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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 HistoryInspections 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 marketingapplication. In particular, clinical trial centres outside the US were never

inspected unless they were contributing in significant terms to the

submission data. The modus operandiof 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 qualityand 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 largepharmaceutical 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

systems that interface with manufacturing activities. For instance, wheninspecting 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-of-

specification 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.

Effective Management of Regulatory Good Clinical Practice

and Pharmacovigilance Inspections

T O U C H B R I E F I N G S 2 0 0 8

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 microbiologyfrom the Swiss Institute of Technology in Zurich in 1982.

E: beat_e.widler@roche.com

Regulatory Affairs and Pathways

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11D R U G D E V E L O P M E N T

Effective Management of Regulatory Good Clinical Practice and Pharmacovigilance Inspections

Nowadays, when partners are involved in the joint development or

commercialisation of a medicinal product, inspections of bothcompanies 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 theapproach 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:

create processes and develop tools for ensuring inspection

readiness across the company;

identify dedicated resources to keep the company in an inspection-

ready 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-to-

date at any given time to ensure a smooth inspection (the bulleted list

just gives the gist of what is needed):

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 anadjacent 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 aninspection; and

ensure key staff are aware of dos and donts during an inspection.

To help establish this inventory, a structured questionnaire was developed,

and all Roche affiliates (more than 100) were asked to complete this self-

assessment. 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

Figure 1: Rising Rate of Regulatory Inspections

0

5

21

4

14

31

18

14

1012

2829

35

28

10

15

20

25

30

35

NumberofInsp

ections

1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 (YTD)

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

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12 D R U G D E V E L O P M E N T

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

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 self-

assessment 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 half-

to 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.

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 InspectionWhen 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.

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.

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 difference between a critical and major f inding 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 toan inspection report or 483 and, equally importantly, checks that any

commitments for CAPAs are followed through. In the case of a re-

inspection 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

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

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.

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.

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.