Regulatory Affairs and Pathways

Effective Management of Regulatory Good Clinical Practice and Pharmacovigilance Inspections

a report by

Beat Widler
Global Head of Clinical Quality Assurance, Hoffman-La Roche

The safety and efficacy of any medicinal product that is made available to doctors and patients is based on data collected in clinical trials and through post-marketing surveillance programmes. For a reliable riskbenefit assessment, the quality of the data collected is critical. Quality builds on robust processes that are supported by a reliable quality management system. A Bit of History Inspections and audits in the areas of clinical trials and pharmacovigilance are nothing new. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines E6 that became effective in the mid-1990s make reference to this type of quality oversight by health authorities. However, in those years, the US Food and Drug Administration (FDA) was practically the only institution that conducted inspections in the areas of clinical trials and pharmacovigilance. In addition, in those times unless there was the suspicion of misconduct a sponsor de facto decided which trials could be subject to inspections and when an inspection was to occur: inspections were always linked to the submission of a new marketing application. In particular, clinical trial centres outside the US were never inspected unless they were contributing in significant terms to the submission data. The modus operandi of the FDA also allowed to some extent a prediction as to which clinical trial centres would be selected for inspection: usually the highest recruiting sites or those whose data showed some peculiarities compared with the bulk of the data. This comfortable situation allowed sponsor companies to prepare for inspections and include sites that were potential targets for inspections in more or less extensive pre-inspection audit and training programmes.

How Inspections Have Evolved These good old days are now gone. With the implementation of the EU Clinical Trials Directive, strong inspectorates have been created in all European countries, and the European Medicines Agency (EMEA) has assumed a co-ordinating role for many pre-approval inspections. European inspectors have moved away from inspecting sponsors and clinical trial centres solely in connection with the filing of a marketing application; instead, they conduct inspections as part of their quality and compliance oversight role. Inspections of pharmacovigilance processes or clinical trials of any phase including phase IV trials are conducted routinely within the country of the inspecting agency and globally. At the same time, the FDA has engaged in a comprehensive training and coaching programme in a variety of foreign countries in Asia and Latin America to help build inspection capability in these territories. In addition, the World Health Organization (WHO), especially through its Tropical Disease Research Unit, has invested in the training and education of auditors who oversee trials in neglected diseases that are conducted in clinical trial centres in developing countries. As a result of these activities, the number of inspections has increased significantly. For example, back in the late 1990s a large pharmaceutical company such as Hoffmann-La Roche hosted fewer than five inspections of clinical trial centres or pharmacovigilance activities per year. Since 2005, this number has increased to about 30 inspections per year (see Figure 1). Inspections have increased not only in number but also in complexity. In the past, a good manufacturing practices (GMP) inspection was basically limited to manufacturing aspects, a GCP inspection to compliance with regulations governing clinical trials and a pharmacovigilance inspection to matters of safety management. Today, it is not uncommon for a GMP inspector to also investigate other

Beat Wilder is Global Head of Clinical Quality Assurance at Hoffmann-La Roche. He joined the company in 1986 as an International Drug Regulatory Affairs Officer. Three years later he moved into the International Clinical Research Department, where he assumed the position of Senior Research Scientist, participating in the planning and conduct of a major international drug development programme. During this time, he also acted as a co-ordinator for the review of clinical safety data. In 1993 he joined the International Clinical Quality Assurance Department (PDQ), where he was primarily responsible for clinical trial centres and adverse event reporting system audits. In 1994, Dr Widler became Head of PDQ Basel, with responsibility for five international clinical auditors located in Switzerland, and in 1997 he was promoted to Head of PDQ Europe. In September 1997, he was appointed International Head of Clinical Quality Assurance (PDQ). Since 2002 he has been Head of the Department for Quality, Ethics and Systems in Roches Pharma Development. In addition to his functional responsibilities, from 2002 to 2006 he was Head of the Welwyn Garden City (UK) Roche Pharma Development site, providing leadership to a group of about 600 development professionals. Dr Widler obtained his PhD in microbiology from the Swiss Institute of Technology in Zurich in 1982. E: beat_e.widler@roche.com

systems that interface with manufacturing activities. For instance, when inspecting recall procedures, the lines of communication and the decision-making steps in manufacturing and pharmacovigilance are assessed, as well as whether the parties involved have compatible quality management systems. A typical issue is whether it be ensured that what seems to be a clinical adverse event is also investigated from a GMP perspective i.e. was there follow-up and management of an adverse event on the manufacturing side because an out-ofspecification medicinal product could result in a lack of efficacy or toxicities because of degradation of the product in the medicinal product dispensed. Similarly, when conducting GCP inspections, the interface between the sponsor and third parties involved in a trial or even a clinical development programme is scrutinised, and lack of evidence of compatible processes, quality systems and well planned and documented quality oversight programmes between partners can result in critical findings or even the equivalent of warning letters.

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Effective Management of Regulatory Good Clinical Practice and Pharmacovigilance Inspections

Figure 1: Rising Rate of Regulatory Inspections

35 31 30 28 29 28 35

Number of Inspections

25 20 15 10 5 2 0 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 (YTD) 1 4 14

18 14 12 10

Local authority inspection US (FDA) Local authority inspection Japan Local authority inspection France FDA foreign inspection Local authority inspection UK Local authority inspection Germany

Other inspection

Nowadays, when partners are involved in the joint development or commercialisation of a medicinal product, inspections of both companies as part of the same inspection assignment should not come as a surprise. In such instances, inspectors have requested the involvement of representatives of both partners during the entire cycle of the inspection. Such systemic and comprehensive inspection endeavours have become the norm rather than the exception. Last but not least, inspectees must be aware that inspection findings are liberally exchanged between the various inspectorates. For instance, there is a formal information exchange programme between the FDA and the EMEA. Time for Sponsors to React The changes on the side of the inspectorates called for a change in the approach by sponsors on how to get inspection-ready and prepare for and manage an inspection. There were three main areas that needed to be addressed as a priority:

On the documentation side: organigrams and job descriptions for each position; training syllabi and training logs for each GxP position; systems inventory and, where appropriate, validation documentation; standard operating procedures (SOPs) maintained as per planned revision cycle; list of status of clinical trials; list of service providers and business partners and the reciprocal roles and responsibilities; and pharmacovigilance agreements with business partners.

On the organisational side: identify facilities where an inspection can be hosted and an adjacent room where inspection support staff can be located; equip these rooms with any needed equipment, e.g. photocopier, telephone lines and Internet access; identify staff who take responsibility for hosting an inspection, and ensure alignment across GxP functions; get commitment from affiliate senior management that rooms are available at any time for inspection purposes (this seems to be a trivial point, but unless this is clarified an embarrassing situation can arise when upon the arrival of inspectors senior company staff may insist on the use of the rooms they have been using, not wanting to give up their territory; brief local security about the procedures to follow in case of an inspection; and ensure key staff are aware of dos and donts during an inspection.

create processes and develop tools for ensuring inspection readiness across the company; identify dedicated resources to keep the company in an inspectionready state, to host and manage the logistics of inspections and to ensure effective and timely completion of corrective and preventative actions (CAPAs) emerging from inspections; and break down the silos between the various GxP areas to drive alignment of the quality systems and sharing of tools relevant to inspections. To cope with the challenges presented by the changes in the inspections landscape, we at Roche have launched the Inspection Readiness Programme. In keeping with the above-mentioned priorities, a new group within the Clinical Quality Assurance (CQA) unit was created that solely deals with all aspects of the inspection process. This group is empowered to manage all aspects of an inspection. Getting Inspection-ready The first task of the newly created group was to draw an inventory of the critical elements that are needed to prepare for and to live through an inspection. Preparation is key, especially for unannounced inspections. The following elements need to be in place and be up-todate at any given time to ensure a smooth inspection (the bulleted list just gives the gist of what is needed):

To help establish this inventory, a structured questionnaire was developed, and all Roche affiliates (more than 100) were asked to complete this selfassessment. This questionnaire allowed strength and weaknesses to be determined, and their follow-up to be planned through targeted corrective actions. These corrective actions were again co-ordinated by the inspection group, who also ensured that best practices were efficiently shared. In addition to these efforts in putting together accurate documentation, a systematic training programme was deployed. Depending on the state of readiness of a function or affiliate, different training and coaching modules were offered. In view of the magnitude of the task globally there were almost 200 entities to be supported, ranging from headquarters functions and teams to the affiliates network a

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Regulatory Affairs and Pathways

train the trainer concept was successfully adopted. This approach not only allowed the scarce resources of the inspection group to be optimised, but also engaged teams and affiliates to a much higher degree of commitment. Keeping the Organisation Inspection-ready To keep the organisation inspection-ready, the self-assessment questionnaire is re-launched once a year, which allows any GxP-relevant changes in the organisation to be reflected in the basic inspection documentation. This effort is absolutely mission-critical as otherwise Professional management of an inspection by the sponsor is key to a positive outcome; it will not make critical findings disappear, but will avoid small problems becoming big, and at times can even contribute to a more positive outcome. Indeed, being able to demonstrate that problems identified by the inspectors are tackled effectively can make The selection of staff interacting with the inspectors is another important criterion for success: choose professionals with an excellent overview of the processes subject to the inspection, good communication skills and the ability to understand when inspectors can or even should be challenged. Aggressiveness or mental capitulation are behavioural tracts that are not helpful at all.

When inspectors show up on the premises it is critical that from the very beginning there is clarity about the roles and responsibilities of the function and individuals who act as hosts.
efforts spent up-front can quickly get lost in the daily routine. We realised that only a centralised and dedicated group could ensure the continuity and sustainability of the inspection readiness programme that has been rolled out to more than 100 countries. To complement the selfassessment and to ensure that the self-assessment did not result in false feedback, a programme of mock inspections was rolled out. These mock inspections can be simple hit and run exercises, i.e. a halfto one-day unannounced visit to a site to verify whether the logistics for hosting an inspection are in place, or more extensive evaluations of processes and documentation available. The latter are conducted like traditional compliance audits.

the difference between a critical and major finding or even a warning letter and just a substantial inspection report. When the Inspection Is Completed Nobody should think that when the fun of an inspection is over that the work is finished. Our inspection group takes responsibility for ensuring that CAPAs are submitted in a timely manner in response to an inspection report or 483 and, equally importantly, checks that any commitments for CAPAs are followed through. In the case of a reinspection there is nothing worse than an earlier commitment for CAPAs not being completed or properly addressed. Missing or incomplete CAPAs upon re-inspection are the ticket for a warning letter or even more serious regulatory action. At times, it can happen that on the basis of comments or observations made by the inspectors we become aware of potential process weaknesses, without these having been identified in the inspection report. Again, the inspection group plays a pivotal role in identifying such instances and overseeing corrective actions for these unofficial inspection findings. How Sponsors Can Learn from Each Other

A proper debrief at the end of any of these activities is of paramount importance to capture learning and make the teams or local organisation fully accountable for the long-term follow-up. To date we have conducted a variety of these mock inspections, and the learning effects have consistently been very high. Unannounced mock inspections can be disruptive to an organisation and therefore must balance the business needs and purpose of the inspection-readiness assessment. In addition to these activities, the accuracy of the inspection-readiness assessments is verified in our routine audits and our quality risk assessment programme. Managing an Inspection When inspectors show up on the premises it is critical that from the very beginning there is clarity about the roles and responsibilities of the function and individuals who act as hosts. First impressions count, and therefore one needs to ensure that an inspection gets off to a smooth start. This is when diligent preparation pays off. Having dedicated staff who act as runners (getting the hundreds of documents that are routinely requested by the inspectors), who act as scribes (noting down questions asked and passing these to colleagues who can address these), who arrange for the collection, copying and compilation of documents and who maintain overall co-ordination and overview is mission-critical. Inspections are hectic times and therefore it is of paramount importance that proper records are kept of what has been asked for or requested and documents and answers are provided in a timely manner. Lack of efficiency in this process has the potential of upsetting the inspectors, and may result in unnecessary inspection observations.

Those who have been in the industry for some time know very well that a disastrous outcome of an inspection in one company is bad news for the industry at large, as such negative events undermine the credibility of the clinical trial and pharmacovigilance systems with the public, the decision-makers in government and health authorities, and may trigger an intensified inspection programme across the industry as a whole. For these reasons, we are investigating options for sharing best practices and specifically the toolkit of checklists, self-assessment questionnaires and quality risk methodology we have developed. The

Those who have been in the industry for some time know very well that a disastrous outcome of an inspection in one company is bad news for the industry at large.
expectation is that the sharing of information while preserving essential confidential business data will allow us to learn from experience, and will lead to the possibility of conducting a continuous benchmarking exercise as part of the insight gained through each companys inspection-readiness activities. We should never forget that the goal of inspections is to instil public trust in what a sponsor does and delivers.

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