Exercises Sheet 4

(W) denotes workshop exercises; (A) denotes homework questions; (E) additional exercises for completion in your own time.

Workshop Exercises

  1. 1.

    (W) What is the key difference between superiority trials and equivalence trials?

  2. 2.

    (W) When planning an equivalence or non-inferiority trial, what key information has to be specified in advance in the study protocol? Give a reason for your answer.

  3. 3.

    (W) In a randomised double-blind A⁢B/B⁢A cross-over trial with 7 day wash-out phase, 18 healthy volunteers received 1000 mg theophyllin (single dose) in form of pellets in two different capsule sizes. It was the aim of the trial to show bioequivalence of the two treatments. Two capsules of each 200 mg and 300 mg served as reference (R). Two capsules containing 500 mg were the test treatment (T). Blood samples were taken and the concentration of theophyllin were measured before and 1, 2, 3, 4, 5, 6, 8, 10, 14, 16, 18, 20, 22, 24, 28, 36, 40, 44, and 48 hours after intake of the capsules. The table below gives the values for area under the concentration curve (AUC; extrapolated to infinity) in mg/l h.

    Sequence Period 1 Period 2
    TR 228.04 288.79
    RT 339.03 329.76
    TR 288.21 343.37
    RT 242.64 258.19
    RT 249.94 201.56
    TR 217.97 225.77
    TR 133.13 235.89
    RT 184.32 249.64
    TR 213.78 215.14
    TR 248.98 245.48
    TR 163.93 134.89
    RT 209.30 231.98
    RT 207.40 234.19
    TR 245.92 223.39
    RT 239.84 241.25
    RT 211.24 255.60
    TR 188.05 169.70
    RT 230.36 256.55
    1. (a)

      What is the motivation for using a cross-over design in trials of bioequivalence?

    2. (b)

      What is the purpose of the 7 day wash-out phase?

    3. (c)

      What are the standard equivalence margins for the ratio of the population means in bioequivalence trials?

    4. (d)

      Why is the Area Under the Curve used as a summary measure? Which transformation of AUC is usually used for parametric models?

    5. (e)

      Perform an analysis [that allows for a period effect. Note: i) be careful and take note of what you have said in d), ii) that this is a cross-over study, iii) that you should use a confidence interval approach.

      Additional Exercises

    6. (f)

      (E) Do equivalence or superiority trials tend to be larger? Explain your answer.

    7. (g)

      (E) What is meant by an intention to treat analysis?

    8. (h)

      (E) Read ICH E9 S 5. What is an ’analysis set’ and what are the potential implications for the choice of analysis set in equivalence studies? This will also feature in your project.