Planning an Academic Clinical Trial

Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1317)

Abstract

Clinical trials are performed to discover or verify the efficacy and safety of one or more investigational medicinal product (IMP). Biological medicinal products, including gene therapies, offer groundbreaking new opportunities for the treatment of disease and injury, but they are also highly regulated and trials with these products can be logistically challenging to set up and execute. To ensure a compliant and successful trial, it is important to know and understand the regulatory framework, and to be aware of available guidance documents published to advise the different stakeholders on how to develop, manufacture, handle, administer, or destroy these products safely and legally. This chapter summarizes the standard requirements and considerations applicable for clinical trials with IMPs and also describes additional requirements for trials with gene therapies or genetically modified microorganisms (GMM).

This chapter has been written from the perspective of a UK noncommercial (academic) sponsor. As such, the discussion and guidance has its basis in gene therapy research as governed by UK law. Nevertheless, European legislation and guidance documents are also referenced; most of the following recommendations will be applicable to clinical trials with a gene therapy medicinal product in any European Member State, and the overriding principles would be applicable to any trial.

Key words

Clinical trial Gene therapy ATMP Academic Sponsor Regulatory guidelines Protocol Feasibility Risk assessment Monitoring Budget 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal productsGoogle Scholar
  2. 2.
    Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004Google Scholar
  3. 3.
    Reflection paper on classification of advanced therapy medicinal products. 7th Dec 2012; EMA/CAT/600280/2010Google Scholar
  4. 4.
    Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human useGoogle Scholar
  5. 5.
    Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use, as well as the requirements for authorisation of the manufacturing or importation of such productsGoogle Scholar
  6. 6.
    Good Clinical Practice: consolidated guidance (ICH E6), international conference of harmonization, 10 June 1996Google Scholar
  7. 7.
    Commission Directive 2003/94/EC, of 8 October 2003, laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human useGoogle Scholar
  8. 8.
    Communication from the Commission—detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial (CT-1) (2010/C 82/01)Google Scholar
  9. 9.
    Jones DR, McBlane JW, McNaughton G et al (2013) A regulatory perspective of clinical trial applications for biological products with particular emphasis on advanced therapy medicinal products (ATMPs). Br J Clin Pharmacol 76(2):203–209PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Wydenbach K (2012) Clinical trial applications for biologicals—a UK regulatory clinical perspective. Regul Rapporteur 9(5):5–7Google Scholar
  11. 11.
    Cohen-Hagenauer O (2013) A comprehensive resource on EU regulatory information for investigators in gene therapy clinical research and advanced therapy medicinal products. Hum Gene Ther 24:12–18CrossRefGoogle Scholar
  12. 12.
  13. 13.
    European Commission. Detailed guidelines on good clinical practice specific to advanced therapy medicinal Products. ENTR/F/2/SF/dn D(2009) 35810Google Scholar
  14. 14.
  15. 15.
    https://eudract.ema.europa.eu/. Accessed 2 July 2014
  16. 16.
    European Commission (2003) Detailed guidance on the European clinical trials database (EUDRACT Database), April 2003, ENTR/CT 5Google Scholar
  17. 17.
    De Angelis C, Drazen JM, Frizelle FA (2004) Clinical trial registration: a statement from the international committee of medical journal editors. N Engl J Med 351:1250–1251PubMedCrossRefGoogle Scholar
  18. 18.
    Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cellsGoogle Scholar
  19. 19.
    Commission Directive 2006/17/EC of 8 February 2006 implementing Directive 2004/23/EC of the European Parliament and of the Council as regards certain technical requirements for the donation, procurement and testing of human tissues and cellsGoogle Scholar
  20. 20.
    Commission Directive 2006/86/EC of 24 October 2006 implementing Directive 2004/23/EC as regards traceability requirements, notification of serious adverse reactions and events and certain technical requirements for the coding, processing, preservation, storage and distribution of human tissues and cellsGoogle Scholar
  21. 21.
    Human Tissue Authority (2010) Guide to quality and safety assurance for human tissues and cells for patient treatment. www.hta.gov.uk. Accessed 12 Nov 2010
  22. 22.
    Directive 2009/41/EC of the European Parliament and of the Council of 6 May 2009 on the contained use of genetically modified micro-organismsGoogle Scholar
  23. 23.
    Directive 2001/18/EC of the European Parliament and of the Council on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EECGoogle Scholar
  24. 24.
    The SACGM Compendium of guidance. Part 6: Guidance on the use of genetically modified microorganisms in a clinical setting. Published by the UK Health and Safety Executive. http://www.hse.gov.uk/biosafety/gmo/acgm/acgmcomp/
  25. 25.
    Frewer LJ, Coles D, Van der Lans IA et al (2011) Impact of the European clinical trials directive on prospective academic clinical trials associated with BMT. Bone Marrow Transplant 46(3):443–447PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Hemminki A, Kellokumpu-Lehtinen P-L (2006) Harmful impact of EU clinical trials directive. Academic clinical research in cancer seems to have no future in Europe. BMJ 332:501–502PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Maciulaitis R, D’Apote L, Buchanan A et al (2012) Clinical development of advanced therapy medicinal products in Europe: evidence that regulators must be proactive. Mol Ther 20(3):479–482PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/ECGoogle Scholar
  29. 29.
    Non-clinical studies required before first clinical use of gene therapy medicinal products, 30 May 2008. EMEA/CHMP/GTWP/125459/2006Google Scholar
  30. 30.
    Vulto AG, Stoner N, Balásová H et al (2007) European Association of Hospital Pharmacists (EAHP) guidance on the pharmacy handling of gene medicines. Eur J Hosp Pharm Pract 13(2007/5):29–39Google Scholar
  31. 31.
    Rajadhyaksha V (2010) Conducting feasibilities in clinical trials: an investment to ensure a good study. Perspect Clin Res 1(3):106–109PubMedCentralPubMedGoogle Scholar
  32. 32.
    Kibby M (2011) Patient recruitment feasibility–defining clinical trial feasibility and establishing a formula for patient recruitment success. Appl Clin Trials Online http://www.appliedclinicaltrialsonline.com/appliedclinicaltrials/Articles/Patient-Recruitment-Feasibility/ArticleStandard/Article/detail/726495
  33. 33.
    Perry N (2014) Tips for research nurses 4; undertaking a feasibility assessment for a clinical trial. Published by The Institute of Clinical Research. http://www.noclor.nhs.uk/sites/default/files/u10/Feasibility%20check%20list.pdf. Accessed 2 July 2014
  34. 34.
    UK Statutory Instruments 2004 No. 1031. The medicines for human use (clinical trials) regulations 2004. http://www.legislation.gov.uk/uksi/2004/1031/pdfs/uksi_20041031_en.pdf. Accessed 2 July 2014
  35. 35.
    WMA Declaration of Helsinki. Ethical principles for medical research involving human subjects. 59th WMA general assembly, Seoul, Republic of Korea, Oct 2008Google Scholar
  36. 36.
    Chan A-W, Tetzlaff JM, Gøtzsche PC et al (2013) SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ 346:e7586PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    MRC/DH/MHRA Joint Project. risk-adapted approaches to the management of clinical trials of investigational medicinal products. Version: 10th Oct 2011. http://www.mhra.gov.uk/home/groups/lctu/documents/websiteresources/con111784.pdf
  38. 38.
    Guideline on follow-up of patients administered with gene therapy medicinal products. EMEA/CHMP/GTWP/60436/2007Google Scholar
  39. 39.
    Communication from the commission. Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from clinical trials on medicinal products for human use (CT-3) (2011/C 172/01)Google Scholar
  40. 40.
    Development Safety Update Report (E2F). International conference of harmonization of technical requirements for registration of pharmaceuticals for human use, 17 Aug 2010Google Scholar
  41. 41.
    Delgado-Rodriguez M, Ruiz-Canela M, De Irala-Estevez J et al (2001) Participation of epidemiologists and/or biostatisticians and methodological quality of published controlled clinical trials. J Epidemiol Community Health 55:569–572PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Guidance on investigational medicinal products (IMPs) and ‘non investigational medicinal products’ (NIMPS) (Rev. 1, March 2011) SANCO/C/8/SF/cg/a.5.001(2011)332855Google Scholar
  43. 43.
    Structure and content of clinical study reports (E3). International conference of harmonization of technical requirements for registration of pharmaceuticals for human use, 30 Nov 1995Google Scholar
  44. 44.
    Guidance for the notification of serious breaches of GCP or the trial protocol. Version 5 (060114).docx. http://www.mhra.gov.uk/home/groups/isinsp/documents/websiteresources/con060111.pdf.
  45. 45.
    Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 340:c332PubMedCentralPubMedCrossRefGoogle Scholar
  46. 46.
    DAMOCLES Study Group, NHS Health Technology Assessment Programme (2005) A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet 365(9460):711–722CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  1. 1.Joint Research OfficeUniversity College LondonLondonUK

Personalised recommendations