Risk Management in Drug Development

Transcription

1 Risk Management in Drug Development Recent changes Are you compliant? by Andy Blackman Senior Partner, PV 5 April 2018

2 Why you might not be compliant Initially, the concept of a Drug Development Risk Management Plan (DDRMP) was a recommendation of the CIOMS Working Group VI (Management of Safety Information from Clinical Trials) in Big pharmaceutical companies, and many smaller companies, have routinely created a DDRMP for their products but a document of this kind has now become an essential exercise to be compliant with clinical trial management. The DDRMP is often referred to as the Core Development Data Sheet (CDDS) or Development Reference Safety Information (DRSI). MHRA and other health authorities have been inspecting against this approach for the last 10 years. ICH Good Clinical Practice (E6) (1) (R2) requires the documentation of an ongoing safety evaluation of the Investigational Medicinal Product. The concept has also now been adopted by the new Clinical Trials Regulation (2), and the EU Clinical Trial Facilitation Group (CTFG) guidance on Reference Safety Information for the Investigator Information Section of the Investigator Brochure (IB) (3). Companies must have one or more similar documents (i.e. DDRMP, CDDS, DSRI) on file, which are regularly updated as new safety information becomes available. Companies that do not have one of these documents risk getting a major or critical finding on inspection or may not get their IBs approved, delaying the start of clinical trials. At worst, lack of a properly developed DDRMP may put healthy subjects and/or patients at risk of serious adverse events, resulting in huge problems for the company concerned. Page 2 of 5

3 Recent clinical trial regulatory information you may have missed The recommendations of the expert group on clinical trials on the implementation of risk proportionate approaches for the implementation of the EU Clinical Trials Regulation (EU) No. 536/2014 (4), states that the evolving safety profile of the developmental product should be a part of an overall risk management system in clinical trials. Risk adaptation to safety monitoring e.g. selective recording and reporting of AEs is also required. AEs and laboratory abnormalities that are critical to safety evaluation (Adverse Events of Special Interest) are required to be documented and reported by the investigator to the sponsor. There must be a core document feeding individual protocols, individual study RMPs and or IBs such as the DDRMP. The EU Clinical Trial Facilitation Group (CTFG; November 2017) was originally set up to provide guidance for the EU Clinical Trials Directive and is now preparing guidance for the EU Clinical Trials Regulation (EU) No 536/2014. The CTFG has issued a Q&A document on Reference Safety Information (RSI) (3). The Q&A document states that all IBs submitted as part of a Clinical Trial Application (CTA) from November 2017 onwards must be compliant with the Q&As, or they will be rejected by the EU Competent Authorities during their review. Development and maintenance of the RSI should be documented in the DDRMP. First in Human (FIH) trials and early development trials come under additional guidance. The revised EU First in Human Guidance (EMEA/CHMP/SWP/28367/07 Rev. 1, effective 1st February 2018) (5) states that when defining a development programme information of safety needs to be integrated from many sources and frequently reviewed in an iterative process. This allows for the identification and mitigation of risks. In addition, to limit the potential for adverse reactions in humans, safety factors should be considered when assessing potential risks applied in the calculation of the starting dose in humans, the dose escalation and maximum exposure. It also states that risk mitigation activities should be proportionate to the degree of uncertainty and the potential risks identified. Such activities concern integrating sources of safety information, identifying and mitigating safety risks and should be documented in the DDRMP. There are many other guidance documents (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), (22) referring to safety risk management in early clinical trials. All such guidelines need to be considered during the development and update of the DDRMP. Page 3 of 5

4 Repurposed products or those being used in combination with marketed products (including excipients) While using the approved label for the marketed products, e.g. the Summary of Product Characteristics (SmPC), as the RSI, it is important that the safety risks of the marketed product are discussed within the DDRMP so that appropriate mitigation measures can be identified. Monitoring of the safety profile of a marketed product includes at the very least, regular literature monitoring, review of published drug analysis profiles (e.g. MHRA interactive Drug Analysis Profiles [idaps]), review of EudraVigilance data (via EU adverse drug reaction Portal), the Pharmacovigilance Risk Assessment Committee (PRAC) outputs and monitoring for the publication of new versions of the SmPCs. In conclusion The DDRMP or an equivalent document (e.g. CDDS or DRSI) is essential to ensure compliance and oversight of the emerging safety profile of a development product, including repurposed products. The DDRMP provides the frameworks for the monitoring and mitigation of known or emerging risks during clinical trial design and ongoing development of the product. How can TranScrip help? TranScrip Drug Safety Experts have hands on clinical development expertise in developing and maintaining DDRMPs in many therapeutic areas. We provide expertise and resourcing to over 200 pharmaceutical companies globally. For further information Contact Andy Blackman andy.blackman@transcrip-partners.com Page 4 of 5

5 References (1) ICH E6 (R2) Good clinical practice, EMA/CHMP/ICH/135/1995, Effective 14 June (2) REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, 16 April 2014 (3) Clinical Trial Facilitation Group November Q&A document Reference Safety Information (4) Risk proportionate approaches in clinical trials Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use, 25 April 2017 (5) Guideline on strategies to identify and mitigate risks for first-in-human and early clinical trials with investigational medicinal products EMEA/CHMP/SWP/28367/07 Rev. 1 CHMP, 20 July 2017 (6) EudraLex - Volume 4 - Good Manufacturing Practice (GMP) guidelines. (7) Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials MA/CHMP/QWP/834816/2015) (8) Guideline on virus safety evaluation of biotechnological investigational medicinal products (EMEA/ CHMP/BWP/398498/2005- corr.). (9) Guidance on non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals (ICH M3(R2)) and related Q&A document (10) Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials (EMA/CHMP/BWP/534898/2008). (11) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk (ICH M7). (12) Note for guidance on toxicokinetics: the assessment of systemic exposure in toxicity studies (ICS3A) and related Q&A document (13) Pharmacokinetics: Guidance for repeated dose tissue distribution studies (ICH S3B). (14) Preclinical safety evaluation of biotechnology derived pharmaceuticals (ICH S6(R1)) (15) Safety pharmacology studies for human pharmaceuticals (ICH S7A). (16) Non-clinical evaluation of the potential for delayed ventricular repolarization (QT interval prolongation) by human pharmaceuticals (ICH S7B). (17) Non-clinical evaluation for anticancer pharmaceuticals (ICH S9) and related Q&A document. (18) Questions and Answers concerning the implementation of Directives 2004/9/EC and 2004/10/EC on Good Laboratory Practice (GLP). (19) EudraLex - Volume 10 - Clinical trials guidelines. (20) Detailed guidelines on good clinical practice specific to advanced therapy medicinal products (ENTR/F/2/SF/dn D(2009) 35810). (21) Clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non - antiarrhythmic drugs (ICH E14) and related Q&A document. (22) Evaluation of anticancer medicinal products in man (CPMP/EWP/205/95 Rev.4). Page 5 of 5