Module 5 Presentations

Module 5: Regulatory Control of Clinical Operations

Date: 17 th – 19 th July 2024

Module: 5 of the TOPRA MSc Data Management and Digitalisation in Regulatory Affairs

Module Leaders: Eva Kopecna & Pierre Omnes

©The Organisation for Professionals in Regulatory Affairs 2023 Presentations are supplied to delegates for their personal reference and are the copyright of the speaker and The Organisation for Professionals in Regulatory Affairs. The presentations must not be copied, stored in a retrieval system or transmitted in any form without prior permission from TOPRA. Agreement must be reached with TOPRA before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 5: Regulatory Control of Clinical Operations 17 th – 19 th July 2024 Location: TOPRA Office, 6 th Floor, Harbour Exchange, London, E14 9GE and Online Module Leader(s) : Eva Kopecna and Pierre Omnes Date: Wednesday 17 th July 2024

Time

Activity

Speaker

13.00 – 13.15

Welcome & Introduction To Module 5

Chairperson Eva Kopecna Acino International Eva Kopecna Acino International

13.15 – 14.15

Lecture 1: GCP - The platform for clinical research. Objective History

Quality & Compliance Audits and Inspections

14.15 – 15.15

Lecture 2: GCP Inspections – Agency Experience

Rachel Mead MHRA

15.15 – 15.45

Refreshment break

15.45 – 17.00

Lecture 3: Progression of clinical trials in relation to the toxicology programme Purpose of toxicology studies in support clinical development Requirements for different stages of clinical development Requirements for different types of medical products (e.g. chronic, acute, delivery system)

Simon Craige EdGe Toxicology Consulting

Module 5: Regulatory Control of Clinical Operations 17 th – 19 th July 2024 Date: Thursday 18 th July 2024

Time

Activity

Speaker

08.30 – 08.45

Introduction

Chairperson: Eva Kopecna Acino International

08.45 – 09.30

Lecture 4: Pharmacovigilance & adverse event reporting in clinical trials Adverse Event Reporting - -General requirements and definitions Safety reporting in the EU Pharmacovigilance. Future Proposals Lecture 5: Regulatory requirements for clinical trials - EU Requirement for and Format of Medical Device Clinical Trials Regulatory Requirements under EU-MDR and MDCG guidance. Role of Standards in Device Clinical Trials Particular considerations for UK-NHS and EU sites. Lecture 5: Regulatory requirements for clinical trials – EU Cont’d Current Legislation Requirements The Clinical Trial Regulation and its Impact CTA applications / Medical Devices Ethics Committee Submissions Reporting of clinical trials. Industry experience Lecture 6: Regulatory requirements for clinical trials of medical devices Refreshment Break

Beatrice Panico Scendea

09.30 – 10.30

Neil R Armstong MeddiQuest Europe, North America and UK

Mariona Casals Cases

10.30 – 11.00

11.00 – 12.00

Pierre Omnes Transperfect Life Sciences

12.00 – 13.00

Deepa Subramaniyan Roche (remote)

13.00 – 14.00

Lunch

14.00 – 14.45

Lecture 7: The successful IMPD Contents of the IMPD Pitfalls Updates

Graham Bell Icon

14.45 – 15.30

Lecture 8: GMP, authorisation and importation requirements, clinical trial

Pierre Omnes Transperfect Life Sciences

supplies management 2003/94/EC GMP Directive

15.30 – 16.00

Refreshment Break

16.00 – 16.05

Introduction to Case Study 1

Pierre Omnes Transperfect Life Sciences

16.05 – 17.00

Manufacturing and importation requirements including the role of the QP Regulatory framework under which clinical supplies are managed Planning of a clinical supplies programme Issues relating to manufacture, packaging and distribution of clinical supplies Case Study 1: Initiation of a Clinical Trial Feedback from Case Study 1

17.00 – 17.30

Module 5: Regulatory Control of Clinical Operations 17 th – 19 th July 2024 Date: Friday 19 th July 2024

Time

Activity

Speaker

08.45 – 08.50

Introduction

Chairperson Eva Kopecna Acino International Mohamed Oubihi Yakumed (remote)

08.50 – 09.50

Lecture 9: Regulatory requirements for clinical trials - Japan Legislation requirements Clinical Trial Notifications

Japanese Regulatory Authorities Consultations with the Authorities Clinical Trials in Japan & GCP

09.50 – 10.30

Refreshment Break

10.30 – 11.30

Lecture 10: Legal aspects of clinical trials Product Information and Informed Consent Data Protection. Enforcement and Sanctions Liability. Clinical Study Contracts Lecture 11: Regulatory requirements for clinical trials – US and Canada Legislation requirements CTA and IND applications & maintenance Ethics Committee GCP & Enforcement

Adela Williams Arnold & Porter (remote)

11.30 – 12.30

Sarah Roberts Icon (remote)

12.30 – 13.30

Lunch

13.30 – 13.45

Introduction to Case study 2: GCP and Clinical Development Programme

Eva Kopecna Acino International

13.45 – 14.45

Case Study 2: GCP and Clinical Development Programme

14.45 – 15.15

Feedback from Case Study 2

05/07/2024

Good Clinical Practice - The platform for clinical research.

Dr. Eva Kopecna, MSc., Ph.D. Head of Global Regulatory, Pharmacovigilance and Medical Affairs Acino International

The Organisation for Professionals in Regulatory Affairs The Organisation for

Professionals in Regulatory Affairs

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Disclaimer

This presentation has been prepared based on own experience of the author and represents author’s own opinion on the subject.

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Learning Outcomes

• Understand the purpose of development of Good Clinical Practice (GCP)

• Objectives & Principles of GCP

• The techniques for monitoring and assurance of GCP

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In this presentation we will cover

• History, objectives and basic principles of GCP • Quality & Compliance & Audits & Inspections • Fraud & Misconduct in clinical research • Case studies & Examples

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History of research: successes, failures and misuses

• In most of the cases the misuses happened on vulnerable populations

• The medical research where these populations were misused was conducted by physicians.

Albert Schweitzer (1875–1965)

“Ethics, too, are nothing but reverence for life. That is what gives me the fundamental principle of morality, namely, that good consists in maintaining, promoting, and enhancing life, and that destroying, injuring, and limiting life are evil.”

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Historically abused populations

• Mentally ill • Development disabilities • Children

• Orphan children • Active military • Prisoners • Immigrants • Minority populations • Pregnant women • Uneducated or minimally educated

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Thalidomide (1)

• In the 1950s, a German company, Chemie Grünenthal, developed thalidomide, which was marketed in Europe as sedative or tranquiliser (trouble sleeping, anxiety), and was seen as a highly effective treatment for pregnant women with morning sickness. • The drug enjoyed such widespread success that in some European countries it became almost as popular as aspirin.

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Thalidomide tragedy (1956-1961)

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Thalidomide (2)

More than 10,000 children in 46 countries were born with severe deformities, including malformed limbs (phocomelia), eye and ear defects or malformed internal organs such as unsegmented small or large intestines.

Dr. Frances Oldham Kelsey

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Thalidomide tragedy (1956-1961)

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Thalidomide (3)

Why?

• The drug was not tested for use in pregnancy in animal models • In many countries it was placed on the market as non-prescription drug

• The original indication – sedative or tranquiliser • Off-label use – morning sickness during pregnancy • Insufficient pharmacovigilance system

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Thalidomide (4)

Revival • Pharmion ltd. (Celgene) submitted new application 22.1.2007 • Centralised procedure • Orphan indication • Indication - Multiple myeloma • Approved 16.4.2008

Manymore indicationsapproved under“orphan status“

Graft versus host disease

Crohn`s disease

Erythema Nodosum Leprosum

Kaposi sarcoma

Severe recurrent aphthous stomatitis

Myelodysplastic syndrome

Primary brain malignancies

Telangiectasia

HIV-associated wasting syndrome

Mycobacterial infection

Recurrent aphthous ulcers

Hematopoietic stem cell transplantation

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Thalidomide tragedy (1956-1961)

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Infamous research studies

• Tuskegee Syphilis Study (1932-1972)

• Harvard Radiation test (1946-1956)

• Willowbrook study (1963-1966)

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Tuskegee Syphilis Study 1932-1972 (1)

• The purpose of the study was to observe the natural progress of the disease (Alabama, USA). • 602 rural illiterate black men, 399 of them had previously contracted syphilis.

• Given free medical care, meals, and free burial insurance.

• The study subjects did not give informed consent and were not informed of their diagnosis.

• Were told they had "bad blood“ , they were never told they had syphilis.

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Tuskegee Syphilis Study (1932-1972)

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Tuskegee Syphilis Study 1932-1972 (2)

• 28 died due to primary disease • 100 died due to complications • 40 wives infected • 19 children with inherited syphilis

The study finished when in 1972 it was brought to public attention by newspapers.

What was wrong in this study?

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Tuskegee Syphilis Study (1932-1972)

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Harvard Radiation test (1946-1956)

• Experiments performed on 19 mentally disabled boys who were fed radioactive milk to study the body's ability to digest minerals (radioactive forms of iron and calcium). • By scientists from Harvard University and the Massachusetts Institute of Technology.

• Neither boys nor their parents were informed. • They did not give informed consent .

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Harvard Radiation test (1946-1956)

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The Willowbrook study (1963-1966)

• The studies carried out at the Willowbrook State School (mentally handicapped children). • Gain understanding of the natural history of infectious hepatitis and test the effectiveness of the agent for inoculating against hepatitis. • Parents were provided with information describing drug administration as vaccination.

• Around 700 children were deliberated infected by hepatitis.

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The Willowbrook study (1963-1966)

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Additional cases (1)

• In Japan, Unit 371 experimented with prisoner vivisection, dismemberment and induced epidemics on a very large scale from the late 1920s onward. • 1940 in the United States, four hundred prisoners in Chicago were infected with malaria to study the effects of new and experimental drugs for the disease. • Beginning in 1942, mustard gas experiments were conducted on 4,000 United States servicemen in order to study the effects on the human nervous system. These tests were concluded in 1945.

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Additional cases (2)

• World War II - Nazi doctors experiments on people in concentration camps.

• 1951 Dr. Albert Kligman undertook dermatological experiments on prisoners at Holmesburg Prison without their consent. • Russia – „komnata“ (development of the poisoning substance C2) - the effect of different poisons tested on the prisoners in Gulag.

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Development of GCP Clinical trial (1)

• The first mention of a clinical trial appears to be in the bible in the Book of Daniel, which contains a reference to an “accidental” clinical study conducted in the reign of King Nebuchadnezzar II (605–562 BC). • He decided that his “ study subjects ” should be fed a strict diet of meat and wine as he believed this would make them a stronger race.

• Four of his subjects of royal blood, including Daniel, refused this diet and instead ate pulses such as wheat and lentils and drank only water. • After ten days the king saw that those consuming pulses and water were fitter than those on the meat and wine diet.

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Development of GCP Clinical trial (2)

Fifteen hundred years later, the Persian philosopher Avicenna (Ibn Sina)

980–1037 AD wrote about testing of medicines in his multi-volume

“Canon of Medicine” which was a standard medical text in Europe and the

Islamic world until the 18 th century. The Canon of Medicine discussed how to

effectively test new medicines in seven points; for example….

• The effect of the drug must be seen to occur constantly or in many cases, for if this did not happen, it was an accidental effect. • The experimentation must be done with the human body, for testing a drug on a lion or a horse might not prove anything about its effect on man.

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Development of GCP Study design

Cider

Vinegar

Oranges and lemons

12 men with scurvy

Extract with suplhuric acid

• Experiment run by James Lind while serving in the British Navy in 1747 • Those fed citrus fruits experienced a remarkable recovery.

Seawater

Mixture of onion, mustard, horseradish

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Development of GCP Informed consent (1)

The idea of informed consent was firstly articulated in 12 th

century by Jewish scholar, physician and philosopher

Moses Maimonides (Rabbi Moshe Ben-Maimon or

Rambam), b1135-d1204, the most influential Jewish

thinker of the Middle Ages, in his work code of Jewish ora

l law, called the Mishneh Torah .

It was more than 700 years later, in the second half of the 20 th century, before any real actions to increase the protection of people who take part in clinical research were taken.

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Development of GCP Informed consent (2)

First documented written informed consent from 1900 (Study with Yellow fever run by Dr. Walter Reed in Cuba)

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Further development Placebo

1863 Dr. Austin Flint - the first placebo experiment

• 13 patients with rheumatism treated with herbal tonic rather than with medicine known to be effective.

• Flint’s experiment did not compare the two against each other in the same trial but this was a significant step forward; contrasting the consequences of an active treatment with the natural course of an untreated disease.

• For the first time the terms “placebo” or “ placeboic remedy ” was used in a clinical trial.

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Development of GCP Statistics

1925 Ronald Aylmer Fischer (1890–1962)

• English statistician, evolutionary biologist, mathematician

• “Statistical Methods for Research Workers” , published in 1925, influenced the practical use of statistics in many fields of study and is one of the 20th century's most influential books • Many important contributions to statistics, including the analysis of variance ( ANOVA ).

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Development of GCP Randomisation

• 1948, D’Arcy Hart & Marc Daniels & Austin Bradford Hill designed a trial to evaluate the effects of streptomycin in tuberculosis

• Patients were assigned to groups using random sampling numbers

• Coded envelopes so that the allocation of treatment was not known by either the patient or the investigators

The first recognised “properly conducted randomised trial”.

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”Ancestors” of GCP

1947 Nuremberg Code 1964 Declaration of Helsinki 1967 Drug Law, Germany 1977 Title 21 Code of Federal Regulations (21 CRF), USA 1974 The IRB National Research Act, USA 1979 The Belmont report, USA 1979 Regulation of Clinical Trials in Japan 1988 Principles of GCP adopted in France 1989 Guidelines on Clinical Trials of Drugs, Nordic Region 1990 Introduction of GCP in Europe 1991 EU Directive 91/507/EEC - Requirements for GCP 1996 ICH GCP - Unified standard for EU, USA and Japan

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Nuremberg Code 1947 (1)

The code was developed in response to the Nuremberg Trials of Nazi doctors

who performed unethical experimentation during World War II and was the

first major international document to provide guidelines on research ethics.

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Nuremberg Code 1947 (2) Principles

1. Participation must be voluntary, and subjects should have the capacity to give consent. Further, subjects should be fully informed of the purposes, nature, and duration of the experiment. 2. The research should yield results that are useful to society and that cannot be obtained in any other way. 3. The research should have a sound footing in animal research and be based on the natural history of the problem under study. 4. Steps should be taken in the research to avoid unnecessary physical or psychological harm to the subjects. 5. Research should not be conducted if there is reason to believe that death or disability will occur in the subjects. 6. The risk involved in the research should be proportional to the benefits to be obtained. 7. Proper plans should be made and facilities provided to protect the subject from harm. 8. Research should be conducted by highly qualified scientists only. 9. The subject should have the freedom to withdraw at any time if he or she has reached the conclusion that continuing in the experiment is not possible. 10. The researcher must be prepared to discontinue the experiment if it becomes evident that continuing will be harmful to the subject.

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Declaration of Helsinki (1)

WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects It is not a legally binding instrument under international law.

1964, Helsinki

•

1975, Tokyo

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1983, Venice

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1989, Hong Kong

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1996, Somerset West

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2000, Edinburgh

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2008, Seoul

•

• 2013, Fortaleza (valid version)

"Even though the Declaration of Helsinki is the responsibility of the World Medical Association, the document should be considered the property of all humanity”.

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Declaration of Helsinki (2)

• Clinical trials must conform to accepted scientific principles and should be based on laboratory and animal experimentation

• Independent review of the Protocol

• Clinical trials conducted only by scientifically qualified persons

• Benefit to subject should exceed the risk

• Freely given Informed Consent required

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Harmonization of GCP

International Conference (now Council ) on Harmonization ( ICH ) of Technical Requirements for Registration of Pharmaceuticals for Human Use, 1990 Partners: pharmaceutical industry + regulatory authorities Aims: • Agreement on interpreting and applying technical guidelines and requirements for product registration

• Standardize approaches and avoid duplication/repetition of clinical trials

• Assure comparable data and safeguard to protect public health

• Provide a unified standard for the European Union, Japan and United States of America to facilitate the mutual acceptance of the clinical data by regulatory authorities. • ICH GCP guideline was developed with consideration of the current good clinical practices in the EU, Japan, United States of America, as well those of Australia, Canada, the Nordic Countries and the World Health Organization.

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Further legislation development

• EudraLex - Volume 10 Clinical trials guidelines • European Directive 2001/20/EC on Clinical Trials • European Directive 2005/28/EC on GCP • European Directive 2003/94/EC for investigational medicinal products (IMP) for human use • Good Pharmacovigilance Practices • Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC • Implementing Regulation (EU) 2017/556 (GCP) • Delegated Regulation (EU) 2017/1569 (GMP) • EU Pharmaceutical Legislation Reform 2023

and many more…..

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Case study on developmentof legislation.

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'Elephant Man' clinical trial - TGN1412(1)

• In March 2006 eight healthy volunteers were selected to take part the Phase 1 trial of TGN1412, organised by the US company Parexel • Humanised monoclonal antibody therapy manufactured by German firm TeGenero • Originally intended for the treatment of B cell chronic lymphotic leukemia (B-CLL) and rheumatoid arthritis • The men aged 19 to 34 were each paid £2,000 to be given the drug in a private unit at Northwick Park Hospital in North-West London • The trial was a double-blind, randomized, placebo-controlled study, with two of the eight study subjects receiving a placebo • The drug was given by intravenous infusion, starting at 8am, with an interval of around 10 minutes between the study subjects , and each infusion lasting from 3 to 6 minutes

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TGN1412

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'Elephant Man' clinical trial - TGN1412(2)

• Roughly 5 minutes after the last participant had received his dose, the participant who had received the first dose complained of headache, and soon afterwards fever and pain. • Unpredicted biological action of the drug in humans The trial resulted in hospitalization of all six volunteers administered the drug, at least four of whom suffered multiple organ dysfunction.

All of the men were reported to have experienced severe cytokine release syndrome, resulting in angioedema, swelling of skin and mucous membranes.

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TGN1412

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'Elephant Man' clinical trial - TGN1412(3)

• Criticism has been raised that six participants were given the drug in such a short time, which is against the recommendations of standard literature. • MHRA had approved a two-hour protocol, the drug was administered to all participants within just twenty minutes. • The drug was administered ten times faster than it had been in monkeys • Critics of animal testing have cited …even in species closely related to humans, are not necessarily predictive of human responses.

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'Elephant Man' clinical trial - TGN1412(4)

• The MHRA’s paved the way for a further independent report that made 22 recommendations to improve the safety of Phase 1 trials — including that volunteers should not be dosed all in the same day. • New guideline for first-in-man clinical trials published 2007 .

AND

• In 2015 it was revealed TGN1412 was making an astonishing comeback as a potential treatment for arthritis. • The rights were bought by Russian company TheraMAB in 2006 and renamed it TAB08. • Trials were once again being conducted on humans - but at just 5% of the dose used in the Elephant Man tests .

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Clinical trial - TAB08

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TAB08

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France clinical trial - BIA 10-2474 (1)

• BIA 10-2474 is an experimental fatty acid amide hydrolase inhibitor developed by the Portuguese pharmaceutical company BIAL.

• It interacts with the human endocannabinoid system.

• The drug was in development for the treatment of a range of different medical conditions from anxiety disorder to Parkinson’s disease, also for the treatment of chronic pain of multiple sclerosis, cancer, or treatment of obesity. • The study was approved by the French regulatory authority on 26 June 2015, and by the Brest regional ethics committee on 3 July 2015.

Kerbrat; et al. (3 November 2016). "Acute Neurologic Disorder from an Inhibitor of Fatty Acid Amide Hydrolase". New England Journal of Medicine. 375 (18): 1717–1725. doi:10.1056/NEJMoa1604221. PMID 27806235.

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France clinical trial - BIA 10-2474 (2)

• “Phase I double-blind, randomised, placebo-controlled, combined single and multiple ascending dose study including food interaction, to investigate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of BIA 10-2474, in healthy volunteers". • The trial commenced on 9 July 2015 at a single centre, and commenced recruitment of 128 healthy volunteers, both men and women aged 18 to 55, out of which 90 people were to receive the investigational drug, and the remainder a placebo. • Participants of the study were to receive €1,900 and, in turn, asked to stay at Biotrial's facility for two weeks during which time they would take the drug for ten days and undergo tests.

According to the protocol, dose levels and numbers of groups could be increased, or were not yet defined, and would depend on what was observed with initial dosing, (an approach known as adaptive trial design).

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France clinical trial - BIA 10-2474 (3)

• For the single dose part of the study, the protocol describes eight groups of eight volunteers who were to receive single doses of BIA 10-2474 at 0.25, 1.25, 2.5, 5.0, 10, 20, 40 and 100 mg, with the possibility of additional groups to be added if no maximum tolerated dose was reached

• 6.1.2016 - 5 th cohort - 6 men received 50 mg dose/day

• 10.1.2016 - the first subject became ill on the evening of the 5th day of dosing and was hospitalized with the symptoms similar to stroke

• 11.1.2016, 8.00 the study team dispense the drug to additional 7 men

• 11.1.2016 in the morning the condition of the first subject deteriorated and he went to coma

• 11.1.2016 in the afternoon the study is suspended

• 17.1.2016 the first subject was declared dead

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France clinical trial - BIA 10-2474 (4)

• Four subjects in the same cohort were also hospitalized with the similar complaints. • The opinion of the treating neurologist was that in 3 of the 4 men who had toxicity, the condition is such that an irreversible handicap is likely to occur despite of the institution of best possible treatment. • All these patients had hemorrhagic and necrotic lesions as seen on brain magnetic resonance imaging (MRI).

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France clinical trial - BIA 10-2474 (5)

Biotrial failed three major issues

1. The study should have been stopped when the first subject was hospitalized so the drug would not have been given to five others; 2. The incident should have been reported immediately, namely January 10, not four days later; 3. All other subjects should have been notified right away asking them if they would like to continue in the study.

The Royal Statistical Society was particularly critical, stating that it had "clear statistical reservations about the trial's study design", and that the protocol lacked features such as a risk assessment.

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France clinical trial - BIA 10-2474 (6)

The final report from the ANSM Committee appointed to investigate the matter concluded in April 2016 that:

• The most likely hypothesis to date is that of toxicity specific to the molecule via its binding to other brain cell structures, facilitated by its low specificity for its target enzyme;

• The use of multiple doses a lot higher than those leading (at least in humans) to complete and lasting FAAH inhibition, and; its probable gradual accumulation in the brain, undoubtedly related to the specific pharmacokinetic features of BIA 10 ‐ 2474.

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France clinical trial - BIA 10-2474 (7)

• Trial tested doses up to 80 times more (100 mg BIA 10-2474) than should have been required. • Although the protocol summary reports no animal deaths during the studies, the ANSM expert committee reported that in fact several monkeys died or had to be euthanised during the dose escalation studies and that an explanation from Bial was pending. • Also, two animals had to be euthanised in the 13-week dog study due to lung lesions - both from the top dose group.

Biotrial stated its position that "The trial was conducted in full compliance with the international regulations and Biotrial’s procedures, in particular the emergency procedures".

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EU Legislative Framework – Directive 2011/20

Legislation

Clinical trials

Ethics

Eudralex– The Rules Governing Medicinal Products in EU Volume 1, 2, 3, 4, 9,10

Declaration of Helsinki ICMR Ethical guidelines for biomedical research

Directive 2003/94/EC on GMP for clinical trials

Directive 2001/20/EC on clinical trials

ICH

Regulation 726/2004/EC on centralised procedures

Directive 2005/28/EC on GCP

Ethics committes

GxP

Directive 2001/83/EC on human medicinal products

National legislation

GDPR

International, national, professional codex/guidelines

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EU Legislative Framework – Regulation 536/2014

Legislation

Clinical trials

Ethics

Eudralex– The Rules Governing Medicinal Products in EU Volume 1, 2, 3, 4, 9,10

Delegated Regulation 2017/1569 on GMP for investigational medicinal products for human use Implementing Regulation 2017/556 on detailed arrangements for the good clinical practice

Declaration of Helsinki ICMR Ethical guidelines for biomedical research

Regulation No 536/2014 on clinical trials on medicinal

products for human use

Regulation 726/2004/EC on centralised procedures

ICH

inspection procedures

Ethics committes

GxP

Implementing Regulation 2022/20 setting up the rules and procedures for the cooperation of the Member States in safety assessment of clinical trials

Directive 2001/83/EC on human medicinal products

National legislation

GDPR

EU Pharmaceutical Legislation Reform

International, national, professional codex/guidelines

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ICH GCP Guideline E6

• Adopted 1 st May 1996, applicable from January 1997.

• ”An international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki , and that the clinical trial data are credible”. Basic reference document for all clinical trials today • Guideline for good clinical practice E6(R2) – came into effect 14 June 2017 • Revision E6(3) under preparation, should come into effect 2025. https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Guideline_GCP_Video_2023_0601.mp4

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ICH GCP Guideline E6 – Revision R2

Why: Modernized to keep pace with the scale and complexity of clinical trials and to ensure appropriate use of technology.

• Detailed approach to best practices for stakeholders to follow during their involvement in the clinical trial process • Discussion of quality management and risk-based monitoring • New and updated definitions • Additional investigator and sponsor responsibilities • Updated standards for electronic records and essential documents • Addresses the life cycle of a clinical trial within a drug development programme and serves as a roadmap to oversight

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ICH GCP Guideline E6 (2)

The document is divided in eight chapters which explain and describe • 13 “golden” rules of GCP • The roles and obligations of main persons and bodies involved in clinical research (e.g. sponsor, clinical investigator, ethics committees, CRO) and Data monitoring committees in clinical trials with respect to GCP • Requirements on clinical trial management • Scope of essential clinical trial documentation • Requirements on data handling and recording, monitoring, management and reporting.

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Main GCP Chapters

1. Glossary 2. The Principles of ICH GCP 3. The Institutional Review Board / Independent Ethics Committee (IRB/IEC) 4. Investigator 5. Sponsor 6. Clinical Trial Protocol and Protocol Amendment(s) 7. Investigator’s Brochure 8. Essential Documents for the Conduct of a Clinical Trial

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In this presentation we will cover

• History, objectives and basic principles of GCP • Quality & Compliance & Audits & Inspections • Fraud & Misconduct in clinical research • Case studies & Examples

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Quality Assurance and Quality Control (1) (ICH GCP §5.1)

• Sponsor should implement quality assurance (QA) and quality control (QC) control systems (QMS = Quality management system) with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded) and reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).

• Direct access to documents required

• QC at each stage of data handling

All agreements in writing

•

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Quality Assurance and Quality Control (2) (ICH GCP §5.1)

QUALITY ASSURANCE

QUALITY CONTROL

The operational techniques and activities undertaken within the quality assurance system to verify that the requirements for quality of the trial-related activities have been fulfilled. ICH GCP §1.47

All those planned and systematic actions that are established to ensure that the trial is performed and the data generated (recorded) and reported in compliance with GCP and the applicable regulatory requirement(s). ICH GCP §1.46

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Monitoring (ICH GCP §5.18)

Verifies that:

• The rights and well-being of human subjects are protected

• The reported trial data are accurate, complete, and verifiable from source documents. • The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s)

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Audit (ICH GCP § 5.19)

A systematic and independent examination of trial related activities and documents to determine whether evaluated trial activities were conducted and the data were recorded, analyzed and accurately reported according to the protocol, sponsor’s standards operating procedures, GCP and the applicable regulatory requirements.”

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Auditing versus Monitoring

• Monitoring

Routine activity

•

• Carried-out by a member of the clinical team

• Equivalent to QUALITY CONTROL step

• Auditing

• Only done for a sample of sites / studies

• Auditors independent of the clinical team

• Part of sponsor’s QUALITY ASSURANCE activities

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Is a Clinical QMS ‘just’ about GCP (1)?

• GMP (Good Manufacturing Practice) Aspects: Quality & Release of Investigational Medical Product • GDP (Good Distribution Practice) Aspects: Shipment & Storage of Investigational medicinal product • GPV (Good Pharmacovigilance Practice) Aspects: Link to Safety Database of Product / Signal Detection • Regulatory: Interactions with Ethics Committees / Competent Authorities for trial submission & Dossiers • Procurement Aspects: Vendor Selection / EHS Aspects / Code of Conduct • Computerized Systems: E.g. for Statistical Analysis (validation requirements!) • QA: TQA (technical Quality Agreements), Audits, Deviations & CAPAs (Corrective and Preventive Measures), Inspections • Legal Aspects: Contracts & Data Protection requirements

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Is a Clinical QMS ‘just’ about GCP (2)?

• Running Clinical Trials has multiple intersection with other GxPs • Must be integrated into Sponsor’s organizational requirements • Must be integrated into Sponsor’s general Pharmaceutical Quality System (ICH Q10)

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Who and what can be audited/inspected? When?

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Data management/ Statistics

Files / Archives

Ethics committees

Medical Writing

Sponsor

Project Team

Pharmacovigilance

Investigator Site

Central Lab

IVRS

CRO

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Example of GCP/GCLP audit outcome – part of sponsor`s QMS

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In this presentation we will cover

• History, objectives and basic principles of GCP • Quality & Compliance & Audits & Inspections • Fraud & Misconduct in clinical research • Case studies & Examples

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Fraud & Misconduct in clinical research

• Fraud can be fabrication, falsification, and plagiarism of data or even deception in conduct. Fabricating data involves creating a new record of data or results. Most commonly fabricated documents are Informed Consent Forms and Patient Diaries. • Falsifying data means altering the existing records. It is the deliberate distortion or omission of undesired data or results. • Deception in clinical research is the deliberate concealment of a conflict of interest or inclusion of deliberately misleading statements in research proposals or other documents.

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Fraud & Misconduct in clinical research

• FDA estimates 4-5%

• A lot of famous cases

Examples..

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CRO GVK Biosciences, Indie (2015)

• 2014 French Competent Authority (ANMS) performed inspection of CRO GVK Biosciences in India. • The inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines, which appeared to have taken place over a period of at least five years. • GVK Biosciences: European Medicines Agency confirms recommendation to suspend 700 licences over flawed studies.

Approved name

GVK Biosciences

Reference number

EMEA/H/A-31/1408

Article 31 referrals This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Type

Status

European Commission final decision

Opinion date

21/05/2015 16/07/2015

EC decisiondate

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https://www.ema.europa.eu/medicines/human/referrals/gvk-biosciences

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Semler Research Centre, Indie (2016)

• 20.6.2016 FDA informs about the outcome of GCP inspection that identified several issues at Semler’s bioanalytical site, including the substitution and manipulation of subjects’ clinical samples. • On 21 July 2016, the European Medicines Agency recommended suspending a number of nationally approved medicines for which bioequivalence studies were conducted at Semler Research Centre Private Ltd, Bangalore, India.

Approved name

Semler

Reference number

EMEA/H/A-31/1443

Article 31 referrals This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Type

Status

European Commission final decision

Opinion date

21/07/2016

EC decisiondate

22/09/2016

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https://www.ema.europa.eu/en/medicines/human/referrals/semler

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Synchron Research Services, India (2019)

• 14.1.2022 FDA informs about the outcome of GCP inspection that identified several issues at Synchron Research Services, indicating that the company was responsible for creation of false data. • Similar concerns have been previously raised in two EU inspections (FR&NL in 2005, and DE in 2009). Data from these studies have been rejected, but these cases were treated as isolated non-compliance.

Approved name

Semler

Reference number

EMEA/H/A-31/1515

Article 31 referrals This type of referral is triggered when the interest of the Union is involved, following concerns relating to the quality, safety or efficacy of a medicine or a class of medicines.

Type

Status

CHMP opinion

Opinion date

19/05/2022

EC decisiondate

28/11/2022

https://www.ema.europa.eu/en/medicines/human/referrals/sync hron#key-facts-section

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Synchron Research Services, India (2019)

https://www.ema.europa.eu/en/medicines/human/referrals/sync hron#key-facts-section

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Ketek case - study 3014 (1)

• Published in New England Journal of Medicine, April 19, 2007 • 2000 - Ketek New Drug application submitted to FDA • 2001 -”Safety concerns“ raised by reviewers

• Federal advisory committee asked applicant to obtain additional safety data by conducting a study involving patients who were likely to receive Ketek if the drug were approved • Recruited more than 1800 physicians to conduct the study (many of them new to clinical investigation), and paid them as much as $400 per patient enrolled, • More than 24,000 subjects were enrolled. • The study was completed in 5 months and purported to show that Ketek was as safe as the other treatment.

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Ketek case - study 3014 (2)

• 2002 - The company learns of fraud in study

• 2002 - The study is submitted to FDA

• June 2002 - A routine FDA inspection of the practices of the physician who enrolled the most patients - more than 400 - uncovered fraud, including complete fabrication of patient enrollment. • The physician was sentenced to 57 months in federal prison for her actions, fined $557,251 , plus $925,774 compensation of damages to sponsor. • Inspections of nine other sites enrolling high numbers of patients revealed serious violations of trial conduct, raising substantial concerns about the overall integrity of the study.

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Ketek case - study 3014 (3)

• 4 of the 10 inspected sites were referred for criminal investigation

• FDA investigators declare study 3014 is unreliable .

but

• On April 1, 2004 Ketek is approved with all proposed indications.

2004 – Ketek launched

•

• February 2005 (7 months after the drug was introduced to the U.S.

market), the first death from Ketek - associated liver failure - in a patient treated for a mild respiratory tract infection was reported to the FDA

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Ketek case - study 3014 (4)

Till June 2006

• 23 cases of acute severe liver injury and 12 cases of acute liver failure , 4 of them fatal , had been linked to Ketek • By the end of 2006, Ketek had been implicated in 53 cases of hepatotoxic effects February 12, 2007 • The withdrawal of approval for two indications, acute bacterial sinusitis and acute exacerbation of chronic bronchitis, for which Ketek’s efficacy had never been demonstrated

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We covered

• History of Good Clinical Practices and development of legislation • Ethical principals of clinical research • ICH GCP • Quality and audits in clinical trials

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Recommended references (1)

• Stokes A. From Bible to EU Regulation: A brief history of the clinical trial. Regulatory Rapporteur – Vol 11, No 7/8, July/August 2014 • A Tibi, E Savage-Smith. ‘Ibn Sina’s Canon of Medicine: 11th century rules for assessing the effects of drugs’, Journal of the Royal Society of Medicine, 2009;102(2):78–80. • Fairchild AL, Bayer R. Uses and Abuses of Tuskegee. Science 7, May 1999; 284 (5416):919–921. • Lerner BH. Subjects or Objects? Prisoners and Human Experimentation. New Engl J Med. 2007; 1806–1807. • Weyers W. The Abuse of Man: An Illustrated History of Dubious Medical Experimentation. New York. Andor Scribendi, 2003. ISBN 1-893357-21-X. • Maimonides/Rambam (1135–1204). http://www.jewishvirtuallibrary.org/jsource/biography/Maimonides.html • Kim JH, Scialli AR. Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease. http://toxsci.oxfordjournals.org/content/122/1/1.full

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Recommended references (2)

• WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. https://www.wma.net/policies-post/wma-declaration-of helsinki-ethical-principles-for-medical-research-involving-human-subjects/ • Guideline for good clinical practice E6(R2). EMA/CHMP/ICH/135/1995. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf • https://www.ema.europa.eu/en/documents/scientific-guideline/draft-ich-e6-r3 guideline-good-clinical-practice-gcp-step-2b_en.pdf • https://database.ich.org/sites/default/files/ICH_E6%28R3%29_Guideline_GCP _Video_2023_0601.mp4 • Reflection paper on ethical and GCP aspects of clinical trials of medicinal products for human use conducted outside of the EU/EEA and submitted in marketing authorisation applications to the EU Regulatory Authorities. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_pr ocedural_guideline/2012/04/WC500125437.pdf • EudraLex - Volume 10 Clinical trials guidelines. http://ec.europa.eu/health/documents/eudralex/vol-10/index_en.htm

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