European Commission Consults On New Clinical Trial Inspection And GMP Rules

The European Commission is in the early stages of drafting legislation that will describe in detail how inspections of clinical trials are to be conducted in the EU and elsewhere once the provisions of the new clinical trials legislation kick in around mid-2016. It is also drafting new guidance on the manufacture of investigational medicinal products (IMPs) used in clinical trials.

Three consultation documents have just been released for comment, one of them covering good clinical practice (GCP) inspection procedures and inspector qualifications, the other two laying out the principles and guidelines of good manufacturing practice (GMP) for IMPs¹.

All three documents are required under the provisions of the new Clinical Trials Regulation (No 536/2014), which covers all aspects of clinical trial approval, registration and conduct, as well as the publication of trial results, and will replace the current Clinical Trials Directive sometime after May 27, 2016².

In each case, the purpose of the consultation is to collect views and relevant information and evidence from stakeholders to help the commission prepare the relevant acts and guidelines. The deadline for comments is Nov. 24.

Good Clinical Practice

According to Article 47 of the CTR, sponsors and investigators have to ensure that trials are conducted in line with the study protocol and with GCP, while Article 78(1) obliges EU member states to check their compliance. Article 78(7) obliges the commission to adopt an implementing act outlining the detailed arrangements for inspection procedures, including inspectors' qualifications and training³.

To help it develop its thinking and prepare the act – which will probably take the form of a new regulation – the commission is asking for views from stakeholders on three specific issues:

• the rules on clinical trial inspection procedures, in particular for the preparation, conduct, reporting, follow-up, communication and record-keeping and archiving of the inspections;
• co-ordinating co-operation among the various member states, and follow-up of inspections; and
• minimum standards of inspector qualification, in particular regarding their education and training.

The implementing act will apply to inspections of trials conducted in the EU, including sites related to these trials but located outside the EU, as well as to studies carried out in third countries and referred to in EU marketing authorization applications.

Under the new legislation, inspectors will have to have completed university-level education, or have equivalent experience, in medicine, pharmacy, pharmacology, toxicology or other fields relevant to GCP principles. They will also have to have had appropriate training.

Particular prerequisites include:

• knowledge of the principles and processes that apply to drug development and clinical research, as well as relevant EU and national legislation and guidelines on clinical trials and marketing authorization procedures;
• familiarity with procedures for recording and managing trial data and the organization of relevant healthcare systems; and
• ability to make professional judgments regarding compliance with the requirements of the CTR, GCP guidelines, and relevant national legislation.

Inspectors will be allowed to inspect sites, documents, facilities, records, quality assurance arrangements, data and any other resources related to the trial, and member states will have to provide adequate resources to meet the aims of the CTR – in particular, ensuring enough inspectors are appointed to ensure effective verification of compliance with GCP and the CTR.

Member state authorities are to collaborate with each other, the commission and the European Medicines Agency to improve EU standards for the conduct of inspections, and the EMA will co-ordinate co-operation among the member states.

All inspectors and other experts involved in inspections must respect national confidentiality rules and comply with national legislation and the CTR when processing personal data.

As with other officials working in the EU pharmaceutical and healthcare sphere, inspectors must have no conflicts of interest and must be independent of the sponsor, the trial site, the investigators, those financing the trial, and any other party involved in running the trial. They must sign a statement declaring any financial or other links to the parties to be inspected, and must be free of any commercial, financial or other constraints that could affect their impartiality or judgment.

Good Manufacturing Practice

Under the CTR, the commission is also required to adopt a delegated act on the principles and guidelines for GMP and arrangement for inspections to ensure the quality of IMPs, and to publish detailed guidelines in line with these principles⁴.

Although the principles and guidelines on GMP for medicines and IMPs are already covered by Directive 2003/94/EC, once the CTR's provisions become applicable, all IMPs used in clinical trials will have to be manufactured or imported under GMP rules laid out in that regulation.

The draft delegated act covers among other things conformity with GMP for IMPs, compliance with the CTR in terms of manufacturing operations, the establishment of the pharmaceutical quality system, the availability of enough appropriately qualified personnel, premises and equipment, documentation, production operations, quality control, responsibilities of the qualified person, and complaints, product recalls and emergency unblinding. Other issues include GMP inspection procedures and reports, the powers, obligations and impartiality of inspectors, and the consequences of non-compliance with GMP.

There are unlikely to be many significant changes because GMP for IMPs already works pretty well. As the commission remarks, "there is no need to reinvent the wheel," so most of the principles and guidance in the current directive will be carried over into the new act.

However, provision is made for adapting GMP requirements to the specific characteristics of advanced therapy medicinal products (ATMPs). The consultation document notes that a targeted consultation on this issue was launched in July, with a deadline for comments of Nov. 12⁵.

Changes to the requirements are needed because the intrinsic characteristics of ATMPs, such as variability of the starting materials, small batch sizes, short shelf-life, etc, pose specific challenges for the manufacturing process. In addition, early phases of research may take place in a hospital setting operating under a quality system different from the quality system typical of the pharmaceutical sector, the commission says.

GMP Guidelines

The consultation document on proposed GMP guidelines for IMPs also notes that the current guidelines work well, so the new guidance will generally refer to, or carry over, specific sections of existing legislation⁶.

The commission says that the application of GMP for the manufacture of IMPs is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are unaffected by quality, safety or efficacy issues arising from manufacturing problems. It is also intended to ensure that there is consistency between batches of the same IMP used in the same or different clinical trials and that any changes made during the development of an IMP are adequately documented and justified.

"For manufacturers to be able to apply and comply with GMP for investigational medicinal products, co-operation between manufacturers and sponsors of clinical trials is required. This co-operation may be described in a technical agreement," the commission notes.

The draft guidelines, which will complement the delegated act on GMP, define an IMP as "a medicinal product which is being tested or used as a reference, including as a placebo, in a clinical trial." Manufacturing is defined as "total and partial manufacture, as well as the various processes of dividing up, packaging and labelling (including blinding)."

Reconstitution is not considered manufacturing when it is simply a question of dissolving or dispersing the IMP for administration to a trial subject, or diluting or mixing the IMP with another substance used as a vehicle for administration.

Issues addressed in the consultation document include personnel, documentation, production, premises and equipment, documentation, production, quality control, batch release, outsourcing, and recalls and returns.

References

1. European Commission announcements, Aug. 28, 2015, http://ec.europa.eu/health/human-use/clinical-trials/developments/index_en.htm 
2. 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/EC:   http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=uriserv:OJ.L_.2014.158.01.0001.01.ENG
3. European Commission, Consultation document, Detailed arrangements for clinical trials inspection procedures including the qualifications and training requirements for inspectors, pursuant to Article 78(7) of Regulation (EU) No 536/2014, Aug.28, 2015, http://ec.europa.eu/health/human-use/clinical-trials/developments/pc_gmp_2/public_consultation_implementing_act_on_clinical_trials_inspections_2015.pdf
4. European Commission, Consultation document, Commission Delegated Act on Principles and guidelines on good manufacturing practice for investigational medicinal products for human use and inspection procedures, pursuant to the first subparagraph of Article 63(1) of Regulation (EU) No 536/2014, Aug.28, 2015, http://ec.europa.eu/health/human-use/clinical-trials/developments/pc_gmp_1/public_consultation_dreg_on_gmp_for_imp_2015_rev_180815.pdf
5. EU Consults On Proposed GMP Requirements For Advanced Therapy Products, Scrip Regulatory Affairs, Aug. 11, 2015
6. European Commission, Consultation document, Detailed Commission guidelines on good manufacturing practice for investigational medicinal products for human use, pursuant to the second subparagraph of Article 63(1) of Regulation (EU) No 536/2014, Aug.28, 2015, http://ec.europa.eu/health/human-use/clinical-trials/developments/pc_gmp_1/public_consultation_gl_on_gmp_for_imp_180815_en.pdf