Review for 10.1186/s12876-020-01399-5 (2020)

Reviewer’ s report
Title: A randomized crossover trial to assess therapeutic efficacy and cost reduction of acid
ursodeoxycholic manufactured by the university hospital for the treatment of primary biliarycholangitis
Version: 0Date: 16 Mar 2020
Reviewer: Research Square Reviewer 1
Reviewer's report:
PEER REVIEWER ASSESSMENTS:OBJECTIVE - Full research articles: is there a clear objective that addresses a testable research
question(s) (brief or other article types: is there a clear objective)?Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for the
objective?No - there are minor issues
EXECUTION - Are the experiments and analyses performed with technical rigor to allow
confidence in the results?No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?No - there are minor issues
OVERALL MANUSCRIPT POTENTIAL - Is the current version of this work technically sound?
If not, can revisions be made to make the work technically sound?Probably - with minor revisions
PEER REVIEWER COMMENTS:GENERAL COMMENTS:
The authors have conducted randomized crossover trial to reduce the costs of ursodeoxycholicacid (UDCA) treatment for primary biliary cholangitis (PBC) by assessing the non-inferiority ofUDCA 300 mg capsules and tablets produced in pharmacy with the reference UDCA. Crossovertrial would help the assess the noninferiority with the help of self-control group after the necessarywashout period based on the pharmacokinetic parameters of the medicine. However, they have not
presented the results to support these and directly concluded without sound evidence. Also, the
authors did not maintain necessary washout period prior to the exchange of the test and control
groups to avoid the carry-over effects.
The authors have compared the liver enzyme parameters such as alkaline phosphatase, gamma
glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin afterusing UDCA 300 mg at various times periods such as time 0, time 1 and time 2 at the gap of 12weeks. These helped compare and assess the non-inferiority in terms of therapeutic efficacy of theformulations. The authors received ethics approval from the concerned authority and registered onthe clinical trial registry (although retrospectively and better to be prospectively registered, which
was not possible on this occasion). These are good sign of the clinical research.
The authors have followed the CONSORT checklist although they have not mentioned it in
Methods section, which should have been mentioned. Since it was a crossover trial, CONSORTflow diagram for crossover trials (i.e., CONSORT extension) would be better, which was notfollowed. Also, the authors have applied the indirect method of compliance checking rather thanthe direct method. Also, randomization and basis of sample size calculation have to be furtherelaborated upon because sample size was too low to conclude the results of the trial.
REQUESTED REVISIONS:
The authors are suggested to address mainly the issues of randomization, sample size calculation,CONSORT extension checklist for the crossover trials, use of direct adherence measurement, andthe cost elucidation in table.ADDITIONAL REQUESTS/SUGGESTIONS:General comments:*Elaborate upon the term 'manipulated drug' or 'drug manipulation' used throughout themanuscript, beginning from the title. Also, elaborate upon the term 'reference pharmaceuticalproduct' used throughout the manuscript. You may elaborate upon these terms once in Methods
section.
*There are lots of problems in the sentence constructs throughout the manuscript. It is better if theauthors went through the language editing vigorously.*Use past tense in Background, Methods, wherever necessary (in both the Abstract and the maintext).*Keep table 1 prior to table 2 although this is minor problem in placement.
Specific comments:
*Since the present study was crossover trial, it would be better if the authors followed theCONSORT flow diagram for crossover trials (i.e., CONSORT extension). The authors can use thediagram based on the reference:Dwan K, Li T, Altman DG, Elbourne D. CONSORT 2010 statement: extension to randomisedcrossover trials. BMJ 2019;366:l4378.*The authors are also suggested to clarify the basis for the sample size calculation (item 7a)because the present sample size was too low to conclude the results and the issues ofgeneralizability i.e., external validity (item 21) of the aforementioned reference.
Abstract:
*Lines 14-16, 19-21, 23-24: Rewrite the sentences clearly.
*Lines 16-18: Mention the treatment costs- both direct and indirect.
*Lines 22-23: The authors have mentioned the study design differently from the title of themanuscript. Be consistent and from the full description of the research, crossover trial would bebetter study design for the present research. Modify your title accordingly.
Background:
*Lines 58-61: Elaborate upon 'clinical investigations'.
Methods:
*Since it was crossover trial, the context of wash-out period between each of the interventions
must have been mentioned to avoid the carry-over effects (or spill-over effects). This has beenmissing in the manuscript.*Lines 78-79: Elaborate upon the location of the hospital (i.e., the study site) and the servicesprovided.*Line 80: Keep full forms of 'EASL', 'AASLD' prior to keeping these acronyms.*Line 87: Statement on randomization needs further elaboration because strict randomization isone of the foundations of the clinical trial including crossover trial. Mention which method ofrandomization you employed (i.e., simple random, stratified random or other). Also, elaborateupon how you achieved the random number just with the help of Excel sheet. Did you followlottery method or table of random numbers or computer (i.e., software)-generated randomnumbers or bottle spinning method or other? R would also generate better list of random numbers.*Lines 103-106, 113-115, 126-128, 129-130, 131-136, 151-152: Rewrite the sentences clearly.*Lines 110-112: Clarify why you did not follow the latest version of the British Pharmacopoeia?*Lines 136-137: Rewrite the sentences clearly and also elaborate upon 'Paris II Criteria ALP 1.5 xULN'.*Line 144: Rewrite the subheading clearly.*Lines 141-142: The authors have used the indirect method of compliance checking (i.e., tablet
count). Clarify why you did not apply any of the direct methods of adherence checking (better
term compared to compliance) such as directly observed therapy, or measurement of level ofmedicines or metabolites in blood or urine, or measurement of biological markers in blood. Thesedirect methods of adherence could be the better markers of the adherence measurement and couldserve as the better measurement of the primary and secondary outcomes.*Lines 153-155: Do not keep unnecessary capital letters. Also, specifically mention the exact non-parametric test applied.Results:*Lines 163-164: Were they different from those four or the same? If different, your sample sizebecomes 26 but from the flow chart, it seems that these four people who were excluded were thesame as previously mentioned. Clarify the issue.*Lines 184 and 191: Show the information in table(s) as well.*Lines 189-190: Elaborate upon the statement.*Lines 192-193: Rewrite the sentence clearly.
Discussion:
*Lines 197-198: Elaborate upon how we could demonstrate an economy to the hospital using drugmanipulation. Also, elaborate upon the term 'economy'.
*Lines 202-209: These sentences are better suited for Methods section but no need for the
exaggerated elaboration of the study design. The information can be kept in Methods section in theabridged form.*Lines 210-213: These sentences are better suited for Methods section under 'Statistical analysis'section. Still, the statement is not convincing because parametric test could also be used forrepeated measures. Choice of parametric or non-parametric test(s) depends on the nature of thedata distribution (i.e., normally distributed or not).*Lines 211-213: Clarify the term 'asymptotic assumptions'.*Lines 213-215, 224-225, 229-230: Rewrite the sentences clearly.
*Lines 215-217: Justify the statement.
*Lines 218-221: These sentences are better suited for Methods section under 'Statistical analysis'section. Still, there is no need to exaggeratedly justify the statistical test as it was not convincing.*Lines 226-227: Rewrite the sentence clearly and also show these adverse events in table.*Lines 231-233: Show the information in table.*Line 237: Keep the full form of 'AUDC' prior to keeping this acronym.*Lines 238-239: Cite reference(s) to support the statement.*Lines 239-241: Rewrite the sentence clearly and cite reference(s) to support the statement.*Lines 241-243: Elaborate upon 'manual steps' and 'longer production time'.*Lines 251-255: Not keeping the information of washout period based on the pharmacokineticparameters of the medicine was the shortcoming of the present research. It was the problem inexecution of the research rather than the inherent limitation of the present research.
Conclusions:
*Lines 265-267: Conclusion on the non-inferiority is still not convincing. Please discuss on the'non-inferiority' and other main objectives of your research prior to concluding these.
Abbreviations:
*Lines 270-271: Check the full form of 'GGT'. It is 'gamma-glutamyl transferase'. Is it 'gamma
glutamyl transpeptidase'?
References:
*References 1, 6: Keep full reference.*Reference 2: Be consistent in referencing in between the names of the authors. Also, keepEnglish reference as far as possible.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
NoDoes the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
No
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
NoAre you able to assess any statistics in the manuscript or would you recommend an
additional statistical review?If an additional statistical review is recommended, please specify what aspects require furtherassessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being publishedDeclaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of thismanuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?6. Do you have any non-financial competing interests in relation to this paper?
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If your reply is yes to any, please give details below.
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