Ethics of drug research - Semmelweis

Kerpel-Fronius S. 1

Ethics of drug research

History, Declaration of Helsinki.

Risks, benefits and burden of study participation.

Ethical review process.

Safety and human dignity of research subjects

Informed consent.

Sándor Kerpel-Fronius, M.D., D.Sc.

Semmelweis University

Department of Pharmacology and Pharmacotherapy

Budapest, Hungary

Email: [email protected]

KERPEL-FRONIUS S. 2

Patient, physician and industry

An uneasy ethical relationship

Differences in ethical opinions

KERPEL-FRONIUS S. 3

Society

Healthy population

Sick persons

Health care

Health insurance Health care

specialists

Opposing

ethical

values

The ethical values of the different groups are influenced by

opposing financial and social interests

Bridging the gaps between the different ethical values is of

outmost social interest

KERPEL-FRONIUS S. 4

Claude Bernard (1813-1878)

Study of Experimental Medicine (1927)

Session at the Vivisection Laboratory, 1889 by Léon Augustin L'hermitte

Claude Bernard postulated that according to medical ethics

no experiemnts can be performed in humans which can

couse any harm even when the results could provide great

benefit for science or for others.

KERPEL-FRONIUS S: ICH-GCP09/eload09 5

Porosz humán vizsgálati rendelet, 1900


Reichsrichtlinien zur Forschung an

Menschen (1931)

Reichsrundschreiben des Reichsminsters des Inneren, 28 Februar, 1931;

Reichsgesundheitsblatt 6(55) 174f

1. (1-3) The definition of difference between clinical trials and human experiments

2. The therapeutic investigational plan must be in line with medical knowledge. If possible it should be based on the results of animal experiements. Finally the risks should be in acceptable relation to the expected benefits

4. The enclosed subjects must provide informed consent.

5. The enclosure of patients below 18 years of age must be done with increased care

6. It is unethical to make advantage of the social vulnerability of patients

KERPEL-FRONIUS S. 7

Reichsrichtlinien zur Forschung an

Menschen (1931)

Reichsrundschreiben des Reichsminsters des Inneren, 28 Februar, 1931;

Reichsgesundheitsblatt 6(55) 174f

8. Human studies can be done only by the chief physician or his/her authorised medical coworker. The entire responsibility is carried by the chief physician.

The investigation must be adequately documented describing the goal and performance of the study, as well as the information provided together with the informed consent given by the patient megadását

KERPEL-FRONIUS S. 8

Main medical experts of the

Nurenberg trial of physicians

Werner Leibbrand

1896-1974

A. C. Ivy 1893-1978

KERPEL-FRONIUS S. 9

Summary of the principles of the

Nurenberg Code

Three basic principles laid down by Drs. Leo Alexander and Andrew Ivy described in 10 paragraphs

Human subjects can be entered into experiemnts only following adequate information and obtaining informed consent.

The experiments must be based on reliable animal experiments.

The experiments must be performed by educated professionals. The risks and the physical and psychic suffering must be kept on the possible lowest level. Human subjects cannot be entered into experiments which will lead to predermined permanent remaining damage or death

KERPEL-FRONIUS S: 10

Principles of the Nurenberg

Code

The 9th paragraph most probably entered by

the presiding judge

The human subjects must be free to

immediately quit the experiment at any

point when they feel physically or mentally

unable to go on


REMARKS BY PRESIDENT CLINTON

IN APOLOGY FOR STUDY DONE IN

TUSKEGEE (May 16, 1997)

Today, all we can do is apologize. But you have

the power, for only you -- Mr. Shaw, the others who

are here, the family members who are with us in

Tuskegee -- only you have the power to forgive.

KERPEL-FRONIUS S. 12

Important documents dealing

with the ethics of human studies

1947 - Nurenberg Code

1948 (revised 1968, 1983, 1994) - Declaration of Geneva

(Svájc) (Általános etikai maximák)

1949 (revised 1968, 1983, 1994) - World Medical

Association International Code of Medical Ethics

1954 - World Medical Association Principles for Those in

Research and Experimentation

1964 (revised 1975, 1983, 1989, 1996, 2000, 2002,

2004, 2008, 2013) - Declaration of Helsinki. (WMA)

1979 - Belmont Report (USA)

1997 - Convention of the European Council, Oviedo,

Convention of the European

Council, Oviedo, 1997.

Convention for the Protection of Human

Beings with regard to the Application of

Biology and Medicine: Convention on

Human Rights and Biomedicine



The scientific, social, ethical and legal

background in the time of globalized

medicines development

ICH-GCP

Scientifically

adequate

methods

Health care research

in different political and

cultural environment

Correct

medical

behaviour

Declaration of

Helsinki

Health care research in

in differently developed

economic environment

Social control:

IEC, audit

Human and

patient rights

Reliable

Documentation

Report of AEs

Evaluation of

benefit/riskr

ratio

World Medical Association Drug Regulatory Agency

Pharmaceutical Industry

Clinical Investigators

KERPEL-FRONIUS S.

Good Clinical Practice (ICH-GCP)

Good clinical practice of drug development

ICH: International Committee for Harmonization unified

the guidelines for clinical trials of Europe, USA and Japan

It specifies exactly the tasks of the sponsor, the

investigator and the ethics committee

GCP is a standard of procedures, the aim of which is to

ensure the scientific quality, reliability and authenticity of

the design, conduct and documentation of clinical trials as

well as the rights and safety of the investigated subjects

and the confidentiality of their personal data

Final result of GCP: the establishment of an authentic

„paper trail“ that may be well followed by the authorities

15

INTERNATIONAL CONFERENCE ON

HARMONISATION OF TECHNICAL

REQUIREMENTS FOR REGISTRATION OF

PHARMACEUTICALS FOR HUMAN USE

ICH HARMONISED TRIPARTITE GUIDELINE

GUIDELINE FOR GOOD CLINICAL PRACTICE

E6(R1)

Current Step 4 version

dated 10 June 1996



EU convention, regulation on the research

and investigation of medicines on human

subjects

Directive 2001/20/EC of the European Parliament and of the

Council of 4 April 2001 on the approximation of the laws, regulations

and administrative provisions of the Member States relating to the

implementation of good clinical practice in the conduct of clinical trials on

medicinal products for human use

REGULATION (EU) No 536/2014 OF THE EUROPEAN

PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on

clinical trials on medicinal products for human use, and

repealing Directive 2001/20/EC

X


The goal of ICH-GCP is to harmonize different

interests for the benefit odf the society

Pharmaceutical

industry

Demonstration of efficacy

and safety

Rapid and cheap

development

Competent Authority

Accurate determination

of benefit/risk ratio

Safety of the society

Independent Ethical Committee

ICH

-GC

P

ICH

-GC

P

KERPEL-FRONIUS S.

The distribution of the tasks of human

clinical trials (ICH-GCP)

The clinical trial may endanger the health and social status of the subjects

In lieu of the society the Independent Ethics Committee determines the

socially acceptable measure of the risk/benefit ratio and continuously

controls its development during the trials

Independent Ethics Committee

Sponsor Investigator

Human

trial

Administrative organization

Drug documentation

Drug supply

Collection and reporting

of adverse events

Data processing

Trial report

Archiving

Trial conduct

Observation, treatment and

reporting of adverse events

Archiving

Opinion Control

19

KERPEL-FRONIUS S.

The Independent Ethics Committee controls the safety of the subject,

asserts his/her rights and the confidentiality of his/her personal data in

the course of the trial

Independent Ethics Committe

Investigator

Health

institute Sponsor Social

rela-

tions

Sponsor

Subject

Tasks of the Independent Ethics

Committee

20


Informed consent

BMJ 1998;316:1000-1005

Obtaining fully informed consent can be needlessly cruel

KERPEL-FRONIUS S.

Legal aspects of clinical trials

The conditions determined in the trial approval

and the prescriptions of the accepted protocol

as well as the requirements laid down in this

law concerning the conduct of clinical trials are considered occupational rules.

1997 Act Nr. CLIV of the Ministry of Health

Detailed regulations of medical investigations performed in human

subjects 22


New challenges for clinical drug

development

Pharmaceutical industry

+

Clinical investigators

+

Competent Authority

+

Society

Medical need

for treating

vulnerable

patients Children

Elderly

Mentally

handicapped

Unconcious

patients, etc.

New scientific

possibilities Genomic research

New targets

New biological

products

Gene therapy

Advanced therapies

Medical device+drug

combinations


Economical interests in clinical

drug development

Pharmaceutical

industry

Healt care provider

Out patient units

Hospitals

Research sites

Reesearch support

Joint ventures

Companies founded by

health care providers

Pharmaceutical

industry

Healt care provider

Out patient units

Hospitals

Research sites


Social challenges created by the globalization of

the clinical drug development

Needs of the society

Many new, more effective and

safer medicinal products

Pharmaceutical industry

Increasing costs of

drug production

The number of patients

enrolled into trials increses

rapidly and significantly

The placement of “hightech”

studies into developing

countries leads frequently to

ethical, cultural and

social tensions

Strategic Initiative for

Developing Capacity of

Ethical Reviews 2002

(SIDCER)


Country dystribution of diagnosed rare diseases

and number of registered orphan drugs in Europe

F. Bignami: Eurordis Survey on Orphan Drugs Availability in Europe, www.Eurordis.org

Kerpel-Fronius S. 27

Equity

Each group of patients, irrespective of their social status,

should receive all drugs essential for their treatment with

appropriate level of reimbursement

Solidarity Very expensive treatments are fully reimbursed

Co-payments for cheaper and/or not essential drugs are fixed

at relatively higher levels to equilibrate drug budget

Ethical issues in drug

application

RAS–BRAF pathway

RTK = receptor tyrosine kinase; GTP = guanosine triphosphate; ERK =

extracellular signal-related kinase; MEK = MAP (mitogen-activated protein).

39. Garnett MJ, et al. Cancer Cell 2004;6:313–9.

41. Wan PTC, et al. Cell 2004;116:855–67.

BRAF

Activated RAS

MEK

ERK

P

Oncogen BRAF pathway41

Normal RAS–RAF pathway39

Growth factors

RTK

Mutated BRAF

Excesszív sejtproliferáció és

antiapoptosis

MEK

ERK

P

P P

RAS–GTP

Normal cell proliferation and survival

Normal RAS activation

PLX 4032

Vemurafenib

Inhibited cell

proliferation

Cell death

With the kind permission of A. Nagy



Inhibition of mutated, activated BRAF

in patients with pretreated melanoma

Flaherty et al., NEJM, 363. 2010


-100

-75

-50

-25

0

25

50

75

100

%C

han

ge

Fro

m B

asel

ine

(Su

m o

f Les

ion

Siz

e)

RECIST 30% decrease)

ORR = 81%

Phase I study in pretreated patients

With the kind permission of A. Nagy

Confirmatory phase III trial Chapman PB et al. NEJM 364: 2507-2516_2011


Stage IIIc/IV, AJCC)

BRAFV600 mutation

Diagnostic mutation test:

cobas® 4800 BRAF V600

Primary treatment 680

patients

No crossover at PD (was

permitted only after

survival end point was

reached

R 1:1

Dacarbazine

(1000 mg/m2

i.v. q3w)

Vemurafenib

(2x960 mg p.o.)

Response rate:

(> 30% RECIST) : 48% vs 5%

RRR 63% halálozás kockázata

RRR 74% halálozás és progresszió

The ethical problem

Are confirmatory phase III

trials always needed?

Vemurafenib vs DTIC

Chapman PB et al. NEJM 364: 2507-2516_2011


Could we develop alternative approaches

for rapidly approving targeted medicines in

patients with precisely diagnosed target?

Chabner B: NEJM 364: 1087-1089, 2011

Suggestions of B. Chabner:

„High response rates (>50%), high disease-control rates

(>75%), and an acceptable toxicity profile in a biomarker-

defined population of 75 to 100 subjects should be

sufficient for accelerated approval if there is a clear unmet

need.

Randomized comparisons with minimally effective

treatments or placebo should not be required.

Specific end points for early approval should be maximally

flexible and adjusted according to the targeted disease

and the effectiveness and toxicity of alternative therapies.”


Translational genomics

Kerpel-Fronius S.: 33

Identifiability of biological

materials of human origin

Steering Committee on Bioethics (CDBI) Recommendaqtion of the Committee of

Ministers to member states on biological materials of human origin.

Identifiable biological materials: the person concerned

can be identified alone or in combination with associated

data

In the case of coded material the investigator has

direct access to the code

Linked anonymised (pseudoanonymised)

material: the investigator has no access to the code

Non identifiable (unlinked anonymised) biological

material: the identification of the person is made

permanently impossible


The harmonization of contradictory

scientific aims, social needs and

ethical principles


Freedom of research

The value of the

scientific results

for the society

Safety and

the protection of

personal rights

and dignity

New medicines, techniques and processes will lead

to new ethical challenges

The harmonization of ethical

requirements associated with the

collection of human biological material

for genetic research within clinical trials


Ethical guidelines

for

research on

human tissues

Ethical guidelines

for

Clinical research

„Combined research” Clinical drug trial

+

Genetic research

How to handle ethical issues satisfying both types of research?

Information and consent for the

primary and secondary use of

biological material and related

personal data

The information should be specific and as detailed as

possible with regard to any foreseen research uses and

the choices available in this respect

The consent should specify the options:

A general consent is recommended when the future

uses cannot be clearly defined

Possibility of refusing or future opting out

Consent limited to only unlinked anonymised use, or

limited only to specific research projects


EU Data Protection Regulation

Critical comments

Article 81: Processing of personal data concerning

health which is necessary for historical, statistical or

scientific research purposes, such as patient registries

set up for improving diagnoses and differentiating

between similar types of diseases and preparing

studies for therapies, is shall be permitted only with

the consent of the data subject, and shall be subject to

the conditions and safeguards referred to in Article 83.

This amendment makes the exemption from consent for

the use of data concerning health in research very

narrow. This will prevent valuable health research that is

currently legal and already tightly regulated under

European and Member State law.



Critical comments

Article 81: (Am 86) The processing of personal data

concerning health, as a special category of data, may

be necessary for reasons of historical, statistical or

scientific research. Therefore this Regulation

foresees an exemption from the requirement of

consent in cases of research that serves a high

public interest.

The concept of “high public interest” is problematic.

“High public interest” suggests the exemption is to be

used only in a very limited set of circumstances. This is

likely to be problematic for many studies, particularly

because the results and impact of the study are not

known at the outset.


Article 83: In accordance with the rules set out in this

Regulation, personal data may be processed for historical,

statistical or scientific research purposes only if:

(a) these purposes cannot be otherwise fulfilled by

processing data which does not permit or not any longer

permit the identification of the data subject;

(b) data enabling the attribution of information to an identified

or identifiable data subject is kept separately from the other

information as long as these purposes can be fulfilled in

this manner under the highest technical standards, and

all necessary measures are taken to prevent

unwarranted re-identification of the data subjects.

This amendment makes the exemption from consent for the

use of health data in research very narrow, which will prevent

valuable research that is currently legal. KERPEL-FRONIUS S:. 40


Critical comments

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Ethics of drug research - Semmelweis