EUROPEAN REGULATORY AUTHORITIES EXPLAINED

1. Introduction of EU Regulatory landscape

The European medicines regulatory system is based on a network of regulatory authorities (national competent authorities (NCA)) from the 28 European Union member states, Iceland, Norway and Liechtenstein, the European Commission and the European Medicines Agency (EMA). This network is what makes the EU regulatory system unique, in comparison with the United States, where the Food and Drug Administration is the regulating agency.

The role of EMA is to prepare the scientific guidelines that govern the development of drugs within the EU, they reflect the latest thinking on scientific developments. EMA guides sponsors in their development programs and ensure that medicines development is conducted consistently and to the highest quality across the EU. The EMA also gives scientific advice, decides on the classification of Orphan Designations, and authorizes the market access of drugs through the centralized procedure.

The role of the national competent authorities (NCA), like for example the Medicines and Healthcare Products Regulatory Agency (MHRA) in the UK or the Federal Agency for Medicines and Health Products (FAMHP) in Belgium, is to approve the marketing authorisations of drugs that are not approved under the central procedure (see further). They are also responsible for the authorisation of clinical studies.

2. Scientific Advice

At any stage of development, a sponsor can request scientific advice from the European Medicines Agency or from a national agency. A Scientific offers the sponsor the occasion to discuss potential roadblocks with regulators and can best be compared with a pre-IND or end of phase I/II/III meeting with the FDA.

Scientific Advice helps the sponsor to ensure that the appropriate tests and studies are performed, so that no major objections regarding the design of the tests are likely to be raised during evaluation of the clinical trial submission or marketing authorisation application. Following the Agency’s advice, therefore, increases the probability of a positive outcome.

Depending on the issue, moment in development, choice of countries where study will be performed, etc…, it needs to be evaluated if it is preferabel to request scientific advice from EMA or from a national authority.

Scientific advice may be sought on the following topics:

• Quality (chemical, pharmaceutical and biological testing);
• Non-clinical/safety (toxicological and pharmacological tests);
• Clinical aspects (clinical safety and efficacy);

3. Clinical Trials

    3.1 EU legal framework

The authorisation and oversight of a clinical trial is the responsibility of the competent authority of the country where the trial is taking place. Each trial must be approved by the competent authority country where the protocol was submitted.

In Europe the framework for clinical trials is set out in EU Directive 2001/20/EC. This directive has harmonized the regulatory landscape for clinical trials in the EU. It sets out the requirements for clinical trials, document requirements, clinical trial applications, timelines etc…

The Directive has been interpreted and implemented differently by each individual country, therefore leading to different requirements and timelines in different countries. Furthermore, there might be considerable differences in the medical practices from country to country. This has led to some European countries to specialize in certain therapeutic fields or phases of research and to offer very competitive timelines, as illustrated in the case-study on Belgium.

To remedy this, a new EU Clinical Trial Regulation (EU 536/2014) has been developed. This regulation will further streamline and harmonize the regulatory requirements for clinical research in Europe. The new Regulation is currently scheduled to be implemented from summer 2016 onwards.

Besides approval by competent authorities, approval from the Ethics Committee (European equivalent of the Institutional Review Board (IRB)) is needed.

Currently the Voluntary Harmonised Procedure (VHP) offers an alternative to the country-by-country approval. This procedure allows for a single submission and a centralized scientific review of the submission package, followed by a national step for the review of the local documents. Due to the long timelines, this procedure is only recommended for large trials and for trials with advanced products like genetherapy. It is also important to notice that not all EU countries accept this procedure, for example Poland.

    3.2 Clinical Trial Applications

The requirements for Clinical Trial Applications (CTA) are set out in Directive 2001/20/EC, with additional document requirements per individual country. The package is submitted on paper, electronically or combination, depending on the requirements of the country.

The core documents of the submission are the coverletter, protocol, Investigator’s Brochure (IB), Investigational Medicinal Product Dossier (IMPD) and the EudraCT application Form. The EudraCT Application form can be seen as the European equivalent of the FDA 1571 form. The EudraCT is completed online and is submitted as part of the submission package, and contains a summary of the trial information. This application form is uploaded into the European Clinical Trials Database (EudraCT) by the competent authorities of the countries where the study was approved. A subset of this information is publicly available in the EU clinical trials register.

In general the requirements for an IND and a CTA are roughly the same, and the below table shows a comparison:

INVESTIGATIONAL NEW DRUG (IND)

CLINICAL TRIAL APPLICATION (CTA)

Form FDA 1571 Table of Contents Introductory Statement General investigational plan Investigator’s brochure (IB) Protocol CMC data Drug label Pharmacology and Toxicology data Previous Human Experience Additional Information If any part of the trial is to be conducted by a CRO, attach power of attorney Name and title of person responsible for evaluating the safety of the drug

EudraCT Application form Cover letter Investigational brochure (IB) Protocol: Investigational Medicinal Product Dossier (IMPD) (A simplified IMPD may be submitted in certain instances (e.g., when a CTA has been approved by the respective regulatory authority) Drug label Risk and benefit assessment (can be part of IB or protocol, or be a stand alone document) If any part of the trial is to be conducted by CRO, attach power of attorney and mention in cover letter; CRO representatives can sign on behalf of sponsors Additional items required by some MS:.

    3.3 CMC Requirements

In general the CMC requirements for IND and CTA are very similar, although there are some differences. In Europe the CMC data are presented in the Investigational Drug Product Dossier (IMPD), which has a slightly different format then the US IND item 7.

Additional differences are the inclusion of an environmental assessment in an IND submission (not needed for submissions in Europe), and the inclusion of TSE/BSE certificates and GMP certification by a Qualified Person in a CTA submission (not needed in US)

    3.4 Clinical Trial Register

The EU Clinical Trial Register was launched in March 2011 and the information contained therein is extracted from EudraCT. The register allows the public to search for protocol related information on interventional clinical trials for medicines which are authorised in the 27 EU Member States and EEA and also on clinical trials authorised to be performed outside of the EU where these trials are part of a paediatric investigation plan. The main difference between Clinical Trial Register and clinicaltrials.gov is that in clinicaltrials.gov the information is uploaded directly by the sponsor, whereas in the EU clinical trial register, the information is uploaded in EudraCT by the agencies, and a data subset published in the EU Clinical Trial Register

Additional differences are that phase I studies and observational studies are not included in the EU clinical trial register, where these can be included in clinicaltrials.gov

Work is ongoing to upgrade the EudraCT database to also satisfy legislative requirements on the entering of results related information on clinical trials.

    3.5 Case Study Belgium

CASE STUDY BELGIUM

This case study illustrates how Belgium and the Belgian Health Authority (the Federal Agency for Medicines and Health Products (FAMHP)) has implemented the European guidelines into his national legislation and created a very favourable environment for early phase clinical research. The timelines for CTA approval in Belgium are: 15 calendar days for phase I single-center studies (both for healthy volunteers as for patient studies) 28 calendar days for phase I multi-center studies and phase II / III / IV studies These timelines are very competitive when compared to the US or other European companies. For many years, the Belgian government has made early phase clinical research a focus point of its scientific policy. This has resulted in a strong experience in early phase research and very forward thinking and openness of the Belgian Agency towards innovative products and ‘out of the ordinary’ study designs and techniques, like ie viral challenge. Belgian was the first authority in Europe to create guidelines around exploratory studies and is a strong supporter of combined protocols (SAD/MAD/FE/DDI in one study with a single approval) and of adaptive trial designs. Furthermore the Belgian HA offers a high quality Scientific Advice, with implication of external experts, and engages in a ‘Problem solving thinking’ together with sponsor’

4. Safety Requirements

All suspected side effects that are reported in view of clinical trials or spontaneously by patients and healthcare professionals must be entered into EudraVigilance, the EU web-based information system that collects, manages and analyses reports of suspected side effects of medicines. These data are continuously monitored in order to identify any new safety information.

The EMA provides public access to reports of suspected side-effects for centrally-authorised medicines in the European database of suspected drug reaction reports. This website allows users to view the total number of individual suspected-side-effect reports submitted to EudraVigilance.

The EMA recently revised it’s pharmacoviglance legislation by the publication of multiple modules covering different aspects of Pharmacovigilance. It also implemented a committee dedicated to the safety of medicines for human use - the Pharmacovigilance Risk Assessment Committee, or PRAC. If there is a safety issue with a medicine that is authorised in more than one Member State, patients and healthcare professionals in all Member States are given the same guidance by the committee and the same regulatory action is taken across the EU.

The PRAC has a broad remit covering all aspects of pharmacovigilance. In addition to its role in risk assessment, the committee provides advice and recommendations to the European medicines regulatory network on risk management planning and post-marketing benefit-risk assessment for medicines

5. Orphan Drug Designation

Orphan medicinal products are those intended to diagnose, prevent or treat life-threatening or very serious conditions that are rare and affect not more than 5 in 10.000 persons in the European Union (compared to less then 200.000 cases in the US). To qualify for orphan designation, a medicine must meet a number of criteria:

• It must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating
• Prevalence of the condition in the EU must not be more than 5 in 10.000
• No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

Once a product has received the Orphan Status, it is eligible for a number of incentives, like a 10 year period of market exclusivity after the grant of a marketing authorization, protocol assistance, fee reductions and direct access to the EMA centralised procedure for the application for marketing authorization (see further)

Orphan designation may be obtained at any stage of development provided proper scientific justification of the intended use is submitted. The EMA, through its Committee for Orphan Medicinal Products (COMP) is responsible for reviewing designation applications and issuing an opinion, which is transformed into a decision by the European Commission.

Contrary to the US legislation on paediatric obligations (PREA), orphan-designated medicinal products are not exempt from the obligations of the paediatric regulation in the EU.

6. Acceptability of EU data in future FDA submissions

Under 21 CFR 312.120, FDA will accept a well-designed, well-conducted, non-IND foreign study as support for an IND or application for marketing approval if the study was conducted in accordance with GCP and if FDA is able to validate the data from the study through an onsite inspection, if necessary. Studies conducted in Europe will be perfectly accepted by the FDA in support of an IND, NDA or BLA.

7. Paediatric Investigational Plan (PIP)
A Paediatric Investigation Plan (PIP) is a development plan aimed at ensuring that the necessary data are obtained to support the authorisation of a medicine for children. Pharmaceutical companies submit proposals for PIPs to the European Medicines Agency's Paediatric Committee (PDCO).

The normal development of a medicine requires that various studies be performed to ensure its quality, safety and efficacy. PIPs include:

• a description of the studies and of the measures to adapt the medicine's formulation to make its use more acceptable in children, such as use of a liquid formulation rather than large tablets;
• the needs of all age groups of children, from birth to adolescence;
• the timing of studies in children compared to adults.

The development plan for a medicine can be modified at a later stage as knowledge increases. Modifications can also be made if the applicant encounters such difficulties with the implementation of a PIP, which render it unworkable or no longer appropriate.
In some cases, studies can be deferred until after the studies in adults have been conducted. This ensures that research in children is done only when it is safe and ethical to do so. Even when studies are deferred, the PIP will include details of the paediatric studies and their timelines.

As some diseases do not affect children (for example Parkinson's disease), the development of medicines for these diseases should not be performed in children. In these cases, a PIP is not required and it will be waived.

An active PIP (approved PIP, deferral or waiver) is required before a Marketing Authorisation can be filed in Europe.

8. Licensure Procedures

In the European Union, several licensure processes exist, depending on the type of drug and the therapeutic area.

In centralised procedure, companies submit a single marketing-authorisation application to the EMA. The EMA’s Committee for Medicinal Products for Human Use (CHMP). The CHMP performs a scientific assessment of the application and gives a recommendation to the European Commission on whether or not to grant a marketing authorisation. Once approval is granted by the European Commission, this procedure results in a single marketing authorisation that is valid in all EU countries, as well as in the European Economic Area (EEA) countries Iceland, Liechtenstein and Norway.

The centralised procedure is compulsory for:

• human medicines for the treatment of cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases;
• medicines derived from biotechnology processes, such as genetic engineering;
• advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines;
• officially designated 'orphan medicines'

For medicines that do not fall within these categories, companies have the option of submitting an application for a centralised marketing authorisation to the Agency, if the product shows a significant therapeutic, scientific or technical innovation.

The majority of medicines do not fall within the scope of the centralised procedure however, but are authorised by national competent authorities (NCAs) in the Member States.

When a company wants to authorise a medicine in several Member States, it can use one of the following procedures:

• the decentralised procedure (DCP): companies apply for the simultaneous authorisation of a medicine in more than one EU Member State if it has not yet been authorised in any EU country and it does not fall within the mandatory scope of the centralised procedure;
• the mutual-recognition procedure (MRP): companies that have a medicine authorised in one EU Member State can apply for this authorisation to be recognised in other EU countries. This process allows Member States to rely on each other’s scientific assessments.

9. Summary

In general the regulatory principles necessary to conduct clinical research in Europe are the same as in the United States. The European regulatory landscape seems more comprehensive then the one in the US, due to the division of the regulatory oversight between EMA and the national authorities.

The European regulatory system however is very flexible and very supportive of sponsors, enabling clinical trials with innovative drugs and advanced therapies to be approved quickly. Furthermore it offers a high level of support and guidance and with many incentives for drug developing companies.

10. References

DIRECTIVE 2001/20/EC 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 use

REGULATION (EU) No 536/2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC

DIRECTIVE 2001/83/EC on the Community code relating to medicinal products for human use

Guidance for Industry FDA Acceptance of Foreign Clinical Studies Not Conducted Under an IND