Lecture 5

To avoid adverse effects

why do we regulate clinical trials?

Any investigation in relation to humans intended to discover/verify effects of medicinal product, identify adverse effects, study absorption, distribution, metabolism and excretion of products

What is the definition of a clinical study?

Clinical study which fulfils ant of the following conditions:

* Assignment of subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice
* Decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in clinical study
* Diagnostic/monitoring procedures

What is definition of clinical trials?

* Food 


* Surgery
* Cosmetics
* Radiotherapy
* Med devices
* Human whole blood

What is not considered a clinical trial?

Human pharmacology – finding best dosage

What is phase I trials?

Therapeutic Exploratory - checking the dosage and adverse effects

what is phase II clinical trials?

Therapeutic confirmatory – comparison

What is phase III trials?

Post-marketing research

What is phase IV trials?

* Increased harmonisation in application requirements


* Promote and enhance pharmaceutical development

What were the advantages of changing from the CTD to the CTR

* Different interpretations


* Separate assessments by national authorities and ethics committees
* Different approaches in assessment
* Separate applications for each member state

What were the major shortcomings of the CTD?

Any member state where an application for the authorisation of a clinical trials has been submitted

What is the member states concerned (MSC)?

Responsible for conducting primary assessment of the part 1 submission and compiling the assessment report for circulation to the other MSC

What is the reporting member state (RMS)?

* Part 1 – scientific part


* Part 2 – National/local part (ethical review)

What are the two parts of the CTR application approach?

Tacit approval

What happens if the sponsor does not respond to the request before deadline?

45 days (can request more time)

How many days do each member state have to complete assessment?

Database for info submitted under the CTR -

Sponsor submits application dossier to intended member states through CTIS portal

What is CTIS used for?

Yes, however there are a number of exceptions in order to protect economic interest of sponsors

Is the CTIS public?

Unique number referenced on a trial doc

What is the EudraCT Number?

EU CT Number

What has replaced the EudraCT number?

* Protocol


* Investigators brochure
* Clinical study reports
* Inspection reports
* Regulators assessment reports

What additional info will be publicly available in CT regulation?

Development safety update report

What does DSUR stand for?

Disguised as authentic medicines but may contain ingredients of bad or toxic quality

What are falsified medicines?

Outline specific legal responsibilities across the whole life of the product

What do marketing authorisation holders do?

To ensure medicines are safer, effective and of high-quality

What is the ultimate purpose of marketing authorisation assessment?

* POM – prescription only


* OTC – over the counter

What are the two conditions of supply?

Less comprehensive clinical data than normally required is available but where benefit of immediate availability outweighs the risk

What is a conditional marketing authorisation?

1 year

How long are conditional marketing authorisation available for?

* SPC summary of product characteristics


* PIL patient info leaflet
* PAR public assessment report

What are the key post authorisation documents?

SPC

What doc is the PIL derived from?

* Safety of approved medicines


* Post market surveillance

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What is pharmacovigilance?

Discovering previously unrecognised adverse effects and monitoring medical errors

What is the main focus of pharmacovigilance?

* Withdrawal of product


* Suspension of authorisation
* Licence remains in place but additional restriction are introduced
* Any updates changes have to communicated un labelling changer or changes to SPS

What are some of the possible outcomes of pharmacovigilance?

Any untoward medical occurrence that present during treatment but may or may not be a consequence of the treatment

What is an adverse event?

Life-threatening

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What is a serious adverse effect?

Undesirable reaction to a drug

What is an adverse drug reaction?

Adverse reaction where the nature or severity us not consistent with market authorisation

What is an unexpected adverse drug reaction?

Not previously observed or documented in SPC

What are unexpected adverse events?

Due to pharmacovigilance effects, dose related

What is a type A effect?

Rare - little dosage relationship

What are type B effects?

After long term therapy - difficult to prove

What are type C effects?

Delayed - years after drug

What are type D effects?

Ending, withdrawl

What are type E effects?

* Association in time between product and event


* Medical plausibility
* Likelihood or exclusion of other causes

What factors are included to determine likelihood of a casual relationship between product exposure and adverse events?

* A causality is highly probable.


* B not adequate proof of causality
* O data are not adequate to assess causality

What are the three categories of the Karch and Lasagna causality assessment scale?

* Mild


* Moderate
* Serious

What is the classification of adverse events?

Determined by genetic alteration, producing response that is not anticipated

What is an idiosyncratic response?

reaction similar to allergy but not mediated by immune system

What is a pseudoallergy?

Administered drug and patient

what are the factors in adverse reactions?

Data processing network for reporting and evaluating suspected adverse reactions of medicinal products in EEA

What is eudraVigilance?

Suspected Unexpected Serious Adverse Reaction

What does SUSAR stand for?

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* Type 1a – do then tell
* Type 1B – advance notification required

What are the 2 minor variations that can occur?

Changes that may have a significant impact on the quality, safety or efficacy of medicinal product

What is the major variation

* Intended to treat diseases so rare that sponsors would be reluctant to develop them under usual marketing authorisation procedure

What are orphan medicinal products?