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Model essay questions – ECPM Exam 2017
Topic: Clinical Development
Question 1:
What does ICH stand for and what does it regulate? Please give some examples of
specific ICH requirements.
Model answer
ICH is the International Conference on Harmonization. It is an international body formed in 1990
to harmonise the requirements for registration and approval of medicinal products in various
countries of the world. It is a joint working body of all stakeholders involved in development and
approval of medicinal products and devices like the regulatory authorities, pharmaceutical
companies, academic institutions and other public health bodies in the participating countries.
Initially the aim was to harmonize requirements for the three big pharmaceutical markets of the
world i.e. USA, EU and Japan. However many other countries joined in the initiatives and have
since adopted the requirements and the guidelines issued by the ICH as laws. The vision of the
ICH is to reduce the time and investment required to develop drugs by preventing repetitive
studies as required by each country. This will benefit the all stakeholders - regulatory agencies,
pharmaceutical companies and society in general. It will prevent excessive use of animals in
research and undue exposure of patients in clinical trials at sub therapeutic or toxic doses. The
ICH is headed by a steering committee and has several sub committees that focus on sub
specialities. Despite of years of work by the ICH not all requirements for the grant of marketing
authorisations have been harmonised even in USA, EU and Japan. Japan sometimes has
separate requirements based on its medical practise or genetically distinct populations. There is
also still reluctance in accepting any foreign data by the Japanese authorities based on the
above facts.
The ICH is also responsible for the MedDRA which is a global medical terminology dictionary to
code adverse events reported in clinical trials to standard preferred terms for ease of
comparison. The MedDRA is periodically updated and released to the users for a license fee.
The ICH holds regular meetings to discuss relevant regulatory issues and update its various
guidelines. It also conducts trainings for all interested professionals and government agencies.
The various guidelines issued by the ICH can broadly be classified into Q, S, E and M i.e.
Quality, Safety, Efficacy and Multidisciplinary. The Quality guidelines deal with Chemistry and
manufacturing issues and are based on GMP. Safety guidelines elaborate the specific
requirements for demonstrating the toxicology and safety of the drugs seeking marketing
authorization. For example S9 is the guideline for Safety of Oncology compounds. Efficacy
guidelines elaborate the specific requirements for demonstrating the clinical effectiveness of
specific therapeutic classes like antibiotics, antihypertensives, anticancer etc. These guidelines
describe broadly the choice of population, the end points to be used in clinical trials to support
the efficacy claim. Any deviations or innovations to these guidelines need to be specifically
agreed upon with the regulators in advance during pre IND (or equivalent) and end of phase 2
meetings. Statistical principles in clinical trials are laid down in these guidelines. Newer topics
like strategies to run clinical trials with enriched populations also form the topic of recently issued
guidelines. The most famous perhaps is the ICH-GCP guideline E6 which has been adopted by
most countries of the world and is now an internationally recognised standard for performing
clinical trials in healthy subjects or patients.
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Topic: Regulatory Affairs
Question:
You plan to apply for registration of a new active substance (new chemical entity) in the
EU. List the options submission and describe the different possibilities you would
choose to achieve market authorisation in more than just one EU country. How flexible
are you in the choice of these options and what are the strategic considerations?
Model Answer
There are the following possibilities for applying for registration in EU: The Centralised
Procedure, the National Procedure, the Mutual Recognition Procedure, and the Decentralised
Procedure.
The Centralised Procedure is mandatory for some drugs as antivirals, for cancer, diabetes,
biotechnological manufactured drugs, immunological diseases, orphan diseases. With this
procedure the sponsor can obtain a marketing authorization for all EU countries plus Norway
and Iceland. There will be one identical Summary of Product Characteristics, one labelling and
packaging for all those countries. The sponsor generates a registration dossier according to
Common Technical Document (CTD) and submits it to EMA (European Medicines Agency). At
the EMA there will be one EU country taking the role as Rapporteur and another country the CoRapporteur role. The Rapporteur assesses the submitted registration dossier, generates an
Assessment report and presents it to the CHMP. CHMP can ask for advice from Scientific
Advisory groups and gives input to the assessment report. The PRAC gives input from the Drug
Safety and Risk perspective. The CHMP makes a recommendation to the EU Commission that
grants the Marketing Authorization. The Report (EPAR) is published and made public on the
EMA website also in case of a negative assessment.
The National Procedure is a procedure, where the Company submits the CTD dossier to a
Competent Authority of the country its choice and follows the local requirement of the
registration procedure. The Marketing Authorization Holder can receive a Marketing
Authorization only for those countries, where the drug has been approved. The procedure has to
be done country by country.
The Mutual Recognition Procedure can be used, when a Marketing Authorization in one EU
country is already obtained and the Marketing Authorization Holder would like to receive
Marketing Authorization in few other or all other EU countries. After the company has submitted
the registration dossier one Competent Authority of a EU country takes the role of the Reference
Member State. The other EU countries, for which the Marketing Application was submitted, are
called the Concerned Member State. The Reference Member State reviews the dossier
according to its local registration procedure and presents a report and the Summary of Product
Characteristics and Labelling, Packaging material to the concerned member States. The
Concerned Member States give their input and the Reference Member State coordinates the
feedbacks. This process lasts 90 days without clock stop. The Report is published on the
website of CMDh, HMA.
The Decentralised procedure is similar to the Mutual Recognition procedure. However, this
procedure applies, if there is no national Marketing Authorization available yet. This process
lasts for 210 days and two clock stops.
The flexibility of those procedures: The Centralised Procedure is a win all or nothing, which
means that if the registration is positive there is a market entry to all EU countries, if the
registration fails, there is no market entry to the whole EU. This could be very critical. The
national procedure is flexible, however, the need to follow each local registration procedure and
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to generate in worst case several different registration dossiers, SmPCs, Labelling, Packaging,
could take a lot of time and resources.
The Mutual Recognition and Decentralised procedure can be convenient for companies of
drugs, that are not required to go through the centralised procedure and that are not globally
organised. Smaller companies with affiliates in few EU countries could benefit from those
procedures.
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Topic: Safety, Pharmacovigilance
Question:
When a humanised antibody was applied in a recent phase I study in humans for the first
time, it caused an unexpected severe immunological reaction. Please express your
thoughts regarding this case. What precautions should have been taken before starting
the study and how could the reaction have been prevented?
Model Answer
Obviously, this is the Tegenero Case where TGN1412 (agonistic CD28 antibody to be
developed for autoimmune / immunodeficiency disease) was given for the first time to 6 healthy
volunteers, at the same time, and all of them developed a cytokine storm / multi-organ failure
with some fatal outcome - as compared to the 2 subjects treated with placebo, who did not show
such reaction.
Which precautions should have been taken before start of the study?
- an appropriate disease model was missing to better understand the mechanism of action
of this new antibody
- no learning from similar drugs as described in the literature
- it was not paid attention to existing pre-clinical data pointing to a potential for
exacerbated immune stimulatory effects
- drug was not tested on human PBMCs to demonstrate the activity of the drug in vitro in a
human disease model compared to PBMCs from the monkey where some pre-clinical
work was performed
- there was no linkage for in vitro - in vivo activity
- it was assumed that based on the amino acid sequence homology there should as well
be same functional activity across different species - however species-specificity
(obvious for the immune system) was not tested appropriately
- anti-CD28 can either activate the T-cell pool thereby leading to an activation of the
immune system - or it may activate T-cells, thereby leading to inhibition of immune
system; however both scenarios were not addressed upfront adequately
- the dose was calculated based on NOAEL / tolerability / toxicology considerations
without looking at pharmacological parameters - however there was 90% target
occupancy at the first dose used in health volunteer, who have not a compromised
immune system
- not all available information was given to the assessors
How could the reaction have been prevented?
- considerations about healthy volunteers as right trial subjects for such a stimulatory
antibody as healthy volunteers do not have an impairment of their immune system
- first dose calculation should have been based on MABEL (minimum anticipated
biological effect level) - as it is a high risk molecule targeting the immune system, and
because it was given to healthy volunteers with no impairment of their immune system;
first dose calculation based on toxicity in most sensitive species is the wrong approach in
such a case - which was further demonstrated by 90% target occupancy
- the design of the trial was not appropriate: 1. it was given to healthy volunteers without
further precautions, 2. it was given to all patients at the same time without any
observation time after first patient, 3. question-based design would have been
appropriate to learn more about the exposure, mechanism, efficacy and safety of the
drug, 4. there was no linkage to a appropriate disease model
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with an appropriate study design, the disaster could at least have been partially
prevented
the health authority (UK) giving the approval for the trial did not do their proper own
critical review of the data provided - as was obvious from some "copy paste" sections in
their letter, taken directly out of the protocol / IB
What needs to be considered for FIH (first in human):
- high risk molecules targeting the immune system need special care in their development
with special emphasis on pre-clinical disease models as well as on the non-clinical safety
package
- first dose calculation (as described above) should be conservative and based not only on
toxicology (NOAEL) but as well on pharmacology (MABEL) - especially with targeted
agents and prototypic drugs
- for such drugs a question-based design would be appropriate
What impact did the Tegenero Case have on drug development?
Ethics committee and health authority have now a higher focus on the use of appropriate
disease models, on the justification to use healthy volunteers, on first dose calculations and trial
designs for FIH, on appropriate safety package for high risk molecules.
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