Clinical testing begins with Phase I studies, which are designed to assess the safety, tolerability, pharmacokinetics and preliminary pharmacodynamic activity of the compound in humans.

Pharmacokinetics refers to what the body does to the drug, while the term pharmacodynamic refers to what the drug does to the body.¹ If these initial tests are favorable, additional, larger Phase II studies are initiated to determine the effectiveness of the compound in the affected population and define appropriate dosing for the compound, as well as identify any adverse effects that could limit the compound's usefulness. If data from the Phase II trials are satisfactory, companies will invest in large-scale Phase III trials to confirm the compound's safety and effectiveness. Upon completion of those trials, if satisfactory, companies submit regulatory filings for marketing approval with the appropriate regulatory agencies around the world to have the product candidate approved for marketing.

Merck conducts clinical trials worldwide to evaluate the safety and efficacy of our products. These trials are fundamental to the development of innovative medicines and vaccines that treat and prevent illness in humans. It is Merck's policy that all investigational studies in human subjects must be conducted in a manner consistent with laws, regulations and guidelines for the protection of human subjects, including International Conference on Harmonization-Good Clinical Practices (ICH-GCP) standards. However, individual country regulations and guidelines should remain the primary source of specific requirements for the conduct of medical research.

Consistent with a trend in the pharmaceutical industry, significantly more than half of the patients participating in our clinical trials are enrolled outside the United States, in more than 70 countries. As a result, we obtain information in diverse populations that ensures a thorough evaluation of the safety and efficacy of our medicines and vaccines, so we can seek regulatory approvals throughout the world and thereby offer our medicines to the wide variety of patients who need our medicines globally.

Clinical Trial Design

We consider many factors when we design a clinical trial:

• Our questions and objectives: Clinical study designs vary based on the specific objectives of the study. For example, the design of a study to assess the efficacy of a medicine in treating a particular condition is different from one seeking to determine the optimal dose of a medicine in a particular group of people.
• Statistical appropriateness and feasibility of conducting the study: To make sure trial results are statistically meaningful, it is necessary before a trial begins to determine the number of patients needed to participate. It is also necessary to assess the ability to successfully conduct the trials.
• Acceptability of the trial design by regulatory agencies: When necessary, Merck Research Laboratories consults with regulatory agencies on design issues.
• We always consider ethical perspectives when we evaluate potential trial designs.

All Merck studies, regardless of the study design, use a standard format:

• The study objectives and endpoints (i.e., measurements) must be clearly stated prior to starting the study.
• The hypothesis or scientific question being asked by the study must be clearly defined.
• The plan for the analysis of the data must be developed before the trial is initiated, and, if necessary, finalized before the trial is completed.

The benefits of this format include strengthening the scientific credibility and the regulatory acceptability of the results and ensuring timely data analysis and publication of results.

Clinical Trial Conduct, Oversight and Monitoring

Our clinical trials are designed, conducted and monitored in adherence to the same Merck global standards whether they take place in the United States or elsewhere around the world. In addition to following Merck global standards, our clinical trials conduct adheres to the ICH-GCP standards and to the principles that have their origin in the Declaration of Helsinki.

Our clinical trials are designed with input from local clinical investigators and external consultants with specific, relevant experience. For early clinical trials in Phases I and II, an internal data monitoring committee of MRL senior managers reviews unblinded data from ongoing trials in a prespecified, scientifically acceptable manner. The goals of the committee are to protect the safety of trial participants, preserve the integrity, credibility and validity of trial results, and provide recommendations based on interim data analyses (when less than 100 percent of the trial data are available). The committee's recommendations are communicated internally to relevant scientists and can be distributed externally to clinical investigators, review boards or regulatory agencies, as appropriate.

For all Phase III and later clinical trials intended to support registration, it is Merck's policy to establish scientific advisory committees composed of external scientific leaders and Merck scientists. With these committees, Merck can obtain expert advice on the design of the trial, provide for transparent review and discussion of the data, and foster a collaborative approach to the publication and presentation of findings. In addition, in 2008 Merck established a company-wide, global approach for assessing clinical safety by implementing internal organ-specific safety boards to support the evaluation and management of organ-specific safety issues.

All protocols and related documents are reviewed and approved by external and independent Institutional Review Boards or Ethical Review Committees.

Compassionate Use Program

Merck has a procedure for early access to non-registered products for named patient programs and country-specific authorizations that recognizes the importance of providing access to new treatments under development to certain patients. Merck may also decide to conduct an expanded access program for a limited number of qualified patients according to a clinical protocol. Merck may conduct these compassionate use programs under the following circumstances: the disease is life-threatening or severely debilitating; no effective alternative treatments are available for patients, or a patient has failed to respond to available treatments; a patient is not eligible for a clinical trial; and a marketing authorization application is planned in the future.

Merck requires assurance that subjects and/or their legal representatives understand the procedures, use and disclosure of personal health information, use of biological samples, and risks/benefits involved in a clinical study and that a subject's participation is voluntary. In circumstances where patients receive payment or reimbursement for trial participation, this compensation is clearly outlined in the consent form for full transparency.

Informed consent is obtained prior to initiation of any clinical study procedures, including those performed solely to determine eligibility for participation in the trial. A consent form, approved by both Merck and the IRB/ERC and translated into a language familiar to the study subject, must be approved by all participants to ensure that their participation in the study is voluntary and informed. The consent procedures conform to all legal statutes and government regulations concerning research in human subjects and the privacy and security of the medical information. In the case that a prospective study participant cannot read the form, a patient advocate may read the consent form, with consent documented and witnessed.

Protecting Personal Health Information

Merck is a member of the International Pharmaceutical Privacy Consortium (IPPC), an association of research-based pharmaceutical companies formed in 2002 that has worldwide responsibility for the protection of personal health information and other types of personal data. Merck has been actively involved in the IPPC since 2006 to engage in a constructive dialogue with European data protection authorities and other regulators on privacy standards for biomedical research.

For certain trials, Merck establishes an external Data Monitoring Committee to safeguard the interests of trial participants and ensure the integrity of the trial. The Data Monitoring Committee is an independent body of clinicians and statisticians that assesses the potential benefits and risks of the investigational therapy, based on interim data from the clinical trial, and makes recommendations to Merck.

In accordance with ICH-GCP guidelines, trial sponsors should appoint clinical trial monitors who are appropriately trained to monitor the trial adequately. Accordingly, GCP training is a mandatory course for all Merck clinical research associates (CRAs) who monitor clinical trials, as well as for all contract research organization (CROs) who monitor clinical trials on behalf of Merck.

Merck's CRAs (or those monitoring on behalf of Merck) will visit sites throughout the study to ensure:

• The principal investigator and site staff are qualified and have adequate facilities and equipment to conduct clinical research throughout the duration of the study
• Site staff are adequately trained on the protocol, procedures and equipment
• Site staff adhere to protocol requirements, sponsor's Development Procedures (DPs) and ICH guidelines
• Clinical supplies are stored and dispensed as per protocol
• Regulatory file documents are accurate and maintained as per ICH guidelines and sponsor DPs
• Source documentation, including drug accountability logs, are maintained as per ALCOA guidelines
• Subject safety, through review of source documentation including drug accountability logs
• Data reported to the sponsor is accurate and reported as per sponsor requirements

Contract Research Organizations

Approximately 25 percent of our trials are outsourced to Contract Research Organizations (CROs) for the execution of the study. Before agreeing to work with a CRO, Merck performs rigorous assessments and due diligence audits to ensure that the CRO complies with Good Clinical Practice (GCP) standards and is aligned with Merck's own Code of Conduct. Merck trial teams structure and rigorously oversee all studies being run by a CRO, and Merck performs periodic audits of all existing CROs with which we do business. If and when we identify violations of the contract or GCP, Merck works with the CRO on a corrective action plan. If improvements are not made within a defined period of time, or if repeat violations are noted and unsatisfactorily remediated, Merck will terminate work with the CRO.

Post-Marketing Activities

Merck continues to research the effectiveness and safety profiles of our products on an ongoing basis. We conduct several types of studies after approval:

• Post-approval studies on new indications: Some drugs may be effective for more than one indication. For example, an oncology product can be developed to treat several types of cancer. In such cases, a clinical trial must be conducted to determine the safety and efficacy of the drug in each new patient population.
• Commitments to Regulatory Authorities: For some products, regulatory authorities require companies to conduct additional studies after the product is approved. The study could be required for multiple reasons, such as obtaining further information on the safety of the product. Merck works closely with regulatory authorities to design a study that will fulfill the specific requirement.
• Epidemiology Studies: Merck has a long history of working closely with external experts in pharmaco-epidemiology to understand the types of patients utilizing our products, as well as to examine the effectiveness and safety profiles of many of our marketed products as they are used in clinical practice in several population-based healthcare systems.
• Pregnancy Registries: For some products, Merck has active data collections in systems, which can facilitate the early detection of teratogenicity and other serious adverse experiences in patients who inadvertently or purposefully use a drug during pregnancy. Useful information about the outcome of exposure in pregnancy can best be obtained by the careful collection and analysis of post-marketing surveillance data. Reports of the aggregate data in each registry are updated annually and shared with regulatory authorities.

Post-Marketing Safety Studies

Merck monitors the use and safety of our products. The company also works closely with external experts in pharmaco-epidemiology and drug utilization to examine the utilization and safety of our marketed products as they are used in several population-based healthcare systems, including, but not limited to, Kaiser-Permanente (KP) Southern California, KP-Northern California, Innovus, Pennsylvania and New Jersey Medicare, Harvard Pilgrim Health Care, and Mayo Clinic Olmsted County, Minnesota. We have a long history of conducting post-marketing safety studies to examine our products as they are used in clinical practice.

Regulatory Agency Training

In 2010, MRL Compliance supported several Good Clinical Practice (GCP) Pharmacovigilence PV training requests fulfilled to help strengthen local regulatory agency capabilities in their GCP/PV compliance oversight role. These efforts aim to help strengthen local agency capabilities in their GCP/PV compliance inspection and oversight role. The venues supported in 2010 were as follows:

• February, 2010: MRL Compliance was invited to support a training request for Pharmaceuticals and Medical Devices Agency (PMDA) inspectors. Training topics covered were focused on GCP initiatives.
• October 7-8, 2010: MRL Compliance was invited to support the 10th Annual Thailand toward Excellence Clinical Trial Forum (ThaiTECT). The conference topics were focused on progressing Thailand's competiveness to become a clinical research destination in Asia. Training and panel discussion topics included "Issues and Challenges in Central Clinical Laboratories".
• October 2010–present: MRL Compliance, representing PhRMA Japan, was invited to participate in the PMDA GCP inspection sub-working group.
• September 2010: MRL Compliance was invited to present at an industry conference on the topic of "FDA/EMA inspections." Conference attendees included Japanese regulators.
• December 2010: MRL Compliance was invited to present at an industry conference on the topic of "Quality of Chinese clinical trials." Conference attendees included the Chinese State Food and Drug Administration.

In addition, Merck invests in and maintains internal access to several population-based electronic healthcare insurance claims and medical record databases. With this database access, we can monitor the utilization and safety of our marketed products as they are used within the healthcare system, but we cannot gain access to patient-identifiable information. These databases include the General Practice Research Database in the United Kingdom, the Health Improvement Network database (U.K.), Innovus Database (U.S.), MedStat (U.S.), IMS Disease Analyzer (U.K., France and Germany), and Medicaid data for eight states in the United States. For example, we have been monitoring the use of ARCOXIA^® (etoricoxib) in the General Practice Research Database. These reports were provided to regulatory agencies in 2006 and 2007.

 

¹ Leslie Z. Benet, Pharmacokinetics: Basic Principles and Its Use as a Tool in Drug Metabolism, p.199 in: Drug Metabolism and Drug Toxicity, JR Mitchell and MG Horning (eds.), Raven Press, New York (1984).