Q&A: changing regulatory expectations in Europe

Later this month, Dr Barbara Jentges, the Managing Director at PhACT GmbH, a regulatory consulting and training firm based in Duggingen (Switzerland), will be speaking at the 2nd Vetter Drug Management Leadership Conference in Germany. Pharmaceutical Technology spoke with her about changing regulatory expectations, with a focus on Europe.

Q1: The global pharmaceutical market is undergoing a tremendous shift as we enter the age of personalized medicine based on biologics, cell products and improved diagnostics. In your experience, how are regulators coping with this shift and what types of changes are they making themselves?
Regulators are monitoring scientific development and are constantly reviewing the legislation in light of new technologies and therapies. Apart from safeguarding medicinal products, it is a necessity to provide an economic and regulatory environment to bring novel treatments to the patients as early as possible. One example of how regulators are coping with this challenge is with Advanced Therapy Medicinal Products (ATMPs). This group of new technologies and therapies is based on genes (gene therapy), cells (cell therapy), and tissues (tissue engineering) and has the potential to treat a number of severe diseases.

In the past, the lack of an EU-wide regulatory framework for these cell-based products led to divergent national approaches. With the Advanced Therapies Regulation that took effect 30 December 2008, an EU harmonized regulation has been achieved. The main elements of this new regulation are a mandatory centralized application procedure for ATMPs marketing approval, technical requirements considering the specific characteristics of these products, and the establishment of a Committee for Advanced Therapies within the European Medicines Agency (EMEA). Additionally, the regulation provides special incentives for small- and- medium-sized enterprises such as facilitated access and reduced fees for scientific advice.

Q2: There has been a greater willingness among the global regulatory authorities to harmonize regulations over the past few years, demonstrated by the final approval of the ICH Quality Trio guidelines (Q10 Pharmaceutical Quality System, Q9 Quality Risk Management; and Q8 Pharmaceutical Development). Do you think individual authorities are also becoming more willing to share information regarding inspections, for example, with each other? Are they willing to give up some domestic regulatory autonomy in order to apply a more harmonized approach?
It is indeed the intention of inspectorates and in the best interest of the pharmaceutical industry to share information on inspections to save significant resources on both sides. The EU has set up the EudraGMP database to share information about manufacturing and importation authorizations and GMP certificates, PIC/S is discussing opportunities to exchange inspection information, and the EU and US have entered into a cooperation in this field via a pilot program. The recently released version of the EudraGMP (version 2.0) provides public access to information about manufacturing and importation authorizations as well as GMP certificates. (http://eudragmp.emea.europa.eu).

Q3: International Conference on Harmonization representatives also adopted the electronic Common Technical Document (eCTD), allowing pharmaceutical companies to submit information electronically to the various regulatory authorities. Authorities are supposed to be ready to take eCTDs only (with no paper submissions) by the end of this year. Are they ready? Is industry ready?
In Europe, EMEA will mandate the use of the eCTD format for the centralized procedure for all electronic-only submissions for all applications (new and existing) and all submission types as of Jan. 1, 2010. Non-eCTD format electronic submissions will be rejected. Although paper-only submissions may be accepted alternatively, this type of submission may lead to significant handling and review issues.

According to an EU eCTD Implementation Survey that covered the period from July 2007 to June 2008, only 1% of all applications in Europe used eCTD format. As for EU member states, the survey revealed that 28% of the authorities did not specify when they will be ready to accept eCTDs. Although both sides need to overcome a number of obstacles, the way to a paperless submission and life cycle management will soon be standard.

Q4: Can you talk about the benefits as well as the challenges that come with eCTD implementation? For example, it seems that applicants still have to submit different information to each region’s authority.
One of the major benefits of the eCTD’ is the paperless submission, but that’s not all. The eCTD is meant to reduce costs in the administration, assessment, and archiving of marketing authorization applications for medicines. However, the implementation of an eCTD requires the creation of a suitable IT infrastructure as well as the commitment to workflow changes and long-range strategic planning. Additionally, new processes need to be considered (e.g., for making the documents ‘eCTD-ready’ by including a number of navigation tools such as hyperlinking and bookmarking). Once a system has been established, further challenges are ahead. Regionally different requirements need to be considered when building eCTDs for the EU, US, and Japan. For example, Study Tagging Files are required for a US-eCTD, but not for a EU-eCTD, and not allowed in Japan.

Q5: Do you see more changes ahead with regard to what regulators expect from industry and in terms of compliance?
It was one of the intentions of ICH Q8, Q9, and Q10 to move away from pure compliance to a risk-based, scientific approach. With that in mind, interaction and communication between industry and regulators need to be intensified to find the safest solution for the patient and thus must balance out efficient manufacturing. Costs need to be controlled on both sides to manage the health system of the society by ensuring compliance with regulations.