REGULATORY PROBLEMS IN CARING OUT PRE- AND POST- AUTHORISATION CLINICAL TRIALS

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REGULATORY PROBLEMS IN CARING OUT PRE- AND POST-
AUTHORISATION CLINICAL TRIALS

• Dr Penka Decheva
• GCP Inspector, BDA

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New Law on Medicinal Products
13 April 2007

• Main goals
• Synchronisation of the National Legislation with
  the European Directives
• Active implementing of EU Regulations
• To guarantee quality, efficacy and safety of
  medicinal products on the Bulgarian, respectively
  European market.
• 14 Titles Title IV Clinical Trials
• 297 articles

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New Law on Medicines

• Direct implementation of
• Directive
  2001/20 EC
• To simplify and harmonise the administrative
  provisions governing clinical trials by
  establishing a clear, transparent procedure
• To facilitate the internal market of medicinal
  products while at the same time maintain
  appropriate levels of protection for public
  health

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New Law on Medicines

• To provide an environment for conducting clinical
  research that protects participants without
  hampering the discovery of new essential
  medicines
• To create conditions condusive to the effective
  co-ordination of such clinical trials in the
  European Community by the authorities concerned

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General provisions

• Clinical trials in human subjects shall be
  conducted with observation of the basic
  principles for the protection of human rights and
  human dignity in any medico-biological study
  according to the Declaration of Helsinki.
• Any clinical trials of medicinal products in
  human subjects including bioavailability and
  bioequivalence shall be planned, conducted, and
  reported in compliance with the principles of
  Good Clinical Practice.
• The rules of Good Clinical Practice shall be laid
  down in an ordinance issued by the minister of
  health.

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General provisions

• The rights, safety, and health
• of the subjects in the clinical trials
• shall be placed above the interests of science
  and society.

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Ethics committee

• Ethics Committee for multicentre clinical trials
  shall be established to the minister of health
  the composition of which shall be determined by
  an order.
• Ethics committees shall be established at the
  healthcare establishments where clinical trials
  are to be conducted the composition of which
  shall be determined by an order of the manager of
  the healthcare establishment.

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Ethics committee

• The BDA shall maintain and keep a public register
  of ethics committees.
• Central Ethics Committee shall be established to
  the Council of Ministers.

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Authorisation to conduct a clinical trials

• The ethics committee shall
• 1. give positive opinion
• 2. refuse in a motivated manner, or
• 3. request amendment of a part of the
  documentation as a condition for obtaining a
  final opinion.

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Authorisation to conduct a clinical trials
Within 60 days from the submission of an
application, the ethics committee shall pass
resolution with an opinion, which shall be sent
to the applicant and the BDA.
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Authorisation to conduct a clinical trials

• Where the opinion of the respective ethics
  committee is negative,
• the applicant can appeal before the Central
  Ethics Committee within 90 days of the date of
  notification.
• The opinion of the Central Ethics Committee shall
  be final and binding on the respective ethics
  committee.

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Authorisation to conduct a clinical trials
Within 60 days of the date of submission of an
application for a clinical trials of medicinal
products , the BDA shall notify the applicant
that a. the clinical trials can be
conducted on the territory of the Republic of
Bulgaria or b. the clinical trials cannot be
conducted indicating the reasons therefore. In
the cases ?, the CRO can submit to the BDA an
application amended in accordance with the
motives set out or submit the required
information in accordance with the requirements
of the BDA within 30 days.
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Authorisation to conduct a clinical trials

• Within 30 days of the submission of the amended
  application or the additional information, the
  BDA shall notify the applicant in writing that
• a. the clinical trials can be conducted on
  the territory of the Republic of Bulgaria or
• b. that it refuses the conduct of the
  clinical trials stating the reasons therefore.

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Authorisation to conduct a clinical trials

• The refusal shall be subject to appeal under the
  terms of the Administrative Procedure Code.
• The clinical trials can be started provided that
  within the time limit the BDA has not issued a
  notification with motives of disapproval of the
  clinical trials.

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Amendments

• Essential amendment in the conduct of the
  clinical trials shall be any amendment in the
  study protocol and/or in the information and the
  documentation , which can affect
• -the safety or the physical and mental
  immunity of the study subjects
• -the scientific value of the clinical trials
• -the conduct or the organization of the
  clinical trials
• -the quality or the safety of any study
  medicinal products.

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Premature Termination or Suspension of the Trial

• The CRO or the investigator can undertake
  urgent measures to protect the study subjects
  from suddenly occurred risks for their safety and
  health.
• In this cases the CRO shall immediately
  notify the BDA and the respective ethics
  committee about the undertaken actions and the
  reasons for the decision.

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Premature Termination or Suspension of the Trial

• In the cases of cessation the BDA shall
  immediately notify the respective ethics
  committee, the other competent authorities, the
  European Medicines Agency, and the European
  Commission about the undertaken measures and the
  reasons therefore.

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Pharmacovigilance

• The sponsor shall notify the BDA, the regulatory
  bodies of all Member States where the clinical
  trials is conducted in case of a multicentre
  trials, and the respective ethics committee of
  any suspected serious adverse drug reaction
  occurring in the course of the clinical trials,
  which has resulted in death or has been
  life-threatening not later than 7 days of receipt
  of information thereof.

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Pharmacovigilance

• The sponsor shall provide additional
  information on the case within 8 days of the date
  of the notification sent.
• The sponsor shall notify any other suspected
  unexpected serious drug reactions occurring in
  the course of the clinical trials not later than
  15 days from the date of receipt of the
  information for their occurrence.

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Pharmacovigilance

• The BDA shall document any information about
  suspected unexpected serious adverse drug
  reactions of the study medicinal products.

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Notification of the end of a clinical trial

• The CRO shall notify in writing the BDA and the
  respective ethics committee of the end of the
  clinical trial on the territory of the Republic
  of Bulgaria
• The notification shall be submitted within 90
  days of the closure of the clinical trials.

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Non-interventional study

• A non-interventional study shall be conducted
  with medicinal products authorised for use in the
  Republic of Bulgaria where these are studied to
  obtain additional information about the product
  prescribed in the usual manner in compliance with
  the conditions determined in the marketing
  authorisation.

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Clinical Trials 2006-2007
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BDA and Clinical Trials Current Experience

• Statistics for 2006-2007

2006 2007
Bioequivalence 23 6
Phase I-I/II 6 2
Phase II 47 12
Phase III 88 9
Phase IV 3 0
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Main challenges

• The most important challenge
• to transpose the written text into a really
  functioning system

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Main challenges

• Harmonisation of assessments, with other member
  states.
• Development of SOPs and guidelines.
• Development of Regulatory Standard for
  evaluation .
• Building up staff abilities.

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Main challenges

• Adequate regulatory approach to the preclinical
  safety studies, adverse events/adverse drug
  reactions in clinical trials and post-marketing
  in terms of evaluation, control, scientific
  advice.
• Building up of adequate IT capacity.

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Main challenges

• Exchanche of information, globalisation of
  regulation at national level .
• Participation in groups and committees of the
  European Commission.
• Scientific assessment of highest quality.

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• We have the self-confidence that the
  Bulgarian Drug Agency is able to meet the high
  requirements and expectations both of the
  European Union and of all the participants on the
  medicines market and above all of the Bulgarian
  citizens.

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Thank you!