Contract Research: Criteria to live by

Jeffery Steinberg and Karoline Dubiel

Contract research organisations (CROs) are playing increasingly vital roles on behalf of manufacturers in the global drug development process, from conducting Phase I safety testing to Phase IV post-market studies. Traditionally, CROs focused on providing additional capacity and expertise to facilitate drug development and reduce R&D costs, while maintaining quality standards. More recently, they have begun highlighting their capacity to support drug safety efforts for products on the market and compounds in the pipeline. Policymakers and the public are closely scrutinising and questioning manufacturers about the controls they have in place to safeguard patients both pre-commercialisation and post-commercialisation.

As an extension of the manufacturers' R&D process, CROs are also under the microscope to promote patient safety, intellectual property security, and sponsor reputation. The manufacturer is, however, ultimately responsible for the quality and integrity of trial data, including safety information. The International Conference on Harmonisation (ICH) states in section 5.2 of its Guideline for Good Clinical Practice that a sponsor is responsible for the ongoing safety evaluation of the investigational products and for reporting any information that could adversely affect the safety of trial subjects.

Brand, reputation, and credibility

Viewed by regulators as an extension of the contracting sponsor, CROs need to maintain the same high-level quality standards and controls as any manufacturer conducting trials. Many CROs have met these criteria and are known for delivering a high level of quality, performance, and therapeutic specialisation. In 2004, the most recent year for which data is available, leading CROs managed nearly 23,000 Phase I - IV studies at 152,000 clinical sites worldwide.

As with any third-party relationship, manufacturers need to remain vigilant and involved in any outsourced R&D, particularly in light of the current public perception of the pharmaceutical industry, the transparency of its R&D process, and drug safety concerns. Monitoring CRO performance and compliance is crucial to mitigating the potential risks that manufacturers face in any third-party collaboration, from R&D to manufacturing, distribution, and advertising. For CROs, this includes reviewing patient records and medical charts. While monitoring ongoing activities is essential to risk mitigation, executives also need to establish a strong foundation for CRO compliance and integrity. The ICH guideline, for example, states that any trial-related duty that is transferred from sponsor to CRO should be specified in writing. In at least one high-profile incident in which clinical trial subject safety was compromised during a CRO-managed trial, regulators found that a contract between the sponsor and the CRO was not in place when the patient safety incident occurred.

Selecting a CRO vendor

Outsourcing clinical research may involve one or several strategic and tactical approaches. Sponsors may:

• Opt for full-service outsourcing, whereby a single CRO conducts the entire clinical project
• Outsource individual services
• Select multiple CROs, depending on their area of expertise, thereby forming an outsourcing network for a particular project

For each of these approaches, as with any third-party service arrangement, sponsors should assess certain risks before engaging in a contract. The more complex the task covered under the contract, the greater the risk. The potential for risk may increase when clinical protocols are developed by multiple physician-investigators and involve multiple investigational sites and other third parties, for example, if the reporting of adverse events is handled by a safety reporting vendor call center. As more people and systems are involved, additional prudence may be needed. Some questions to consider when selecting CROs include:

• How are the policies of our CRO partner harmonized globally, and how do those policies account for local differences, including culture?
• What is the trend in human resources in the market in which a potential CRO partner is located? How might that impact the continuity and quality of our outsourced R&D efforts?
• How does the CRO communicate, report, and record adverse events or signs of potential safety effects in early- to late-stage trials?
• How and when does the CRO share the draft protocol for the trial?
• What controls are in place to govern the final signoff procedures for the protocol?

Once a company has decided to outsource clinical trials, the next step is to identify a reliable service provider with a proven track record that best meets the sponsor's requirements. Business continuity is a critical prerequisite in the relationship between a manufacturer and a CRO and sets a strong foundation for success. This requires a manufacturer to screen potential partners using more than the traditional list of vendor selection criteria. Some of the key considerations when selecting a CRO include, compliance with all applicable safety regulations, validated experience in target therapeutic areas, strong track record of studies performed, robust data management and biostatistics capabilities, commercial or home-grown IT system stability, appropriate pool of human resources (e.g., scientists, project managers, clinical research associates).

Besides these, they should also have substantial experience with regulatory submissions in markets of interest, validated technical facilities, strong relationships/alliances with outside vendors and contractual compliance, significant central laboratory expertise, ability to manage investigational sites, permission to conduct precontract and postcontract audits of personnel, infrastructure, facilities, good laboratory and clinical practices compliance, and quality assurance systems, robust processes with strong oversight function and clear roles, responsibilities, and requirements, sound financials and adherence to financial processes (e.g., invoice processing) and leading IT security and information management practices, e.g., protecting data privacy and compliance, with Title 21, Part 11 of the Code of Federal Regulations.

Partnering in India

Global pharmaceutical companies continue to increase their R&D activities in India; the CRO market is expected to surpass US$1 billion by 2010. In response, multinational and domestic CROs are quickly building capacity. Sponsors are also looking for signs that selected CROs can sustain unexpected workload increases while meeting high standards for clinical operations, quality assurance, business processes, and project management.

Given the rapid growth in the local market, CROs need to demonstrate, in addition to their cutting-edge operations, their steadfast commitment to transparency of financial reporting, business processes, and compliance controls. They must also show how they are integrating clinical operations into the business context and attaining efficient and effective project tracking and cost management. Executives at some multinational pharmaceutical subsidiaries in India have expressed some concern about the quality of some newly emerging CROs. They point to high employee turnover and a growing scarcity of qualified management-level executives, from project managers to compliance officers, among their top concerns.

Manufacturers must also address public sensitivities about the growth of clinical trials in India, particularly those conducted by foreign multinationals. India's Union Minister for Health and Family Welfare, Anbumani Ramadoss, denied that the country has "opened up as a guinea pig," noting that, "if you do clinical trials in India you have to be transparent. We are very, very guarded. We will not allow our population to suffer."

Outlook

As the pharmaceutical business model relies increasingly on third parties to perform complex and critical processes on their behalf, they will need to continue to monitor their relationships vigilantly and benchmark against others in the industry. For example, the vibrant and growing CRO industry in India provides opportunities for manufacturers to reduce costs, increase R&D productivity, and focus on growing other business areas. As with any third-party vendor, however, collaborating with CROs raises new risks. As the CRO landscape evolves, manufacturers need to continue mitigating potential compliance, cost management, and patient safety risks involved in outsourcing R&D. Ultimately, the company's reputation - and the welfare of patients and clinical trial subjects - are on the line.

(The writers are Global Pharmaceutical Sector, Risk Advisory Services Leader, Ernst & Young and Sr Manager, Risk Advisory Services (Healthscience), Ernst & Young respectively)