We were all blind (except Detlew) [🇷 for BE/BA]

posted by Helmut Homepage – Vienna, Austria, 2020-07-15 16:27 (1521 d 05:00 ago) – Posting: # 21700
Views: 18,428

Hi ElMaestro,

we were all blind!
Just to make clear what I mean by “we”: Myself, you, the EMA’s PKWP (and the BSWP fabricating the example datasets and the evaluation by ‘Method C’), and Patterson & Jones.
Detlew read the guidance’s Step 1 thoroughly enough to realize that \(\small{s_\textrm{wR}^2}\) is not an REML-estimate (see this post). Fortunately the templates for Phoenix are correct. Quick & dirty R-code at the end. Results:

      file             descr       s2wR       swR CVwR (%)      PHX match
  ds02.csv            EMA II 0.01298984 0.1139730 11.43441 11.43441   yes
 ds02a.csv     EMA II imbal. 0.01038611 0.1019123 10.21774 10.21774   yes
  DS04.csv Patterson & Jones 0.32489813 0.5699984 61.95883 61.95883   yes
  ds01.csv             EMA I 0.2188968  0.4678640 46.96431 46.96431   yes

In the Q&A we find for DSII the REML-based CVwR 11.5% (PHX 11.43%). Patterson & Jones reported for their dataset 61% (SAS); I got in PHX 61.96%. For DSI the Q&A gives 47.3% (PHX 46.96%).

Therefore, congratulations to all of us answering a question which was not asked by the FDA. :-(

GetData <- function(path) {
  D        <- NULL # paranoia
  D        <- read.csv(path, comment.char = "#")
  D        <- D[, 1:5]
  D[, 5]   <- log(D[, 5])
  names(D) <- c("Subj", "Per", "Seq", "Trt", "PK")
  return(invisible(D))
}
CalcSwR <- function(path) {
  D    <- GetData(path)
  R    <- D[D$Trt == "R", ]
  R    <- cbind(R, Diff = NA)
  seqs <- sort(unique(D$Seq), decreasing = TRUE)
  des  <- NA
  if (sum(seqs %in% c("TRR", "RTR", "RRT")) == 3) des <- "partial"
  if (sum(seqs %in% c("TRTR", "RTRT")) == 2) des <- "full"
  if (is.na(des)) stop("Design not supported.")
  if (des == "partial") {
    TRR <- R[R$Seq == "TRR", c(1:3, 5:6)]
    RTR <- R[R$Seq == "RTR", c(1:3, 5:6)]
    RRT <- R[R$Seq == "RRT", c(1:3, 5:6)]
    # keep only subjects with two observations
    TRR <- TRR[duplicated(TRR$Subj, fromLast = TRUE) |
               duplicated(TRR$Subj, fromLast = FALSE), ]
    RTR <- RTR[duplicated(RTR$Subj, fromLast = TRUE) |
               duplicated(RTR$Subj, fromLast = FALSE), ]
    RRT <- RRT[duplicated(RRT$Subj, fromLast = TRUE) |
               duplicated(RRT$Subj, fromLast = FALSE), ]
    # first minus second administration
    # too lazy to vectorize
    for (j in 1:(nrow(TRR)-1)) {
      if (TRR$Per[j] == 2) {
        TRR$Diff[j] <- TRR$PK[j] - TRR$PK[j+1]
      }
    }
    for (j in 1:(nrow(RTR)-1)) {
      if (RTR$Per[j] == 1) {
        RTR$Diff[j] <- RTR$PK[j] - RTR$PK[j+1]
      }
    }
    for (j in 1:(nrow(RRT)-1)) {
      if (RRT$Per[j] == 1) {
        RRT$Diff[j] <- RRT$PK[j] - RRT$PK[j+1]
      }
    }
    R <- rbind(TRR[, c(3, 5)],
               RTR[, c(3, 5)],
               RRT[, c(3, 5)])
  } else {
    TRTR <- R[R$Seq == "TRTR", c(1:3, 5:6)]
    RTRT <- R[R$Seq == "RTRT", c(1:3, 5:6)]
    TRTR <- TRTR[duplicated(TRTR$Subj, fromLast = TRUE) |
                 duplicated(TRTR$Subj, fromLast = FALSE), ]
    RTRT <- RTRT[duplicated(RTRT$Subj, fromLast = TRUE) |
                 duplicated(RTRT$Subj, fromLast = FALSE), ]
    for (j in 1:(nrow(TRTR)-1)) {
      if (TRTR$Per[j] == 2) {
        TRTR$Diff[j] <- TRTR$PK[j] - TRTR$PK[j+1]
      }
    }
    for (j in 1:(nrow(RTRT)-1)) {
      if (RTRT$Per[j] == 1) {
        RTRT$Diff[j] <- RTRT$PK[j] - RTRT$PK[j+1]
      }
    }
    R <- rbind(TRTR[, c(3, 5)],
               RTRT[, c(3, 5)])
  }
  R    <- R[!is.na(R$Diff), ]
  m    <- lm(Diff ~ as.factor(Seq), data = R)
  s2wR <- anova(m)["Residuals", "Mean Sq"]/2
  res  <- c(s2wR = s2wR, swR = sqrt(s2wR), CVwR = 100*sqrt(exp(s2wR)-1))
  names(res)[3] <- "CVwR (%)"
  return(res)
}
p <- paste0("https://",
       c("bebac.at/downloads/ds02.csv",
         "bebac.at/downloads/ds02a.csv",
         "raw.githubusercontent.com/Helmut01/replicateBE/master/inst/extdata/DS04.csv",
         "bebac.at/downloads/ds01.csv"))
d <- c("EMA II", "EMA II imbal.", "Patterson & Jones", "EMA I")
res <- data.frame(file = basename(p), descr = d, X1 = NA, X2 = NA, X3 = NA,
                  PHX = c(11.43441, 10.21774, 61.95883, 46.96431), match = "no")
names(res)[3:5] <- c("s2wR", "swR", "CVwR (%)")
for (j in 1:4) {
  res[j, 3:5] <- CalcSwR(path = p[j])
  if (round(res[j, 5], 5) == res$PHX[j]) res$match[j] <- "yes"
}
print(res, row.names = FALSE)

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! [image]
Helmut Schütz
[image]

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

UA Flag
Activity
 Admin contact
23,224 posts in 4,878 threads, 1,654 registered users;
26 visitors (0 registered, 26 guests [including 7 identified bots]).
Forum time: 21:27 CEST (Europe/Vienna)

One of the symptoms of an approaching nervous breakdown
is the belief that one’s work is terribly important.    Bertrand Russell

The Bioequivalence and Bioavailability Forum is hosted by
BEBAC Ing. Helmut Schütz
HTML5