We conduct 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.
Pharmacokinetics refers to what the body does to the drug, while pharmacodynamics refers to what the drug does to the body. If initial testing of these is favorable, additional, larger Phase II studies are initiated to determine the effectiveness of a compound in the affected population, to define appropriate dosing for the compound and to identify any adverse effects that could limit the compound’s usefulness.
In addition to disclosing results of clinical trials, we respond to requests from external researchers to share our clinical trial data.
If data from the Phase II trials are satisfactory, companies will invest in large-scale Phase III trials to rigorously evaluate the compound’s safety and efficacy. Upon satisfactory completion of those trials, companies submit regulatory filings for marketing approval with the appropriate regulatory agencies around the world to have the product candidate approved for marketing.
It is our company’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 those issued by the International Conference on Harmonisation Good Clinical Practice (ICH GCP). However, individual country regulations and guidelines should remain the primary determinant of specific requirements for the conduct of medical research.
In keeping with the trend in the pharmaceutical industry, significantly more than half of the patients participating in our clinical trials are enrolled outside the U.S., in more than 50 countries. We have a commitment to the study of diverse patient populations, including minorities, women and children, in our clinical trials in all regions of the world. As a result, we strive to obtain information among diverse populations, ensuring a thorough evaluation of the safety and efficacy of our medicines and vaccines. These efforts allow us to seek regulatory approvals throughout the world and thereby offer our medicines globally to patients who need them.
Our company is committed to the timely registration of clinical trial information and the disclosure of trial results—regardless of their outcome.
We comply with all applicable laws and regulations associated with the registration of clinical trials in publicly accessible registries and subsequent posting of the results from these trials. We have put into place the processes necessary for compliance with the Food and Drug Administration Amendments Act of 2007 and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, including those related to clinical trial registration and posting results.
Registration provides patients and physicians with information about clinical trials that are open and are recruiting patients. The registration of trials and posting of results after trials are completed enable medical researchers to have timely information about our medicines and vaccines.
CLINICAL TRIAL REGISTRATION
We believe that clinical trial registries serve an important function for patients and their health care providers by enabling them to learn about and gain access to relevant clinical trials of experimental treatments or preventive agents. We continually assess changing global requirements for clinical trial registration, and update our clinical processes and practices to make sure the company is compliant with them.
For those who analyze, report or publish the results of clinical trials, a clinical trial registry also provides information on trials in progress and the ability to track such trials over the course of development. We register clinical trials in patients of investigational and marketed products, in which treatment is assigned, that we sponsor and conduct on www.clinicaltrials.gov, www.clinicaltrialsregister.eu and www.encepp.eu at trial initiation.
For our position on clinical trial registries, click here.
DISCLOSURE OF CLINICAL TRIAL RESULTS
Our company has long been committed to sharing the results of our clinical trials, regardless of their outcome, in a timely manner. If a clinical trial of a marketed product is terminated early for safety reasons, we will promptly disclose medically important information to regulatory authorities and the public, update the status on clinicaltrials.gov within 30 days, and submit a manuscript to a journal (or post a summary online) within 12 months after the last patient’s last visit occurs. If the trial was terminated for efficacy reasons, the results will be disclosed within 12 months after the last patient’s last visit occurs. Summaries of terminated trials will provide information about patient disposition, safety and adverse experiences, as well as an explanation as to why the trial was terminated early.
For many years, our company has been committed to publishing the results of hypothesis-testing trials in the peer-reviewed medical literature. Our Publication Guidelines have been in place since 2003 and are posted online, with periodic updates to incorporate any changes in good publication practices for industry-sponsored clinical trials. These guidelines describe our commitment to publishing complete, balanced and accurate information about the results of our registered clinical trials regardless of their outcome.
How we work with external investigators in order for our clinical trials to produce high-quality manuscripts is also outlined in our Publication Guidelines. We adhere to the International Committee of Medical Journal Editors (ICMJE) recommendations for authorship, requiring that authors meet all of the following criteria:
- Make substantial contributions to study conception and design, or to acquisition, analysis, or interpretation of data for the work
- Draft the article or revise it critically for important intellectual content
- Give final approval of the version to be published
- Be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved
Our company adheres to the authorship criteria of respected biomedical journals if their criteria differ from those of the ICMJE. In addition, individuals who do not meet the criteria for authorship, but who provide support, are recognized in acknowledgments when the manuscript is published. Our staff or the contract writers we hire may facilitate the development of a manuscript when the lead author provides oversight and direction; the efforts of the writers will then be acknowledged in the publication.
Our company also adheres to ICMJE or journal-specific guidelines for disclosure of potential conflicts of interest, including both financial and nonfinancial conflicts, for the full author team. Our Protocol Transparency Initiative, a voluntary practice of providing the clinical study protocol to biomedical journals upon submission of a manuscript reporting clinical trial results, allows journal editors and peer reviewers to use this protocol in their evaluation of the manuscript for publication. If the journal accepts the manuscript, we then allow the journal—at its sole discretion—to post key sections of the protocol on its website when the manuscript is published.
ACCESS TO OUR CLINICAL TRIAL DATA
In addition to disclosing the results of clinical trials, we respond to requests from external researchers to share our clinical trial data. We have multiple clinical trial databases that are of high value to the external clinical research community. We evaluate each request based on criteria that balance the need to advance science with the need to protect intellectual property and confidential information. Our evaluations comply with applicable privacy and data-protection laws, rules and regulations. We are committed to the PhRMA/EFPIA Principles for Responsible Clinical Trial Data Sharing.
Learn more about our policies and perspectives on data sharing:
- Procedure on Access to Clinical Trial Data
- Procedure on CSR Synopsis Posting
- External Scientific Review Board (ESRB) Charter
Scientific and medical researchers who wish to submit a proposal for access to our data may send an inquiry by clicking here.
Clinical Trial Design
All of our clinical trials are designed, conducted and monitored in accordance with the same global standards, whether they take place in the U.S. or elsewhere around the world.
We consider many factors when we design a clinical trial:
- Our questions and objectives: Clinical study designs vary according to 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 that of 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 that trial results are statistically meaningful, it is necessary before the trial begins to determine the number of patients needed to participate. It is also necessary to assess the feasibility of successfully conducting the trial.
- Acceptability of the trial design by regulatory agencies: When necessary, our Research Laboratories consult with regulatory agencies on design issues.
- Ethical perspectives: We enable patient diversity in our clinical trials to broaden the knowledge of the safety and efficacy of a new drug across different patient populations.
All of our company studies, regardless of the study design, use a standard format:
- The study objectives and endpoints (i.e., measurements) must be clearly stated before the study begins.
- The hypothesis or scientific question being asked by the study must be clearly defined.
- A plan for the analysis of the data must be developed before the trial begins, and finalized before the trial is completed.
The benefits of this format include strengthening the scientific credibility and regulatory acceptability of the results and ensuring the timely data analysis and publication of results.
CLINICAL TRIAL SITE MONITORING DESIGN, CONDUCT AND OVERSIGHT
In addition to complying with our company’s global standards, the conduct of our clinical trials adheres to the International Conference on Harmonisation Good Clinical Practice (ICH GCP) standards and to the principles that have their origin in the Declaration of Helsinki.
We seek input from local clinical investigators and external consultants with specific, relevant experience when designing our clinical trials. For early clinical trials in Phase II, studies are monitored on an ongoing basis by the clinical director and study team; when appropriate, an internal standing data-monitoring committee (DMC) of MRL senior managers reviews unblinded data from ongoing trials in a prespecified, scientifically acceptable manner. The goals of the DMC are to protect the safety of trial participants and assess whether the risk-benefit profile is favorable. The DMC’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 other clinical trials intended to support registration, studies are monitored by the clinical director and study team. In addition, if unblinded data will need to be monitored to ensure patient safety or to make decisions about continuing a study, a DMC composed of external experts independent of our company is assembled to review and make recommendations to us about the further conduct of the study.
In addition, it is our policy to establish scientific advisory committees composed of both external scientific leaders and our own scientists. With the participation of these committees, we can obtain expert advice on the design of a trial, provide for transparent review and discussion of data, and foster a collaborative approach to the publication and presentation of findings. We also have established a companywide, 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 (IRBs) or Ethical Review Committees (ERCs). We require assurance that patients involved in trials, and/or their legal representatives, understand the procedures and the use and disclosure of personal health information, the use of biological samples, and the risks/benefits involved in a clinical study. A consent form, approved by both our company and the IRB/ERC and translated into a language familiar to the study subject, must be carefully reviewed and signed by all participants to document that their participation in the study is voluntary and informed.
Informed consent is obtained prior to the initiation of any clinical study procedures, including those performed solely to determine eligibility for participation in the trial. In circumstances where patients receive payment or reimbursement for trial participation, the compensation is appropriate for the cost and inconvenience incurred and is clearly outlined in the consent form for full transparency. The consent procedures conform to applicable legal statutes and government regulations concerning research in human subjects and the privacy and security of medical information. If a prospective study participant cannot read the consent form, a patient advocate may read it, with consent documented and witnessed.
In accordance with ICH GCP guidelines, trial sponsors should appoint clinical trial monitors who are trained to monitor the trial adequately. Accordingly, ICH GCP training is mandatory for all of our clinical research associates (CRAs) who monitor clinical trials, as well as for all contract research organizations (CROs) that monitor clinical trials on behalf of our company.
CRAs monitoring on behalf of our company will visit sites throughout the study to ensure that:
- 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 per protocol
- Regulatory file documents are accurate and maintained per ICH guidelines and sponsor’s DPs
- Source documentation, including drug accountability logs, is maintained per ALCOA (attributable, legible, contemporaneous, original and accurate) guidelines
- Subject safety is maintained through review of source documentation, including drug accountability logs
- Data reported to the sponsor are accurate and reported per sponsor requirements
PROTECTING PERSONAL HEALTH INFORMATION
We are 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. We have been actively involved in the IPPC since 2006, in order to engage in a constructive dialogue with European data-protection authorities and other regulators on privacy standards for biomedical research.
CONTRACT RESEARCH ORGANIZATIONS
Our company’s primary clinical trial operating model includes the use of clinical research organizations on a limited basis. The use of CROs is generally reserved for circumstances such as:
- A company acquisition that includes clinical trial work already outsourced to CROs
- Clinical trial work that requires a large, rapid and global deployment of resources for a finite period of time
- A need for access to development markets that fall outside our company’s own development footprint
- Therapeutic indications that draw on a CRO’s specific development expertise in areas where our company does not have specific development execution experience (this is infrequent, given our breadth and depth)
When engaging a CRO, we perform rigorous capability assessments to ensure that the CRO has procedures, infrastructure and expertise that are adequate to ensure compliance with Good Clinical Practice (GCP) standards, and are aligned with our own Code of Conduct.
Due diligence is performed and remedies implemented on CROs previously working for a company that is then acquired by our company. Clinical trial teams within our company oversee the studies being run by CROs, and periodic audits are performed on CROs with which we do business. If and when we identify violations of the contract or GCP standards, we work 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, we will limit and possibly cease future award opportunities with the CRO until the issues have been fully remediated. Importantly, our expectations of the performance of CROs we engage with are no different from the expectations we have of our internally managed projects.
We regularly monitor the effectiveness and safety profiles of our marketed products and conduct formal post-marketing studies to evaluate signals of serious safety concerns about our products, including those requested by regulatory agencies.
We conduct several types of studies after approval, as appropriate:
- Commitments to regulatory authorities: For some products, regulatory authorities require companies to conduct additional interventional or noninterventional studies after the product is approved. A study could be required for multiple reasons, such as obtaining further information on the safety of the product. We work closely with regulatory authorities to design a study that will fulfill the specific requirement.
- Epidemiological studies: We have a long history of working closely with external experts in pharmacoepidemiology 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 health care systems based in several different populations.
- Pregnancy registries: For some products, we have systems of active data collection that can facilitate the early detection of teratogenicity, or interactions that alter normal embryonic development, and other serious adverse experiences in patients who, inadvertently or purposefully, use a particular drug during pregnancy. Useful information about the effects 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
We monitor the use and safety of our products, and we have a long history of conducting post-marketing safety studies to examine our products as they are used in clinical practice.
We also work closely with external experts in pharmacoepidemiology and drug utilization to examine the utilization and safety of our marketed products as they are used in health care systems based in several populations. These include Kaiser-Permanente (KP) Southern California, KP Northern California, United Healthcare, Pennsylvania and New Jersey Medicare, Harvard Pilgrim Health Care, Nordic Country Registries, the Clinical Practice Research Database, and Mayo Clinic Olmsted County, Minnesota.
To see select post-marketing safety studies, please click here.
PHASE II–V CLINICAL TRIALS
|PATIENTS BY REGION||2012||2013||2014||2015||2016|
|Central & Eastern Europe, Middle East & Africa||5%||8%||7%||7%||12%|
|European Economic Area||26%||33%||21%||22%||36%|
|TRIAL DISCLOSURE ACTIVITIES||2012||2013||2014||2015||2016|
|Manuscripts of clinical trial results and related papers submitted to peer-reviewed journals||238||137||146||216||152|
|Number of GCP/PV inspections conducted by regulatory agencies worldwide||44||149||99||119||103|
|NUMBER OF NEW PRODUCT & DEVICE REGISTRATIONS||2012||2013||2014||2015||2016|
|Central & Eastern Europe, Middle East & Africa||61||60||63||49||54|
|European Economic Area||29||28||22||22||8|
|GCP/PV audits by regulatory agencies of the company or clinical trial investigators that led to significant fines, penalties, warning letters or product seizures||0||–||0||0||–|
|* Complete Response Letter Received for Sugammadex (MK-8616)|
** Complete Response Letter Received for Januvia (sitagliptin; MK-0431)