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Review of the Fialuridine (FIAU) Clinical Trials H Statistical Analysis of Mortality in the FIAU/FIAC Clinical Trials Table H-1 provides a synopsis of the design features of the 4 trials. The first trial (R89) involved AIDS patients with CMV. The second trial involved HIV+ patients some of whom also had HBV. The 3rd trial involved previously untreated (in the sense of exposure to FIAU or FIAC) patients with chronic HVB. The fourth trial involved HVB patients, the majority of whom had been previously treated with FIAU (11 of the 15 enrolled). None of the trials involved a randomized control group, hence, statistical assessments of the results observed must be based on the assumed background mortality rates applying to the populations under study. Three hypothetical death rates (proportion of the patients expected to die each year) were used for each of the analyses that follow:   Low Int High R89 0.10 0.15 0.20 R90 0.04 0.08 0.12 R91 0.02 0.03 0.04 PPPC 0.02 0.03 0.04 These rates correspond to the median life expectancies in years listed below. The median life expectancy, assuming a constant mortality rate, is 0.7 divided by the rate (Kalbfleisch and Prentice, 1980). The corresponding standard error for the rate is the rate divided by the square root of the number of events observed.   Low Int High R89 7.0 4.7 3.5 R90 17.5 8.75 5.83 R91 35.0 23.3 17.5 PPPC 35.0 23.3 17.5

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Review of the Fialuridine (FIAU) Clinical Trials The labels low, intermediate, and high are labels of convenience for the presentation that follows. They are not to be construed as qualitative labels for the presumed actual underlying mortality rates for the populations of interest. The true underlying rates may, in reality, be higher than the levels indicated for the set carrying that label. For example, the median life expectancy for the population enrolled into R89 (AIDS patients with CMV) is, in all probability, less than the 3.5 years listed for the ''high'' rate. The same is likely to be true for the population studied in R90. The estimated median life expectancy is around 10 years from conversion. The population studied is likely to have been positive for some time and, hence, has a life expectancy considerably less than that. The data used for the reanalyses are as given in Table H-2, as derived from the FDA report. The closing date for recruitment into the individual trials is assumed to correspond to the date of the last dose for the trials, as recorded in the report. The period of recruitment is assumed to be that interval from enrollment of the first patient into a trial and the date of the last dose. The rate of enrollment was assumed to be constant over that interval. The actual period is less than that used herein by a matter of days or a few weeks, depending on the trial. For the analyses presented below to be informative on a real time basis, one would have to have close surveillance of each study person so as to learn of deaths as they occur or within a matter of days after they occur. Lags in detection or reporting of deaths to the analysis site would degrade the value of the analyses as a real time decisionmaking tool. Similarly, to be useful, one has to have 100% surveillance of all persons enrolled for mortality, regardless of their status in the trial (i.e., such surveillance including dropouts). We have no way of knowing the extent to which deaths noted in the FDA are the result of such surveillance. The report does not indicate the methods used to identify deaths occurring after the defined period of treatment and followup for the trials discussed. Hence, we have no way of knowing the extent to which the surveillance can be viewed as complete. There is, in fact, intrinsic evidence to suggest it is incomplete simply from the counts of deaths provided. For example, one would expect most of the patients in R89 to have died by mid 1993. The median life expectancy for the population enrolled into that trial was not likely to be much more than a year, if that. The caveats regarding followup need to be kept in mind when reviewing the results below. An under-reporting of deaths would mean that the actual p-values noted in the tables below would be smaller than given and that the powers would be larger than indicated. Since the ability to trace people diminishes as a function of the time of the last contact, we surmise that the quality of followup was better for the 26 week period of followup than for followup through 27 June 1993. Hence, the emphasis is on analyses relating to 26 weeks of followup. The results for each trial analyzed separately is given in Tables H-3, -4, and -5 for the low, intermediate, and high rates. The first panel of each table is at the close of each trial assuming 26 weeks of followup for each person enrolled. Note that for this method of analysis only 4 of the 9 deaths observed in the first three trials are counted. The other 5 deaths occurred beyond the closing date for followup and are censored. The second panel is for followup through 27 June 1993. The sample size, assuming a uniform rate of enrollment over the interval defined by enrollment of the first patient to the last administration of treatment in a given trial is given in the column labeled N.

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Review of the Fialuridine (FIAU) Clinical Trials Expected deaths are calculated assuming the specified event rate for a table or a panel within a table. The total number of expected person years contributed by a total of N persons followed to death or to the indicated end of followup, is given in the fifth column of the tables 3, 4, 5 and 6. For example, it is 5.40 person years for R89 assuming 26 weeks of followup (i.e., 0.90 times 6.0). The expected number dead is 0.60 (i.e., 6.0 times 0.10). The expected deaths in table 6 correspond to the sum of expected deaths at the time of a death. For example, the value of 1.700 at the start of PPPC for first panel of table 6 is the sum of 0.60 + 0.86 + 0.24 (for R89, R90, and R91, respectively). The p-values are for differences between the observed and expected numbers of deaths, and are derived using a technique described by Breslow and Day (1987) involving standardized mortality rates and the Poisson distribution. The p-values are for a two-tailed alternative. The calculations are made assuming the comparison of two groups, each having the sample size of that for the indicated trial. The direction of the observed treatment effect is determined by the sign of the difference resulting from subtracting expected deaths from observed deaths (column 9 in Table H-s 3, 4, and 5, column 6 in Table H-6). A positive difference corresponds to an excess (measured against the number expected given the underlying mortality rate) of deaths associated with the test treatment. A negative difference corresponds to fewer than the number of deaths expected. The latter difference is indicative of a positive treatment effect and the former is indicative of a negative treatment effect. For the 3 trials done prior to PPPC and for the 26 weeks of followup, two were indicative of varying degrees of a negative treatment effect (R89 and R91) and one of varying degrees of a positive effect (R90). A positive treatment effect is one where the expected number of deaths is larger than the number actually observed and a negative treatment effect is one where the reverse is true. Powers are presented in the last two columns of Tables H-3, -4, and -5 for a specified negative and positive alternative. Power is the probability of rejecting the null hypothesis, that the test treatment has no effect on mortality, when, in fact, it has the indicated negative or positive effect. Powers of 0.80 or higher are desired when designing randomized controlled trials with a calculated sample size. The power calculations are made with the type I error (a) fixed at 0.05 and correspond to powers calculated prior to the start of the trials. The negative alternative considered is that the test treatment produces a 100% increase in mortality and the positive alternative is that it produces a 50% reduction in mortality. For example, if the assumed background mortality rate is 0.10, than the negative alternative is that the actual rate, in the presence of the test treatment, is 0.20 instead of the of the 0.10 hypothesized and that it is 0.05 instead of the 0.10 hypothesized if the effect of the test treatment is positive. In the case of R89, for 6 months of followup for a presumed low underlying mortality rate of 0.10 (Table H-3), the calculated power prior to the start of the trial against the two alternatives, given a sample size of 12 for both the test and control treated groups, is 0.08 and 0.07, respectively. A power of 0.08 means that, given the sample size of 12 per treatment group, the trial would have only about 1 chance in 12 (8 in 100) of detecting a 50% true positive effect of the drug and about the same chance of detecting a 100% negative effect of the drug, given a hypothesized underlying rate of 0.10 for the control treated group. Not surprisingly, given the size of the trials, all of the powers are low. Given the relatively nominal nature of the observed difference and the resulting p-values, the calculated

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Review of the Fialuridine (FIAU) Clinical Trials powers suggest the need for a good deal of skepticism in concluding for or against the test treatment based on any single trial. In other words, one runs the risk of drawing the wrong conclusion regarding the treatment, even when the observed difference in a trial is indicative of harm. The only trial that produces, according to a criterion based on p-values, any convincing evidence of harm is PPPC, and all of that information accumulated after the investigators had already taken action, based on morbidity, to stop the trial. Even if one were to assume the form of analysis described in Table H-6, combining data from all trials in cumulative fashion, the information against the drug prior to the deaths in PPPC is weak. The smallest p-values are after the third death. The p-values observed at the start of PPPC are unimpressive, ranging in size from 0.19 to 0.77 for differences (observed minus expected deaths) ranging from 2.300 to -0.260. The approach for Table H-6 is that of an analyst performing a new analysis each time another death is observed over the course of the 3 trials. The three panels in the Table are for 26 weeks of followup, with censoring occurring at the start at the 27th week after enrollment of a patient. The person-years recorded in Table H-6 are the sums of those available from the three trials at the indicated point of analysis. For example, the maximum amount available for 26 weeks of followup at the death of patient 4D, 6 Jan 1993, was 6.000 person years for R89, 21.500 for R90, and 11.099 for R91, for a total of 38.6 person years. (The study still generating information at 26 weeks of followup at that point in time was R91. R89 and R90 would have completed 26 weeks of followup on patients enrolled in those trials prior to 6 Jan 1993. There were 3 deaths observed within the defined period of followup prior to the one in question, for a total of 4 at the point of analysis.) The expected number of deaths is the sum of the products of person years of experience from a specific trial multiplied by the presumed underlying mortality rate for that study population; for example, 0.10(6.0) + 0.04(21.5) + 0.02(11.1) for a total of 1.68. The analyses summarized in Table H-6 are for deaths occurring within 26 weeks of enrollment. Deaths beyond that point are not counted. The analyses do not take account of the redosing of 4 patients in R90 (401, 406, 408, and 409) or of the 3 deaths occurring among them them (401,406, and 408) because the redosing and deaths occurred after their respective 26th weeks of followup. A different approach is needed to deal with all deaths regardless of time from enrollment. That approach is represented in Table H-7. The meta-analytic approach underlying Table H-7 is akin to that which could be used if investigators, just prior to starting their next trials, were to perform an analysis using all data accumulated up to that point to help them decide whether they should proceed to the next trial. The smallest p-value indicated of possible harm is the one for low underlying mortality rates for data accumulated just prior to the start of R90. The smallest p-value indicative of possible benefit is the one for high underlying mortality rates for data accumulated just prior to the start of PPPC. The analyses are instructive only to the degree that one has faith in the underlying morality rates used and in the validity of the assumptions made, and among those, principally the one having to do with completeness of followup. The likelihood is that we have been conservative in the range of morality rates investigated. Hence, "low" may be too low and "high" may not be high enough. Obviously, any increase in assumed underlying rates weakens

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Review of the Fialuridine (FIAU) Clinical Trials the case for harm known in advance of PPPC. Conversely, the analysis is, in effect, a "best case" analysis in regard to completeness of followup for deaths. The analyses performed assume 100 percent ascertainment for deaths. Under that assumption, persons not located when the FDA task force report was complied are assumed to have been alive. The report does not contain details on completeness of followup. Hence, we could not perform analyses under other assumptions regarding patients not located at the time the report was complied. Neither of the analyses in Tables H-6 or -7 take account of actual amount of drug administered and, hence, are not helpful in addressing the broader question as to whether the studies taken together are indicative of increasing probability of death with increased exposure to the drug. The relative risk (per unit increase of dose on the log scale) are 2.6 and 4.6, respectively, for censoring of followup at 26 weeks after enrollment (4 deaths) and March 24, 1993, (9 deaths; the point just prior to the start of PPPC), as obtained via Cox proportional hazards analyses (Cox, 1972). The p-values corresponding to the relative risks resulting from the two forms of censoring were 0.18 and 0.013, respectively. To be sure, all analyses involving dosage administration are problematic to the extent that dosage is a function of other intervening variables. Hence, the interpretation given to these results, even differences yielding a p-value as small as the one for the latter form of censoring, has to be treated with caution. Tables H-1 through H-7 follow.

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Review of the Fialuridine (FIAU) Clinical Trials Table H-1. Design Features of Individual Trials   R89-001 R90-001 R91-010 H3X-PPPC Phase I/II Dose escalation I/II Dose escalation I/II Dose escalation I/II Treatment Randomized control None None None None IND Oclassen 33,638 Oclassen 34,973 Oclassen 34,973 Lilly No. of centers 2 3 1 1 Investigators Richman Corey Richman Corey Straus Hoofnagle Hoofnagle Performance sites U. of Cal. S.D. U. of Wash., Seattle U. of Cal., S.D. U. of Wash., Seattle NIH, Bethesda NIH, Bethesda NIH, Bethesda Drug FIAC FIAU FIAU FIAU Treatment period 28 days 14 days 28 days 168 days 1st dose 17 Nov 89 9 Oct 90 13 Apr 92 24 Mar 93 Last dose 25 May 90 29 Jun 92 10 Sep 92 28 Jun 93 No. enrolled 12 43 24 15 Enrollment period 188 days 628 days 150 days 95 days Enrollment rate 15.67 days 6.05 days 6.25 days 6.33 days No. of Deaths 4 4 1 5 Prior FIAC/FIAU No No No Yes (11) Study pop. AIDS (2) AIDS+CMV (10) HIV (13) HIV+HVB (30) Compensated HVB Compensated HVB Treatment and follow-up 35 days 42 days 168 days 168 days Dose Low 0.6 mg/kg/day 0.1 mg/kg/day 0.05 mg/kg/day 0.10 mg/kg/day High 1.0 mg/kg/day 1.7 mg/kg/day 0.5 mg/kg/day 0.25 mg/kg/day Project titles: R89-001: Efficacy and safety of oral FIAC in AIDS patients with cytomegalovirus infection: A dose-ranging study. R90-001: The tolerance of HIV-infected patients with herpes-group infections to oral doses of FIAU. R91-010: FIAU oral dose-ranging study in patients with compensated chronic hepatitis B. H3X-MC-PPPC: FIAU redosing for the treatment of patients with compensated chronic hepatitis B: a six-month course.

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Review of the Fialuridine (FIAU) Clinical Trials Table H-2. Death Experience by Calendar Time   Event PI Cum. N Deaths Cum. % Dead Study Time 17 Nov 89 1st dose R89-001 Richman, 1       10 Jan 90 103 enrolled           6 Feb 90 105 enrolled           22 Feb 90 107 enrolled           15 Mar 90 110 enrolled           15 Apr 90 105 died     1   10 wks 18 May 90 110 died     2   9 wks 25 May 90 Last dose R89-001 (n=12)   12   16.7   2 June 90 107 died       3 17 wks 9 Oct 90 1st dose R90-001 Richman, 13       11 Mar 91 103 died Corey,   4   60 wks 16 Apr 91 401 enrolled Straus         29 May 91 101 enrolled           4 Jun 91 406 enrolled           3 Nov 91 408 enrolled           13 Apr 92 1st dose R91-010 Hoofnagle 56       16 May 92 408 died     5   27 wks 29 Jun 92 Last dose R90-001 (n=43)   55   9.1   5 Aug 92 4D enrolled           11 Aug 92 406 died     6   62 wks 2 Sep 92 101 died     7   65 wks 10 Sep 92 Last dose R91-010 (n=24)   79   10.1   18 Oct 92 401 died     8   78 wks 6 Jan 93 4D died     9   22 wks 24 Mar 93 1st dose H3X-MC-PPPC Hoofnagle 80       24 Mar 93 001-2002 enrolled           24 Mar 93 001-3001 enrolled           7 Apr 93 001-6003 enrolled           14 Apr 93 001-3004 enrolled           15 Apr 93 001-5003 enrolled           28 Jun 93 H3X-MC-PPPC stopped (n=15) 94     10.4   5 Jul 93 001-2002 died     10   14 wks 6 Jul 93 001-3004 died     11   13 wks 16 Jul 93 001-5003 died     12   14 wks 30 Jul 93 001-3001 died     13   19 wks 31 Aug 93 001-6003 died     14   17 wks           14.9  

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Review of the Fialuridine (FIAU) Clinical Trials Table H-3. Results per Individual Trial for Low Underlying Mortality Rates         Person-yrs Deaths Power   Rate N Avg FU Exp Obs Exp Obs Diff p-value Neg Pos 26 week followup R 89 0.10 12 0.50 5.40 5.19 0.60 3 2.40 0.05 0.08 0.07 R 90 0.04 43 0.50 20.64 21.50 0.86 0 -0.86 — 0.13 0.09 R 91 0.02 24 0.50 11.76 11.92 0.24 1 0.76 0.43 0.06 0.06 Total   79 0.50 37.80 38.61 1.70 4 2.30 0.19     27 June 93 followup R 89 0.10 12 3.58 38.66 30.49 4.30 4 -0.30 0.75 0.19 0.13 R 90 0.04 43 1.50 61.92 62.97 2.58 4 1.42 0.52 0.20 0.12 R 91 0.02 24 1.33 31.28 31.01 0.64 1 0.36 0.94 0.08 0.06 PPPC 0.02 15 0.13 1.91 1.95 0.04 0 -0.04 — 0.08 0.06 Total   94 1.50 133.77 126.42 7.56 9 1.44 0.69     Assumptions and notes: Enrollment period from 1st dose to last dose; uniform rate of enrollment over that period; instantaneous treatment effect (ie, no treatment lag); instantaneous reports of deaths; 100% followup for mortality over defined followup period; assumed underlying annual mortality rates: R89, 0.10; R90, 0.04; and R91, 0.02. Table H-4. Results per Individual Trial for Intermediate Underlying Mortality Rates         Person Deaths Power   Rate N Avg FU Exp Obs Exp Obs Diff p-value Neg Pos 26 week followup R 89 0.15 12 0.50 5.10 5.19 0.90 3 2.10 0.12 0.10 0.07 R 90 0.08 43 0.50 19.78 21.50 1.72 0 -1.72 — 0.22 0.13 R 91 0.03 24 0.50 11.64 11.92 0.36 1 0.64 0.60 0.07 0.06 Total 79 0.50 36.52 38.61 2.98 4 1.02 0.70       27 June 93 followup R 89 0.15 12 3.58 36.52 30.49 6.44 4 -2.44 0.23 0.24 0.16 R 90 0.08 43 1.50 59.34 62.97 5.16 4 -1.16 0.49 0.32 0.20 R 91 0.03 24 1.33 30.96 31.01 0.96 1 0.04 1.00 0.09 0.07 PPPC 0.03 15 0.13 1.89 1.95 0.06 0 -0.06 0.24 0.05 0.05 Total 94 1.50 128.71 126.42 12.62 9 -3.62 0.24       Assumptions and notes: Enrollment period from 1st dose to last dose; uniform rate of enrollment over that period; instantaneous treatment effect (i.e., no treatment lag); instantaneous reports of deaths; 100% followup for mortality over defined followup period; assumed underlying annual mortality rates: R89, 0.15; R90, 0.08; and R91, 0.03.

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Review of the Fialuridine (FIAU) Clinical Trials Table H-5. Results per Individual Trial for High Underlying Mortality Rates         Person-yrs Deaths Power   Rate N Avg FU Exp Obs Exp Obs Diff p-value Neg Pos 26 week followup R 89 0.20 12 0.50 4.80 5.19 1.20 3 1.80 0.24 0.11 0.08 R 90 0.12 43 0.50 18.92 21.50 2.58 0 -2.58 — 0.29 0.18 R 91 0.04 24 0.50 11.52 11.92 0.48 1 0.52 0.76 0.07 0.06 Total 79 0.50 35.24 38.61 4.26 4 -0.26 0.77       27 June 93 followup R 89 0.20 12 3.58 34.37 30.49 8.59 4 -4.59 0.06 0.27 0.19 R 90 0.12 43 1.50 56.76 62.97 7.74 4 -3.74 0.10 0.43 0.26 R 91 0.04 24 1.33 30.64 31.01 1.28 1 -0.28 0.56 0.10 0.08 PPPC 0.04 15 0.13 1.87 1.95 0.08 0 -0.08 — 0.10 0.08 Total 94 1.50 123.64 126.42 17.69 9 -8.69 0.02       Assumptions and notes: Enrollment period from 1st dose to last dose; uniform rate of enrollment over that period; instantaneous treatment effect (ie, no treatment lag); instantaneous reports of deaths; 100% followup for mortality over defined followup period; assumed underlying annual mortality rates: R89, 0.20; R90, 0.12; and R91, 0.04. Table H-6. Analysis on the Occurence of Each Death Based on 26 Weeks of Followup from Enrollment   Enrolled Deaths   N N-yrs Obs Exp Diff p-value 26 week followup Low Mortality (R89 0.10; R90 0.04; R91 0.02) 105 10.6 1.931 1 0.193 0.807 0.35 110 11.5 2.881 2 0.288 1.712 0.07 107 12.0 3.230 3 0.323 2.677 0.01 4D 79.0 36.920 4 1.648 2.352 0.17 PPPC 79.0 39.500 4 1.700 2.300 0.19 Intermediate Mortality (R89 0.15; R90 0.08; R91 0.03) 105 10.6 1.931 1 0.290 0.710 0.54 110 11.5 2.881 2 0.432 1.568 0.14 107 12.0 3.230 3 0.485 2.515 0.03 4D 79.0 36.920 4 2.903 1.097 0.66 PPPC start 79.0 39.500 4 2.980 1.020 0.70 High Mortality (R89 0.20; R90 0.12; R91 0.04) 105 10.6 1.931 1 0.386 0.614 0.64 110 11.5 2.881 2 0.576 1.424 0.23 107 12.0 3.230 3 0.646 2.354 0.06 4D 79.0 36.920 4 4.167 -0.167 0.81 PPPC start 79.0 39.500 4 4.260 -0.260 0.77 Assumptions and notes: Enrollment period from 1st dose to last dose; uniform rate of enrollment over that period; instantaneous treatment effect (ie, no treatment lag); instantaneous reports of deaths; 100% followup for mortality over defined followup period; new analysis at the time of each death.

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Review of the Fialuridine (FIAU) Clinical Trials Table H-7. Analysis at the Start R90, R91, and PPPC Bases on all Deaths Regardless of Time Since Enrollment   Enrolled Deaths Start No. No. PYs Obs Exp Diff p-value Follow up to start of indicated trial Low (R89 0.10; R90 0.04; R91 0.02) R90 12 6.6 3 0.6 2.400 0.05 R91 51 49.0 4 3.1 0.900 0.75 PPPC 79 113.1 9 5.7 3.300 0.25 Intermediate (R89 0.15; R90 0.08; R91 0.03) R90 12 6.6 3 1.0 2.000 0.16 R91 51 49.0 4 5.3 -1.300 0.45 PPPC 79 113.1 9 10.0 -1.000 0.66 High (R89 0.20; R90 0.12; R91 0.04) R90 12 6.6 3 1.3 1.700 0.28 R91 51 49.0 4 7.4 -3.400 0.13 PPPC 79 113.1 9 14.2 -5.200 0.11 Assumptions and notes: Enrollment period from 1st dose to last dose; uniform rate of enrollment over that period; instantaneous treatment effect (ie, no treatment lag); instantaneous reports of deaths; 100% followup for mortality over defined followup period; new analysis just prior to start of a new trial. PY = person-years.