At the end of this module you should:

• Know the 3 basic principles of research ethics: Respect for persons; Beneficience/Non-
maleficience; Justice
• Be aware that any project/trial involving human subjects must have ethical approval from
the corresponding ethics committee before the start of the project
• Be aware of personal data protection regulations and applicability

OUTLINE
• Introduction and history
• Basic ethical principles: complexities and perspectives
• International health research
• Personal data protection
• Clinical records
• Human tissue samples and genetic testing

INTRODUCCION AND HISTORY ===========================================

Research with human is problematic because… humans are being used in experiments, possibly
at great personal risk, for the benefit of others.

1747 James Lind conducted the first experimental trial – giving seamen different dietary
supplements to find a cure for scurvy.

1774 Benjamin Jesty, a farmer, inoculated pus from cowpox udder's lesions into his sons and
wife. In 1796 Edward Jenner inoculated a young boy of 8 years old, with material from the
cowpox blisters of a milkmaid who had caught cowpox from a cow.

1897 Guiseppe Sanarelli announced that he had isolated the organism causing yellow fever and
to prove it he injected 5 people with his isolate without their knowledge. He was publicly
condemned for this.

1900 Walter Reed was commissioned to identify the cause of yellow fever in an epidemic in
Cuba. One of the first written consent forms was developed for this investigation.

Late 1890s

“Albert Neisser published clinical trials on serum therapy in patients with syphilis. He injected
cell free serum from patients with syphilis into patients who were admitted for other medical
conditions. However, the patients were not informed about the experiment or asked for their
consent. ”

“On 29th December 1900, Neisser was found guilty of an offence for having vaccinated
persons admitted for healing with blood serum of syphilitic persons or had them vaccinated
without the consent of these persons or their legal representatives . On the same day, the
Prussian Ministry of Spiritual, Educational and Medical Affairs instructed the heads of the clinics,
polyclinics and other hospitals to permit human experiments only after detailed instruction
and explicit consent of the test persons. Trials against minors were completely banned.”

1939 By the start of World War II the need to obtain permission from potential study
participants was widely accepted…
1939 – 45: Nazi Germany: Experiments done with thousands of prisoners in the concentration
camps. “Human experiments included “high-altitude” experiments in which concentration
camp inmates were forced, without oxygen, into high-altitude chambers that duplicated
conditions at up to 68,000 feet; removal of sections of bone, muscle, and nerves, including whole
legs removed at the hips to transplant to other victims; artificial wounding and exposure to
mustard gas; wounding of two limbs and treatment of one but not the other with sulfanamide
antibiotics; intramuscular injection with fresh typhus; and collection of skeletons from 112 live
Jewish inmates who were killed and defleshed.”

1946 – 47: Nuremberg “Doctors Trial”.

From 9 December 1946 to 20 August 1947.

1947: The Nuremberg Code was published.

The Nuremberg Code:
• Was designed to protect the integrity of the research subject.
• Set out the conditions for the ethical conduct of research involving human subjects,
emphasizing the voluntary consent to research.

THE NUREMBERG CODE

1. The VOLUNTARY CONSENT of the human subject is absolutely essential…

2. The experiment should be such as to YIELD FRUITFUL RESULTS for the GOOD OF
SOCIETY, unprocurable by other methods or means of study, and not random and
unnecessary in nature.
3. The experiment should be so designed and BASED ON THE RESULTS OF ANIMAL
EXPERIMENTATION and a knowledge of the natural history of the disease or other problem
under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to AVOID ALL UNNECESSARY PHYSICAL AND
MENTAL SUFFERING and injury.
5. NO experiment should be conducted where there is an a priori reason to believe that DEATH
OR DISABLING INJURY will occur; except, perhaps, in those experiments where the
experimental physicians also serve as subjects.
6. The DEGREE OF RISK to be taken should never exceed that determined by the
humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to PROTECT the
experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by SCIENTIFICALLY QUALIFIED PERSONS…
9. During the course of the experiment the human subject should be at LIBERTY to bring the
experiment to an end if he has reached the physical or mental state where continuation of the
experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to
TERMINATE THE EXPERIMENT AT ANY STAGE, if he has probably cause to believe, in
the exercise of the good faith, superior skill and careful judgment required of him that a
continuation of the experiment is likely to result in injury, disability, or death to the experimental
subject.

But…
“The trial of the Nazi doctors had only modest resonance with the popular press and the medical
establishment in the United States because their misdeeds were considered an anomaly
attributable to a totalitarian regime of unquestionable brutality. The assumption was that
researchers working in democratic countries would never do such things. Thus the Nuremberg
Code was viewed as a document that was not applicable to ‘the rest of us’ ’’

1948

The General assembly of United Nations proclaimed the Universal Declaration of Human Rights.

Nevertheless, in 1963…
In Brooklyn Chronic Disease Hospital…
A researcher injected live cancer cells into elderly debilitated patients without their consent and
there were several more unethical cases in the previous and following years!!

1964
Saw the publication of the fundamental document in the field of biomedical ethics, which was a
comprehensive international statement of the ethics of research involving human subjects:
Declaration of Helsinki
The World Medical Association adopted the Declaration of Helsinki.
Since 1964 it has been periodically amended, last time in 2013.

1966
The General assembly of United Nations adopted the International Covenant on Civil and
Political Rights.
Art.7: “No-one shall be subjected to torture or to cruel, inhuman or degrading treatment or
punishment. In particular, no-one should be subjected without his free consent to medical or
scientific experimentation”

1972
A report appeared in New York Times…
Syphilis victims in U.S. study went untreated for 40 years

The Tuskegee Syphilis Study

Over 400 mostly illiterate African American men with syphilis & 200 uninfected controls were
recruited in 1932 to study the natural history of the disease. Men were not informed about the
true nature of the study, nor about their condition. Their partners were also not informed.

The natural history of syphilis was already understood since the turn of century, and penicillin
became available in late 1940s - but Tuskegee men did not receive it and it was assured they
were not aware of it. It wasn’t until 1972 when a New York Times article (Syphilis victims in
U.S. study went untreated for 40 years) prompted the Dept. Health, Educ & Welfare to stop the
study. “ I don’t know what they used us for. I ain’t never understood the study” a survivor.

In 1972 when the study was stopped 74 subjects were still alive “at least 28, but perhaps more
than 100, had died directly from advanced syphilitic lesions”. Compensation for survivors and
families was only given in the late 1970s. No formal apology until 1997 from President Bill
Clinton.

Additional resources on the Tuskegee study:

- Bad Blood. The Tuskegee Syphilis experiment (Book)
- Miss Ever’s boys (Film)

In 1979 as a result of the Tuskegee scandal → The Belmont Report

US National Commission for the Protection of Human subjects of Biomedical and Behavioural
Research identifies the 3 basic ethical principles relevant to research involving human
research…
The 3 basic ethical principles are:
• Respect for persons
• Beneficence (Includes Non-Maleficence, which is sometimes regarded as a separate
principle)
• Justice

The Council for International Organizations of Medical Sciences (CIOMS) published in

1991 - International Guidelines for Ethical Review of Epidemiological Studies (Updated in
2009)
2016 - International ethical guidelines for health-related research involving humans

BASIC ETHICAL PRINCIPLES - COMPLEXITIES AND PERSPECTIVES ============

ETHICAL PRINCIPLE 1 is: Respect for persons = which ensures: Individual autonomy; and:
Protection of vulnerable populations; by way of: Informed consent.

ETHICAL PRINCIPLE 2 is: Beneficence & Non-Maleficence = which ensures: maximisation of

possible benefits, minimisation of possible harms; by way of: Assessment of risks and benefits

ETHICAL PRINCIPLE 3 is: Justice = which ensures: Fair distribution of burdens and benefits; by
way of: Fair selection and recruitment of subjects.

What does the PRBB code say about it?

8.2. Research involving human subjects

All research protocols, information sheets and informed consent forms involving the direct
participation of human subjects or based on any form of information or biological samples obtained
from such subjects must always have received, as a minimum requirement, approval from the
corresponding clinical research ethics committee. Participants must also have been informed
about how their data will be used, reused, accessed, stored and deleted, in compliance with the
EU General Data Protection Regulation (GDPR) or applicable data protection rules. When
research involves patients, members of the research team who are not responsible for treating the
study participants must collaborate and not interfere with any decisions made by the physician
responsible for treatment.

Which Ethics Committee should review the protocol?

• Parc de Salut Mar Drug Research Ethical Committee (CEIm) for: Clinical and
Biomedical Research; Health-related research.
• UPF Institutional Committee for the Ethical Review of Projects (CIREP) for: Non-
biomedical research involving humans and/or personal data processing.

8.3. Common requirements in all research involving human subjects and/or human biological
samples
Particular diligence is required in relation to all information regarding the purpose, potential
discomfort/inconvenience and risks, and the benefits of the research, in obtaining the express,
specific, and written consent of the participants, and in attending to the confidentiality of data,
samples, and results obtained. In addition, given that in clinical research the process of data
collection is complex and cannot always be repeated, the research group must pay particular
attention to the quality of data collection and the procedures for data storage.
All this is quite straight forward on paper - but in real life… Principles are not always interpreted in
the same way by everyone….

In 1997 the British Medical Journal published two trials in which no informed consent was obtained
from participants. Were these trials ethical? The BMJ invited their readers to debate the issue.
Informed consent: the intricacies. Should the BMJ reject all studies that do not include informed
consent?

Different philosophical perspectives can be adopted with respect to the importance of each of the
ethical principles:
• Rights based (libertarian) approaches emphasise the autonomy of the participant.
• Duty based (paternalistic) approaches emphasise the duties of the research worker to
provide benefit.
• Consequentialist (utilitarian) approaches weigh up the outcomes ‘now’ versus in the
‘future’.

INTERNATIONAL HEALTH RESEARCH =====================================

What ethical issues are raised when international researchers conduct health research in low and
middle income countries?

In 1996 Pzifer goes to Nigeria. The company conducted a trial to test Trovan, and experimental
antibiotic against meningitis, with 200 children. 11 children died and dozens were left
disabled. Apparently the families did not know that their children were participating in an
study. In 2011 Pfizer agreed an out of court compensation settlement with the victims of the Trovan
case.

Montreal Statement on Research Integrity in Cross-Boundary Collaborations

The Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of
Benefits Arising from their Utilization to the Convention on Biological Diversity is an
international agreement which aims at sharing the benefits arising from the utilization of genetic
resources in a fair and equitable way. It entered into force on 12 October 2014.

PERSONAL DATA PROTECTION ===========================================

Personal Data = any information relating to an identified or identifiable natural person (“data
subject”). According to GDPR.

Special categories of personal data (formerly known as ‘sensitive data’): Racial or ethnic
origin, political opinions, religious or philosophical beliefs, or trade union membership, and the
processing of genetic data, biometric data for the purpose of uniquely identifying a natural
person, data concerning health or data concerning a natural person's sex life or sexual
orientation
IDENTIFIERS: Name, ID number, Location / Geolocation / Geotracking, Factors (physical,
physiological, genetic, mental, economic, cultural or social identity), Combination (rare disease,
sex, DoB), Voice / Images.

According to Article 8 of the CHARTER OF FUNDAMENTAL RIGHTS OF THE

EUROPEAN UNION and to Article 18 of the Spanish Constitution, everyone has the right to
the protection of their personal data.

More recently, these general rights have been specified in laws and regulations…
• The General Data Protection Regulation EU 2016/679 (GDPR) aims to “protect
fundamental rights and freedoms of natural persons and in particular their right to the
protection of personal data.”
• In Spain, the Organic law 3/2018 on the Protection of Personal Data and Guarantees of
Digital Rights (LOPD-GDD) adapts the GDPR to the Spanish legal regime.

Personal Data Protection by Design and by Default

BY DESIGN: implement technical and organizational measures to protect personal data, at the
earliest stages of the design of the processing operations, in such a way that safeguards privacy
and data protection principles right from the start
BY DEFAULT: only personal data which are necessary for each specific purpose of the
processing are processed (adequate, relevant and limited). Refers to: the amount of personal
data collected, the extent of their processing, the period of storage and accessibility.

Confidentiality = Human data may be:

• Un-Identifiable – Anonymous / Anonymised
• Identifiable – Identified / Pseudonymised

Anonymous: human data or biological materials originally collected without identifiers and
impossible to link with their sources.

Anonymised: human data or biological materials that were originally identified, but have been
irreversibly stripped of all identifiers and are impossible to link to their sources.
Implies the removal or key destruction of name, address, NHS number, etc. Once data is truly
anonymised and individuals are no longer identifiable, the data will not fall within the scope of
GDPR.

Pseudonymised: human data or biological materials that are unidentified for research purposes,
but can be linked to their sources through the use of a code. The code must be held by third
parties (pseudonymisation).

Identified: human data or biological materials to which identifiers, such as a name, patient
number, or clear pedigree location, are attached and available to the researchers.

Key tips for managing the confidentiality of personal health data within a clinical research
project: All research groups utilising personal data should comply with GDPR policies and should
consider:
• WHY the data may be accessed/used;
• WHO is permitted to see the information;
• WHAT classes of data may be accessed;
• HOW the data is protected and accessed;
• until WHEN they may be accessed, and what should happen to the data afterwards.
The answers should be considered in order to develop the informed consent and any participant
information leaflets etc.
What does the PRBB code say about it?
8.8. Protection of personal data
All research plans that involve the use of institutional computer records or the preparation of
databases containing information relating to individuals must guarantee the anonymity of the
participants and be subject to current regulations on data protection.

CLINICAL RECORDS ====================================================

Using secondary data
It is common for scientists & doctors to undertake research using patient records. In this case the
patient is not actively involved in the study and may even have died. What are the responsibilities
of the investigator in protecting confidentiality?

Access to clinical records

Data Protection Legislation exceptionally allows the use of clinical records for research without
consent. Check applicable legislation: GDPR and LOPD-GDD.
NOTE: clinical data from dead people can be used for research since they are not regulated by
GDPR.
BUT: explicit consent should usually be obtained to use identifiable personal data for research.
If patients cannot be contacted or have died, whenever possible confidentiality should be preserved
through anonymisation. In any case, specific approval from an Ethics Committee is always
required.

HUMAN TISSUE SAMPLES AND GENETIC TESTING ==========================

What does the PRBB code say about it?

8.6. Research with human biological samples
All research involving the use of human tissue or other biological samples derived from humans
requires the specific informed consent of the donor. Specific donor consent must also be given
before research may be done on samples obtained as part of diagnostic or health care
procedures.
8.7. Human samples
Storage, use and sharing of human biological samples of any kind, collected as part of a
research project must comply with current legislation on biobanks and treatment of human
biological samples for biomedical research. Where applicable, collections must be registered at
the National Register of Biobanks of the Instituto de Salud Carlos III.

What about genetic testing? Should scientists do genetic testing on your tissue without your
consent?

What does the PRBB code say about it?

8.4. Genetic research
All research protocols that include the collection, manipulation, and/or storage of biological
samples for the purposes of genetic analysis will be prepared according to the applicable
legislation. In particular, the privacy of the subjects and their right to be informed about their
personal results must be guaranteed. The consent of the participating subjects can foresee the
use of samples in other projects related to the initially proposed research. Consent must be
renewed whenever biological samples are to be used for purposes other than those indicated in
the informed consent at the time they were donated.

Genetic testing
The donors of tissues or other biological samples have rights to:
Autonomy: to determine the final destination of their tissue or samples
Privacy: to prevent dissemination to third parties of personal, clinical and research information
Therefore donors must consent to participate.

Genetic testing - Identifiability in genomic data

Genome-wide association studies routinely use more than 100,000 SNPs to genotype
individuals; an individual can be uniquely identified with access to just 75 (30-80) SNPs from
that person! Linking to non-genetic databases (health-care, administrative, criminal,…) +
profiling from genomic data (DNA analysis inference of physical attributes such as gender, blood
type, manifestations of Mendelian disorders…). All in all, the growth and availability of genomic
data and big data is making complete anonymization more difficult!!

The emerging technologies around whole genome sequencing and the large-scale collection of
genomic data, big data, etc. has many potential medical benefits but also important privacy risks.
A big challenge nowadays is to balance public data-sharing with the respect for the privacy of
research participants. Read the interesting example of the HeLa cells genome, where scientists
and the Lacks family (where HeLa cells come from) finally worked together to ensure access to
the data while having some control over its use.

Ownership/Commercial use
Donors should agree to donate tissue for storage and research without financial incentives. Tissue
banks should be not-for-profit. Consent procedures for potential donors should clearly outline
the possibility of the use of their tissue by companies. However, there have been many
controversial cases where tissues obtained without consent have lead to great financial gains:
Henrietta Lacks, John Moore, etc.