CLINICAL RESEARCH IN EUROPE AFTER THE EU DIRECTIVE ON CLINICAL TRIALS. DOMENICO CRISCUOLO, MD, FFPM CMO at CREABILIS THERAPEUTICS IFAPP PAST PRESIDENT

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1 CLINICAL RESEARCH IN EUROPE AFTER THE EU DIRECTIVE ON CLINICAL TRIALS DOMENICO CRISCUOLO, MD, FFPM CMO at CREABILIS THERAPEUTICS IFAPP PAST PRESIDENT

2 EU : SOME FACTS 25 MEMBERS + 3 CANDIDATES PEOPLE 4,5 sq.km (7 largest country) In variaetate concordia

3 EU MAJOR ACHIEVEMENTS the European Parliament the Euro ()

4 THE EU DIRECTIVE ON CLINICAL TRIALS: WHY? HARMONIZATION OF PROCEDURES BETTER PATIENTS PROTECTION COMPETITIVENESS

5 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME DATES Issued on May 1st, 2001 By May 1st, 2003 all EU countries had to issue rules for local implementation By May 1st, 2004 the Directive is active NOTE : first draft circulated in 1992

6 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS General Introduction on: Good Clinical Practice Protection of Clinical Trial Subjects Clinical Trials on Minors Clinical Trials on Incapacitated Adults Ethics Committee

7 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 6 : Ethics Committee The Ethics Committee shall have a maximum of 60 days from the date of receipt of a valid application to give its reasoned opinion to the applicant and the competent authority in the Member State concerned.

8 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 6 : Ethics Committee Within the period of examination of the application for an opinion, the Ethics Committee may send a single request for information supplementary to that already supplied by the applicant.

9 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 6 : Ethics Committee No extension to the 60-day period shall be permissible except in the case of trials involving medicinal products for gene therapy or somatic cell therapy or medicinal products containing genetically modified organisms. In this case, an extension of a maximum of 30 days shall be permitted.

10 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 7 : Single Opinion For multi-centre clinical trials limited to the territory of a single Member State, Member States shall establish a procedure providing, notwithstanding the number of Ethics Committees, for the adoption of a single opinion for that Member State.

11 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 7 : Single Opinion In the case of multi-centre clinical trials carried out in more than one Member State simultaneously, a single opinion shall be given for each Member State concerned by the clinical trial.

12 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 9 : Commencement of a clinical trial The sponsor may not start a clinical trial until the Ethics Committee has issued a favourable opinion and inasmuch as the Competent Authority of the Member State concerned has not informed the sponsor of any grounds of non-acceptance.

13 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 9 : Commencement of a clinical trial Before commencing any clinical trial, the sponsor shall be required to submit a valid request for authorisation to the Competent Authority of the Member State in which the sponsor plans to conduct the clinical trial.

14 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS Article 9 : Commencement of a clinical trial In consultation with Member States, there will be guidance on: the format and contents of the request, and the documentation to be submitted (quality and manufacture of investigational product, tox, pharmacology, clinical data and IDB); the presentation and content of amendments; the declaration of the end of the clinical trial.

15 THE EU DIRECTIVE ON CLINICAL TRIALS: SOME KEY ASPECTS IN 2002 I WROTE: The Directive represents a significant effort to harmonize European procedures to start a clinical trial, in order to have a common approach and to speed up the process. Work is in progress, in order to prepare guidelines and to modify local regulations which are not in line with the Directive.

16 INDEED I AM AN INCURABLE OPTIMIST! The EU Directive will produce great results!

17 MAIN REASONS FOR A PARTIAL SUCCESS STORY RESISTANCE TO ABANDON LOCAL PROCEDURES DUALISM EC vs COMPETENT AUTHORITY LACK OF GUIDELINES ON FORMATS TO BE USED CONCERNS FROM ACADEMIC RESEARCH THE EXPLOSION OF ADRs NOTIFICATIONS THE ARRIVAL OF NEW MEMBER STATES (languages)

18 THE PARADOX OF THE COMPETENT AUTHORITY ETHICS COMMITTEE COMPETENT AUTHORITY OPINION SITUATION IN UK OPINION

19 THE PARADOX OF THE COMPETENT AUTHORITY ETHICS COMMITTEE COMPETENT AUTHORITY OPINION SITUATION IN ITALY OPINION

20 THE PARADOX OF THE COMPETENT AUTHORITY ETHICS COMMITTEE COMPETENT AUTHORITY OPINION OPINION SITUATION IN THE NETHERLANDS

21 THE PARADOX OF THE COMPETENT AUTHORITY FIRST ISSUE: THE DUALISM (ANTAGONISM?) BETWEEN ETHICS COMMITTEE AND COMPETENT AUTHORITY NEEDS URGENT CLARIFICATION OF RESPECTIVE ROLES!

22 THE COMPLAINTS OF ACADEMIC RESEARCHERS ACADEMIA HAS NO RESOURCES TO COMPLY WITH ALL GCP AND GMP REQUIREMENTS OF THE EU DIRECTIVE. THE EU DIRECTIVE IS KILLING ACADEMIC (NON-PROFIT) RESEARCH!

23 THE OPINION OF THE DANISH MEDICINES AGENCY MOST HOSPITALS HAVE GCP UNITS TO SUPPORT INVESTIGATORS TRIALS ACADEMIC TRIALS STARTED TO DECLINE IN THE EARLY 90s TRIALS IN DENMARK : total number industry academia from: L.Berendt Dan.Med.Agency poster EACPT 2007

24 THE COMPLAINTS OF ACADEMIC RESEARCHERS SECOND ISSUE: EU MUST ENSURE THAT EU DIRECTIVE DOES NOT LIMIT THE INDIPENDENCE OF ACADEMIC RESEARCH

25 THE WORKLOAD AT ETHICS COMMITTEES Article 17: ALL SUSPECTED SERIOUS ADVERSE REACTIONS SHALL BE REPORTED TO C.A. AND TO E.C. EACH MEMBER STATE SHALL ENSURE THAT ALL SUSARs.. ARE RECORDED

26 THE WORKLOAD AT ETHICS COMMITTEES AFTER THE PROVISIONS OF ARTICLE 17, NOTIFICATIONS OF ADRs TO ECs MOVED FROM AN AVERAGE OF 10 TO MORE THAN 500 PER MONTH. MOST ECs HAD TO INCREASE STAFF TO EVALUATE AND RECORD ALL SUSARs. THE QUALITY OF NOTIFICATIONS HAS DEFINITELY NOT IMPROVED.

27 THE WORKLOAD AT ETHICS COMMITTEES THIRD ISSUE: MODIFY ARTICLE 17 IN ORDER TO IMPROVE THE CLINICAL SIGNIFICANCE OF SUSARs NOTIFICATIONS.

28 CONCLUSIONS THE EU DIRECTIVE ON CLINICAL TRIALS REPRESENTS A SIGNIFICANT EFFORT TO HARMONIZE AND STREAMLINE PROCEDURES ACROSS THE EUROPEAN UNION. THE IMPLEMENTATION OF A EUROPEAN LAW OVER EXISTING REGULATIONS IS A COMPLEX MATTER. THE BALANCE AFTER 3 YEARS IS NOT SATISFACTORY: ADDITIONAL EFFORTS MUST BE GRANTED TO OVERCOME OBSTACLES AND ALSO TO MODIFY SOME WEAK PARTS OF THE DIRECTIVE.