First in Human Studies - ABPI

1 First in Human Studies : Points to Consider in Study Placement, Design and ConductJanuary 2011 AcknowledgementsThe primary authors were: Pauline Williams, DamianO'Connell, and Odile article was produced under the auspices of theABPI Experimental Medicine Expert Network. The authors based the article on FIH guidelines thathad been produced within GSK and Pfizer. The authors thank David Sciberras, Cyril Clarke,Corinne Cummings, Jo Collier, Juliet McColm, GerryParker and Oliver Schmidt from the Network forreview, and Jan de Hoon for external in Human (FIH) clinical trials are part of theexploratory phase of drug development and represent asignificant milestone in the clinical development of newmedicines.

2 When only preclinical data are available toguide dose-selection, population, study design, safetymonitoring and appropriate expertise are all critical tomaximise the safety of the study subjects and thequality of the has been intense focus on the risks of FIHclinical trials since the TeGenero TGN1412 incident in2006, and much has been published on the evidenceand recommendations [1, 2, 3, 4]. The European MedicinesAgency s (EMA) Guideline on strategies to identifyand mitigate risks for First in Human clinical trials withInvestigational Medicinal Products (IMPs) [5]providesan excellent overview of points to consider.

3 Inaddition, the ABPI Guidelines for Phase I ClinicalTrials [6]summarise recognised industry standards. Thepurpose of this document is to supplement theseguidelines with practical considerations for theplanning, design and conduct of FIH clinical include sections on: Choice of study population Selection of an appropriate study site and principal investigator Formulation and site pharmacy considerations Study design considerations Dose escalation decisions Informed consent considerationsChoice of study populationThe majority of FIH clinical trials use healthyvolunteers.

4 This approach has the advantage of speedof recruitment and ease of scheduling cohorts ofsubjects throughout the study. It also removes potentialconfounding factors such as concomitant medicationand disease pathology when reviewing adverse eventand pharmacokinetic (PK) data. Healthy volunteers cangenerally tolerate more intensive interventions andadverse effects than would be expected from asymptomatic patient. FIH clinical trials are part of the exploratory phase ofdrug development and therapeutic benefit is not anobjective.

5 Clearly healthy individuals do not stand togain any therapeutic benefit from an investigationaldrug, and ethical principles dictate that they should notbe exposed to any more than minimal risk [7]. Inpatients, the foreseeable risks should also be kept aslow as possible. Historically, the use of patients hasbeen commonplace for oncology agents and agentswith low therapeutic index intended for life-threatening decision whether to conduct an FIH trial inhealthy volunteers or patients should be carefullyconsidered and fully justified on a case-by-case pros and cons are detailed in Table 1.

6 The safetyof subjects and the value of the information that islikely to be obtained should be considered, especially:a) the risks inherent in the type of medicinal productand its molecular target b) potential immediate and long term toxicitypredicted from non-clinical or literature information c) the presence of the target, key biomarker or asurrogate marker in healthy subjects or in patientsonly, and d) the possibility and impact of higher variability inpatients versus lower external validity in in Human Studies Points to Consider in Study Placement, Design and ConductJanuary 20111 Table 1.

7 Selection of Patients versus study designs may include bridging betweenhealthy volunteers and a patient population once theexpected therapeutically relevant dose is achieved inthe escalation paradigm. This allows a more time- andcost-efficient early evaluation of PK, PD and safetyparameters at lower doses in healthy subjects tofacilitate improved dose-selection and/or regime athigher doses in the target patient population, in whommore informative safety or PD data can be of women as early as possible in drugdevelopment programmes is encouraged.

8 The ICH M3 Revision 2 (R2) guideline [8]describes the nonclinicalstudy guidelines for enrolling women of child-bearingpotential into clinical Studies . In the FIH clinical trial,women will typically be of non-child bearing addition, a risk evaluation should be conducted toestablish the need for protection from seminal IMPexposure, or the need to add a highly effective methodto avoid pregnancy for the women of child-bearingpotential who are partners of male subjects in the FIHclinical trial. Highly effective methods to avoidpregnancy are defined in the ICH guideline [8]as those,alone or in combination, that result in a low failure rate( , less than 1% per year) when used consistently is important to confirm the medical history of thevolunteers or patients prior to inclusion in a FIHclinical trial, which is usually done by contacting theprimary care physician.

9 Choice of research siteThe sponsor should conduct a site evaluation toconsider the site s capabilities to meet the specificdemands of a particular protocol such as appropriatemedical governance, drug-specific biomarkermethodologies or sample acquisition/analysis, theability to recruit study participants, and pharmacycapabilities. FIH clinical trials of IMPs with identified factors of risk(as discussed in [Appendix 1]) should be conducted inresearch units with sufficient expertise and know-howand which, in the UK, have been awarded the MHRAP hase 1 Supplementary Accreditation [9]as they willhave undergone a comprehensive scrutiny of theiremergency equipment, procedures and , this does not negate the importance of a site-evaluation by sponsor staff.

10 Furthermore, the MHRAP hase 1 Accreditation is voluntary, there is nomandatory requirement for it. Site assessment by thesponsor staff should include, but not be limited to,evaluation of the experience of the site with FIHclinical trials and the ability to carry out appropriatesafety monitoring, the site s experience with IMPs of alllevels of risk, the site s process and experience withdose escalation decisions, the site s facilities and abilityfor stabilising individuals in an acute emergency andthe site s ability to conduct resuscitation.