be delegated to an appropriately licensed and qualified individual, i.e. pharmacist. Drug Storage and Handling

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Each CPU should have adequate facilities for the secure and environmentally appropriate storage of investigational drugs. Access to drug supply should be limited to those individuals involved in dispensing and dosing. In addition, storage and accountability of narcotics should be in alignment with federal requirements. Temperature and humidity should be monitored in drug storage areas. If the CPU is involved in formulation and compounding, then either internal or external access to an established Investigational Drug Service (IDS) is recommended to ensure that Investigational and Study Drug studies involving non-marketed and marketed drugs in the CPU are carried out safely, effectively, and efficiently. The IDS is responsible for the integrity of drug management for clinical studies. Routine monitoring of drug accountability records is done and drug accountability records are reviewed before new supplies of drug are acquired. If the pharmacy is involved in mixing intravenous medications or compounding medications there should be at a minimum access to a hood with particle size control to be used for drug preparation. Detailed records of the preparation process should be kept to ensure reproducibility of the process. Drug Accountability Each CPU should have administrative systems and procedures that provide for required levels of study drug accountability and that ensure compliance with applicable drug receipt,

dispensing, retention, and disposal requirements. Drug accountability procedures should be performed anytime the drug is accessed and should include a drug accountability log that accounts for all investigational products related to the study. Emergency Drugs Each CPU should maintain an adequate supply of drugs on hand to respond appropriately to all foreseeable and common unforeseeable adverse events associated with study drug or procedures. These emergency drugs should be accessible to personnel qualified in their use but be stored securely in an appropriately controlled environment with at least monthly inspections to replace expired medications.

LABORATORY Clinical Laboratory Services Each CPU should maintain documentation of the certification/licensure of all external laboratories performing clinical testing for its studies and normal values for all tests that might be ordered and performed. Sample integrity is the cornerstone of the CPU laboratory and the source of the CPU’s main product, i.e. clinical data. There should be a defined process for the collection, processing and shipping of all biological samples. There should be a documented sample inventory maintained at all times. Instruments used in sample management should receive both

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routine and preventative maintenance. All sample handling should be performed implementing standards of Universal Precautions. A local policy should be in place regarding collection and storage of genetic sampling. A CPU may perform clinical tests in-house for which it has appropriate facilities, expertise, and procedures. Laboratories performing clinical safety sample analysis should consider operating in alignment with standards of Good Laboratory Practice (GLP) as defined by local regulatory requirements (21 CFR, Part 58). Although CPUs are not held to these standards, it is encouraged to develop processes that are support by GLP. As described in 21 CFR, Part 58, the key elements of GLP are as follows:

1. All data should be traceable to the specimen and the study participant.

2. All methods must be validated using acceptable methods.

3. Laboratory should have quality control processes in place.

4. Laboratory personnel must be properly trained.

5. Laboratory equipment must be maintained and calibrated and this must be documented on a regularly scheduled basis.

6. All data and specimens must be archived for a number of years.

7. The laboratory and records must be available for audit

by the Regulatory authority 24hrs/day, 7days/week.

8. The head of Quality Assurance has the final authority on lab data used for clinical trials.

GLP is the process of documenting and assuring the quality of data from the laboratory much like GCP is documenting and assuring the quality of data in the conduct of a given study. The emphasis (time and expense) is on proper documentation of the maintenance and weekly calibration of all equipment and documentation of the qualifications and training of all laboratory personnel. Data Management The CPU should have an established process for collecting and managing study data. Data collection can be paper, electronic or a hybrid. If electronic data collection (EDC) is used for source data, the system must be validated in the CPU environment with audit trail capabilities. There should be supporting processes that ensure the quality of data collected using EDC. The system and process should be in alignment with local regulatory requirements (21 CFR, Part 11). When a hybrid environment is used, then there should be a process that defines data to be collected using paper and data to be collected using the electronic source. There should be a process for archiving data in such a manner it is easily retrieved for future reference. When data is entered into an electronic case report form (eCRF), there should be a process in place for ensuring the

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security of the data and the system. At the completion of the study, there should be an electronic file of the eCRF data retained by the site.

CONCLUSION

The conduct of a clinical study in a highly regulated, CPU environment requires a team of individuals

experienced in clinical research and in the clinical management of the specific population(s) of subjects, These recommendations are meant to provide the minimal framework required for establishing an infrastructure which will meet the guidelines of Good Clinical Practice (GCP) and will ensure that the rights, safety and well-being of trial subjects are protected at all times.

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REFERENCES

ICH Harmonized Tripartite Guideline: Guideline for Good Clinical Practice; E6, April 1996

E6 Good Clinical Practices: Consolidated Guideline; 4.0 (Investigator Responsibilities); DHHS, FDA, CBER, CDER, April 1996

Guidance for Industry: Investigator Responsibilities - Protecting the Rights, Safety, and Welfare of Study Subjects’ DHHS, FDA, CDER, CBER, CDRH, October 2009

ICH Harmonized Tripartite Guideline: General Considerations for Clinical Trials; E8, 17 July 1997

Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting Improving Human Subject Protection; DHHS, FDA, CDER, CBER, CDRH, GCPP; April 2007

Guidance for Industry: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting;

Information Sheet Guidance for Institutional Review Boards, Clinical Investigators, and Sponsors: Clinical Investigator Administrative Actions Disqualification; DHHS, FDA, May 2010FDA/ORA Compliance

Guidance for Industry: S7A Safety Pharmacology Studies for Human Pharmaceuticals; DHHS, FDA, CDER, CBER, ICH; July 2001

Guidance for Industry: Safety Testing of Drug Metabolites; DHHS, FDA, CDER; February 2008

Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers; DHHS, FDA, CDER; July 2005

Program Guidance; Program 7348.811 (48) Bioresearch Monitoring. Clinical Investigators and Sponsor-Investigators. 8 December 2008.

21 CFR Part 11, “Electronic Records; Electronic Signatures; Final Rules.” Federal Register 62(54), 13429, March 1997

Part 11, Electronic Records; Electronic Signatures: Scope and Application, FDA, 2003

Guidance: Computerized Systems Used in Clinical Investigations; DHHS, FDA, OC; May 2007

FDA Institutional Review Board Inspections; Information Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: DHHS, FDA, January 2006

FDA Inspections for Clinical Investigators; Information; Sheet Guidance for IRBs, Clinical Investigators, and Sponsors: DHHS, FDA, January 2006

Compliance Program Guidance Manual - CPGM 7348.810. Advises FDA on procedures to follow in Inspections ...

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Lawrence Friedman & Curt Furberg & David DeMets. The Fundamentals of Clinical Trials. 3rd Edition, Springer

SOPs for GCP at the Investigative Site. Thomson Publishing.

SOPs for GCP by Sponsors. Thomson Publishing

Final Guidance Document: Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection; May 5, 2004

acpu guidance and recommendations for the operation of clinical pharmacology · pdf...

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