Clinical Trial Applications Process

Introduction

As a new pharmaceutical company on the market, our development will depend on the success of the clinical trial process. However, to start it, we must first apply for approval by Authority Body. As an employee of the regulatory affairs department, I like to describe a process of clinical trial application.

The Information defined below is to understand the importance of steps required to receive validation and acceptation by HPRA.

The Directive 2001/20/EC tells us that the sponsor can`t start a clinical trial until “the Ethics Committee has issued a favourable opinion (…) and has not informed the sponsor of any grounds for non-acceptance.” Before starting any clinical trial, the sponsor is obligatory to submit a valid request for authorisation to the competent authority in which the sponsor plans to lead the clinical trial. [1]

Under the New Clinical Trial Regulation 536/2014 sponsor should pursue the documents relevant to the Clinical Trials Directive. Complete collection of rules and regulations governing medicinal products in the European Union are included in Eudralex, Volume 10. It`s a Guidance Documents applying to Clinical Trials.

My work presents stages of Clinical Trial Application process, required timeline for the assessment, purpose and duties of the Ethics committee and new consideration of the Clinical Trial Regulation.

From the Application to the Authorisation

Eudralex document defines a Clinical Trial as a clinical study, an investigation to discover the pharmacodynamics effects of any medicinal products. The Clinical Trial it`s to verify reaction, absorption, metabolism of one or more medicinal products to the human body.[2]

a) Clinical Trial application procedure and timeline for the assessment

Regulation 536/2014 tells us that in Ireland the HPRA establishes a pilot project for assessment of clinical trial applications. Under the Clinical Trial Regulation, assessment of Clinical Trial application dossiers will be split into two parts. Part I documents will be valued by the (HPRA) and ethics committee (EC), and Part II documents will be reviewed by the ethics committee only.

The sponsor should submit the applications and any responses to the HPRA, who will provide relevant documents to the EC chosen by the sponsor through the HPRA IT communication platform.

By law, all information entered in the clinical trial database is publicly available, except personally and commercially confidential information.

• Application procedure

Applications should be submitted via CESP, or by the submission of a dossier on CD. The application can also be sent to email submissions@hpra.ie.

Figure 1   Application process

New application timeline:

1. Day 7- prior to cut-off date    Submission of CTA to HPRA with request about contribution in CTR pilot project. The applicant must also nominate EC.

2.  Day 5         HPRA shares CTA with EC via IT platform 

          3. Day 1   HPRA validates the Part I dossier. Within that time EC validate Part II dossier

          4. Day 0  HPRA sends automatic notice of validation of PART I and II to the applicant

 5. Day 14                                      CTA presented to the Clinical Trials Subcommittee at its monthly meeting

           6. Day 15                             HPRA shares the draft Part I AR with the EC for       input

 7. Day 22      EC complete draft section of Part I

         8. Day 25                                      List of grounds for non-acceptance on Part I and II are separately from EC and HPRA send to the applicant

 9. Day 39  Response to Part I and Part II are submitted by the applicant to the HPRA. HPRA communicate with EC

         10. Day 46  The HPRA updates the draft Part I AR on the IT platform including the proposed conclusion

11. Day 49  If necessary EC updates the draft Part I. If is differences between two notes a teleconference is organised between the chair of the EC and the HPRA to discuss the concerns

          12. Day 57   HPRA Management Committee proceeds and reviews the recommendation on the CTA and gives the final decision to the Part I

          13. Day 60  End of procedure. HPRA decision letter on the CTA is sent to the applicant, and to the EC for information. Final EC issues its opinion directly to

the applicant and AR Part I and II decision letters     are stored on the IT platform. [4]

b) Ethics committee involvement

Ethics committee (EC) is formally accepted by the Department of Health under current legislation and can review clinical trial.

• Clinical Trial is also appraised by the Ethics committees.
• Draft Part I is shared via IT platform with EC.
• EC validates the Part II dossier and provides notification to the HPRA.
• EC can fill in appropriate sections at any point up to Day 22. EC opinion on Part I need to be provided within 22 days of the validation date (within 7 days of the HPRA opinion).
• EC sends the grounds for non-acceptance on Part II, directly to the applicant. 
• If necessary, the EC updates the draft Part I on the IT platform in light of the responses from the applicant.
• Final EC opinion on Part I need to be provided 10 days after responses from the applicant have been received and 3 days after the final AR has been circulated.
• EC advises the applicant directly of their opinion on the CT (including aspects covered by the Part I AR), and provides this opinion to the HPRA.
• EC issues its opinion directly to the applicant. 

Key Considerations for the New EU Regulation

New EU Regulation covers several primary components such as:

• Authorization procedures
• Start of trial
• Suspension or temporary holds
• Early termination
• Protection of subjects
• Informed consent
• Conduct of trials
• Safety reporting
• IMP manufacturing
• Labelling and import
• Insurance [5]

I described several of them below.

a)  Safety reporting procedures

The sponsor should ensure that Non-Investigational Medicinal Products and Investigational Medicinal Products are of suitable quality for the principles of the trial. Would also taking into account the source of the raw materials and repackaging. A trial has to be conducted through the protocol. All clinical trial information must be recorded, handled and stored. Traceability of medicinal products should take into account the purpose of the trial and trial subjects ‘safety. [6]

The substances and products used in the clinical trial must guarantee quality and safety.

“Safety reporting documents including suspected unexpected adverse reactions (SUSARs), and development safety update reports (DSURs) should be submitted to the HPRA, and to the local EC in the usual way.”[7]

In low intervention trials, safety reporting and recording can be simplified applying a risk proportionate approach.

b) Early termination

Under the Regulation 536/2014 sponsor can withdraw an application for a clinical trial any time until the decision is made. After a withdrawal is possible re-submit application again. Once the decision is made and Clinical trial starts but does not continue, early termination can be cause. If the clinical trial does not start and the sponsor decides to not proceed, the application will expire after 2 years from the notification date of the authorisation.

c) IMP manufacturing

The Clinical Trial Regulation applies also to the manufacturing and import of IMP. If the process of preparation of IMP which is an officinal or magistral formula and preparation of radiopharmaceuticals is carried out in clinics, hospitals, health centres, pharmacy does not require a manufacturing authorisation. Regarding auxiliary medicinal products requirement of manufacturing must according to the good manufacturing practice referred to in Regulation (EU) No 536/2014. Relating to documents of good manufacturing practice for an investigational medicinal product, if the product has EU authorisation no document is required. An authorisation and a QP declaration of GMP equivalence is required if IMP is manufactured, import from outside of EU.

d) Suspension or temporary holds

If the CT temporarily suspended will not resume within two years, the date of the expiry of this period is considered to be the end date of the CT.  In case of early termination of CT, the date of early termination is considered to be the date of termination of CT.

e) Informed consent

Informed consent is a permission granted in full knowledge of the possible consequences. Regulation tells us that informed consent should be written, dated and signed by the person performing the interview and by the representative in cases when the subject is unable to give informed consent (unable to write). Informed consent shall be recorded and kept as evidence.[8]  

Summary

New Clinical Trial Regulation creates an environment favourable to conducting clinical trials within the EU. It also establishes new rules on how to conduct and perform clinical trials. This will increase the effectiveness of all trials in Europe, with the greatest benefit for those conducted in several member states. It aims to boost innovation and research, preventing unnecessary duplication of clinical trials or repetition of unsuccessful trials.

This will guarantee that the rules for conducting clinical trials throughout the EU are identical, guaranteeing that all the member states, stand on identical rules when authorizing and supervising the conduct of a clinical trial.

 The regulation reduced the paperwork, staff and fees and simplifies the authorization process.  Clinical trial data submitted in an application dossier must be based on clinical trials registered.

The ultimate goal of protecting and improving patient safety is EU regulation to improve knowledge, align regulation and procedures and increase efficiency and reliability for manufacturers, distributors, service provide and member states.

Any additional information required by the Organisation to process Clinical Trial and which are not included in this document is available in the New Clinical Trial Regulation 536/2014 and additional sources included in the references section.

References

• https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/regulation5362014_qa_en.pdf
• https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/imp_03-2011.pdf
• https://www.clinicaltrialsarena.com/news/exploring-the-impact-of-the-new-european-directive-on-the-pharmaceutical-industry-5998990-2/
• https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-8-general-considerations-clinical-trials-step-5_en.pdf
• https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-clinical-trials-regulation-(eu)-no-536(2014)-pilot-project---ireland.pdf?sfvrsn=4

[1] Directive 2001/20/EC

[2] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/regulation5362014_qa_en.pdf

[3] https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-clinical-trials-regulation-(eu)-no-536(2014)-pilot-project---ireland.pdf?sfvrsn=4

[4] https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-clinical-trials-regulation-(eu)-no-536(2014)-pilot-project---ireland.pdf?sfvrsn=4

[5]   https://www.clinicaltrialsarena.com/news/exploring-the-impact-of-the-new-european-directive-on-the-pharmaceutical-industry-5998990-2/

[6] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/imp_03-2011.pdf

[7] https://www.hpra.ie/docs/default-source/publications-forms/guidance-documents/guide-to-clinical-trials-regulation-(eu)-no-536(2014)-pilot-project---ireland.pdf?sfvrsn=4

[8] https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/regulation5362014_qa_en.pdf