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International Clinical Trials

On the Level

The use of clinical endpoints in translational research is a cost-effective vehicle for moving study findings into viable drugs – providing relevant information to patients, clinicians and decision-makers.

Clinical endpoints are disease- or treatment-related events that demonstrate clear signs of improvement, remission, stabilisation, or even cure – all of which are important measures for patients who consent to clinical trials. Studies that utilise these endpoints can measure outcomes that impact survival, improve symptoms, or lower the possibility of developing a disease process or complication.

The final determination of a clinical endpoint – called adjudication – becomes the responsibility of a clinical event committee (CEC), independent of the sponsor company or CRO. This provides a standardised and unbiased assessment of the endpoint, and allows for consistent application in a global trial.

Success or Failure

Typically, trial research follows a protocol to investigate the primary and secondary objectives of the study with respect to an investigational product. This is designed to anticipate the occurrence of a pre-specified number of defined endpoints in a trial population, and to emphasise the most significant objective of the research (1).

Clinical endpoints are the principal measures of a treatment's success or failure; they define and answer research questions, and may have a direct impact on the claims of the investigational product.

Referred to as the response of dependent variables and generally directly observable, endpoints must be prospectively determined, well-defined, clearly recognisable and quantifiable, so there is no doubt as to when they have been reached. According to the FDA, “the most reliable method for demonstrating efficacy is to show a statistically significant improvement in a clinically meaningful endpoint in blinded randomised controlled trials” (2).

As part of the translational research process, clinical endpoints can be clinically relevant and minimise bias (3,4). In addition, they can add value to trial design, as well as providing more transparency and informing decision-making for patients, their families, healthcare providers and payers (5).

Types of Endpoints

Clinical endpoints can be considered primary, surrogate or composite, depending on the protocol and specific information required by the sponsor company and regulatory authorities (6). Primary endpoints are defined by the protocol and directly measure a clinical outcome of interest in a trial.

A surrogate endpoint is a marker used to measure the response of the underlying disease to the treatment or intervention. The relationship between the marker and the true, or primary, clinical endpoint must be clearly identified in the protocol and accepted by regulatory agencies. For example, in a trial for glaucoma, the true endpoint would be loss of vision; the surrogate endpoint would be increased ocular pressure. In an oncology trial, the true endpoint would be survival; the surrogate endpoint would be time to reappearance of the cancer.

A composite endpoint “combines clinically relevant endpoints (usually called components of the composite) into a single combined endpoint that can characterise clinically meaningful benefits of the treatment” (7). This type of endpoint is useful in smaller trials or events that may occur less frequently.

Caution should be used when utilising composite endpoints, since they must result in empirical evidence that supports the disease and treatment under study. Multiplicity arises when the sponsor company attributes findings to the entire study population from one component of the composite endpoint. “There is no multiplicity issue if the trial has a single composite endpoint as the sole primary endpoint, and there is no intention to claim treatment efficacy for its specific components” (7).

Clinical endpoint trials often examine cardiovascular events such as acute coronary syndrome, myocardial infarction, angina, revascularisation, hospitalised congestive heart failure, transient ischemic attacks and cerebrovascular accidents. Other types of endpoint-based research scrutinises bleeding events – for example, gastrointestinal bleeds, pancreatitis, thyroid-related issues, cancer and all-cause mortality.

Unbiased Evaluation

Adjudication – the final determination of a clinical endpoint – is the responsibility of an independent CEC, which offers an unbiased evaluation of the endpoints and ensures its consistent application across all regions in an international study.

As emphasised by the FDA, at a minimum these assessments should be subjected to a blinded independent adjudication team (2). Blinding to study treatment is the most effective way of controlling bias.

The criteria for determining if a clinical endpoint is to be adjudicated is established prior to the start of the trial, and endpoint criteria should not change as the study progresses. The criteria are determined through collaboration between the sponsor, CRO (if applicable) and the CEC. Adjudication processes are also predetermined, including the expertise of committee members, identification of the committee chairperson, location of members (regional versus global), and timing of meetings.

CEC members are therapeutic and adjudication experts independent from the sponsor, CRO and regulatory agencies. Committee members remain blinded to study treatment and use the protocol, source documents provided by investigational sites, and patient profile information (demographics, medical history, relevant medications and treatments, laboratory and/or diagnostic test results, etc) to complete the adjudication in a timely manner. These experts undergo targeted training with respect to protocol and adjudication procedures, and call on their clinical background and expertise to evaluate the endpoint consistently, reliably and accurately (8).

Package Review

Protocol-specified clinical endpoints are identified by the sponsor company through remote review of patient information, such as serious adverse event reports or laboratory and diagnostic test results. The site is then asked to provide the appropriate documentation. The second method of endpoint identification is by the site investigator; in this instance, the investigator is responsible for collecting and submitting source documents in support of the potential endpoint quickly after discovery.

Clinical endpoint packages generally undergo quality control methods that include medical review for relevance, identification of missing information, and redaction or blinding of protected healthcare information. This is a necessary step in minimising bias, and making sure that information fulfils the protocol-specific criteria and is clinically relevant to the identified potential endpoint. Such packages are not submitted to the CEC until queries are addressed, anonymity is ensured, and the package is complete and ready for adjudication.

A paper clinical endpoint package is transmitted via courier, fax or secure email transmission in order to guarantee timely receipt and allow for tracking of the delivery. The packages can also be processed electronically via a seamless and transparent workflow, which may afford time and cost efficiencies for larger trials (8).

Coordinating the Process


Regardless of the manner of data collection, adjudicators assess the potential endpoint independently with discordant assessments – requiring committee discussion, agreement, and final determination by the chairperson.

The process is often facilitated by a clinical endpoint coordinator, whose role is to act as a liaison between the investigational sites, clinical operations and adjudicators. This liaison further helps to expedite the identification of events, collection of potential endpoint information, transmission of endpoint packages, resolution of queries, and tracking of the final determination. In most cases, the coordinator is a nurse with expertise in the protocol, endpoint reporting processes, and the requisite organisational skills.

Empirical Evidence

The decision to embark on a clinical endpoint trial should take into account the purpose of the research, added value, as well as cost considerations. Such studies – and subsequent endpoint adjudication – can be instrumental in providing information to clinicians, patients and their families, and insurance providers in order to facilitate cost-effective treatment.

In line with FDA guidance, regular approval of drugs will occur when the sponsor company demonstrates clinical benefit through rigorous research and testing which results in empirical evidence. A drug may receive accelerated approval if the sponsor is able to predict, through the use of a surrogate endpoint, the reasonable likelihood that clinical benefit will occur. As such, endpoint trials will continue to provide valuable information in a global research environment which demands empirical data that is key to drug R&D and critical to patients.

References
1. Gnanasakthy A, Lewis S, Clark M, Mordin M and DeMuro C, Potential of patient-reported outcomes as nonprimary endpoints in clinical trials, Health and Quality of Life Outcomes 11(83): pp1-7, 2013. Visit: http://dx.doi.org/10.1186/1477-7525-11-83
2. FDA Guidance for Industry: Clinical trial endpoints for the approval of cancer drugs and biologics, 2007
3. Hastings CE, Fisher CA and McCabe MA, Clinical research nursing: A critical resource in the national research enterprise, Nursing Outlook, pp149-156.e3, 2011. Visit: http://dx.doi.org/10.1016/j.outlook.2011.10.003
4. Pageler L, Diener H, Pfaffenrath V, Peil H and Aicher B, Clinical relevance of efficacy endpoints in OTC headache trials, The Journal of Head and Face Pain, pp646-654, 2009. Visit: http://dx.doi.org/10.1111/j.1526-4610.2008.01242.x
5. Zhu CW et al, Bridging from clinical endpoints to estimates of treatment value for external decision makers, The Journal of Nutrition, Health & Aging 13(3): pp256-259, 2009
6. Pazdur R, Endpoints for assessing drug activity in clinical trials, The Oncologist 13(2): pp19-21, 2008. Visit: http://dx.doi.org/10.1634/theoncologist.13-S2-19
7. Huque MF, Alosh M and Bhore R, Addressing multiplicity issues of a composite endpoint and its components in clinical trials, Journal of Biopharmaceutical Statistics 21: pp610-634, 2011. Visit: http://dx.doi.org/10.1080/10543406.2011.551327
8. Tyner C and El-Assi Z, Electronic endpoint adjudication, Applied Clinical Trials Online, pp1-6, 2010. Visit: www.appliedclinicaltrialsonline.com


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Rachel Swierzewski RN, MSN, is an Assistant Director in Medical and Safety Services at ICON Clinical Research. She has been responsible for multinational endpoint studies involving cardiovascular, oncology, endocrine and renal trials. This includes accurate tracking of all endpoint events, medical review of endpoint records, and communication with sites and study teams. Prior to joining the clinical research industry, Rachel worked for over 30 years in nursing, including roles as a Nursing Instructor, Nursing Program Coordinator and Staff Nurse.

Adele Mueller PhD Candidate, MSN, RN, was formerly Drug Safety Manager at ICON Clinical Research, and is currently Team Manager at Telerx. Following a nursing career in cardiology, she expanded her expertise into clinical research, with a particular focus on drug safety/pharmacovigilance. After receiving her MSN from Gwynedd Mercy College, Adele is now pursuing a Doctorate in Organisational Leadership at Northcentral University.
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Rachel Swierzewski
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Adele Mueller
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