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CHAPTER

Clinical TrialsDOI:

© 2012 Elsevier Inc. All rights reserved.2012

10.1016/B978-0-12-391911-3.00010-4

I. INTRODUCTION

Endpoints are used to assess efficacy of a drug, medical device, counseling, physical exercise, or other form of treatment under evaluation in a given clinical trial. Typically, in designing a clinical trial, an investigator includes more than one type of endpoint. Endpoints include efficacy endpoints and sometimes safety endpoints.

a. Phase I clinical trial endpointsPhase I clinical trials are primarily conducted for arriving at an optimal dose, for use in Phase II and III clinical trials, but only secondarily, if at all, for acquiring data on effi-cacy. In comments about Phase I trials in the context of oncology, Llovett et al. (1) find that, “[i]n current oncological practice, phase 1 studies are intended to define appropri-ate dosage by using endpoints such as dose-limiting toxicity, maximum tolerated dose, pharmacokinetic profile, and pharmacodynamic profile. The primary endpoint of these studies is the safety profile or change in measures that reflect relevant biologic processes.”

b. Clinical endpointsThe endpoints that are most relevant to the study subject are events of which the study subject is aware or afraid of, such as death, a heart attack, loss of vision, or the aris-ing need for a liver transplant due to viral infection (2). These endpoints are classified as clinical endpoints. In clinical trials on life-threatening disorders, the most common clinical endpoint is overall survival (OS). But, according to Le Tourneau et al. (3) “[t]he main drawback of overall survival is that it usually requires larger patient numbers and longer follow-up than surrogate time-to-event end points.”

c. Surrogate endpointsAnother class of endpoints is surrogate endpoints. Where the natural time course of a particular disease is extremely long, or where the window of drug therapy is extremely

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1 Llovet JM, Di Bisceglie AM, Bruix J, et al. Design and endpoints of clinical trials in hepatocellular carcinoma. J Natl Cancer Inst. 2008;100:698–711.

2 Fleming RT, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996; 125:605–613.

3 Le Tourneau C, Michiels S, Gan HK, Siu LL. Reporting of time-to-event end points and tracking of failures in randomized trials of radiotherapy with or without any concomitant anticancer agent for locally advanced head and neck cancer. J Clin Oncol. 2009;27:5965–5971.

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long, trial design may include one or more surrogate endpoints. When included in trial design, surrogate endpoints can reduce the cost and duration of the trial. According to Fleming and DeMets (4) a surrogate endpoint is a laboratory measurement or a clinical sign used as a substitute for a clinically meaningful endpoint. The surrogate endpoint measures how a patient functions, survives, or feels. The surrogate endpoint is supposed to operate as follows. Changes induced by a therapy on the surrogate endpoint reflect changes in the clinically meaningful endpoint.

Examples of surrogate endpoints include tumor size and number, or time to detec-tion of tumor metastasis in clinical trials in oncology, LDL-cholesterol in clinical trials with drugs for atherosclerosis, and reduction in brain lesions in clinical trials on mul-tiple sclerosis. In the context of clinical trials on infections, Smith et al. (5) expressly categorized endpoints as clinical endpoints (relates to signs and symptoms of the infec-tion) and as bacteriological endpoints (measures the titer of the infecting agent).

The proper place of surrogate endpoints in trial design has been reviewed by Dhani et al. (6) Gil and Sargent (7) Pazdur (8) McKee et al. (9) Allegra et al. (10) Hoos et al. (11) Soria et al. (12) Lamborn et al. (13) and Armstrong and Febbo (14).

While surrogate endpoints may be included in the list of endpoints for any clinical trial, surrogate endpoints are of increased importance for the FDA’s accelerated drug approval program. According to one of the FDA’s Guidance for Industry documents, surrogate endpoints may be a basis for FDA approval for drugs used to treat serious or life-threatening diseases, and “[i]n this setting, the FDA may grant approval based on an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit” (15).

5 Smith C, Burley C, Ireson M, et al. Clinical trials of antibacterial agents: a practical guide to design and analysis. Statisticians in the Pharmaceutical Industry Working Party. J Antimicrob Chemother. 1998;41:467–480.

6 Dhani N, Tu D, Sargent DJ, Seymour L, Moore MJ. Alternate endpoints for screening phase II studies. Clin Cancer Res. 2009;15:1873–1882.

7 Gill S, Sargent D. End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival? Oncologist. 2006;11:624–629.

8 Pazdur R. Endpoints for assessing drug activity in clinical trials. The Oncologist. 2008;13(Suppl 2):19–21. 9 McKee AE, Farrell AT, Pazdur R, Woodcock J. The role of the U.S. Food and Drug Administration review process:

clinical trial endpoints in oncology. Oncologist. 2010;15(Suppl 1):13–18.10 Allegra C, Blanke C, Buyse M, et al. End points in advanced colon cancer clinical trials: a review and proposal. J Clin

Oncol. 2007;25:3572–3575.11 Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst.

2010;102:1388–1397.12 Soria JC, Massard C, Le Chevalier T. Should progression-free survival be the primary measure of efficacy for

advanced NSCLC therapy? Ann Oncol. 2010;21:2324–2332.13 Lamborn KR, Yung WK, Chang SM, et al. Progression-free survival: an important end point in evaluating therapy

for recurrent high-grade gliomas. Neuro-Oncol. 2008;10:162–170.14 Armstrong AJ, Febbo PG. Using surrogate biomarkers to predict clinical benefit in men with castration-resistant

prostate cancer: an update and review of the literature. Oncologist. 2009;14:816–827.15 U.S. Dept. of Health and Human Services. Food and Drug Administration. Guidance for Industry. Clinical trial

endpoints for the approval of cancer drugs and biologics. 2005;(23 pages).

4 Fleming RT, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996; 125:605–613.

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d. Relatively objective endpoints versus relatively subjective endpointsThe following chapters concern endpoints used in clinical trials on solid tumors, hema-tological cancers (non-solid tumors), immune disorders, and infections. Following these accounts are chapters on health-related quality of life (HRQoL). HRQoL refers to sub-jective information collected from study subjects by way of questionnaires. HRQoL data may be used, as an endpoint, in efforts to gain FDA approval for various drugs and medical devices.

Publications that systematically address the utility and reliability of HRQoL ques-tionnaires include the following. The publications are cited for studies of cancers, includ-ing breast cancer (16) colorectal cancer (17) lung cancer (18) melanoma (19) and liver cancer (20) as well as for diseases that are not cancer, such as hepatitis C virus (21) tuber-culosis (22,23) multiple sclerosis (24,25) and asthma (26).

At the objective end of the endpoint spectrum is overall survival (death), while at the subjective end of the spectrum is HRQoL. Regarding survival, Slamon et al. (27) refer to this as “an end point free of ascertainment bias.”

Endpoints that reside at intermediate points in this spectrum include endpoints that rely on tumor size and number. Even though tumor size and number seem straightfor-ward, these are often determined by measurements by an independent radiologist, and by the investigator’s radiologist, and they are often determined at a given time point, and then confirmed at a later time point. Other endpoints can reside in between the far-objective and far-subjective ends of the spectrum. For Patient-Reported Outcomes

16 Twelves CJ, Miles DW, Hall A. Quality of life in women with advanced breast cancer treated with docetaxel. Clin Breast Cancer. 2004; 5:216–222.

17 Cornish D, Holterhues C, van de Poll-Franse LV, Coebergh JW, Nijsten T. A systematic review of health-related quality of life in cutaneous melanoma. Ann Oncol. 2009;20(Suppl 6):51–58.

18 Gridelli C, Ardizzoni A, Le Chevalier T, et al. Treatment of advanced non-small-cell lung cancer patients with ECOG performance status 2: results of a European Experts Panel. Ann Oncol. 2004;15:419–426.

19 Cornish D, Holterhues C, van de Poll-Franse LV, Coebergh JW, Nijsten T. A systematic review of health-related quality of life in cutaneous melanoma. Ann Oncol. 2009;20(Suppl 6):51–58.

20 Yeo W, Mo FK, Koh J, et al. Quality of life is predictive of survival in patients with unresectable hepatocellular carcinoma. Ann Oncol. 2006;17:1083–1089.

21 Gutteling JJ, de Man RA, Busschbach JJ, Darlington AS. Overview of research on health-related quality of life in patients with chronic liver disease. Neth J Med. 2007;65:227–234.

22 Guo N, Marra F, Marra CA. Measuring health-related quality of life in tuberculosis: a systematic review. Health Qual Life Outcomes. 2009;7:14.

23 Marra CA, Marra F, Colley L, Moadebi S, Elwood RK, Fitzgerald JM. Health-related quality of life trajectories among adults with tuberculosis: differences between latent and active infection. Chest. 2008;133:396–403.

24 Ramp M, Khan F, Misajon RA, Pallant JF. Rasch analysis of the Multiple Sclerosis Impact Scale MSIS-29. Health Qual Life Outcomes. 2009;7:58.

25 Mowry EM, Beheshtian A, Waubant E, et al. Quality of life in multiple sclerosis is associated with lesion burden and brain volume measures. Neurology. 2009;72:1760–1765.

26 Ehrs PO, Nokela M, Ställberg B, Hjemdahl P, Wikström Jonsson E. Brief questionnaires for patient-reported outcomes in asthma: validation and usefulness in a primary care setting. Chest. 2006;129:925–932.

27 Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. New Engl J Med. 2001;344:783–792.

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(PRO) (28,29) the question of objectivity and subjectivity depends on the exact out-come that is being measured. The Patient-Reported Outcomes of migraine headaches (30) hot flashes (31) and tinnitus (32) are relatively objective. But the Patient-Reported Outcomes of fatigue or depression are relatively subjective.

For oncology clinical trials, various scales and questionnaires that are used include ECOG performance status, Karnofsky performance status, and health-related quality of life (HRQoL).

e. Using multiple endpoints, and choosing the endpoint on which to base conclusions

The ICH Guidelines provide a general warning, applicable to many diseases, regarding endpoint choice. According to the ICH Guidelines (33):

When two treatments are used for the same disease or condition, they may differentially affect various outcomes of interest in that disease, particularly if they represent different classes or modalities of treatment. Therefore, when comparing them in a clinical trial, the choice and timing of endpoints may favor one treatment or the other. For example, thrombolytics in patients with acute myocardial infarction can reduce mortality but increase hemorrhagic stroke risk. If a new, more pharmacologically active, thrombolytic were compared with an older thrombolytic, the more active treatment might look better if the endpoint were mortality, but worse if the endpoint were a composite of mortality and disabling stroke. Similarly, in comparing two analgesics in the management of dental pain, assigning a particularly heavy weight to pain at early time points would favor the drug with more rapid onset of effect, while assigning more weight to later time points would favor a drug with a longer duration of effect.

While any given drug may have three distinct benefits, and where each benefit can be measured at three different time points, failure to be aware of these variables can result in artifactual conclusions from the clinical trial. The next few chapters detail the endpoints used in clinical trials of oncology, clinical trials in multiple sclerosis, and clinical trials on hepatitis C virus. The chapters on oncology endpoints provide guid-ance on deciding which endpoints to include in the clinical trial, for example objec-tive response, progression-free survival (PFS), time to progression (TTP), disease-free survival (DFS), and overall survival. These chapters document the fact, for example, that

28 U.S. Dept. of Health and Human Services. Food and Drug Administration. Guidance for Industry. Patient-reported outcome measures: use in medical product development to support labeling claims. December 2009.

29 Bharmal M, Viswanathan S. Late-phase patient reported outcomes. Applied Clinical Trials. 2009;18:(5 pages).30 Acquadro C, Berzon R, Dubois D, et al. Incorporating the patient’s perspective into drug development and

communication: an ad hoc task force report of the Patient-Reported Outcomes (PRO) Harmonization Group meeting at the Food and Drug Administration, February 16, 2001. Value Health. 2003;6:522–531.

31 Freedman RR. Patient satisfaction with miniature, ambulatory, postmenopausal hot flash recorder. Open Medical Device J. 2009;1:1–2.

32 Meikle MB, Stewart BJ, Griest SE, Henry JA. Tinnitus outcomes assessment. Trends Amplif. 2008;223–235.33 ICH Harmonised Tripartite Guideline. Choice of control group and related issues in clinical trials E10. (Step 4

version, July 2000);(33 pages).

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reduction in tumor size and number, as measured by the RECIST criteria, do not nec-essarily correlate with long-term survival to the cancer.

f. In choosing endpoints keep in mind the eventual goals of the clinical trial

For any given parameter collected during a clinical trial, the sponsor of the trial needs to determine if the parameter is properly used as an endpoint in the clinical trial, and whether the FDA will accept data on that particular parameter for:l Regulatory approval of the drug;l Including in the package insert for the drug; andl Use in advertising to the public, that is, promotional claims.A document used by pharmaceutical companies and called the Target Product Profile can be used to keep track of these goals (34,35).

34 U.S. Dept. of Health and Human Services. Food and Drug Administration. Guidance for Industry. Target Product Profile – A Strategic Development Process Tool; March 2007;(25 pages).

35 Lambert WJ. Considerations in developing a target product profile for parenteral pharmaceutical products. AAPS PharmSciTech. 2010;11:1476–1481.