qa-015 good clinical practices (gcp)medavante.vo.llnwd.net/v1/regqa/qa/qa-015 good clinical...

QA-015 Good Clinical Practices (GCP)

Version: 4

Effective Date: ___________

DocuSign Envelope ID: 003B2DEE-DD6A-4208-968C-FEBC3E202C62

30 Mar 2017

Good Clinical Practices (GCP) QA-015, Version 4

2 of 26 Confidential and Proprietary

Signatures/Approvals

Prepared by: I am signing this document as the Author.

Gail Carroll Assistant Director QA, Regulatory & QA Date

Reviewed by: I am signing this document as a Reviewer.

Samantha Zecca QA Associate, Regulatory & QA Date

Approved by: I am signing this document as the Approver.

Angela Wilmer Vice President Regulatory & QA,

Regulatory & QA

Date


02-Mar-2017

02-Mar-2017

02-Mar-2017



Table of Contents

I. OBJECTIVES ............................................................................................................ 4

II. GOOD CLINICAL PRACTICES (GCP) .................................................................. 4

A. Examples of Regulatory Agencies: ...................................................................... 4 B. International Conference on Harmonization (ICH E6) ........................................ 4

III. DRUG DEVELOPMENT PROCESS ....................................................................... 5 A. Phases of a Clinical Trial ..................................................................................... 5

IV. MEDAVANTE’S INTERNAL PROCESSES ........................................................... 8

A. Controlled Documents ......................................................................................... 9 B. Clearly Defined Roles and Responsibilities ...................................................... 10 C. Roles and Responsibilities ................................................................................. 11

D. MedAvante’s Documentation Process ............................................................... 11

E. Employee Training............................................................................................. 12 F. MedAvante’s Regulated Computer System ....................................................... 13

V. SUBJECT CONFIDENTIALITY AND DATA SECURITY ................................. 14 A. MedAvante’s Privacy Standards ........................................................................ 14

B. Subject Informed Consent Form ........................................................................ 15 C. Health Insurance Portability and Accountability Act of 1996 (HIPAA) ........... 16

VI. MAINTAINING REGULATORY COMPLIANCE ............................................... 17

A. Better Business Practices ................................................................................... 17 B. The Role of Quality Assurance at MedAvante .................................................. 18

VII. MAINTAINING SPONSOR CONFIDENTIALITY .............................................. 18

VIII. OTHER INTERESTED PARTIES INVOLVED IN THE DRUG DEVELOPMENT

PROCESS ......................................................................................................................... 18 A. Monitors – the purposes of trial monitoring are to verify that:.......................... 18

B. Audit “Do’s” and “Don’ts” of Auditing ............................................................ 20

IX. GLOSSARY ............................................................................................................ 21

A. GCP Terms......................................................................................................... 21

B. Title 21 Code - Relevant Sections ..................................................................... 23

C. Selected GCP Guidance Documents .................................................................. 25

X. REFERENCES ........................................................................................................ 26




OBJECTIVES

This document has been prepared to provide Good Clinical Practices (GCP) training to MedAvante employees (when applicable). This document is representative of the fulfillment of the following objectives:

A) The Drug Development Process

B) An Overview of Good Clinical Practice

C) A High Level Review of MedAvante Processes

D) The Relationship of GCP to MedAvante Processes

E) The Role of Key Parties in the Drug Development Process

I. GOOD CLINICAL PRACTICES (GCP) GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials. Regulatory authorities and their regulations are global in scope. The regulations and expectation set forth by the regulatory authorities are adhered to internationally. Each country or region (several countries) has its own regulatory agency.

A. Examples of Regulatory Agencies: U.S.A. Food and Drug Administration (FDA) European Union European Medicines Agency (EMA)

Russia Ministry of Health (in Russian only) Germany Federal Ministry of Health (in German only) Japan Pharmaceuticals and Medical Devices Agency (PMDA) China China Food and Drug Administration (CFDA) Canada Health Canada UK Medicines and Healthcare Products Regulatory Agency

(MHRA)

B. International Conference on Harmonization (ICH E6) ICH E6 (R2) sets forth GCP initiatives on a global platform. ICH E6 (R2) was organized to provide an opportunity for tripartite (U.S., Japan, and EU) harmonization initiatives to be developed with input from both regulatory and industry representatives. ICH E6 (R2) is concerned with the harmonization of


http://www.fda.gov/Drugs/default.htm

http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp

http://www.mednet.ru/

http://www.bmg.bund.de/

http://www.pmda.go.jp/english/

http://eng.sfda.gov.cn/WS03/CL0755/

http://www.hc-sc.gc.ca/index-eng.php

http://www.mhra.gov.uk/index.htm

http://www.mhra.gov.uk/index.htm

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__Step_4.pdf





technical requirements for the registration of pharmaceutical products among these three regions.

II. DRUG DEVELOPMENT PROCESS

A. Phases of a Clinical Trial Clinical trials involving new drugs are commonly classified into four phases. Each phase of the drug approval process is treated as a separate clinical trial. The drug-development process will normally proceed through all four phases over several years. If the drug successfully passes through Phases I, II, and III, it will usually be approved by the regulatory authority for use in the general population. Phase IV are Post-Marketing Surveillance Trials (see information below). Before pharmaceutical companies start clinical trials on a drug, they conduct extensive pre-clinical studies. Pre-clinical studies involve in vitro (test tube or cell culture) and in vivo (animal) experiments using wide-ranging doses of the study drug to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist pharmaceutical companies to decide whether a drug candidate has scientific merit for further development as an Investigational New Drug (IND).

Phase I studies include the initial introduction of an investigational new drug into humans. Phase 1 studies are typically closely monitored and may be conducted in patients or normal volunteer subjects. These studies are designed to determine the metabolism and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. During Phase I, sufficient information about the drug's pharmacokinetics and pharmacological effects should be obtained to permit the design of well-controlled, scientifically valid, Phase II studies. The total number of subjects and patients included in Phase I studies varies with the drug, but is generally in the range of 20 to 80. Phase II studies include the controlled clinical studies conducted to evaluate the effectiveness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually involving no more than several hundred subjects. Phase III studies are expanded controlled and uncontrolled trials. They are performed after preliminary evidence suggesting effectiveness of the drug has been obtained, and are intended to gather additional information about effectiveness and safety that is needed to evaluate the overall benefit-risk


http://www.merriam-webster.com/medlineplus/pre-clinical

http://www.merriam-webster.com/medlineplus/in%20vitro

http://www.merriam-webster.com/medlineplus/in%20vivo

http://www.merriam-webster.com/dictionary/efficacy

http://www.merriam-webster.com/medlineplus/toxicity

http://www.merriam-webster.com/medlineplus/pharmacokinetic

http://www.merriam-webster.com/medlineplus/investigational%20new%20drug

http://www.merriam-webster.com/medlineplus/metabolism

http://www.merriam-webster.com/medlineplus/pharmacologic

http://www.merriam-webster.com/medlineplus/pharmacokinetics

http://www.merriam-webster.com/medlineplus/pharmacology



relationship of the drug and to provide an adequate basis for physician labeling. Phase III studies usually include several hundred to several thousand subjects. While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, in order to obtain approval from the appropriate regulatory authorities. Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. Based on the assessment, the regulatory authorities will determine whether the drug can be marketed for human use.

Post-Marketing Surveillance Trials Phase IV studies are also known as Post-Marketing Surveillance Trials. They involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being no longer sold, or restricted to certain uses.

Graph Depicting the Drug Development Process


http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm188665.htm

http://www.drugs.com/dict/pharmacovigilance.html



The patent on a newly discovered molecule that is approved for Investigational New Drug (IND) Application lasts 20 years. This patent begins after the IND application is submitted and approved by the FDA. This means that a sponsor company has 20 years to complete the Drug Development Process and profit from the sales of the drug without direct competition from generic versions of the drug. On average, the Drug Development Process takes 12 years to complete. This gives the sponsor approximately 8 years of drug sales without competition from generic versions of the drug. Each day that the Drug Development Process is extended, it costs the sponsor company approximately $1 million dollars per day in lost revenue and costs associated with the continuation of the clinical trial. In this “Time = Money” industry, sponsors are extremely motivated to shorten the Drug Development Process. This is typically done either by proving the safety and efficacy of the drug through the collection of accurate data during efficiently ran clinical trials, or by determining that the drug is not safe or effective early in the drug development process.


http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDeviceExemptionIDEProcess/default.htm

http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/InvestigationalNewDrugINDorDeviceExemptionIDEProcess/default.htm




III. MEDAVANTE’S INTERNAL PROCESSES

This section describes the processes that MedAvante has in place to incorporate GCP into its operations. MedAvante’s business purpose is to address the pharmaceutical industry’s need to reduce the number of failed central nervous system (CNS) clinical drug trials and time to market by providing high quality clinical services. MedAvante centralizes methods and procedures to reduce the risk of failed clinical trials of treatments for CNS disorders.

Responsibilities involved in a clinical trial vary according to the organization. Below lists some of the study activities and who is responsible for the activity.




Clinical Trial Responsibility

Requirement Sponsor Investigator MedAvante

FDA form 1572 X X

Informed Consent X X

Internal Review Board Independent/Central Ethics Committee X X

Financial Disclosure X X

Study/Protocol Design X

Study Conduct X X

Monitoring/Auditing X

MedAvante’s responsibilities are documented in the contract with the sponsor.

A. Controlled Documents

Controlled Documents are written instructions which outline and describe MedAvante’s processes. Controlled Documents are created to help achieve uniformity in processes and to provide a basis for employee training. Controlled Documents are generally the starting point for most audits/inspections. Some examples of MedAvante Controlled Documents are:

1) Document Management 2) Office Access Security Procedures 3) IT New Hire Training 4) Network Security

Essentials in Maintaining Controlled Documents:

1) Keep documents up-to-date a) Operating under obsolete documents is a primary source of

regulatory agency observation during an audit b) It is better not to have a document than to not comply with a

document

2) Review documents when appropriate to ensure they are current




a) Review document(s) based on SOP QA-011 Creating, Reviewing, Maintaining and Retiring Controlled Documents

i. All documents except Guidelines are to be reviewed biennially

ii. Guidelines are to be reviewed on the one year anniversary date and either converted to an SOP or Work Instruction

3) Modify documents as processes change

a) Ensure changes are reflected appropriately in related documents, including referenced documents

4) Archive obsolete documents

a) Archiving obsolete documents will ensure that we know what the process was at any point in time and can reconstruct the process

5) How much detail should be included in a Controlled Document?

a) Enough to define who, what, when, where, how, and why b) Too much detail will make it difficult to maintain compliance c) Details should be written in a Work Instructions document

B. Clearly Defined Roles and Responsibilities MedAvante has dated organizational charts that describe and support the organizational structure of the company. GCP stipulates that every employee (regardless of full-time, part-time, or on-demand status) must qualify to engage in a clinical trial based on education, experience, and training. Every MedAvante employee must have a CV/Resume and Job Description. Together, these documents must show that every employee qualities to engage in a clinical trial based on their education, experience, and training. In addition, MedAvante checks the FDA’s Debarment List and the Health and Human Services/Office of Inspector General’s List of excluded individuals/entities to ensure that employees are not barred or excluded from engaging in clinical trials. If an employee is listed on either website as having engaged in criminal misconduct, that employee is disqualified from engaging in clinical trials. Examples of Job Titles:

1) Director, Clinical Trial Services 2) Manager, Logistics 3) Project Manager 4) Project Coordinator 5) Clinician


http://www.fda.gov/ICECI/EnforcementActions/FDADebarmentList/default.htm

http://exclusions.oig.hhs.gov/

http://exclusions.oig.hhs.gov/



C. Roles and Responsibilities Current dated job descriptions quantify and support job responsibilities. Outdated organizational charts and job descriptions are not destroyed but are archived. This supports MedAvante in identifying the responsibilities that were in place previously and helps to reconstruct earlier processes.

D. MedAvante’s Documentation Process The documentation process is outlined in SOP QA-010, Document Management. MedAvante’s documents are generated to track and evaluate the ethical and procedural conduct of a trial and the quality of the data that is produced. Proper documentation is key in the creation, maintenance, storage, and archiving of data which may be needed to recreate an event. There are different types of files in which most of MedAvante’s documents are stored.

1. General Document Files – documents pertaining to corporate regulated

activities, for example: a) Current and archived controlled documents b) Current and archived general templates

2. Client–Specific Files – documents that govern or pertain to a specific

client but not a specific project, for example: a) Master Service Agreement b) Confidentiality Agreement c) Financial Information d) Proposals e) General Correspondence

3. Study–Specific Files – documents that govern or pertain to specific

projects, for example: a) Study Protocol b) Project Plan c) Clinician Manual d) Work Instructions

4. Validation–Specific Files – governed or pertain to regulated systems;

for example: a) Project Plan b) Validation Plan c) Validation Summary d) User Acceptance Testing

5. Source Data

MedAvante is required to prepare and maintain adequate and accurate records (source data) that describe all observations and other data




pertinent to the clinical assessment as outlined in 21 CFR part 312.62 – “An investigator is required to prepare and maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation...” ICH E6 (R2) defines source data as all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. MedAvante clinicians or site raters conduct the assessments, compose assessment notes, and derive the assessment scores, which according to the above definition, are source data.

6. Potential Clinical Events and Adverse Events

When conducting Centralized Ratings, MedAvante clinicians are responsible for reporting Potential Clinical Events to the Investigative Site as described in the Subject Risk and Potential Clinical Event (PCE) Assessment and Documentation Manual. If you are a clinician, please refer to this manual for specific details. An Adverse Event (AE) is any undesirable experience associated with the use of a medicinal product in a patient. The event is a Serious Adverse Event (SAE) and the investigator must report this to the sponsor, local authorities, and/or IRB/IEC/CEC when the subject outcome is: a) Death b) Life-threatening c) Hospitalization d) Disability e) Congenital anomaly f) Requires intervention to prevent permanent impairment or damage. It is the responsibility of the Principal Investigator to report AEs or SAEs to the sponsor, local authorities, and/or IRB/IEC/CEC.

E. Employee Training MedAvante maintains a robust training program for its employees. The reason for such a robust training program is outlined in 21 CFR 312.53 – “a sponsor shall select only investigators qualified by training and experience as appropriate…” Examples of types of training and qualifications are as follows:

1) Controlled Documents training 2) Clinician training and calibration 3) Clinician Manual 4) Guidelines for the Destruction of Recordings



http://www.fda.gov/safety/medwatch/howtoreport/ucm053087.htm





GCP guidelines for employee training and qualification processes are outlined below.

1) Training is completed within specified time 2) Training is documented 3) Training records are current 4) Training records are available for review 5) Designees are trained 6) CV and training records reflect qualifications to conduct current

responsibilities 7) CVs are signed, initialed, dated, and kept current

F. MedAvante’s Regulated Computer System Computer System Validation is the technical discipline that MedAvante uses to ensure that software applications fulfill their intended purpose. Stringent quality requirements in regulated industries impose the need for specific controls and procedures throughout the Software Development Life Cycle. Evidence that these controls and procedures have been followed, and that they have resulted in quality software (software that satisfies its requirements), must be documented correctly and completely. These documents must be capable of standing up to close scrutiny by trained inspectors since the financial penalty for failing an audit can be extremely high. More importantly, a problem in a Life Science software application that affects the production environment could result in serious adverse consequences, including possible loss of life. MedAvante’s automated processes follow GCP guidelines as outlined below.

1) Virgil and MAVTAB, MedAvante’s regulated computer systems, which facilitate collection, verification, storage, transmission, analysis, and reporting source document assessments, are validated. a) Source document data is entered directly into Virgil and

MAVTAB b) Validation is achieved by documenting the processes proving

that the systems were developed and work properly. c) Virgil and MAVTAB meet the requirements of 21 CFR part 11

(electronic records and electronic signatures). 2) MedAvante has

a) Logical and physical security that is described in Controlled Documents.

b) Backup and recovery processes that are described in Controlled Documents.

c) Contingency planning for situations which may jeopardize the system or the data.




IV. SUBJECT CONFIDENTIALITY AND DATA SECURITY

A. MedAvante’s Privacy Standards MedAvante respects and complies with the privacy practices established by sponsors and regulatory authorities to ensure the protection of personal health information. MedAvante’s Privacy Policy regarding confidentiality requirements is publicly available on our website. Below are controls and processes that MedAvante has implemented to ensure subject confidentiality and data security.

1) MedAvante collects only the following information on a subject in a clinical

trial: subject identification number, year of birth, gender, initials (when applicable), and an alias (for reference during the assessment). The above described subject information collected by MedAvante is not sufficient to identify the subject’s identity or personal information.

2) Information collected by MedAvante is stored on secure database servers (in

whatever country they may be located) or hosted by third party agents who have entered into agreements with MedAvante that require them to observe MedAvante’s Privacy Policy. MedAvante has a firewall and other technology to prevent individuals from accessing information without authorization. Data centers are designed to be physically secure and protected from unauthorized access by unauthorized persons.

3) MedAvante is compliant and certified with the EU - US Privacy Shield

Framework to ensure compliance with subject confidentiality and data security standards as described in the EU Data Protection Directive 95/46/EC.

4) As a condition of employment, employees must sign a Confidentiality Agreement that holds in the strictest confidence the confidential information of MedAvante and any third-party who has given MedAvante the right to use the third-party’s Confidential Information.

5) MedAvante has a contractual agreement with the sponsor to maintain subject confidentiality and data security.

6) Access to information at MedAvante is limited as follows: only the

information, required by qualified MedAvante employees to perform their job and required function(s) within the clinical study, is released to those MedAvante employees.


http://www.medavante.com/privacy-policy/

http://www.medavante.com/privacy-policy/

https://www.privacyshield.gov/welcome


http://www.dataprotection.ie/viewdoc.asp?DocID=89

http://www.dataprotection.ie/viewdoc.asp?DocID=89



7) MedAvante’s Speech Privacy system is designed to diminish the possibility of subject information disclosure by incorporating a white noise solution throughout its facilities and clinician offices.

8) Access to MedAvante’s facilities is limited and secure. Specifically, MedAvante’s facilities are locked at all times and can only be opened with a specially programmed key. Every employee is assigned a unique key. The key is programmed to allow entrance into the building during an employee’s normal work hours. Visitors must sign in, wear a badge, and be escorted at all times.

9) MedAvante’s proprietary electronic record systems are designed, tested and audited to ensure compliance with the requirements of 21 CFR part 11, the electronic records/electronic signatures final rule and Annex 11. MedAvante’s technical controls and auxiliary procedural controls regarding electronic record protection have been designed to ensure the authenticity, integrity, security, and confidentiality of electronic records and subject information.

10) All media containing subject information is stored electronically on a secure server or in a secure, limited access, location.

11) Retention of the subject information is performed in accordance with the documented process and/or the agreement between MedAvante and the sponsor.

12) Destruction of all subject information is performed in accordance with the documented process and upon agreement between MedAvante and the sponsor.

13) MedAvante performs study-specific reviews to ensure that the study has been executed in compliance with regulations and study-specific requirements.

B. Subject Informed Consent Form Informed consent is a vital part of the research/clinical study process, and as such entails more than obtaining a signature on a form. Investigators must educate potential subjects to ensure that they can reach a truly informed decision about whether or not to participate in the study. Their informed consent must be given freely, without coercion, and must be based on a clear understanding of what participation involves. Consent should only be obtained after the subject has achieved an understanding of the relevant medical facts and the risks involved.




MedAvante provides standard informed consent language to the sponsor to ensure that MedAvante personnel are permitted to observe and/or record assessments. This language is given to the Sponsor prior to informed consent approval by the International Review Board (IRB) and/or Independent Ethics Committee/Clinical Events Committee (IEC/CEC).

C. Health Insurance Portability and Accountability Act of 1996 (HIPAA)

The HIPAA Privacy Rule gives subjects rights over their health information and sets rules and limits on who can look at and receive health information. The HIPAA Privacy Rule applies to all forms of subject protected health information, whether electronic, written, or oral. The HIPAA Security Rule protects health information in electronic form, requires entities covered by HIPAA to ensure that electronic protected health information is secure. The HIPAA Privacy and Security Rules apply to covered entities. MedAvante is not a covered entity as described by HIPAA. However, MedAvante incorporates subject confidentiality and data security in its business practices (see MedAvante Privacy Standards above). The covered entities that must follow the HIPAA regulations are 1) Health Plans, 2) Health Care Providers, and 3) Health Care Clearinghouses. Personal Heath Information (PHI) that is protected by HIPAA is listed below.

Information that health care providers put in a subject’s medical record

Conversations health care providers have about a subject’s care or treatment

Information about a subject in a health insurer’s computer system

Billing information

Most other health information about a subject held by those who must follow these laws

How HIPAA Information Is Protected: Safeguards must be in place to protect health information.

Use and disclosure of information must be reasonably limited to the minimum necessary to accomplish the intended purpose.

Contracts must be in place with subcontractors ensuring that they use and disclose health information properly and safeguard it appropriately.


http://www.hhs.gov/ocr/privacy/hipaa/understanding/index.html





http://www.hhs.gov/ocr/privacy/hipaa/understanding/coveredentities/index.html







Procedures must be in place to limit who can view and access health information.

MedAvante follows the procedures described in controlled document OP-035 Work Instructions for Managing Documents and/or Recordings Containing Subject Personal Identifiers if we receive PHI not typically collected in a particular study. Generally, personal health information cannot be used or shared without the subject’s written consent. Personal Health Information (PHI) is protected by federal law.

V. MAINTAINING REGULATORY COMPLIANCE

A. Better Business Practices

1) There must be clarity in the recording of data. Write legibly.

2) There must be clarity in the changing/editing of data. a) Must denote who, what, when, and why b) Do not obscure (erase, whiteout, blackout, scribble) original entries.

i. If an error is made, draw a line through the error, initial and date it, and then write the correct information

c) Use blue or black ink only for manual records d) Do NOT use pencil or red ink; do NOT use white-out e) Must have the ability to reconcile changes to data f) Must have the ability to reconstruct a process at any point in time

3) Controlled documents are generated and maintained to support regulated

activities a) Review and approval of documents is performed by more than one

employee b) Version history must be accurate to record edits and changes to

documents c) Documents must be retained/archived properly for future retrieval for

review

4) Security must be provided and maintained a) Adequate, safe, dry, storage b) Limited access to rooms, cabinets, and electronic files c) Visitor logs to track the who, what, when, why of visitors to the facility




d) Visitors must be escorted at all times

5) Meaning of signatures a) Signatures are used to enforce accountability b) Review for technical accuracy and reasonableness c) Approval granted for operational use of equipment or software

6) Prudent use of Email

a) Be prudent in your use of email when discussing client issues b) Ensure any email (or phone call) regarding a subject’s adverse event

is brought to attention of MedAvante management ASAP c) Remember that email is discoverable information

B. The Role of Quality Assurance at MedAvante 1) The role of the Quality Assurance (QA) team at MedAvante is to provide an

independent evaluation of activities of regulatory significance, to help assure that policies and procedures are being adhered to and that regulatory compliance is being maintained.

a) QA conducts internal and vendor audits b) QA reviews controlled documents as applicable for regulatory

compliance c) QA conducts regulatory training when necessary d) QA hosts audits when MedAvante is the auditee e) QA operates independently from other departments at MedAvante

VI. MAINTAINING SPONSOR CONFIDENTIALITY MedAvante has a contractual obligation to maintain the confidentiality of sponsors. MedAvante employees must not disclose the name of any sponsor to anyone who is not a MedAvante employee.

VII. OTHER INTERESTED PARTIES INVOLVED IN THE DRUG DEVELOPMENT PROCESS

A. Monitors – the purposes of trial monitoring are to verify that:

o The rights and well-being of human subjects are protected o The reported trial data are accurate, complete, and verifiable




o The conduct of the trial is in compliance with the currently approved protocol/amendment

1) The sponsor shall monitor the progress of all clinical investigations being

conducted under its IND application.

2) Monitoring is study-specific

3) Monitoring helps ensure that the Investigator/sub-investigator is in compliance with:

a) FDA form 1572 b) Study protocol c) Applicable regulations

4) During the site visit, monitors generally:

a) Review the study timeline b) Review final study plans/protocols c) Review any observed deviations d) Review procedures for the revision of documents e) Review subject safety data f) Review source documentation and how it is maintained g) Review audit trail reports h) Check for all applicable documentation on file i) Assure that all discrepancies are resolved and that a remedial

action is in place if required j) Verify that all procedures are followed and that all deviations are

properly recorded and resolved k) Assure that all previously agreed to activities are being followed l) Assure that current, complete, and accurate records (e.g. source

documents) are kept m) There is an explanation for subjects that fails to complete the

study.

5) During Close-out Visits monitors generally: a) Assure completeness of all study-related files b) Ensure that there are no outstanding issues c) Ensure that all data discrepancies have been resolved

6) The Sponsor may also have a Quality Assurance team that:

a) Is independent from the monitors b) Can be used for one of the following purposes:

1. Due diligence 2. Study specific audit 3. Continuing evaluation of an outsource partner/vendor




B. Audit “Do’s” and “Don’ts” of Auditing

Do Don’t Be honest Try to be fake

Be prepared Rely on your good looks and charm

Answer only the questions asked Ask inappropriate questions

Provide information promptly Be afraid to disagree with a finding

or recommendation

Reserve a Conference Room Be afraid to say, “I don’t know”

Request audit agenda and confidentiality Volunteer information

agreement

Make photocopies for auditors Leave proprietary information on

desks

Escort them around the facility Share results of internal or vendor

audit reports

Respond promptly and fully Share written information about

another client

Be consistent Bad-mouth auditor’s colleagues




VIII. GLOSSARY

A. GCP Terms

Blinding is a procedure in which one or more parties of the trial are kept unaware of the treatment assignment(s). Single blinding usually refers to the subject(s) being unaware. Double blinding usually refers to the subject(s), investigators(s), monitor, and in some cases, data analyst(s) being unaware of the treatment assignments. Case Report Form is a printed, optical, or electronic document designed to record all of the protocol-required information to be reported to the sponsor on each trial. Clinical Assessment is the administration of assessment scales to evaluate a subject’s treatment response. Clinical Trial is a research study in human volunteers to answer specific health questions.

Controlled Clinical Trial - A clinical trial involving one or more test treatments, at least one control treatment, and concurrent enrollment, treatment, and follow-up of all patients in the trial. Employee – means employee, contractor, and consultant employed by MedAvante.

Ethics Committee is an independent body in a Member State, consisting of healthcare professionals and nonmedical members, whose responsibility it is to protect the rights, safety and wellbeing of human subjects involved in a trial and to provide public assurance of that protection, by, among other things, expressing an opinion on the trial protocol, the suitability of the investigators and the adequacy of facilities, and on the methods and documents to be used to inform trial subjects and obtain their informed consent. European Medicines Agency (EMA or EMEA) – The European Medicines Agency is a decentralized agency of the European Union (EU), located in London. The Agency is responsible for the scientific evaluation of medicines developed by pharmaceutical companies for use in the European Union.

FDA form 1572 Form – is a federal form and is the statement of the Investigator that he will abide by the federal guidelines set forth in the Code of Federal


http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp&jsenabled=true



Regulations for the use of drugs in an investigational setting. The Investigator submits the completed form to the Sponsor. The form is available at http://www.fda.gov.

Food and Drug Administration (FDA) – An agency within the Unites States Department of Health and Human Services which holds the responsibility to protect and promote public health through regulation and supervision of food safety and biopharmaceuticals.

Good Clinical Practice (GCP)– An international quality standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial participants are protected. Institutional Review Board (IRB), Independent Ethics Committee (IEC), Central Ethics Committee (CEC) means any board, committee, or other group formally designated by an institution to review, to approve the initiation of, and to conduct periodic review of, biomedical research involving human subjects. The primary purpose of such review is to assure the protection of the rights and welfare of the human subjects.

Investigational New Drug Application (IND) is a request for authorization from the FDA to administer an investigational drug or biological product to humans. Such authorization must be secured prior to interstate shipment and administration of any new drug or biological product that is not the subject of an approved New Drug Application or Biologics/Product License Application. Investigator is an individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispensed to a subject. The investigator is directly involved in the treatment or evaluation [emphasis added] of research subjects. New Drug Application (NDA) is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the U.S. The data gathered during the animal studies and human clinical trials of an IND become part of the NDA. Randomization is the process of assigning trial subjects to treatment or control groups using an element of chance to determine the assignments in order to reduce bias. Source Data is all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.


http://www.fda.gov/

http://www.fda.gov/

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=56





Source Documents are original documents, data, and records (e.g. clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklist) in hardcopy or electronic form. Sponsor is the entity that takes responsibility for and initiates a clinical investigation. The sponsor may be an individual, pharmaceutical company, governmental agency, academic institution, private organization, or other organization. Subject is an individual who is or becomes a participant in research, either as a recipient of the test article, or as a control. Uncontrolled Clinical Trial - A clinical trial that does not involve a control treatment. Any study that does not have a control group made up of subjects treated and followed over the same time period as those in a treated group.

B. Title 21 Code - Relevant Sections

Title 21 Code of Federal Regulations part 50 (21 CFR part 50) is the FDA regulation which outlines the Informed Consent Process. The Informed Consent process in the primary manner in which the potential subject is explained the complete nature of the trial in order to protect the subject by allowing them to make an educated, informed decision on whether to participate in the study. The Informed Consent is a process whereby the investigator provides potential subjects sufficient information about:

Nature and extent of planned research

Study procedures

Potential risks and benefits

Confidentiality of patient records

Other therapeutic options or alternatives. Title 21 Code of Federal Regulations part 56 (21 CFR part 56) is the FDA regulation which details Institutional Review Boards (IRBs). An IRB is a group formally designated to review and monitor biomedical research involving human subjects. An IRB assures, in advance and by periodic review that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. IRBs review research protocols and study related materials (e.g. informed consent documents and investigator brochures) to ensure protection of the rights and welfare of human subjects in research. Title 21 Code of Federal Regulations part 11 (21 CFR part 11) is the FDA regulation detailing electronic records and electronic signatures. Adhering to 21 CFR part 11 allows the ability to rely on electronic records and electronic


http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=50

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=56




signatures to the same degree as when using paper records and handwritten signatures. Title 21 Code of Federal Regulations part 314 (21 CFR part 314) is the FDA regulation outlining the Application for FDA Approval to Market a New Drug. This is the final step before a drug is approved for Market for human use. Title 21 Code of Federal Regulations part 312 (21 CFR part 312) is the FDA regulation which outlines the Investigational New Drug Application (IND). The IND is a request for exemption from Federal law so unapproved drugs can be shipped in interstate commerce. The IND is also the vehicle through which a sponsor advances to the clinical trials (trials using human subjects) stage of drug development. Title 21 Code of Federal Regulations part 54 (21 CFR part 54) is the FDA regulation which outlines the process of Financial Disclosure by Clinical Investigators. 21 CFR part 54 is intended to ensure that financial interests and arrangements of clinical investigators that could affect the reliability of data submitted to FDA are identified and disclosed by the applicant (the clinical investigator).


http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRsearch.cfm?CFRPart=314


http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=54&showFR=1



C. Selected GCP Guidance Documents

A) ICH Harmonised Tripartite Guideline, Guideline for Good Clinical Practice E6

B) Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection

C) Guidance for Industry: Computerized Systems Used in Clinical Investigations

D) General Principles of Software Validation; Final Guidance for Industry and FDA Staff

E) Guidance for Industry: Oversight of Clinical Investigations – A Risk-Based Approach to Monitoring

F) Guidance for Industry on Part 11, Electronic Records; Electronic Signatures: Scope and Application

G) Annex 11: Computerized Systems

H) EU - US Privacy Shield Framework


http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf

http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf

http://www.hhs.gov/ohrp/archive/humansubjects/finreltn/fguid.pdf

http://www.hhs.gov/ohrp/archive/humansubjects/finreltn/fguid.pdf

http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.PDF

http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.PDF

http://www.fda.gov/MedicalDevices/deviceregulationandguidance/guidancedocuments/ucm085281.htm

http://www.fda.gov/MedicalDevices/deviceregulationandguidance/guidancedocuments/ucm085281.htm

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm269919.pdf

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm269919.pdf

http://www.fda.gov/regulatoryinformation/guidances/ucm125067.htm

http://www.fda.gov/regulatoryinformation/guidances/ucm125067.htm

http://ec.europa.eu/health/files/eudralex/vol-4/annex11_01-2011_en.pdf




IX. REFERENCES

1. FDA Drug Development Guide – Drug Development Chart

2. FDA Information Sheet Guidance for Institutional Review Boards (IRBs), Clinical Investigators, and Sponsors

3. FDA Basic Questions and Answers about Clinical Trials

4. FDA Running Clinical Trials

5. FDA – What is a Serious Adverse Event?

6. Guidance – Financial Disclosure by Clinical Investigators

7. ICH E6 GCP

8. Title 21 Code of Federal Regulations part 50.3



11. Title 21 Code of federal Regulations part 312.56


Good Clinical Practices (GCP)

QA-015, Version 3

1 of 2 Template Version 7 Confidential and Proprietary

Revision History:

Revision Number Section(s) affected List of and reasons for revision 4 Whole Company Logo Change

4 Signatures/Approvals Updated Signatories

4 Clinical Trial Responsibility

Updated table for Informed Consent removed MedAvante responsibility

4 B Clearly Defined Roles & Responsibilities – Example of Job Titles

Updated list of titles to align with current organization structure

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V (A) MedAvante Privacy Standards #3

Changed from US-EU Safe Harbor Privacy Shield to EU-US Privacy Shield Framework

4

Glossary Revised Good Clinical Practice (GCP) definition

4 G. Selected GCP Reference Documents

Removed US. – UE & US – Swiss Safe Harbor Framework and added EU-US Privacy Shield Framework

4 IV. MedAvante’s Internal Processes, Section E

Updated name from Rater Manual to Clinical Manual to coincide with manual name

3 IV. MedAvante’s Internal Processes,

Section D

Updated paragraph for clarity Updated examples of Study-Specific Files and Validation-Specific Files to coincide with actual documents


Section B

Updated examples of Job Titles to match company titles


Section A

Updated examples of MedAvante Controlled Documents to coincide with actual documents

3 IV. MedAvante’s Internal Processes

Updated MedAvante’s Business Purpose Removed workflow charts because they are not representative of MedAvante’s primary services

2 Whole Document Document was completely revised from



2 of 2 Template Version 7 Confidential and Proprietary

MS PowerPoint presentation to a more detailed MS Word format document for clarity.

1 New document MS PowerPoint presentation
