Thursday, October 18, 2018

Pharmacology and toxicology I - Trials, controls and trial

types; Human research protection
Trials, controls and trial types
Phase 3 trials are required generally for marketing approval; these are comparative studies, as the
patients involved are possibly presenting co-morbidities, since the population is large; hence it is
difficult to define the control group, that is important for the trial mean, allowing removal of a
good portion of bias; some biases are related to the placebo effect, others to the presence of other
simultaneous therapies; we need also to assess if the drug is more effective than current
treatments. Choosing the right control is essential; one type of control is historical control, that is
we know perfectly the history of the disease, and we can hence test the drug studying historical
data and controls; this one is not very controlled, as they could have been recruited years ago
(and the epidemiology might have changed, as well as other factors that might impact on
diseases history), so these are almost never used in clinical trials; another type is concurrent
control group, where we choose the control group within the same population, so the treated and
control group are supposedly identical, except for treatment; this last one is more prone to bias;
some of them are resolved thanks to randomization, eliminating the selection bias, and blinding.
Control group could be treated with placebo, that is convenient, as we can surely double, or triple
blind the study; another possibility is giving no treatment (very rare, generally only done when
we have not drug to treat the disease); different dose or regimen, most common, where we
compare these two different regimens; a different active treatment (more related to ethics, as we
cannot suspend the treatment in a group of people just to test drugs).
Inside reports, we have some terminology used; parallel means that we have the two groups start
the treatment together; cross over, meaning that a study starting parallels, at some point presents
a switch in treatment (we check both drugs in controls and treated groups both); we have
different trials as well. We have ???. Non-inferiority trial means that one drug is not inferior than
the other, and does not go lower than the bottom confidence limit value; in equivalence trials we
need to be kept inside the upper and lower confidence limits.
If a trial is successful, we go to health ministry, or the competent authorities, and we bring all the
documentation to have approval for market; in the beginning, it has a narrow indication
(treatment of only one pathologies), to generally widen; for any new indication we have another
phase 3 trial, being necessary (widening of indications need new phase 3); sometimes, if we have
large trials, we might use nestled trials (sometimes the competent authorities are satisfied with
this information, but most of the times we need new trials); sometimes we need to have again
phase 2 as well.
Phase 4 starts with marketing; it is useful, with the widespread diffusion of the drug, to discover
rare adverse effects (that a phase 3 clinical trial could not address due to the low frequency).

Human research protection

There are many ethical problems tied with clinical trials, and new drugs development (or also
with disease natural history researches). Misguided trials for syphilis (where patients did not
consent, and were not treated once a drug was found for syphilis), as well as the Nazi

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 Thursday, October 18, 2018
experiments, lead to the formulation of new guidelines for ethical conduct, with the Nuremberg
code being the first, most prominent example; the declaration of Helsinki followed, broader than
the first. The National Research Act was the milestone for medical research itself, leading to
Belmont Report; this one is statin respect for people (treating people as autonomous creatures
and not means to an end), beneficence (minimize harm and maximize benefits), justice (treat all
people fairly, and make sure that treatments are equally distributed). A joint regulatory project
was also issued, ???.
Ethical norms for clinical trials came up with Institutional review boards (IRB), and informed
consent; the former is protecting participant’s rights, and usually provides the participants with
the informed consent before they take part in the study. The IRB is any board committee or other
groups formally designated by an institution to review, approve the invitation of biomedical
research involving human subjects; they are responsible for many procedures, including issuing
written notes of approval or disapproval of the study, as well as providing informed consent.
The IRB in Italy is made of at least three clinicians, a pediatrician, a biostatistics, a
pharmacologist, a general territory physician, then depending on the type of studies, we have
other entities involved, related to the specialty that is involved.
Informed consent is the process through which the patients is informed and learns key facts
about the research study, and makes voluntary adhesion to it; the consent must include
statements that the study is involving research, explanation of purposes, expected duration,
description of procedures involved in the sett, risks or discomforts, benefits, alternatives to the
research study, statements about medical care and compensation in case of injury, alternative
therapies. We have vulnerable populations to think about as well, including children, mentally
impaired or dementia affected individuals, prisoners; others might be unduly influenced to
participate, like students, subordinates, pregnant women (there is debate for this, as there are still
drugs that need to be taken also in pregnancy, but it is borderline ethical to involve pregnant
women in studies), patients (when the caregiver is the researcher).
Transparency is also important; it is necessary that all trials are published, as also negative
outcomes are good for future reference, and are informative. FDA in the ‘90 established a
website, ClinicalTrials.gov, with informations about all ongoing trials, and the drugs tested; on
site, we have stated conditions, intervention, outcome measures, sponsors, locations, phases,
dates and results (all should be clearly stated); in USA, it is mandatory by law to fill in this
registry. Not all trials need to be registered, for example phase 1 trials, as these are poorly
informative, especially for the general population, so in general we only have phases 2 to 4.
Another reason to publish the trial on the site is because we do want the results published, and
this would not happen, in some journals, if the trial is not published first in the site (editors do
not care about ethical issues themselves, but only about reputation, as they need only clinical
trials that are registered, so we have convergence of interests); nowadays, also preclinical trials
are registered and published, obtaining ethical committee approbation, to guard also animal
rights.
In Italy, most of the times pharmaceutical marketing and development are generally in the hands
of pharmaceutical companies, starting as familiar, private organizations, and generally grown
over time (we do not have a national, state owned company); we have sites for multi-centrical
international experimentations, and all sites need approval from their ethical committees, but in
general we have a coordinator site, that gives first approval and it is difficult not to obtain
approval once the coordinator has given it.