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Science Medicine and Society:
-In general, for drugs and vaccines: Describe the adverse reporting procedures
from all phases of clinical trials to post marketing surveillance.
-Include the procedures in Ireland and Europe.
-Describe how patients/families can seek redress.

Adverse events have been defined by the European Parliament and the Council of
the European Union as, “any untoward medical occurrence in a patient or
clinical trial subject administered a medicinal product and which does not
necessarily have a causal relationship with this treatment.” These changes are
compared to baseline health status (i.e. hypertension) before the beginning of
the trial.

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Ireland and Europe:
Reporting Procedures (for drugs and vaccines);

Clinical trials

Phases of Clinical Trials;
4 phases (1) (2)

1: Initial administration of the drug under investigation. Safety is assessed.
Dosage ranges are determined by volunteers who may be perfectly healthy or
specifically chosen. The drug is characterised by how it is metabolised,
absorbed and excreted, as well as potential drug-drug interactions. Side
effects are evaluated.
Adverse event??

2: Randomised trials where both a placebo and experimental drug are involved.
These trials can be ‘blinded’ to prevent biasness and for a full comparison to
be made on the safety of the new drug as well as its effectiveness. Criteria’s
are usually made for those who can be involved in the testing and are closely
monitored. From this, further objectives and targets can be set out for Phase
3. Dosages are also determined for phase 3 trials here.
Adverse event??

3: Large scaled, randomised testing is done. Over these few years,
pharmaceutical companies can determine the effectiveness and efficiency of the
drug under investigation. A range of potential adverse reactions are
established. Therapeutic benefits are established. Companies can then go on to
look for the European Medicines Agency’s (EMA) approval.
Adverse event??

4: Post Marketing Surveillance Trials. Searching for drug optimisation that
were not previously considered before approval. These may include new formulas,
doses or combinations.
“Yet the approved drugs or devices will possibly be used by millions of
people. This combination of incomplete information about clinical outcomes,
relatively short duration, and limited size means that sometimes the balance
between benefit and harm becomes clear only when larger phase IV studies are
done, or when there is greater clinical experience. One example is some of the
cyclooxygenase 2 (COX 2) inhibitors, which had been approved for arthritis
pain, but only disclosed cardiovascular problems after larger trials were done.
These larger trials were examining the effects of the COX 2 inhibitors on
prevention of colon cancer in those with polyps 61, 62. Similarly, only after
they had been on the market were thiazolidinediones, a class of drugs used for
diabetes, found to be associated with an increase in heart failure” (2)
Adverse event??

 (1) ICH Expert Working Group, General
Considerations for Clinical Trials E4 (1997), current step 4 version, page 6
(2)  Lawrence F, Curt F, David DM, Fundamentals of
Clinical Trials. (2010) Springer ISBN: 978-1-4419-1585-6

****Fundamentals of Clinical Trials (Adverse events page 231)

As outlined by the Health Products Regulatory Authority (HPRA):

for assessing clinical trials of medical products that are produced in Ireland

clinical trial begins with small studies in controlled populations of both
volunteers or patients

are later expanded to larger scaled studies in patients with collected data being
used to investigate the new product. These results are then used to compare the
new product to the currently used treatment aka perhaps less adverse drug
reactions in patients.

larger amounts of information being obtained, larger numbers of patients are
exposed to the new product

safety of the product in the intended patient population can then be

on the quality of the product and its non-clinical safety will have been
obtained before the clinical trial programme commences. (2)

Accessed 29 Jan. 2018.

Practically the same procedures as outlined by the ICH in their ‘General
Considerations for Clinical Trials’ as the stages were adopted for use in the
European Union, Japan and USA.

by the European Communities

A new Clinical Trials Regulation (EU) No
536/2014 was adopted on 16 April 2014, and implementation is planned to take
place in 2019.

the HPRA work with the European Commission and the EMA many of the regulations
and reporting procedures are much the same in Ireland as the rest of the
European Union.


trials conducted in the European Union are conducted under the standard of a
guideline created by the International Council for Harmonisation, called ‘Good
Clinical Practice’ (GCP). The authors of ‘Fundamental of Clinical Trials’ also
reflected on the phases of clinical trials as displayed by the ICH; “An
excellent summary of phases of clinical trials and the kinds of questions addressed
at each phase was prepared by the International Conference on Harmonisation”

2001 each European country had clinical trial regulations of their own, which
made national European research a very complex task. In an attempt to resolve
these difficulties, the first European Clinical Trials Directive was created.

Replaced by the Clinical Trials Regulation in 2014

happens if an adverse event occurs within clinical trials?
There are expected and unexpected adverse events.
Expected toxicities should be listed in the products label.

The risks that are believed to arise
from the study drug are also written and explained.
Unexpected adverse events would not have been listed or maybe at the severity
that was initially expected

A grading scheme was established by the Food
and Drug Administration (FDA) in 2007 and later, by the European Pharmaceutical
Market Research Association (EphMRA) in their adverse event reporting
guidelines (2013), where toxicity grading was scaled.
These can be simplified as the following;

1: Mild symptoms

2: Moderate symptoms

3: Severe symptoms; not life threatening but hospitalisation may be necessary

4: Life threatening symptoms; urgent intervention required

5: Death
With reference to;
 Accessed 30 Jan. 2018.

adverse events within the European Union must be reported by law.
“Adverse events may be collected within Individual Case Safety Reports
or as Signals within Periodic Safety Update Reports collated by the marketing
authorisation holders’ pharmacovigilance department and forwarded to the
regulators.” EphMRA

marketing surveillance- Considered in Phase 4 of clinical trials

events after product is marketed?

can seek redress by;

Adverse Events:
“The assessment of adverse events encompasses the whole spectrum of
research from laboratory work during drug and device development, animal
studies, and early work in small numbers of human beings, to case reports,
clinical trials, and postmarketing surveillance” (COX2 as example again)

Advantages to assessing adverse events:

hypothesis testing

group allow non-biased comparisons to the study group

also eliminates biases in the collection and evaluation of safety data

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