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 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.

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 to 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 ensure trial results are statistically meaningful, before a trial begins it is necessary to determine the number of patients needed to participate. Also, an assessment of the ability to successfully conduct the trials is necessary.
• 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.

In order to provide transparency about the research we conduct, Merck registers all clinical trials conducted in patients on clinicaltrials.gov at trial initiation. In addition, registration of our trials allows patients to identify appropriate clinical trials for their disease conditions and to pursue participation in the trials. For more information please see Clinical Trial Registration and Disclosure of Clinical Trial Results section.

Clinical Trial Conduct

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.

Consistent with a trend in the pharmaceutical industry, more than half of the patients participating in our clinical trials are enrolled outside the United States, in more than 50 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.

Our clinical trials are designed with input from local clinical investigators and external consultants with relevant, specific experience. For early clinical trials in Phases I and II, an internal data monitoring committee of MRL senior management 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, to preserve the integrity, credibility, and validity of trial results, and to provide recommendations based on interim data analyses (when less than 100% of the trial data are available). The recommendations of the committee 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 policy to establish scientific advisory committees composed of external scientific leaders and Merck scientists. These enable Merck to 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 evaluation and management of organ-specific safety issues.

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

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 their participation is voluntary. In circumstances where patients receive payment or reimbursement for trial participation, this 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 for the purpose of determining 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 completed 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, the consent form may be read by a patient advocate, with consent documented and witnessed.

Merck has a new procedure for a compassionate use program that recognizes the importance of providing access to new treatments under development to certain patients. Merck may conduct a compassionate use program under the following circumstances: the disease is life-threatrening or severely debilitating; no alternative treatments are available for patients; a patient is not eligible for a clinical trial; and a marketing authorization application is planned in the future.

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

Clinical Trial Monitoring

In accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines, clinical trial monitors should be appointed by the trial sponsor and should be appropriately trained to monitor the trial adequately. Accordingly, GCP training is a mandatory course for all Merck Clinical Research Associates (CRA) who monitor clinical trials, as well as for all Contract Research Organization CRAs who monitor clinical trials on behalf of Merck.

Contract Research Organizations

Before agreeing to work with an outside Contract Research Organization (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 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.

Adverse Event Reporting

The Worldwide Product Safety Department at Merck is responsible for the collection, management and reporting of adverse experience (AE) reports received by Merck worldwide. Merck has a custom-designed computer-based system that stores information received for AEs with Merck products.

Regulations vary by country, however most countries require that drug manufacturers promptly review AE information that they receive from any source, domestic or foreign, relating to their products. In addition, regulations require that manufacturers adopt written procedures for managing and reporting of post-marketing adverse experiences. In accordance with these regulatory requirements Merck has developed a written procedure to provide Merck personnel worldwide — including all contract personnel — with a consistent and thorough process for identifying, reporting and processing AEs occurring while patients are using Merck products (but not necessarily due to their use). These procedures relate to the reporting of AEs originating in clinical studies and those associated with use of marketed products. Adherence to these procedures ensures the timely and accurate monitoring of the safety profile of Merck’s investigational and marketed products globally.

To report an adverse experience to regulatory authorities, we need minimal information: The name of the Merck medicine involved, an adverse experience, an identifiable patient and an identifiable reporter. In addition to submission of individual adverse experience reports to regulatory authorities, either within 15 days or periodically, we also file aggregate reports (quarterly, six monthly, annually) for as long as we market a medicine or vaccine.

Our safety teams review all pharmacovigilance data and determine what actions need to be taken with reference to the evolving safety profile of our products. These teams include physicians and epidemiologists who are trained to review this type of data.

It can be difficult to determine the exact cause of an adverse experience because many patients have more than one condition and may be taking multiple medicines. Our pharmacovigilance staff takes great care to ensure that adverse experience reporting is as accurate as possible. We consolidate the data to determine if there are any patterns or signs of problems that need additional surveillance. Ongoing oversight and monitoring of our product labels is a major focus of our safety efforts. Our label review teams monitor information on our products and work with our product safety teams to develop or update product labeling. Information is then communicated to regulatory agencies worldwide.

Training

Employees responsible for monitoring and reporting adverse experiences undergo rigorous training every other year. New Merck Research Laboratories (MRL) employees — including all contract personnel — working in areas related to clinical research undergo training on Merck's adverse experience policies and procedures when they join the Company. All MRL employees are encouraged to complete the training.

Communicating About Product Risks

If we determine that a potential risk relating to one of our products requires product information to be changed and communicated, we work with regulatory authorities to contact physicians in a timely manner, through “Dear Doctor” letters, advertisements in pharmacies, and, in some cases, by issuing a media release and other communication mechanisms as appropriate. In consultation with regulatory agencies, we develop appropriate strategies as needed to minimize risks when that is feasible.

All of our information leaflets in our product packaging contain information on possible side effects. We include contact details for patients, care givers and health professionals to report adverse experiences in the United States on our corporate website. Outside the United States, adverse events are reported according to local laws and practices.

Clinical Quality Assurance Auditing

The Worldwide Clinical Quality Assurance Resources department at Merck is responsible for conducting independent, periodic audits of the processes, computerized systems, technology and collaborative partners supporting Merck clinical development. This comprehensive audit program encompasses a broad range of audits and assessments of the following:

• Clinical investigator sites: Audits to assess compliance with the protocol and Good Clinical Practice regulations and guidelines.
• Collaborative Partners: Pre-contractual assessments and post-contractual audits of contracted research organizations (CROs), central laboratories and other third-party vendors.
• Computerized Systems and Technology: Audits and assessments of the computerized systems and technology supporting clinical development.
• Internal Process Audits: Systematic evaluations of compliance of clinical developments processes to Standard Operating Procedures, Global Development Procedures, ICH-GCP and applicable regulations.
• Pharmacovigilance Audits – Audits of the processes, systems and departments supporting Pharmacovigilance.
• Subsidiary Audits: Periodic and systematic assessments of our subsidiaries worldwide.
• Due Diligence Assessments of potential new licensing candidates.

The primary objectives of the audits are to assess compliance with GCP and Pharmacovigilance (PV) regulations and guidelines, clinical study protocols and contractual agreements, divisional and departmental standard operating procedures and applicable corporate policies and procedures; and to assure the accuracy and integrity of the clinical trial data in support of our regulatory applications.

Post-Marketing Commitments to Regulatory Authorities

For some products, regulatory authorities require that companies conduct additional studies after the product is approved. The study could be required for multiple reasons, including to obtain further information on the safety of the product. Merck works closely with regulatory authorities to design a study that will fulfill the specific requirement.

Post-Marketing Safety Studies

Merck monitors the use and safety of our products. The Company also works closely with external experts in pharmacoepidemiology and drug utilization to examine the utilization and safety of our marketed products as they are used in several population-based health care systems, including, but not limited to Kaiser-Permanente (KP) Southern California, KP-Northern California, Ingenix United Healthcare, 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. Currently we have eight safety studies ongoing in partnership with external academic and research institutions:

• GARDASIL^® [human papillomavirus quadrivalent (types 6, 11, 16, 18) vaccine, recombinant]: We are conducting two studies— the first is a safety study of over 44,000 adolescents and women vaccinated with GARDASIL in the United States and a second study examines safety in pregnancy and long-term effectiveness of GARDASIL vaccination in the Scandinavian countries.
• ROTATEQ^® (rotavirus vaccine, live, oral, pentavalent): We are examining the overall safety and effectiveness of over 44,000 infants vaccinated with ROTATEQ vaccine in the United States. This includes ongoing evaluation of intussusception and Kawasaki's Disease. We are monitoring the safety of ROTATEQ in conjunction with the Centers for Disease Control and Prevention and the Food and Drug Administration.
• VARIVAX^® [varicella virus vaccine live (Oka/Merck)]: In 2008 we completed year 12 of a 15-year study to examine safety and effectiveness of VARIVAX vaccination in children and adolescents. We send an annual report on this study in June of each year to regulatory agencies.
• SINGULAIR^® (montelukast sodium): We have been studying women who use SINGULAIR and other asthma drugs during pregnancy to examine pregnancy outcomes in asthma and asthma treatment. An interim report was sent to the regulatory agencies and we are continuing to monitor safety in a U.S. health insurance database.
• ISENTRESS^® (raltegravir): We are conducting a study in the European Union to examine the safety of the use of ISENTRESS in a population of HIV patients. An additional study in a health care system in the United States will begin in 2009.
• PROQUAD^® (measles, mumps, rubella and varicella [Oka/Merck] virus vaccine live): We completed a safety study to examine the general safety and occurrence of febrile seizures following PROQUAD vaccination in at least 25,000 infants in the United States. The final report was sent to regulatory agencies.
• ZOSTAVAX^® (zoster vaccine live): We are conducting a study to examine the safety of ZOSTAVAX vaccination in over 20,000 subjects who are 60 years of age or older.
  

In addition, Merck invests in and maintains internal access to several population-based electronic health care insurance claims and medical record databases that allow us to monitor the utilization and safety of our marketed products as they are used within the health care system, but these databases do not allow Merck to have access to patient identifiable information. These databases include the General Practice Research Database in the United Kingdom, The Health Improvement Network database (U.K.), Ingenix United Healthcare 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. For more information about how we ensure confidence in the safety and quality of our products, please click here.

The content on this page was last modified on September 15, 2009.

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