Potential Unblinding due to Imbalance in Adverse Event Profiles

In a previous post “Is blinded study really blinded? - assessment of blinding/unblinding in clinical trials”, we discussed the potential unblinding if the subjects on different treatment groups experienced a different type of adverse events. For the ethic reasons, the informed consent form needs to list all the potential side effects of the experimental drug. As required by GCP, the investigator’s brochure needs to discuss the details of the potential side effects caused by the experimental drug. If there is an obvious imbalance in adverse event profiles between the two treatment groups (experiment drug versus control), it is possible that the study blinding is not well maintained and the patient or the investigator can guess or predict based on the AE profile which treatment group the patient is on.

This potential unblinding issue can be even more evident if the crossover design is employed where the same subject will have an chance to experience two different drugs. If there are differences in side effects, the subjects will be likely to feel the difference.

In FDA’s recent guidance for industry “Hematologic Malignancy and Oncologic Disease: Considerations for Use of Placebos and Blinding in Randomized Controlled Clinical Trials for Drug Product Development”, the potential unblinding issue was brought up.

“In many cases, because of the toxicity profile of the active treatment, patients and investigators may infer which treatment patients are receiving and thus use of a placebo control may not, in fact, blind the treatment. …”

The guidance also cited the ethic issue for maintaining blinding when the unblinding is necessary to give the best care for the subjects (patients).

“Continued blinding of patients and investigators at the time of disease progression or occurrence of serious adverse events presents additional challenges. For example, in a blinded immunotherapy trial, a patient who develops adverse events on the control arm may receive unnecessary treatments (e.g., immunosuppressive drug products including a high dose of glucocorticoids, cyclophosphamide, interleukin-6 antagonist, or infliximab) for management of adverse events incorrectly attributed to the investigational drug product. Maintaining the blind after disease progression could also affect a patient’s subsequent therapy, potentially preventing a patient who had been on a placebo arm from receiving an approved therapy, or delaying or preventing the patient’s entry into other clinical trials (for those trials of similar drug products that may have specific exclusion criteria based on prior treatment with an active drug or class of drugs). Unblinding would allow informed decision-making with respect to additional treatment 61 options (see below). “

In an analysis by Shah et al Adverse events appear to unblind clinical trials in irritable bowel syndrome, the result “suggests that higher AE incidence on active therapy is associated with more beneficial patient‐reported outcomes in IBS clinical trials. This raises the issue of spontaneous unblinding”

Maintaining the blinding is one of the cornerstones of the RCT (randomized, controlled trial). As mentioned in an article by Stefan Dürr Avoid Unintentional Unblinding In Clinical Trials

“The knowledge of the patient’s treatment could potentially lead to conscious or unconscious bias in the way the site staff recruits the patients (selection bias), how they are treated (performance bias), the assessment of endpoints (detection bias), the handling of withdrawals, and how data is excluded from analysis. The patient attitude to the treatment if known can lead to a difference in reporting symptoms (response bias) or withdrawal from the study (attrition bias). To reduce the chance of bias to the data, clinical trials should be conducted in a double-blind design whenever possible.”

However, in some situation especially when there is an imbalance in the side effects of two treatment groups, blinding may either be difficult to maintain or not be ethical to implement, and alternative approaches are needed. As suggested in FDA's guidance "

“Hematologic Malignancy and Oncologic Disease: Considerations for Use of Placebos and Blinding in Randomized Controlled Clinical Trials for Drug Product Development”, an open-label study or an add-on trial design may be more appropriate. In an early post, I also discussed some blinding techniques. 

Latin Squares for Constructing "Williams Designs" - Balanced for First-order Carry-over (Residual) Effects

Courtesy from the website http://statpages.info/latinsq.html, the list below contains the Williams design with 2 to 26 treatment groups. It is unlikely to have a clinical trial with 26 treatment groups. The most number of treatment groups I see is a study with 6 treatment groups. 

In one of my previous posts, I described the Williams design and its usefulness in phase I or clinical pharmacology studies. In a SAS SUGI paper "Generating Randomization Schedules Using SAS Programming", I described how to use SAS program to construct the randomization schedule for a study with Williams design. 

With the limited sample size, the Williams design is the most efficient design and minimizes the potential impact of the carryover effect. In Williams design with an even number of n treatment groups, there will be n number of sequences or an "n by n" square. Each treatment only occurs one time in one sequence, in one period. Furthermore, each treatment only follows another treatment one time. 

If the number of treatments (n) is an odd number, there will be 2 x n number of sequences or two n by n squares. Each treatment only occurs once in one sequence and in two periods. Each treatment only follows another treatment twice. 

With the Latin Square listed below, we can easily construct the crossover design with treatments, periods, and sequences. For example, a study design with 3 treatment groups will have the following assignments: three treatment groups (A, B, C), three periods (period 1, period 2, and period 3), and six sequences (ABC, BCA, CAB, CBA, ACB, and BAC). 

Treatment Sequence	Period 1	Period 2	Period 3
1	A	B	C
2	B	C	A
3	C	A	B
4	C	B	A
5	A	C	B
6	B	A	C

• Since it is the crossover design, there should be a washout period between each period. It is very common that the washout period is 5 times the half-life. 
• Randomization is for the sequence, not the treatment group. 
• Once we know the number of subjects is needed for each sequence, we will know the total number of subjects for the entire study. 
• Usually, the mixed model is needed for statistical analysis. The statistical model will need to consider the treatment, period, and sequence. An example of the SAS codes for analysis was provided in one of the previous posts "Cookbook SAS Codes for Bioequivalence Test in 2x2x2 Crossover Design"

Williams Design by the Number of Treatment Groups:

Size = 2

A B 
B A 
 

Size = 3

A B C 
B C A 
C A B 
C B A 
A C B 
B A C 
 

Size = 4

A B D C 
B C A D 
C D B A 
D A C B 
 

Size = 5

A B E C D 
B C A D E 
C D B E A 
D E C A B 
E A D B C 
D C E B A 
E D A C B 
A E B D C 
B A C E D 
C B D A E 
 

Size = 6

A B F C E D 
B C A D F E 
C D B E A F 
D E C F B A 
E F D A C B 
F A E B D C 
 

Size = 7

A B G C F D E 
B C A D G E F 
C D B E A F G 
D E C F B G A 
E F D G C A B 
F G E A D B C 
G A F B E C D 
E D F C G B A 
F E G D A C B 
G F A E B D C 
A G B F C E D 
B A C G D F E 
C B D A E G F 
D C E B F A G 
 

Size = 8

A B H C G D F E 
B C A D H E G F 
C D B E A F H G 
D E C F B G A H 
E F D G C H B A 
F G E H D A C B 
G H F A E B D C 
H A G B F C E D 
 

Size = 9

A B I C H D G E F 
B C A D I E H F G 
C D B E A F I G H 
D E C F B G A H I 
E F D G C H B I A 
F G E H D I C A B 
G H F I E A D B C 
H I G A F B E C D 
I A H B G C F D E 
F E G D H C I B A 
G F H E I D A C B 
H G I F A E B D C 
I H A G B F C E D 
A I B H C G D F E 
B A C I D H E G F 
C B D A E I F H G 
D C E B F A G I H 
E D F C G B H A I 
 

Size = 10

A B J C I D H E G F 
B C A D J E I F H G 
C D B E A F J G I H 
D E C F B G A H J I 
E F D G C H B I A J 
F G E H D I C J B A 
G H F I E J D A C B 
H I G J F A E B D C 
I J H A G B F C E D 
J A I B H C G D F E 
 
 
Size = 11

A B K C J D I E H F G 
B C A D K E J F I G H 
C D B E A F K G J H I 
D E C F B G A H K I J 
E F D G C H B I A J K 
F G E H D I C J B K A 
G H F I E J D K C A B 
H I G J F K E A D B C 
I J H K G A F B E C D 
J K I A H B G C F D E 
K A J B I C H D G E F 
G F H E I D J C K B A 
H G I F J E K D A C B 
I H J G K F A E B D C 
J I K H A G B F C E D 
K J A I B H C G D F E 
A K B J C I D H E G F 
B A C K D J E I F H G 
C B D A E K F J G I H 
D C E B F A G K H J I 
E D F C G B H A I K J 
F E G D H C I B J A K 
 

Size = 12

A B L C K D J E I F H G 
B C A D L E K F J G I H 
C D B E A F L G K H J I 
D E C F B G A H L I K J 
E F D G C H B I A J L K 
F G E H D I C J B K A L 
G H F I E J D K C L B A 
H I G J F K E L D A C B 
I J H K G L F A E B D C 
J K I L H A G B F C E D 
K L J A I B H C G D F E 
L A K B J C I D H E G F 
 
 
Size = 13

A B M C L D K E J F I G H 
B C A D M E L F K G J H I 
C D B E A F M G L H K I J 
D E C F B G A H M I L J K 
E F D G C H B I A J M K L 
F G E H D I C J B K A L M 
G H F I E J D K C L B M A 
H I G J F K E L D M C A B 
I J H K G L F M E A D B C 
J K I L H M G A F B E C D 
K L J M I A H B G C F D E 
L M K A J B I C H D G E F 
M A L B K C J D I E H F G 
H G I F J E K D L C M B A 
I H J G K F L E M D A C B 
J I K H L G M F A E B D C 
K J L I M H A G B F C E D 
L K M J A I B H C G D F E 
M L A K B J C I D H E G F 
A M B L C K D J E I F H G 
B A C M D L E K F J G I H 
C B D A E M F L G K H J I 
D C E B F A G M H L I K J 
E D F C G B H A I M J L K 
F E G D H C I B J A K M L 
G F H E I D J C K B L A M 
 
 
Size = 14

A B N C M D L E K F J G I H 
B C A D N E M F L G K H J I 
C D B E A F N G M H L I K J 
D E C F B G A H N I M J L K 
E F D G C H B I A J N K M L 
F G E H D I C J B K A L N M 
G H F I E J D K C L B M A N 
H I G J F K E L D M C N B A 
I J H K G L F M E N D A C B 
J K I L H M G N F A E B D C 
K L J M I N H A G B F C E D 
L M K N J A I B H C G D F E 
M N L A K B J C I D H E G F 
N A M B L C K D J E I F H G 
 
 
Size = 15

A B O C N D M E L F K G J H I 
B C A D O E N F M G L H K I J 
C D B E A F O G N H M I L J K 
D E C F B G A H O I N J M K L 
E F D G C H B I A J O K N L M 
F G E H D I C J B K A L O M N 
G H F I E J D K C L B M A N O 
H I G J F K E L D M C N B O A 
I J H K G L F M E N D O C A B 
J K I L H M G N F O E A D B C 
K L J M I N H O G A F B E C D 
L M K N J O I A H B G C F D E 
M N L O K A J B I C H D G E F 
N O M A L B K C J D I E H F G 
O A N B M C L D K E J F I G H 
I H J G K F L E M D N C O B A 
J I K H L G M F N E O D A C B 
K J L I M H N G O F A E B D C 
L K M J N I O H A G B F C E D 
M L N K O J A I B H C G D F E 
N M O L A K B J C I D H E G F 
O N A M B L C K D J E I F H G 
A O B N C M D L E K F J G I H 
B A C O D N E M F L G K H J I 
C B D A E O F N G M H L I K J 
D C E B F A G O H N I M J L K 
E D F C G B H A I O J N K M L 
F E G D H C I B J A K O L N M 
G F H E I D J C K B L A M O N 
H G I F J E K D L C M B N A O 
 

Size = 16

A B P C O D N E M F L G K H J I 
B C A D P E O F N G M H L I K J 
C D B E A F P G O H N I M J L K 
D E C F B G A H P I O J N K M L 
E F D G C H B I A J P K O L N M 
F G E H D I C J B K A L P M O N 
G H F I E J D K C L B M A N P O 
H I G J F K E L D M C N B O A P 
I J H K G L F M E N D O C P B A 
J K I L H M G N F O E P D A C B 
K L J M I N H O G P F A E B D C 
L M K N J O I P H A G B F C E D 
M N L O K P J A I B H C G D F E 
N O M P L A K B J C I D H E G F 
O P N A M B L C K D J E I F H G 
P A O B N C M D L E K F J G I H 
 

Size = 17

A B Q C P D O E N F M G L H K I J 
B C A D Q E P F O G N H M I L J K 
C D B E A F Q G P H O I N J M K L 
D E C F B G A H Q I P J O K N L M 
E F D G C H B I A J Q K P L O M N 
F G E H D I C J B K A L Q M P N O 
G H F I E J D K C L B M A N Q O P 
H I G J F K E L D M C N B O A P Q 
I J H K G L F M E N D O C P B Q A 
J K I L H M G N F O E P D Q C A B 
K L J M I N H O G P F Q E A D B C 
L M K N J O I P H Q G A F B E C D 
M N L O K P J Q I A H B G C F D E 
N O M P L Q K A J B I C H D G E F 
O P N Q M A L B K C J D I E H F G 
P Q O A N B M C L D K E J F I G H 
Q A P B O C N D M E L F K G J H I 
J I K H L G M F N E O D P C Q B A 
K J L I M H N G O F P E Q D A C B 
L K M J N I O H P G Q F A E B D C 
M L N K O J P I Q H A G B F C E D 
N M O L P K Q J A I B H C G D F E 
O N P M Q L A K B J C I D H E G F 
P O Q N A M B L C K D J E I F H G 
Q P A O B N C M D L E K F J G I H 
A Q B P C O D N E M F L G K H J I 
B A C Q D P E O F N G M H L I K J 
C B D A E Q F P G O H N I M J L K 
D C E B F A G Q H P I O J N K M L 
E D F C G B H A I Q J P K O L N M 
F E G D H C I B J A K Q L P M O N 
G F H E I D J C K B L A M Q N P O 
H G I F J E K D L C M B N A O Q P 
I H J G K F L E M D N C O B P A Q 
 
 

Size = 18

A B R C Q D P E O F N G M H L I K J 
B C A D R E Q F P G O H N I M J L K 
C D B E A F R G Q H P I O J N K M L 
D E C F B G A H R I Q J P K O L N M 
E F D G C H B I A J R K Q L P M O N 
F G E H D I C J B K A L R M Q N P O 
G H F I E J D K C L B M A N R O Q P 
H I G J F K E L D M C N B O A P R Q 
I J H K G L F M E N D O C P B Q A R 
J K I L H M G N F O E P D Q C R B A 
K L J M I N H O G P F Q E R D A C B 
L M K N J O I P H Q G R F A E B D C 
M N L O K P J Q I R H A G B F C E D 
N O M P L Q K R J A I B H C G D F E 
O P N Q M R L A K B J C I D H E G F 
P Q O R N A M B L C K D J E I F H G 
Q R P A O B N C M D L E K F J G I H 
R A Q B P C O D N E M F L G K H J I 
 

Size = 19

A B S C R D Q E P F O G N H M I L J K 
B C A D S E R F Q G P H O I N J M K L 
C D B E A F S G R H Q I P J O K N L M 
D E C F B G A H S I R J Q K P L O M N 
E F D G C H B I A J S K R L Q M P N O 
F G E H D I C J B K A L S M R N Q O P 
G H F I E J D K C L B M A N S O R P Q 
H I G J F K E L D M C N B O A P S Q R 
I J H K G L F M E N D O C P B Q A R S 
J K I L H M G N F O E P D Q C R B S A 
K L J M I N H O G P F Q E R D S C A B 
L M K N J O I P H Q G R F S E A D B C 
M N L O K P J Q I R H S G A F B E C D 
N O M P L Q K R J S I A H B G C F D E 
O P N Q M R L S K A J B I C H D G E F 
P Q O R N S M A L B K C J D I E H F G 
Q R P S O A N B M C L D K E J F I G H 
R S Q A P B O C N D M E L F K G J H I 
S A R B Q C P D O E N F M G L H K I J 
K J L I M H N G O F P E Q D R C S B A 
L K M J N I O H P G Q F R E S D A C B 
M L N K O J P I Q H R G S F A E B D C 
N M O L P K Q J R I S H A G B F C E D 
O N P M Q L R K S J A I B H C G D F E 
P O Q N R M S L A K B J C I D H E G F 
Q P R O S N A M B L C K D J E I F H G 
R Q S P A O B N C M D L E K F J G I H 
S R A Q B P C O D N E M F L G K H J I 
A S B R C Q D P E O F N G M H L I K J 
B A C S D R E Q F P G O H N I M J L K 
C B D A E S F R G Q H P I O J N K M L 
D C E B F A G S H R I Q J P K O L N M 
E D F C G B H A I S J R K Q L P M O N 
F E G D H C I B J A K S L R M Q N P O 
G F H E I D J C K B L A M S N R O Q P 
H G I F J E K D L C M B N A O S P R Q 
I H J G K F L E M D N C O B P A Q S R 
J I K H L G M F N E O D P C Q B R A S 
 

Size = 20

A B T C S D R E Q F P G O H N I M J L K 
B C A D T E S F R G Q H P I O J N K M L 
C D B E A F T G S H R I Q J P K O L N M 
D E C F B G A H T I S J R K Q L P M O N 
E F D G C H B I A J T K S L R M Q N P O 
F G E H D I C J B K A L T M S N R O Q P 
G H F I E J D K C L B M A N T O S P R Q 
H I G J F K E L D M C N B O A P T Q S R 
I J H K G L F M E N D O C P B Q A R T S 
J K I L H M G N F O E P D Q C R B S A T 
K L J M I N H O G P F Q E R D S C T B A 
L M K N J O I P H Q G R F S E T D A C B 
M N L O K P J Q I R H S G T F A E B D C 
N O M P L Q K R J S I T H A G B F C E D 
O P N Q M R L S K T J A I B H C G D F E 
P Q O R N S M T L A K B J C I D H E G F 
Q R P S O T N A M B L C K D J E I F H G 
R S Q T P A O B N C M D L E K F J G I H 
S T R A Q B P C O D N E M F L G K H J I 
T A S B R C Q D P E O F N G M H L I K J 
 

Size = 21

A B U C T D S E R F Q G P H O I N J M K L 
B C A D U E T F S G R H Q I P J O K N L M 
C D B E A F U G T H S I R J Q K P L O M N 
D E C F B G A H U I T J S K R L Q M P N O 
E F D G C H B I A J U K T L S M R N Q O P 
F G E H D I C J B K A L U M T N S O R P Q 
G H F I E J D K C L B M A N U O T P S Q R 
H I G J F K E L D M C N B O A P U Q T R S 
I J H K G L F M E N D O C P B Q A R U S T 
J K I L H M G N F O E P D Q C R B S A T U 
K L J M I N H O G P F Q E R D S C T B U A 
L M K N J O I P H Q G R F S E T D U C A B 
M N L O K P J Q I R H S G T F U E A D B C 
N O M P L Q K R J S I T H U G A F B E C D 
O P N Q M R L S K T J U I A H B G C F D E 
P Q O R N S M T L U K A J B I C H D G E F 
Q R P S O T N U M A L B K C J D I E H F G 
R S Q T P U O A N B M C L D K E J F I G H 
S T R U Q A P B O C N D M E L F K G J H I 
T U S A R B Q C P D O E N F M G L H K I J 
U A T B S C R D Q E P F O G N H M I L J K 
L K M J N I O H P G Q F R E S D T C U B A 
M L N K O J P I Q H R G S F T E U D A C B 
N M O L P K Q J R I S H T G U F A E B D C 
O N P M Q L R K S J T I U H A G B F C E D 
P O Q N R M S L T K U J A I B H C G D F E 
Q P R O S N T M U L A K B J C I D H E G F 
R Q S P T O U N A M B L C K D J E I F H G 
S R T Q U P A O B N C M D L E K F J G I H 
T S U R A Q B P C O D N E M F L G K H J I 
U T A S B R C Q D P E O F N G M H L I K J 
A U B T C S D R E Q F P G O H N I M J L K 
B A C U D T E S F R G Q H P I O J N K M L 
C B D A E U F T G S H R I Q J P K O L N M 
D C E B F A G U H T I S J R K Q L P M O N 
E D F C G B H A I U J T K S L R M Q N P O 
F E G D H C I B J A K U L T M S N R O Q P 
G F H E I D J C K B L A M U N T O S P R Q 
H G I F J E K D L C M B N A O U P T Q S R 
I H J G K F L E M D N C O B P A Q U R T S 
J I K H L G M F N E O D P C Q B R A S U T 
K J L I M H N G O F P E Q D R C S B T A U 
 


Size = 22

A B V C U D T E S F R G Q H P I O J N K M L 
B C A D V E U F T G S H R I Q J P K O L N M 
C D B E A F V G U H T I S J R K Q L P M O N 
D E C F B G A H V I U J T K S L R M Q N P O 
E F D G C H B I A J V K U L T M S N R O Q P 
F G E H D I C J B K A L V M U N T O S P R Q 
G H F I E J D K C L B M A N V O U P T Q S R 
H I G J F K E L D M C N B O A P V Q U R T S 
I J H K G L F M E N D O C P B Q A R V S U T 
J K I L H M G N F O E P D Q C R B S A T V U 
K L J M I N H O G P F Q E R D S C T B U A V 
L M K N J O I P H Q G R F S E T D U C V B A 
M N L O K P J Q I R H S G T F U E V D A C B 
N O M P L Q K R J S I T H U G V F A E B D C 
O P N Q M R L S K T J U I V H A G B F C E D 
P Q O R N S M T L U K V J A I B H C G D F E 
Q R P S O T N U M V L A K B J C I D H E G F 
R S Q T P U O V N A M B L C K D J E I F H G 
S T R U Q V P A O B N C M D L E K F J G I H 
T U S V R A Q B P C O D N E M F L G K H J I 
U V T A S B R C Q D P E O F N G M H L I K J 
V A U B T C S D R E Q F P G O H N I M J L K 
 


Size = 23

A B W C V D U E T F S G R H Q I P J O K N L M 
B C A D W E V F U G T H S I R J Q K P L O M N 
C D B E A F W G V H U I T J S K R L Q M P N O 
D E C F B G A H W I V J U K T L S M R N Q O P 
E F D G C H B I A J W K V L U M T N S O R P Q 
F G E H D I C J B K A L W M V N U O T P S Q R 
G H F I E J D K C L B M A N W O V P U Q T R S 
H I G J F K E L D M C N B O A P W Q V R U S T 
I J H K G L F M E N D O C P B Q A R W S V T U 
J K I L H M G N F O E P D Q C R B S A T W U V 
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Randomized Withdrawal Design - Examples for Defining the Criteria for Run-in and Randomized Withdrawal Periods

In a previous post, we discussed the "Randomized Withdrawal Design and Randomized Discontinuation Trial". The randomized withdrawal design and the randomized discontinuation design may be used interchangeably. The randomized withdrawal design is one of the clinical trial designs with enrichment strategy and is more efficient design if it is applied in the appropriate situation.

The diagram for a typical randomized withdrawal design will be something like below (with efficacy measure in the run-in period).

or with safety or tolerability as the measure in the run-in period.

The randomized withdrawal design contains a run-in period and a randomized, controlled period. For each period, the criteria will need to be defined. For open-label run-in period, the criteria are needed to define what is considered as 'responder' (for efficacy measure) or 'tolerable' (for safety measure). For the randomized, controlled period where the formal hypothesis testing is based on, the study endpoint will need to be defined.

The table below listed some examples of clinical trials using the randomized withdrawal design. The criteria for the run-in period and for randomized withdrawal period are listed. 

	Criteria for Responder or tolerability	Endpoint for Randomized Withdrawal Period
ICE Study (immunoglobulin in CIDP)	10-point INCAT score improve by 1 point	Time to relapse where the relapse was defined as 10-point INCAT score worsen by 1 point
Droxidopa for Symptomatic Neurogenic Orthostatic Hypotension	based on symptom and BP response where the response is determined by improvement of at least one point on a symptom question (Orthostatic Hypotension Symptom Assessment (OHSA) Item 1) and an improvement in SBP of at least 10 mmHg at 3 minutes post-standing]	the mean change from Randomization (Visit 4) to the End of Study Visit (Visit 5) in the OHSA Item 1 (dizziness, lightheadedness, feeling faint or feeling like you might black out) score
Nifedipine for vasospastic angina	Stable	recurrence of severe vasospastic angina leading to study withdrawal
Gamma-hydroxybutyrate (GBH, sodium oxybate) for treatment of cataplexy	Median Attacks every 2 weeks	Median Attacks every 2 weeks
Double-blind, Placebo-controlled, Randomised Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17	Completed a minimum of 4 weeks of double-blind treatment, reached Visit 4 and completed the 1-week post-treatment washout in the antecedent study (SPD489-325), without experiencing any clinically significant AEs that would preclude exposure to LDX	Treatment failure defined as 50% increase (worsening) in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) total score and greater than and equal to 2 point increase (worsening) in the Clinical Global Impression-Severity of Illness (CGI-S) score observed at any visit during the randomized withdrawal period compared to the respective scores at baseline of randomized withdrawal period.
A double-blind, placebo-controlled, randomized withdrawal study of lurasidone for the maintenance of efficacy in patients with schizophrenia	To achieve and maintain clinical stability for at least 12 weeks during the open-label stabilization phase and to have remained on a stable dose of lurasidone for four weeks prior to randomization. Clinical stability was defined as a PANSS total score less than or equal to 70, with PANSS item scores less than or equal to 4 on all positive subscale items and the item for "uncooperativeness”, (item G8), and a CGI-S score less than 4.	Time to relapse (based on Kaplan–Meier survival analysis), with relapse defined as greater than and equal to 1 of the following during the double-blind phase: (1) An increase of greater than and equal to 25% from double-blind baseline in PANSS total score and CGI-S worsening of greater than and equal to 1 point for two consecutive visits no more than ten days apart. (2) At any single visit, a PANSS item score of greater than and equal to 5 (moderately severe) on hostility or uncooperativeness, or a PANSS item score of greater than and equal to 5 on two or more items of unusual thought content, delusions, conceptual disorganization, or hallucinatory behavior. (3) Initiation of supplemental treatment with an antipsychotic agent other than lurasidone, an increased dose of an antidepressant or mood stabilizer, an increase in lorazepam (or benzodiazepine equivalent) dose by greater than and equal to 2 mg/d for at least 3 days, or electroconvulsive therapy. (4) Insufficient clinical response or exacerbation of underlying disease reported as an adverse event, as determined by the study investigator. (5) Deliberate self-injury or repeated aggressive behavior, active suicidal or homicidal ideation or attempt. (6) Psychiatric hospitalization due to worsening schizophrenia. Secondary
A Randomized Withdrawal, Placebo-Controlled Study Evaluating the Efficacy and Tolerability of Tapentadol Extended Release in Patients With Chronic Painful Diabetic Peripheral Neuropathy	Patients who tolerated tapentadol ER and had 1-point improvement in average pain intensity from the pre-titration evaluation period to the last 3 days of the open-label titration period were randomly assigned (1:1) to receive tapentadol ER or placebo during a subsequent 12-week double-blind maintenance phase	The primary efficacy endpoint was the mean change in average pain intensity from baseline to week 12
Long-term Maintenance of Response Across Multiple Fibromyalgia Symptom Domains in a Randomized Withdrawal Study of Pregabalin	meeting response criteria for pain [Z50% reduction in pain 100-mm Visual Analog Scale (VAS) score from OL baseline] and PGIC (self-rating of much improved or very much improved) at the end of the OL treatment phase	Time to LTR (loss of therapeutic response)
The randomized discontinuation trial: a phase II design to assess growth-inhibitory agents	Radiologic stable	Fraction with radiologic stable disease

FDA Guidance: Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics

Two years ago, I had a post discussing "Dose Cohort Expansion Study - A Never Ending Phase I Study Design". Last month, FDA officially issued the guidance for industry "Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics".

With this guidance, we expect that more sponsors will adopt this study design in oncology trials and beyond the oncology trials.

The dose cohort expansion study design completely changed the traditional phased approaches for clinical trials for drug development. The phases I, II, III, IV are no longer critical.

Splitting p-value and estimate of the treatment difference

When we perform the statistical test to compare the difference between two treatment groups, we usually construct a test statistic, calculate the treatment difference, and then obtain the p-value corresponding to the test statistic and the treatment difference.

For example, for a study with primary efficacy endpoint of proportion of subjects with hemostasis, Treatment difference was estimated using risk ratio and the corresponding p-value was calculated to indicate if the risk ratio is statistically significant. 

Another example is for a study with 6-Min walk distance (6MWD) as the primary endpoint. The treatment difference was estimated using least-squares mean difference. The corresponding p-value was calculated using the analysis of covariance (ANCOVA) approach. 

In these examples, the p-value and the estimate of the treatment difference were from the same test statistic. 

We see many examples where two different methods are used for estimating the treatment difference and for calculating the p-value - I call it 'splitting the p-value and the estimate of the treatment difference'. Here are two situations where this splitting situation occurs.

Analysis of Time to Event: log-rank test for calculating the p-value and proportional hazard model for estimating the hazard ratio 

In clinical trials with time to event endpoint, it is very common to provide the Kaplan-Meier estimate and calculate the p-value using log-rank test - a non-parametric method. The treatment difference or magnitude of treatment effect is usually measured using hazard ratio. Kaplan-Meier estimate does not give an estimate of the hazard ratio. The hazard ratio needs to be estimated using the Proportional Hazard model (or Cox regression model). 

In a study by Sitbon et al, the primary efficacy endpoint was a composite endpoint of time to death or a complication related to PAH. The hazard ratio and p-value were provided in the primary efficacy table below. However, it needs to be noted that two different methods were used to calculate the hazard ratio and the p-value. As stated in the Statistical Analysis section, the statistical methods were provided as the following:  

"In time-to-event analyses, end points were estimated with the use of the Kaplan–Meier method and were analyzed with the use of the log-rank test. Hazard ratios with 99% confidence intervals (for primary and secondary end points) and 95% confidence intervals (for exploratory end points) were estimated with the use of proportional-hazard models."

 

p-value corresponding to the hazard ratio can also be obtained from the proportional hazard model, but is usually not presented in the place where p-value from the log-rank test is provided - to avoid the confusion about two different p-values. 

Why do we present the hazard ratio from one method and p-value from another method? why can't we present both the hazard ratio and the corresponding p-value from the proportional hazard model? 

   

Wilcoxon Rank Sum Test to calculate the p-value and Hodges-Lehmann method to calculate the difference in median

Wilcoxon is also called Mann Whitney U Test and is a non-parametric method to compare the difference in medians for non-normal distributed data. Wilcoxon rank sum test converts the original data into ranks and the p-value is calculated to compare the total ranks between groups. However, the statistics of ranks has no meaning in measuring the magnitude of the treatment effect. Therefore, when the Wilcoxon method is used to calculate the p-value, a different method needs to be employed to estimate the treatment difference (magnitude of the treatment effect). Hodges-Lehmann method is now commonly used to estimate the treatment difference - location shift in medians between two treatment groups. 

Here is a link to FDA's statistical review for Xermelo (telotristat ethyl) oral tablets in indication of  Carcinoid Syndrome. p-value was calculated from Wilcoxon rank test and treatment difference (location shift in median) and confidence interval were calculated from Hodges Lehmann method.

The primary efficacy endpoints in studies LX301 and LX303 were analyzed by the blocked 2- sample Wilcoxon rank sum statistic stratified by the baseline urinary 5-HIAA levels (≤ upper limit of normal reference range [ULN], >ULN, and Unknown). Descriptive statistics of the primary endpoints and the Hodges-Lehmann estimator of location shift with its respective CLs were reported for each comparison.

In a paper by Jing et al, "Efficacy and Safety of Oral Treprostinil Monotherapy for the Treatment of Pulmonary Arterial Hypertension A Randomized, Controlled Trial", the endpoint of 6MWD was analyzed using Wilcoxon method for p-values and using the Hodges-Lehmann estimator for the treatment effect (location shift in medians).

Geriatric Investigational Plan - Clinical Trials for Elderly

Every clinical trial should have a protocol and the protocol needs to include the inclusion/exclusio criteria to define the study population (i.e., who can participate in the trial). The first inclusion criterion is usually the age limit. In many clinical trials sponsored by AstraZeneca, the 'Ages Eligible for Study' was defined as "18 Years to 130 Years (Adult, Older Adult)". Here are links to entries in clinicaltrials.gov for two of these studies: NEPTUNE study and MYSTIC study The upper limit of 130 years old for the study triggered me to look into the age range for clinical trials in adult population (especiaily the upper limit in elderly patients).

The clinical trials in the pediatric population and the age groups in the pediatric population have been discussed in previous posts.

• Age Group in Pediatric, Perinatal or Preterm, and Geriatric Subjects
• Pediatric use and geriatric use of drug and biological product

The reason to have an upper limit of age for study participants is to have a homogeneous population for the study to maximize the chance to have a positive study.  Nowadays, many trials do not set an upper limit for age. An 80-85-year-old individual can be very healthy and an 80-85 years old patient can participate in clinical trials without problems.

For pediatric population, in order to obtain the indication or label, a separate set of clinical trials need to be conducted. There are many requirements and rules for pediatric clinical trials. Regulatory agencies encouraged the sponsors to do clinical trials in pediatric population – pediatric investigational plan (PIP).

Similarly, the safety and efficacy of the specific drug product should also be studied in the geriatric population. The safety and efficacy of a product may be different between the geriatric population and the general adult population. There was an ICH E7 STUDIES IN SUPPORT OFSPECIAL POPULATIONS:GERIATRICS and its Questions and Answers. FDA has a guidance on "Content and Format for Geriatric Labeling". Below are some additional discussions about the clinical trials in the geriatric population.

• Disparate Inclusion of Older Adults in Clinical Trials: Priorities and Opportunities for Policy and Practice Change
• Why Do Clinical Trials Need Older and Diverse Participants?
• https://www.fda.gov/downloads/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/UCM410474.pdf
• FDA-ASCO Public Workshop: Geriatric Oncology Workshop
• Clinical Discussion of Specific Clinical Discussion of Specific Populations
• GAO 2007 Prescription Drugs: FDA Guidance and Regulations Related to Data on Elderly Persons in Clinical Drug Trials

For a study in adult including elderly patients, the typical criteria for age will be 18 years and older with no upper limit for age. In this way, the geriatric subjects can be enrolled into the study if the subject meets all other inclusion/exclusion criteria and the very older patients can be enrolled into the study if they are healthy enough. However, if we look at the various studies, different sponsors use different criteria for age in their studies.

Using Phase III studies in NSCLC, here are some examples from clinicaltrials.gov. We can see that different clinical trials use different ranges for age. 

Study	Inclusion Criterion for Age
A Study of Nivolumab + Chemotherapy or Nivolumab + Ipilimumab Versus Chemotherapy in Patients With EGFR Mutation, T790M Negative NSCLC Who Have Failed 1L EGFR TKI Therapy (CheckMate722)	18 Years and older (Adult, Older Adult)
Evaluate the Efficacy and Safety of IBI305 in Patients With Advanced or Recurrent Non-squamous NSCLC	18 Years to 70 Years (Adult, Older Adult)
MIL60 Versus Bevacizumab in Patients With Treatment-naïve Non-squamous Non-small Cell Lung Cancer	18 Years to 75 Years (Adult, Older Adult)
A Study Comparing MB02 and Avastin® in Subjects With Stage IIIB/IV Non-Squamous Non-Small Cell Lung Cancer (NSCLC) (STELLA)	18 Years to 80 Years (Adult, Older Adult)
Effect of Tumor Treating Fields (TTFields) (150 kHz) Concurrent With Standard of Care Therapies for Treatment of Stage 4 Non-small Cell Lung Cancer (NSCLC) Following Platinum Failure (LUNAR)	22 Years and older (Adult, Older Adult)
Study of ONO-4538 in Non-Squamous Non-Small Cell Lung Cancer	20 Years and older (Adult, Older Adult)

Whether or not the upper limit is set to 70, 75, 80 years old or have no upper limit, if the drug is approved, the indication for the drug will be the same and the only difference may be the descriptions in section 8.5 of the drug label per FDA's guidance "Labeling for Human PrescriptionDrug and Biological Products –Implementing the PLR Content and Format Requirements".