Regulatory Affairs for Medicinal Products in Europe

The pathway to market for Medicines in Europe:

Europe, with a population of 740 million people, is an attractive market for Pharmaceutical Companies worldwide. Many Europeans live in high income countries with advanced healthcare systems. The pathway to market access in Europe is governed by the main legislative regions being the European Union (EU) and The United Kingdom (UK). Some territories like Norway and Iceland, although not full members of EU, have implemented most EU legislation. Other territories like Switzerland are less aligned with EU but regulate based on the same basic principles.

To market a Medicine in Europe, it is required to obtain a Marketing Authorization (MA) which defines the authorized clinical use. The MA application dossier must contain a complete description of the production process, quality control parameters, pre-clinical and clinical data, pharmacovigilance system as well as the proposed clinical use description.

The clinical use of the medicine is described in a Summary of Product Characteristics (SmPC) which aimed towards healthcare professionals. The MA must also contain the proposed information for the patients in the package leaflet and the proposed package labelling. There may also be requirements for additional risk minimization materials to be distributed to healthcare professionals and/or patients.

To obtain MA, it is also required to have an appointed Qualified Person for Pharmacovigilance (QPPV) and a pharmacovigilance system that is compliant with GVP (Good Pharmacovigilance Practice)

In addition to the MA, a company supplying medicines in Europe also needs a distribution license and a quality management system (QMS) that ensures compliance with Good Distribution Practice (GDP). A manufacturing license and QMS to comply with Good Manufacturing Practice is needed in case the company performs any manufacturing activities.

In addition to the above, entry into the market normally requires application for reimbursement and price, participation in tenders or negotiations with retailers such as pharmacies.

Three main pathways to the Marketing Authorization

In the EU, there are three main application procedure types leading to an MA. The simplest one is the National procedure by which the company applies for MA in a single member state. If the company wishes to apply in several countries simultaneously, the Decentralized (DCP) procedure may be the preferred choice. For companies seeking an MA for the entire EU the Centralized procedure (CP) through the European Medicines Agency is the preferred choice. The CP is compulsory for:

• orphan medicinal products
• new active substances intended for use in:
  • AIDS
  • cancer
  • neurogenerative disorders
  • diabetes
  • auto-immune disorders
  • immune dysfunctions and
  • viral diseases.
• Biotech medicines developed by:
  • recombinant DNA technology
  • controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells and
  • hybridoma and monoclonal antibody methods
  • ATMP:s (Advanced Therapy Medicinal Products), e.g. cell and gene therapies

The national, DCP and CP procedures are all similar in terms of dossier requirements and evaluation timeline, but they differ in application fee where CP is normally the most expensive. The evaluation time in all procedures is 210 days excluding so called “clock stop” time allowing the applicant to submit additional data.

Mutual Recognition and Repeat Use Procedure

In case a marketing authorization already exists in one country, it may be possible to obtain MA in another country using mutual recognition or repeat use procedures.

Clinical Trials

To start a clinical trial in the EU, it is required to submit one single application in the CTIS system. The clinical trial application is divided into two parts, part I is the common EU part that contains the core documents and is assessed mainly by authorities. Part II contains national specific documents assessed mainly by ethics committees. The data package must contain the following:

• Part 1 (core):
  • Cover letter and application form
  • Trial protocol
  • Investigators Brochure (IB)
  • Documentation GMP compliance investigational medicinal product
  • Investigational Medicinal Product Dossier (IMPD) manufacture and quality control data from non-clinical and clinical use.
  • Auxiliary Medicinal Product Dossier
  • Scientific advice and paediatric investigation plan (PIP)
  • Labelling
• Part 2 (national)
  • Patient recruitment arrangements
  • Subject information and informed consent
  • Suitability of the investigator
  • Suitability of the facilities
  • Proofs of insurance, financial arrangements, payments and data protection.

Generic Medicines

Requirements for a generic medicine are simplified as applicants may refer to the innovator medicines clinical data package, if bioequivalence (BE) has been shown. BE is normally investigated in a clinical trial involving healthy volunteers. In a BE study, the applicant needs to demonstrate that the generic drug has the same bioavailability as the innovator drug. A bioequivalence study is therefore a clinical study comparing pharmacokinetics without measuring other clinical endpoints.

Apart from this the requirements for generic medicines are the same as innovators with regards to the dossier describing the manufacturing, quality, pharmacovigilance and intended use.

To access the market as generic often involves an assessment of substitution that comes after the MA is granted. This assessment focuses on whether the generic can substitute an original product or other generics at pharmacy or prescriber level without impacting the medical treatment of the patient. The basic criteria is bioequivalence, but other factors such as method of administration details may play a role as well depending on the rules in the specific country. Medicines with a narrow therapeutic interval may not be substituted at all.

Biosimilars

To obtain MA for a biosimilar, the applicant must demonstrate a high degree of similarity in terms of protein structure, contamination patterns, biological activity, efficacy, safety and immunogenicity. In addition, the biosimilar must be manufactured according to the quality standards that apply to all biological medicines in the EU.

The equivalence of protein structure and biological function requires an identical amino acid sequence of the biosimilar and the reference, but small differences in, for example, glycosylation can be accepted. It is worth noting that the manufacturing method of biological drugs gives rise to variation in the structure of both original drugs and biosimilars.

Efficacy, safety and immunogenicity are studied in clinical studies in humans. The clinical studies are designed to confirm equivalence between the biosimilar and the reference medicine.

Generic substitution with Biosimilars is not as common as with chemical active substances. But the biosimilar manufacturer can often compete by participation in hospital tenders