Laying with the Lions

A significant part of clinical development activity is outsourced by pharmaceutical companies, which must still maintain responsibility for the oversight of the service providers to whom they outsource. Pharma companies fulfill this responsibility through quality management, which includes precontract and in-process audits of these service providers. Conducting such audits not only requires significant pharma resources but also significant additional time and resources from the service providers to facilitate these regular and routine audits from different sponsor companies.

As these audits from different sponsors often seek the same information, it should be possible to use our limited resources more efficiently. This duplication of effort could be avoided and efficiencies maximized for both sponsor companies and service providers if sponsor companies entered into a Cooperation Agreement solely for, and limited to, the sharing of objective and nonproprietary information gained from auditing activities.

The principles of such a Cooperation Agreement would relate to audit scope, what information may/may not be shared, protection of sponsor's proprietary information, the rights to use audit reports, and respect for existing confidentiality agreements.

Other safeguards built in would ensure that there would be no sharing of information on commercial matters between the collaborating sponsor companies and no cooperation to achieve commercial leverage. The scope of the Agreement would include only the sharing of objective information from audits conducted under strict controls and with the prior agreement of the auditee. None of the collaborating sponsor companies would have the right to access other sponsors' proprietary information during the conduct and reporting of audits.

Once the audit is completed, the objective findings and any related follow-up actions (excluding any reference to proprietary information) is shared between the collaborating sponsor companies who have the right to cross reference the audit activities in applications and submissions to regulatory authorities on a global basis.

This initiative has been tested by six big pharmaceutical companies. Benefits for both sponsor companies and about 30 service providers taking part in the program have been demonstrated.

Quality oversight

A continually increasing and significant part of a sponsor's clinical development activities is outsourced to a variety of service providers, including:

• full or single service contract research organizations (CROs)

• data management service providers

• laboratories (clinical, bio-analytical laboratories, specialty laboratories)

• central reading laboratories (ECG, imaging)

• clinical trial supplies, storage, and distribution companies

• IVR service providers.

Even with such outsourcing, the ultimate responsibility for the quality and integrity of the work performed always resides with the sponsor.¹ Sponsors fulfill such responsibility through quality management oversight of their service providers, including qualification and in-process audits. Therefore, the increasing use of service providers by pharma, with concomitant increases in auditing, still poses a significant requirement for resources from the sponsoring companies and specifically from the auditing functions of these companies.

Many of the service providers used routinely by pharma are audited by companies often seeking the same information related to the same generic systems used for activities performed. Moreover, the time required of service providers to facilitate routine audits from different sponsor companies performing similar audits should not be underestimated. It should be possible, however, to more efficiently use the limited time and resources of both pharma and service providers and avoid duplication of effort in quality management oversight.

To avoid this duplication of effort and to maximize efficiencies, F-Hoffmann-La Roche and five other peer companies have entered into a Cooperation Agreement. This agreement is solely for, and limited to, the sharing of objective and nonproprietary information gained from auditing activities.

Required resources

Typical resource requirements for pharma to conduct a service provider audit and the resources required of the latter to host one are provided in Tables 1 and 2.

Table 1. Time and personnel are two key resources required when a sponsor company conducts an audit.

These resource requirements are based on a standard auditing methodology that involves the assessment of the service providers compliance to international and local regulations and guidance, standard operating procedures (SOPs), and contracts; reviewing/verifying data and evaluating control documentation; interviewing key personnel; presenting observations according to a root cause approach; and following up after receipt of a corrective action plan and audit closure.

It may also be the case that the service provider personnel taken away from their normal activity to host audits as per Table 2 may be the same personnel used for activities relating to more than one pharma company, thus compounding the inefficiency and effects of duplicative efforts.

Table 2. The type of time commitment service providers can expect to make when they host an audit.

It is the intent of the inter company audit collaboration initiative described here to avoid such duplication of efforts and achieve greater efficiencies for both pharma and service providers in the quality management oversight of routinely used and cyclically audited service providers.

The initiative

The basic concept of this initiative is the pre-agreed (with service provider) sharing of objective and nonproprietary data in audit reports between clearly identified sponsor companies. These reports are used as one component of each sponsor company's risk management strategy related to their service providers. Each company draws its own conclusions from the report in the context of the scope of the audit performed and their specific needs at the time. The auditing company does not make recommendations to the other sponsor companies receiving the report—an important facet of the program with regard to anti-trust legislation. The initiative is not:

• one of performing joint audits or

• one of performing audits on behalf of another company or partnership.

Nor is it for any collusive discussion to exert commercial leverage. Rather, it is an initiative for the simple sharing of objective information in audit reports. The detailed concept is made clear in the Cooperation Agreement signed between the sponsor companies taking part and in the agreement letter signed by service providers prior to the sharing of the audit reports. Principles embedded in the Cooperation Agreement include mutual recognition of auditor capability, audit conduct, and audit reporting of the different parties; protection of proprietary information; controlling the use and distribution of information obtained during pre-agreed and approved processes; respect for existing confidentiality agreements, especially no sharing of information on commercial matters.

Tools and tactics

Tools developed for the management of the collaboration process and the standardization of audit report presentations and interpretations are presented in Table 3.

Table 3. Standardization plays an important role in successfully managing the collaboration process.

Participating sponsor companies meet at regular quarterly face-to-face meetings and hold monthly teleconferences to share and align selected QA programs related to service providers of mutual interest. Minutes are kept and archived. No participating sponsor company will perform an audit that was not already on their own audit plan. Agreeing upon which company will conduct a particular audit will depend on when each company had intended to conduct it, the particular audit scope, and the priority of the audit for the individual members.

The overriding principle is to maximize the efficient use of the participating sponsor companies' resources in performing quality audits of service providers normally audited in a routine cyclical fashion by group members. The aim is to avoid the duplication of time and effort required by these service providers in facilitating multiple audits of similar scope.

The principles of the Cooperation Agreement that effect the service provider relate to audit scope, what information may/may not be shared with whom and when, protection of the sponsor's proprietary information, the rights to use audit reports, and respect for existing confidentiality agreements. This is detailed in the standard service provider letter of consent, which also provides the identity of the sponsor companies with whom the report will be shared and which must be signed before any audit report is shared.

Audits are conducted in accordance with the normal SOPs of the auditing company who will have access only to its own information and will not have right of access to proprietary information of the other sponsor companies during the conduct and reporting of these audits. All conditions of confidentiality agreements between the service provider and any of the named collaborating companies remain fully in force and nothing in this process shall be in conflict to this.

All proprietary information related to the auditing company gathered through the review of documents and relevant interviews is used to test the generic systems (people, processes, and equipment) of the service provider that are also used routinely during the provision of similar services to the group members who have signed the Cooperation Agreement.

The detailed scope of the audit will be described, as usual, in the audit confirmation letter sent by the auditing company. Upon completion of the audit, the objective findings and related follow-up actions (excluding any reference to proprietary information) will be discussed with the service provider, and only then will be shared between the named collaborating sponsor companies in a standardized process. In this way, the nonauditing group members will only see the audit report when it is completed in the context of the auditee comments and provision of follow-up action plans.

These shared audit reports and follow-up action plans may be transferred within the individual group sponsor companies in a controlled manner and to the extent that this is already allowed in the individual agreements between the service provider and individual sponsor companies.

A key element of the collaboration process, and of benefit to both the group of sponsor companies and service providers alike, is the focus on standardization of audit conduct and, in particular, standardization of interpretation of audit reports.

Progress to date

Six big pharma companies have joined forces to share the generic results of some of the cyclical routine audits each conduct, thereby obviating the need for the other five to conduct the same audit. All have significantly benefited from significant cost and time savings. These audits have been conducted in Europe, the United States, and Australasia by group sponsor companies. About 30 service providers have signed up for the program and have also begun to see the benefits of time and cost savings comparable to those seen by big pharma.

Future outlook

It is clear from the initial proof of concept phase for this initiative that by increasing (in a controlled way and with the consent of all present parties) the number of collaborating companies in the group, we can even more efficiently share limited resources involved in the strategic risk management of independent third-party service providers of common interest.

It is envisaged that a controlled expansion phase of the project to allow, at least initially, for up to 10 collaborating QA groups will enable all parties participating to derive even significantly more benefit. The number and size of participating service providers are not limiting factors, but the type of service provider is. Specifically, investigator sites and clinical pharmacology units are not suited to such a program since such audits may be of a more project orientated and proprietary nature.

In addition to maximizing efficiencies and avoiding duplication of effort, it is also envisaged that this initiative will encourage the development of auditing criteria and standards so that audits become more standardized in the ways they are conducted and the kind of issues they are trying to assess. Challenges still remain both within pharma and within the service provider sector. These challenges include the conservatism of especially those pharma companies that could contribute to and benefit from maximizing the initiative, as well as an unfounded fear by the service provider of collusive discussion to exert commercial leverage. However, progress to date is showing that these barriers are being broken down.

Brian O'Neill, PhD, is global head of CQA external alliances at F-Hoffman-La Roche Ltd., Bldg. 670/515, CH-4070 Basel, Switzerland, email: brian.oneill@roche.com.

1. ICH GCP Part 5.2 Contract Research Organization, http://www.fda.gov/cder/guidance/959fnl.pdf.