“Want to volunteer for
a clinical trial and get paid?” This was the unexpected advertisement which
appeared on my Twitter feed and triggered my curiosity for clinical trials. “A
clinical trial is any research study that prospectively assigns human
participants or groups of humans to one or more health-related interventions to
evaluate the effects on health outcomes.”1
. In a matter of clicks and a completion of one short form you can be
considered to take part in a clinical trial. I wondered why someone would put
their life at risk for money, especially in light of the clinical trial
involving the drug TGN1412 that went horribly wrong. However, to my surprise
there are many willing individuals around the world participating in clinical
trials. According to ClinicalTrials.gov, currently there are 246,719 clinical
studies with locations in all 50 States and in 201 countries. Experimenting and
testing have long been a part of medicine and these clinical trials are a key
research tool for advancing medical knowledge and patient care. They can detect
and reduce the risk of disease. However, despite the widespread use of clinical
trials and their integral part in medical research, there exist moral issues
surrounding this type of experimentation. Risks from participation may not
balance with the clinical benefit; some trials may not lead to any significant
results or conclusions, but the participants could be harmed in the process. There have been many cases where trials have
been unsuccessful and have negatively impacted patients, sometimes leading to
mortalities.  I explore the causes for
the failure of one particular trial, the TGN1412 case and cover other examples
of recent failed trials as a result of ethics, bad process and scientific
factors. I also explore other general ethical issues and recommendations during
the conduct of clinical trials. The findings will allow me to evaluate and
summarise the lessons learned.

I will demonstrate that many of these examples of bad process could have
been avoided if those who conducted the trials followed the Declaration of Helsinki, which is a list of ethical codes regarding
human experimentation developed for the medical community.

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!


order now

The term ‘human experimentation’ can still remind many
of the infamous experiments conducted on war prisoners during World War II. The
unethical handling of human subjects in medical research was also carried on in
the post-war period. The trials targeted vulnerable populations such as the mentally-ill,
disabled, the poor and ethnic minorities. A prime example was the Tuskegee
syphilis study, which aimed to observe the natural progression of untreated
syphilis in rural African-American men in Alabama under the appearance of
receiving free health care from the United States government2.
However, following these cases many ethical guidelines and regulations were put
in place, including the Declaration of Helsinki, which I have mentioned above.
Despite the introduction of these, there are still areas where clinical trials
could be improved.  

Monitoring subject welfare during the conduct of
research is an area for improvement according to an article on the ‘Ethical Issues during the Conduct of
Clinical Trials’. The ethical conduct of a clinical trial does not end with the
signature on the informed consent form. The rights, interests, and safety of
research subjects must be protected continually throughout the study duration.
Subject safety monitoring is the responsibility of several groups, including
institutional review boards (IRBs) research ethics committees (RECs) investigators
and their research staffs, sponsors, and data monitoring committees (DMCs). The
IRB has many roles, including the task of reviewing reports of unanticipated
problems (UAPs) and of adverse events (AEs).This is a very important task
because AEs can indicate whether the drug is harming the human body, which
means the trial can be stopped before it seriously damages anyone. A trial will
be stopped if there have been an excessive number of AEs in one of the study
groups.  However, there are concerns with
monitoring AEs because sometimes it is unknown if the AE is due to the toxic
effect of the drug or due to the underlying illness of the patient. This is
particularly a concern in phase two and three of clinical trials because in
these phases the drug is tested on patients that are ill. For example, patients
who have advanced cancer and have received all possible current treatments often
participate in clinical trials, therefore it may be unclear if some of the
adverse effects are due to the cancer or the drug. To determine the cause of an
AE would “require measuring the excess events in the intervention group
compared with the AE rate in the control group which would require the receipt
of aggregated data on AEs and the number of subjects currently enrolled in the
clinical trial as a whole”3.  However, the IRBs don’t receive this
information; therefore they can’t determine the possible cause of an AE
occurring during the trial of a drug. Additionally, IRBs receive little
assistance on how to handle such reports. Regulatory inconsistencies can lead
to confusion concerning what AEs must be reported and how they should be
reported. The reporting of AEs plays an integral part in preventing serious
complications, therefore it is essential that this is done faultlessly.  

 

Furthermore, given that there are lots of parties
involved in the conduct of a clinical trial, the following are recommended for system-wide
improvement: overlapping responsibilities and possibilities for communication
breakdown and the ethical responsibility associated with research in human
subjects. The life of a volunteer should not be put at risk due to lack of
communication and complacency.   

Moreover, participants in clinical research have
rights which they should expect, including the following4:

·      
Right to Informed consent                                                                      

·      
Shared decision-making

·      
Privacy for research participants

·      
Return of results

·      
Right to withdraw

 

The right to informed consent is widely accepted as an
integral part of ethical clinical research. Participants should understand the
purpose, risks, benefits, alternatives and requirements of the research.
Nevertheless, empirical data show that participants often do not have a good understanding
of the details of the research because the information is too complex.
Personally I think this is unfair for the potential volunteers because in order
for them to make an informed decision they should be completely clear with the
side effects and other significant information about the drug. There is a need
to balance the goal of being comprehensive with the amount and complexity of
information in order to give the participants the information they need to
understand the study details and make an informed decision.

Additionally, another ethical concern with clinical
trials, especially in phase 1 is that these volunteers are asked to accept risk
in order to develop knowledge that may not directly benefit them. Also, the probability
of progressing from Phase I to U.S. FDA (The Food and Drug Administration) approval
(LOA) reveals that only 9.6% of drug development programs successfully make it
to market5.
Consequently, it seems unjust that many of these individuals put themselves at
risk which may cause health problems for them later on in life for a drug that
eventually doesn’t enter the market or benefit others. One would think that all
the testing in laboratories and on animals would show clear data if the drug is
beneficial and worth proceeding to clinical trials. However, the way a
potential treatment works in animals may not mimic what will happen in humans.
According to CenterWatch, only about one out of every 50 drugs tested in
animals is determined to be safe and effective enough to test in humans. There
are cases where the drug does not affect the animal dramatically, only minor
adverse effects, but when tested in humans at a lower dosage the results prove differently,
and the humans are affected seriously. A prime example of this is the famous TGN1412
trial (phase one) that began at 8am on 14th March 2006 with 8 healthy
male volunteers. Phase I trials are often referred to as “first-in-man
studies” as they are the first stage of testing in human subjects. They
are designed to determine the maximum amount of the drug that can be given to a
person before adverse
effects become dangerous and it normally takes place with a small group of healthy
volunteers. They are usually monitored until several half-lives of the drug
have passed.

TGN1412 is a monoclonal antibody that was being
developed as a new medicine for the treatment of B cell leukaemia and
autoimmune diseases. Six volunteers were injected with the drug and two with
placebo. All of the men given the drug experienced cytokine release syndrome
resulting in angioedema, swelling of skin and mucous membranes. The first
patient was transferred to the Northwick Park hospital’s intensive care unit 12
hours after infusion and after 16 hours all of the men were in the intensive
care unit; all six experienced multi-organ failure. Not only did this trial
rise ethical concerns, but also highlights how clinical trials can be improved
with regards to the safety of the volunteers.

However, the biggest question that arose from this
trial was “What went wrong?”  The answer
to this question provides a platform for what improvements and precautions can
be put in place for trials involving
immunomodulatory drugs (drugs that modify the immune response or the functioning
of the immune system as by the stimulation of antibody formation or the
inhibition of white blood cell activity)6,
which are high risk drugs because they target the immune system and clinical
trials in general. In a report
issued by the Medicines and Healthcare products Regulatory Agency concludes
that the serious adverse reactions experienced by the healthy volunteers were
the result of an “unpredicted biological action of the drug in humans”. Nonetheless,
I don’t think that is a acceptable reason for the failure of the trial. These
volunteers nearly died and it has caused them potential problems in later life
because on discharge some were warned they may suffer an increased risk of
cancers and auto-immune diseases. This reason may also be used in future
clinical trials when with enough investigation another cause could be found.

Nevertheless, other investigations show potential
reasons why the clinical trial was unsuccessful. The primary objectives were to
assess the safety and tolerability of increasing single doses of TGN1412 in
separate cohorts and to assess pharmacokinetics (the movement of drugs within
the body.)  TGN1412 binds to and is a
strong agonist for the CD28 receptor of the immune system’s T cell (these are a
subgroup of white blood cells vital for……..) Being a CD28 agonist means that
TGN1412 stimulates the physiological function of CD28 causing more T cells to
be created (TH1 and TH2 cells). WHAT T CELLS DO………..  Th1 cells promote ‘cellular immunity’ in host
defence and are also involved in reactions such as transplant rejection. Th2
cells promote ‘humoral immunity’ by helping B lymphocytes to proliferate and
secrete antibodies. CD28 is the co-receptor for the T cell receptor; it binds
to the receptors on the interacting partner in reaction through one of its
ligands (B7 family). A ligand is an ion or molecule that binds to a central
metal atom to form a coordination compound7. The
dose of TGN1412 given to the human volunteers induced a rapid and large release
of cytokines, which are small protein molecules that transmit signals between
immune cells and tissue cells. A ‘cytokine release syndrome’ was identified in
all of the individuals who were given the drug, which is a rapid release of
cytokines causing organ failure. This did not occur in the trial with the
cynomolgus monkey, the animal model chosen for studies to calculate the dose
for the first human exposure to TGN1412, at a dose that was numerically 500
times larger than that given to human volunteers.  This shows that the pre-clinical development
studies that were performed with TGN1412 did not predict a safe dose for use in
humans, even though current regulatory requirements were met.  

1 World Health Organisation. http://www.who.int/topics/clinical_trials/en/ (Accessed 09/06/2017)

2 https://en.wikipedia.org/wiki/Tuskegee_syphilis_experiment (Accessed 11/07/2017)

3 Silverman, H. (2007) Ethical Issues during the Conduct of Clinical
Trials. Proceedings of the  American
Thoracic Society, Vol. 4, No. 2 | May 01, 2007. 
 http://www.atsjournals.org/doi/full/10.1513/pats.200701-010GC (Accessed 04/08/2017)

4 Clinical research ethics https://en.wikipedia.org/wiki/Clinical_research_ethics (Accessed 04/08/17)

5 Clinical Development Success Rates 2006-2015 –
BIO, Biomedtracker, Amplion 2016 https://www.bio.org/sites/default/files/Clinical%20Development%20Success%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Amplion%202016.pdf (Accessed 04/08/2017)

6 https://www.merriam-webster.com/dictionary/immunomodulator (Accessed 05/08/2017)

7 https://www.quora.com/What-are-ligands (Accessed 07/08/2017)