1 Module 4. 2 History of Good Clinical Practice Regulations Barbara Novak

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Module 4

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History of Good Clinical Practice Regulations

Barbara Novak

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US Food and Drug Law Chronology

• 1848 Congress banned importation of adulterated drugs after a bad batch of quinine was imported for U.S. Army. (Did not affect domestic issues of adulteration)

• 1879 Congress began investigating incidents involving contamination of food and drugs through the USDA

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• 1902 Biologics Control Act – Required licensing of serums and

vaccines• 1906 Pure Food and Drug Act

– Congress began investigating incidents involving contamination of food and drugs through the USDA

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1906 Pure Food and Drugs Act

AKA Wiley or Heyburn Act

• Dr. Wiley’s lunch crew

• Upton Sinclair’s The Jungle

• Prohibited interstate transportation of adulterated and misbranded foods and drugs

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• 1912 Sherley Amendment– Prohibited false and fraudulent

curative claims or therapeutic claims on labels (snake venom, elixirs, wonder cures)

• 1938 Food, Drug and Cosmetic Act– Added cosmetics to the 1906 Act

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1938 Food, Drug and Cosmetic Act

• Elixir of Sulfanilamide - 1937

• Required pre-market approval of new drugs for safety

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Food, Drug and Cosmetic Act

• Authorizes FDA to inspect at reasonable times

• Authorizes FDA to promulgate and enforce regulations

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• 1962 Kefauver Act– Amendments to the 1938 ACT

that set up a mandatory reporting system for drug safety

– Led to the Spontaneous Reporting System which catalogues ADR reports for marketed drugs

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1962 Kafauver Act

• Thalidomide tragedy

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1987 IND Rewrite

• 21 CFR Part 312 Introduced– Laid out the responsibilities of

sponsors, monitors and investigators

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Prescription Drug User Fee Act (PDUFA)

•1992 & 1997•FY2001 Fees

–Application fee - $309,647–Establishment Fee - $145,987–Annual product fee - $21,892•FY 2005FY 2005 Fees–Application fee - $672,000/ 336,00 (SNDA)

–Establishment Fee - $262,000–Annual product fee - $41,710

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Good Clinical Practices (GCPs)

• Phrase coined by industry• Includes Regulations, Guidelines and

Industry practices which address responsibilities of:

– the Sponsor

– the Investigator

– Institutional Review Boards

and requirement for Informed Consent.

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Regulations vs Guidelines

• Regulations = LAW

• Guideline = Clarification

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Purpose of GCP’s

• To protect the rights and safety of subjects

• To assure the quality and integrity of the clinical research data

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GCP Regulations

• 21 CFR Part 312 – IND Regulations• 21 CFR Part 312.50 to 312.59

– Sponsor/monitor responsibilities• 21 CFR Part 312.60 to 312.69

– Investigator responsibilities• 21 CFR Part 50

– Informed consent regulations

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GCP Regulations

• 21 CFR Part 56 - IRB regulations

• 21 CFR Part 11 – Electronic signatures

• 21 CFR Part 54 – Financial disclosure

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GCP Guidelines

• FDA Information Sheets

• Guidelines for Monitoring, Investigators, etc

• ICH GCP Guideline

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FDA Organization

• FDA is 1 agency within the Dept. of Health and Human Services (HHS)

– Reports to Secretary of HHS– Funding is through the HHS budget

(FDA has a separate budget)– Small agency – frequent visit to

Capitol Hill

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FDA• FDA is comprised of 8 Centers/Offices

CDER – Center for Drug Evaluation and Research (most therapeutic biologics recently transferred to CDER)

CBER- Center for Biologics Evaluation and Research)

CDRH – Center for Devices and Radiological Health

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FDACFSAN – Center for Food Safety and

Applied NutritionCVM – Center for Veterinary

MedicineNCTR – Nat’l Center for Toxicological

ResearchOC - Office of Commissioner (head of

FDA)ORA – Office of Regulatory Affairs

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Office of Medical Policy

• Reports to CDER Director• Division of Scientific Investigations

– Select sites for inspection– Assist on inspections– Review inspection reports– Final classification of

reports/regulatory action

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Office of Regulatory Affairs (ORA)

• Associate Commissioner for Regulatory Affairs

• Office of Resource Management• Office of Regional Operations• Office of Enforcement• Office of Criminal Investigations

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Field Set-Up• Report to Office of Regional

Operations• 5 Regions

– Northeast Region• Regional office in New England & NY• District offices in NE, NYC, Buffalo

– Central Region• Regional office in Phila, Baltimore & Chicago• District offices in Philadelphia, Baltimore,

Chicago, NJ, Cincinnati, Detroit, Minneapolis

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Field Set-Up

– Southeast Region• Regional office in Atlanta• District offices in Atlanta, New Orleans,

Florida, San Juan

– Southwest Region• Regional office in Dallas, Denver, KC• District offices in Dallas, Denver, Kansas

City, and a Southwest Import District

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Field Set-Up

– Pacific Region• Regional office in San Francisco & Seattle• District offices in Los Angeles, San

Francisco & Seattle

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Submissions• Drugs

– IND: Investigational New Drug Application

– NDA: New Drug Application• Biologics

– BB-IND: Biologics Investigational Drug Application

– BLA: Biologics License Application

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FDA Website

• www.fda.gov• Each center is represented• Can access guidelines, regulations,

speeches• Warning letters are posted, and

investigator disqualifications

http://www.fda.gov/

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Module 9

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International Conference on Harmonization (ICH)

• US, EU, Japan• Industry, trade organizations and

regulatory representatives• 5 step process, with Step 5 being

FINALIZATION of the individual guideline– i.e., acceptance of the guideline

by each country

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Purpose of ICH

• Harmonize standards• Improve quality and reliability of data• Protect rights & welfare of subjects• Minimize human new drug exposure• Speed up marketing of new drugs• Decrease cost

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ICH GCP Guideline

• Published as guideline in US• Includes requirements for

– Sponsors– Investigators– IRB/IEC– Informed consent– Essential documents

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ICH GCP Guideline

• Similar to FDA regulations

• FDA very involved in ICH process

• More detailed in most places

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FDA Bioresearch Monitoring Program

• Kefauver Harris amendments• Field survey 1972 – 1974• Sponsors, Investigators, Contract

research Organizations (CROs), IRBs, Toxicology Laboratories

• Drugs, Devices, Biologics, Foods, Veterinary Medicine

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Why GCPs?

• Mandated by regulatory authorities• History indicates need• Uniform way of conducting research• Drug/biologic/device development is

expensive – DO IT RIGHT THE FIRST TIME

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Office for Good Clinical Practice (OGCP)

• Within the Office of the Commissioner

• Agency-side coordinating functions• Work with OHRP• Improve conduct and oversight of

clinical research• Ensure protection of participants in

FDA-regulated clinical research

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Responsibilities

• Promote protection of human research participants

• Support quality and integrity of clinical trials and applications

• Support global harmonization and implementation of GCP standards

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HHS

• OHRP – Office of Human Research Protections

• More inspections of IRBs• Required training for sites• Loss of funding

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Module 8

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Obligations of Sponsors 21CFR 312.50 to 312.59

DEFINITIONSponsor: An individual,

company, institution or organization that takes responsibility for and initiates (and/or finances per ICH) a clinical investigation

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Obligations of Sponsors 21CFR 312.50 to 312.59

KEY POINTS:

Select and Update InvestigatorsStudy MonitoringRecordkeepingDrug DistributionMaintain the Regulatory Submissions

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Obligations Of Sponsors 21CFR 312.50 to 312.59

SPECIFIC OBLIGATIONS:Sponsor commits to: Obtain a signed FDA form 1572 and

Curriculum Vitae from each investigator

Ensure investigator understands his/her obligations per the regulations

Provide investigator with a current Investigator Brochure

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SPECIFIC OBLIGATIONS:Sponsor commits to: Obtain sufficient, accurate financial

information to submit the required certification or disclosure statements, and obtain commitment from investigator to update this information if relevant changes occur

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Continued...

Keep investigator informed of new observations discovered or reported, particularly with respect to adverse effects and safety

Monitor study by on-site visits

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Continued...

Ensure that investigator and staff are following approved protocol and ensure that case report forms are being adequately completed

Assure that qualified IRB will be involved

Assure investigator will inform IRB of any protocol changes except to eliminate an immediate hazard to subjects

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Continued...

Evaluate evidence relating to safety and efficacy as it is received from the investigator

Discontinue study if it is determined that the study drug presents an unreasonable and significant risk to subjects. Notify FDA, all IRBs and all investigators of a discontinuation for such reasons

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Continued...Submit to FDA annual progress reports,

updated Investigator Brochure, and IND safety reports as required

Maintain records showing any financial payments to clinical investigators

Maintain records of drug shipment, receipt, and disposition, including date, quantity, and batch

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Continued...

Assure the return or disposition of unused supplies

Retain all records for 2 years after NDA is approved or study is discontinued

Allow for FDA inspections of records and reports of clinical investigations


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Continued...

Discontinue drug shipment or secure compliance from any investigator who has not maintained or made available his/her records to FDA for inspection

Assure compliance with storage and record-keeping requirements

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Continued...

Notify FDA and all participating investigators of any serious and unexpected adverse experience associated with the use of the study drug

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Continued...

Notify FDA and all participating investigators of any preclinical findings that suggest a significant risk for human subjects (e.g., mutagenicity, teratogenicity, or carcinogenicity findings)

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Obligations Of Clinical Investigators

DEFINITION

Investigator: An individual who actually conducts a clinical investigation (i.e., under whose immediate direction the drug is administered or dispense to a subject). If conducted by a team, the inv. is the responsible leader of the team.

ICH: A person responsible for the conduct of the clinical trial at a site

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REGULATION: 21CFR 312.60 to 312.70

KEY POINTS:

Conduct Clinical Study

Protection of Patients

Control of Drug

Compliance with IRB requirements

Recordkeeping

Reporting

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Specific Obligations:

The Investigator commits to:

Personally conduct or supervise the described investigation

Provide a list of the names of subinvestigators who will be assisting in the conduct of the investigation


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Continued…

Ensure that all associates, colleagues, and employees assisting in the conduct of the study are informed about their study obligations. Such associates, colleagues, and employees must be listed on the FDA form 1572


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Continued…

Assure that study is conducted in accordance with the protocol, and only make changes after notifying the sponsor

Obtain informed consent from all patients prior to their participation in the study


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Continued…

Prepare and maintain adequate and accurate case histories that record all observations relevant to the study. Case histories include study CRFs, informed consent forms, and medical records including progress notes, hospital charts, nurses notes, and lab records


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Continued…

Promptly report to the sponsor all adverse effects that may reasonably be suspected to have been caused by the study drug. If the adverse effect is serious and unexpected, it should be reported to the sponsor immediately


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Continued…

Assure that study drug is administered only to subjects under the investigator’s personal supervision or the supervision of a subinvestigator in his/her study

Return or otherwise dispose of all unused study medication in accordance with the sponsor’s instructions

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Continued…

Maintain accurate and adequate records of drug disposition and drug accountability

Assure that an IRB that complies with the IRB regulations will be responsible for the initial and continuing review and approval of the proposed protocol

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Continued…

Assure that the study informed consent form is approved by an IRB prior to initiation of the study

Assure that all changes in the protocol are reported to an IRB, and assure that no changes will be made to the protocol without prior IRB approval, except where necessary to eliminate apparent, immediate hazards to human subjects

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Continued…Submit annual progress reports to an IRB

Submit progress reports of study findings to the sponsor

Provide sponsor with a final study report shortly after completion of participation in the clinical investigation

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Continued…

Maintain study records for 2 years after NDA approval or 2 years after discontinuation of study

Provide sponsor with sufficient, accurate financial information to submit the required certification or disclosure statements, and obtain commitment from investigator to update this information if relevant changes occur

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Continued…

Permit access to, including copying of study records and reports by FDA, sponsor, or sponsor-designated individual(s)

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Laboratory Records

Form 1572 lists laboratory and its location

Lab accreditation stored with investigator

Lab normals retained

Label lab samples with patient ID, study number and date

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Module 6

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Obligations of IRBsDEFINITION:Institutional Review Board (IRB): any board,

committee or group formally designated by an institution to review, approve and conduct periodic review of biomedical research involving human subjects.

ICH definition: An independent body constituted of medical, scientific and nonscientific members whose responsibility it is to ensure the protection of the rights, safety and well-being of human subjects involved in a trial.

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Obligations of IRBsREGULATION: 21CFR 56Purpose:

Protect the rights and welfare of research subjects both before and during their study participation

Determine:Should the study be approved (do benefits outweigh the risks)?What constitutes adequate informed consent?

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IRB Membership & Organization

• At least five members with appropriate qualifications to review the research

• At least one member whose primary area of interest is in a nonscientific area

• At least one member who is independent of the institution/trial site

• Should not consist entirely of men or women

• A list of IRB members should be maintained

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IRB Functions• Reviews protocols, consents, and ads• Reviews amendments• Provides expedited review—i.e. minor

changes to a protocol that don’t increase risk

• Provides continuing review of trials (at least annually)

• Reviews qualifications of investigators• Has the authority to suspend research• Reviews all adverse drug reactions both

serious and unexpected

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IRB Records• Copies of research proposals/protocol (and

accompanying documentation)

• Minutes of meetings

• Correspondence

• List of members

• Written operating procedures (SOPs) for IRB

• Kept for 3 years after completion of research

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IRB: Expedited Review

An IRB may use an expedited review procedure to review minor changes in previously approved research during the period (1 year) for which the approval is authorized

Expedited review may be carried out by the IRB Chairperson or by one or more experienced reviewers designated by the IRB Chairperson from among the members of the IRB

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IRB: Expedited Review Procedures

IRB’s which use expedited review must have a method of keeping all IRB members informed of research proposals which have been approved under this procedure

FDA may restrict, suspend, or terminate an IRB’s use of expedited review when necessary to protect the rights of subjects

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Module 5

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Informed Consents (IC)

IC overviewIC audit checklist

Class examples of IC showing required elements

FDA Warning Letters from ICHandout example of industry IC

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Informed Consent

REGULATION: 21CFR 50

Purpose:

Patient protection

Patient information

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Informed Consent Process

• Exchange of meaningful information• Begins with subject first learns of

the study• Ends when there is no more new

relevant information• Prior to the performance of study

procedures

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Informed Consent Content

Required ElementsAdditional Elements, as applicableInstitution, local, state requirementsLanguage understandable to subjectProvide information subject needs to

make an informed decision about participation

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Informed Consent

Required Elements of Informed Consent: 21CFR 50.25

Purpose, duration and procedures of the research

Foreseeable Risks to subject and benefits to subject or others

Alternative procedures or courses of treatment

Confidentiality of records – must note the possibility of FDA inspection or others

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Informed Consent

Required Elements of Informed Consent:

Explanation of compensation, if any, for research-related injury

Contacts for pertinent questions or reports of research related injuries

Statement of voluntary participation-No penalty or loss of benefit upon refusal to participate or withdrawal of consent

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Informed Consent

Additional Elements of Informed Consent where applicable (required by ICH):

May involve unforeseeable risks to subject (embryo/fetus)

Circumstances in which the study may be terminated without subject’s consent

Any additional costs to subject from participation

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Informed Consent

Additional Elements of Informed Consent where applicable (required by ICH ):

Consequences of early withdrawal Significant new findings during study Approximate number of subjects in

study

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Informed Consent Problems

50% of FDA inspections at clinical investigator sites identify inadequacies in the informed consent

Lack of required elementsLack of proper documentationNot obtained prior to enrollmentImproper IRB approval

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HIPAAHealth Insurance Portability and

Accountability Act (HIPAA)

-Enacted in 1996 to protect the security and confidentiality of electronic health information.

-Primarily directed at the health care industry, insurers and medical providers.

-Original deadline for privacy rule by Congress missed in 1999- finally published in Dec. 2000 , with a compliance date of April 14, 2003.

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HIPAALaw applies to “Covered Entities and

Business Associates” that use or disclose protected health information.

Requires the “de-identification” of individually identifiable health information, and disclosure of uses of protected health information (PHI).

Although no FDA regulation specifically addresses HIPAA, clinical research certainly deals with PHI.

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HIPAAClinical research now includes HIPAA

authorization –either in the IC directly or in a separate document, depending on institutional or IRB policy.

- must specifically give permission to use PHI for the purpose of research

- have the right to withdraw permission to use PHI

- expiration date of the authorization- suspension of access rights to study records

until study is completed.

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Issues Noted in Recent Warning Letters and FDA

483’sInformed ConsentStudy procedures performed prior to

signing and dating the ICFailure to obtain appropriate IC (e.g., no

signature, incorrect signature/date, not in a language understandable to the subject)

Not current/correct version of ICElements missing from the IC

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Documents

1 Module 4. 2 History of Good Clinical Practice Regulations Barbara Novak