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Summary Clinical Development and Clinical Trials (AM_1180)
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This document consists of a summary of the course Clinical Development and Clinical Trials (AM_1180).
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Lecture 1. Introduction to clinical researchAssignment
o Use the content discussed in the video’s. Do not answer the questions without using the
discussed content.
o Talk in the video as if you are explaining it to someone.
o Group assignment: based upon request of information of the US government. Wanted to
know from stakeholders a number of things. What do you think? Select one question and
formulate a response like you would send it back to the US government (professional and
realistic).
Typically something goes wrong every 10 years. In 2006 there was the elephant men trial that went
wrong in the UK, in which hands and faces were swelling up. There were 6 people in the trial, in which
5 had organ failure and 1 had no problem (control). All the 5 that had organ failure, experienced this at
the lowest possible doses. The drug was supposed to be save, as was seen in animal studies. This showed
how different animals and humans react to drugs. In 2016, something went wrong in France. One person
experienced severe side effects after a couple days. By the time this person experienced side effects
and was hospitalized, another person already got dosed. When something like in the UK and France
happens, the companies are gone. This shows that clinical research has high cost and high risk, but also
high profit.
Companies need 2 money making products to survive. If a product from one country, which is already
on the market, interacts with a new product that comes to the market, the first product is the problem
(chemically determined) and it needs to be taken of the market. This happened to Bayer. When a
product is taken off the market, companies have to options to survive. They can sell their company to
another company with enough products or buy another company that has enough products. When a
company loses a product, by taking it off the market, it is not attractive to be bought. The only option
that remains is then to buy another company. Luckily this was not a problem for a big company like
Bayer.
Normally, the development of drugs takes a lot of years. This was not the case for the Corona vaccine.
The Corona vaccine was made so fast because the financial risk was taken off the table by the
government. This cannot be happening for every single product because the government does not have
the money for that.
Definitions
Efficacy Does the product do what you want it to do?
Efficiency Products can have a high efficacy and effectiveness but a low efficiency. An example
of low efficiency is when a product does what you want it to do, and does that well,
but it takes a long time to get to that outcome.
Effectiveness Hoe well does the product do what you want it to do?
Safety is always an outcome of a trial. How tolerable the side effects of a drug are encountered depends
on de desirability of a drug and the severity of the illness. Together with safety, efficacy is always
important but efficacy is not tested in the early trials.
A “me too” product is a product that does the same thing as a product that is already on the market. It
does not add anything (no extra benefit) and should not be added to the market. It always depends on
which drug comes first on the market, which makes the industry very competitive. If somebody comes
to the market first, they beat you and you become the “me too” product. There is thus a big commercial
aspect.
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,Aim of drug development is to get the drug to the market. This gives the scientific proof of that products
safety, efficacy, efficiency, effectiveness, etc. Authorities, like the EEA, EMA, FDA, etc., also need to be
convinced to reimburse the product. Reimbursement is the process in which the money that has been
put into the development of the drug is paid back. Reimbursement typically occurs through the sales of
the drug, where healthcare providers or payers, such as insurance companies or government healthcare
programs, pay for the drug when it is prescribed to patients. For a drug to be reimbursed, a new data
set is needed which contains real world evidence.
Clinical trials
A clinical trial is one step in the drug development process and involves human subjects. Some people
do not like the word subjects and like to call them participants. Clinical trials are used to investigate new
methods of preventing, diagnosing or treating a disease. Most of these clinical trials are interventional
trials in which subjects undergo procedures other than the usual practice. It is difficult to determine
whether something is interventional. A questionnaire could also be an intervention, because when the
questions about psychological states have a mental impact which are interventional. Even asking people
to participate in a trial is already an intervention. Sometimes there are observational trials in which
subjects are observed without undergoing any interventions which is according to the usual practice.
During observational trials, people know that they are being watched. This results in the fact that people
experience thing differently, because they want to report everything, leading to over-reporting of
events. Clinical trials can also be done in a commercial setting or in an academic setting (non-
commercial). When clinical trials are performed in academic setting and it needs to go to the market, a
collaboration with a company is necessary.
Parties involved
Sponsor A sponsor is a company that takes the responsibility for the entire trial
(outcome, financing, publish results, setting up the protocol, etc.), but is not
responsible for the data. The outcome of the trial that the sponsor works with
and thus the basis of which they write their articles is never the responsibility
of the company because otherwise they are able to influence the data and it
cannot be scientifically clean.
Investigator/site The investigator is responsible for the data, but they do not own the data.
After all the data is gathered, it is locked, and it is given to the sponsors.
Institutional review The institutional review board (IRB), also known as the independent ethics
board (IRB) or committee (IEC), review the ongoing trials. They ensure the safety and
independent ethics protection of the human participants involved in research studies.
committee (IEC)
Regulatory The regulatory authorities, also known as health authorities, are government
authorities/health organizations like, European Medicines Agency (EMA), Competent Authority
authorities (CA) for every country, Food and Drug Administration (FDA) in America, and
Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. These
authorities are responsible for overseeing and regulating various aspects of
public health, including the safety, efficacy, and quality of medical products
and healthcare practices.
Vendors Vendors are external entities or companies that are used for the outsourcing
of trials by the sponsors. Some examples of Vendors are the Contract
Research Organization (CRO), Site Management Organization (SMO), central
laboratory, central ECG reading, IVRS/IWRS vendor, RNPS Services, Tech
vendors, etc.
2
,Tasks and parts of clinical trials
There are many different tasks involved in clinical trials: (1) set objectives/hypothesis for trial, (2)
development of protocol and other trial related documents, (3) recruitment of subjects, (4) management
of execution of trial, and (5) data analysis.
A clinical trial starts with the (1) trial preparation (prep).
During this, essential documents are developed and
collected, site selection takes placed, IEC/CA approval is
obtained, site initiation takes place and the report is
written. (2) When they can start enrolling subjects the
first recruitment activity takes place and the trial
execution (do) starts. During this procedure site
management activities take place, there are routine
monitoring visits, the essential documents are updated,
the report is written, query resolution takes place, and
there are close-out visits (visit arranged by the sponsor
of the research study to ensure that all necessary aspects of the study closure have been addressed).
(3) After the database is locked, the trial execution stops, and the trial analysis & reporting (analyze)
starts. During this process, there is mainly administrative tasks, filling, and updating of the database.
This trial analysis & reporting takes place until the Clinical Study Report (CSR) is finished.
The sponsors have an R&D department which involves many tasks like (1) monitoring/site management,
(2) data management, (3) statistics, (4) medical writing, (5) drug safety/pharmacovigilance, (6) quality
assurance, and (7) regulatory affairs. Besides the R&D department, sponsors also have a non-R&D
department that is involved in tasks like (1) sales and marketing, (2) supporting sales and R&D, the
medical department with a medical director as head and is supports both the sales and the R&D, and
(3) finance and legal tasks (business department).
The clinical trial team consists of many
different people: (1) a trial manager who
leads the trial, (2) a Clinical Research
Associate (CRAs) who monitors the
running of clinical trials, (3) a Clinical Trial
Administrator who is responsible for the
planning and coordination of the clinical
trials, and (4) line managers who are
responsible for directly managing
individual employees or teams.
3
, Lecture 2. Lifecycle of a drug
There are different stages of drug research. (1) In silico research are experimentations performed by the
computer. (2) In vitro (meaning “in glass”) research describes experiments performed outside of a living
organism, e.g. in a test tube or petri dish on cells. (3) In vivo (meaning “within the living”) research refers
to experiments performed in or on whole living organisms like a laboratory animal. (4) In humano
research refers to research performed an humans.
There are two aims of the drug development process. (1) Obtaining a market authorization application
(MAA) in which a drug is shown the be (a) safe, (b) efficacious, and (b) there is clean and reproducible
manufacturing. (2) Another aim is to sell the drug on the market.
The drug development process consists of many different stages that
together take a lot of years. These stages are discovery,
synthesis/testing/selection, pre-clinical, clinical (stage I, II, and III), and
MMA. After the drug development process goes to the next stage, the
chance on market introduction increases.
De drug development process is (1) complex, with law/regulations,
many disciplines/departments involved, and technically complex, (2) expensive, (3) full of risks, and (3)
have a short period for Return on Investment (ROI). The drug development process takes up to 20 years
and the patent life is short. There are 10 000 compounds tested to get 1 on the market. Of these 10-15
are tested on humans. More than 50% are dropped out in phase I. The development of a drug costs
between 900 million euros and 1.5 billion euros per marketed drug and 1.5 million euros per day
marketing delay. Only 1 in 4 recoups it own development cost. This means that only 1 in 4 drugs
generate the revenue from the sale or use that is sufficient to cover the expenses incurred during its
development. In addition, only 1 in 100 is a blockbuster. A blockbuster is a drug that generates more
then 1 billion euros per year sales.
The cost of
drug
development is
increasing over
the years. The
Tufts Center for
the Study of Drug Development showed that in
2014 is costs 2.6 billion dollars to bring a drug to the market where it was in 2009 1.6 billion dollars.
Each stage of the research costs millions of dollars, depending on the therapeutic area. The area of the
respiratory system is the most important area, costing a total of 115.3 million dollars. The least
expensive therapeutic area is the genitourinary system, costing a total of 44.0 million dollars.
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