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. 2021 May 26;16(5):e0252155. doi: 10.1371/journal.pone.0252155

Characteristics and conflicts of interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee meetings

Rishad Khan 1, Karam Elsolh 2,3, Nikko Gimpaya 2, Michael A Scaffidi 2,4, Rishi Bansal 2,3, Samir C Grover 1,2,5,*
Editor: Claudio Gentili6
PMCID: PMC8153474  PMID: 34038480

Abstract

Introduction

The United States Food and Drug Administration (FDA) Gastrointestinal Drug Advisory Committee (GIDAC) is involved in gastrointestinal drug application reviews. Characteristics and conflicts of interest (COI) in GIDAC meetings are not well described. This study analyzed FDA GIDAC meetings and characteristics that predict recommendations.

Methods

In this cross-sectional study, all publicly available GIDAC meetings where proposed medications were voted on were included. Data were collected regarding indications, medication sponsor, primary efficacy studies, and voting member characteristics (e.g. committee membership, COI). Univariate analyses were conducted at per-meeting and per-vote levels to assess for predictors of committee recommendation and individual votes respectively.

Results

Thirty-four meetings with 476 individual votes from 1998–2018 were included. Twenty-three (68%) proposals were recommended for approval and 25 (74%) received FDA approval. Most proposals involved >1 primary study (n = 27, 79%). At least one voting member had a COI in 24 (71%) of 34 meetings. Twelve (35%) meetings had at least one sponsor COI. Among 476 individual votes, 74 (15.5%) involved a COI, with 33 (6.9%) sponsor COI. COI decreased significantly over time, with fewer COI in 2006–2010, 2011–2015, and 2016–2020 compared to 1996–2000 and 2001–2005 (p<0.01). There were no significant associations between pre-defined predictors, including COI, and committee level recommendations or individual votes (p>0.05 for all univariate analyses).

Conclusions

The GIDAC reviewed 34 proposals from 1998–2018. The majority were recommended for approval and later approved by the FDA, highlighting the GIDAC’s prominence in the regulatory process. COI are present among GIDAC panelists but decreasing over time and not associated with recommendations.

Introduction

The United States Food and Drug Administration (FDA) Gastrointestinal Drug Advisory Committee (GIDAC) plays an important role in the evaluation and approval of new gastrointestinal (GI) drug applications [1]. Little is known, however, about the characteristics of GIDAC meetings. With calls for more transparent and impartial processes in medication approval pathways [2], a systematic understanding of the GIDAC’s role is needed.

Advisory committees are typically convened when the FDA requires additional clinical expertise to review a drug application, assess medications with controversial risk-benefit profiles, or independently review data for a new product [3]. While committees are strictly advisory, the high concordance between committee recommendations and the FDA’s final actions suggest a prominent role in determining approvals [4]. From 2008 to 2012, the GIDAC recommended approval for 77% of reviewed products, with the FDA later approving 83% of the same products [1]. Despite the committee’s presumed importance, the features of GIDAC meetings and factors that influence recommendations, including the prevalence of conflicts of interest (COI), are unknown.

COI are common in other areas of gastroenterology practice. While these relationships between the medical and corporate pharmaceutical companies are necessary for innovation and research [5, 6], they can affect the objectivity of clinical and scientific recommendations and decision making [7–9]. The prevalence of COI has been demonstrated in GI society guidelines [10–14] and been shown to correlate with increased prescribing of expensive biologic medications [15]. COI among FDA panelists has been studied broadly across all committees and specifically for oncology drug applications [16–18], but are not well described for GIDAC panelists.

To address this gap in the understanding of the GIDAC its role in the approval process, we analyzed FDA GIDAC meetings and evaluated characteristics that predict positive recommendations.

Materials and methods

We conducted a cross-sectional analysis of all GIDAC meetings available from the FDA website [19]. We did not restrict our search by time. As this study uses publicly available data, it does not qualify as human subjects research, based on the Tri-council Policy Statement on Ethical Conduct for Research Involving Humans and is thus exempt from ethical review [20].

Sample

Two authors (RK, KE) independently and in duplicate searched all GIDAC meetings and identified meetings in which voting took place. We included meetings in which votes were cast on questions regarding 1) whether to recommend approval for a medication for a specific indication, 2) whether a medication had demonstrated safety and efficacy, or 3) whether a medication had a favorable risk-benefit profile. We excluded meetings if they voted on broad topics that did not concern a specific clinical indication (e.g. voting on a class of drugs) or did not concern approval of a medication (e.g. voting on necessity of post-marketing safety studies).

We counted a single proposed indication for one medication as a single meeting. If there were votes on multiple medications and/or multiple indications for one medication, we counted each indication for each medication as a single meeting. For example, if GIDAC panelists voted on two indications each for two medications each on a single day, we would have considered this as four unique meetings.

Data collection

We extracted data primarily from meeting transcripts. We also used other documents that were available on the FDA website alongside meeting transcripts, including meeting minute summaries, presentation slides, medical officer review documents, and COI waivers [19].

Two authors (RK, KE) collected the following data from meeting transcripts independently and in duplicate: medication name, proposed indication, country of the medication sponsor, type of application (new drug or biological licensing), and whether the majority of the committee voted for approval of a medication for the proposed indication. We used the medication application number to determine if the FDA approved the medication for the proposed indication after the meeting. A third author (SCG) reviewed the data collected and discrepancies were resolved by consensus.

For each proposed indication, we also collected data on the underlying primary studies used as evidence of efficacy and safety, including number of trials reviewed at meetings, and for the pivotal trial(s), study design, sample size, study phase, type of primary endpoint (clinical or surrogate), study result, and whether the study’s corresponding author had any COI with the medication sponsor.

We then identified all individual voting members at each meeting. For each vote, we collected the following data on the individual casting the vote: role within the GIDAC, educational degree (if applicable), whether they had any COI, and if so, if the COI were with the medication sponsor or a competitor. We also identified the value of COI in United States Dollar (USD) and classified them as general payments (e.g. consulting, speaker’s fees, food and travel), research payments, or equity, in keeping with Centres for Medicare and Medicaid Services definitions of industry payments [21]. Data regarding COI were available in the meeting transcript as part of the executive secretary’s statement.

Analysis

We calculated descriptive statistics with proportions and median with interquartile range (IQR) for categorical and continuous variables respectively. We presented summary data on a per-meeting and per-vote basis. For COI, we presented data stratified by five time periods: 1996–2000, 2001–2005, 2006–2010, 2011–2015, 2016–2020.

We conducted univariable logistic regression to evaluate the relationship between meeting level factors and a positive recommendation for the medication. Predictor variables were dichotomized and included disease subgroup (inflammatory bowel disease vs. other), number of clinical trials reviewed in the meeting (1 vs. >1), sample size of the pivotal trial (<500 vs. ≥500), endpoint (clinical vs. surrogate), efficacy (whether the primary endpoint was achieved or not), medication sponsor (US-based vs. other), type of application (new drug vs. biological licensing). We also included predictor variables for three types of COI: COI present for the corresponding author of the pivotal trial, COI present for any GIDAC member, and COI present for any GIDAC member with the sponsor of the medication. We intended on including the type of study (randomized trial vs. other) and study phase (phase 3 vs. other) for the pivotal trial but were limited by small subgroups.

To evaluate the relationship between characteristics of GIDAC members and voting pattern, we conducted univariable logistic regression with the following dichotomous predictors: committee membership (chair or standing member vs temporary member), degree (medical vs. other), any COI, COI with the medication sponsor, and COI with a competitor of the medication sponsor. Statistical significance was set at p<0.005 for the logistic regression of meeting level votes and p<0.001 for the logistic regression of GIDAC member voting, as we applied a Bonferroni adjustment for multiple comparisons. We did not use multiple regression analyses to avoid over-fitting this small data set.

We conducted post-hoc analyses with chi-squared testing to determine if there were differences with respect to proportion of votes with COI between time periods (1996–2000, 2001–2005, 2006–2010, 2011–2015, 2016–2020). We followed this analysis with pairwise chi-squared tests between the five different 5-year time periods. All analyses were performed with SPSS version 26 (IBM corporation, Armonk, New York, United States).

Results

There were 42 available meetings on FDA GIDAC webpage, ranging from 1998 to 2018. Of all meetings, 34 involved voting on proposed indications and comprised our study sample. There were 476 votes cast in the 34 meetings. All primary data are available in S1 File.

Meeting, study, and vote characteristics

Meetings most commonly involved medications for the management of inflammatory bowel disease (n = 14, 41%), functional GI disease (5, 15%) and liver disease (3, 9%). The majority of medication sponsors were US-based pharmaceutical companies (18, 53%). New drug applications (23, 68%) were more common than biological licensing applications (11, 32%) (Table 1).

Table 1. Meeting characteristics.

Characteristic Number of meetings
n (%) N = 34
Disease group
Inflammatory bowel disease 14 (41)
Functional gastrointestinal disease 5 (15)
Liver disease 3 (9)
Other † 12 (35)
Sponsor
United States 18 (53)
United Kingdom 7 (21)
Europe 6 (17)
Other ‡ 3 (9)
Type of application
New drug 23 (68)
Biological licensing 11 (32)
Approval
Committee recommended approval 23 (68)
FDA provided approval 25 (74)
    Approval for proposed indication 21 (62)
    Approval for modified indication 4 (12)
Conflict of interest
One member with COI 24 (71)
    With sponsor 12 (35)
    With competitor 18 (53)
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† Heartburn, chemotherapy associated nausea and vomiting, short bowel syndrome, Barrett’s esophagus, post-operative ileus, exocrine pancreatic insufficiency, and neonatal hemolysis

‡ Japan, Canada

FDA, Food and Drug Administration; IQR, interquartile range

The committee recommended approval for 23 (68%) indications and the FDA approved 25 (74%) indications, with 21 (62%) approvals for proposed indications and 4 (12%) modified approvals (Table 2).

Table 2. Committee recommendations and subsequent FDA approvals.

Applications, n (%) FDA decision
N = 34 Yes–proposed indication Yes–modified indication No
GIDAC recommendation Yes 20 (59) 2 (6) 1 (3)
No 1 (3) 2 (6) 8 (23)
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FDA, Food and Drug Administration; GIDAC, Gastrointestinal Drug Advisory Committee

The committee reviewed one primary study in seven (21%) meetings, and more than one trial at 27 (79%) meetings (Table 3). The median sample size of pivotal trials was 263 (IQR 80–672). The majority of pivotal trials were phase 3 (33, 97%) randomized controlled trials (30, 88%), had a clinical primary outcome (30, 88%), achieved the primary outcome (30, 88%), and had corresponding authors with COI (23, 68%).

Table 3. Characteristics of studies evaluated for drug applications.

Study characteristic Number of meetings
n (%) N = 34
Number of trials evaluated in meeting
1 7 (21)
>1 27 (79)
Sample size †, median (IQR) 263 (80–672)
Type of study
Randomized controlled trial 30 (88)
Other ‡ 4 (12)
Study Phase
Phase 3 33 (97)
Phase 2 1 (1)
Primary endpoint
Clinical endpoint 30 (88)
Surrogate endpoint 4 (12)
Efficacy
Primary endpoint achieved 29 (85)
Primary endpoint not achieved 5 (15)
COI present for corresponding author 23 (68)
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† For meetings which evaluated multiple trials, the sample size from the pivotal trial, or when there were multiple pivotal trials, the largest trial was used

‡ Includes two non-randomized trials and two single arms trials

COI, conflict of interest

Among the 476 votes cast at 34 meetings, there were 310 (65.1%) yes votes, 161 (33.8%) no votes, and 5 (1.1%) abstentions (Table 4). With respect to panelists who cast votes, they were most commonly a temporary committee member/expert consultant (222, 46.6%) or standing GIDAC member (106, 22.3%). There were 34 (7.1%) committee chairs, corresponding to one chair per meeting. Most panelists had medical degrees (360, 75.6%).

Table 4. Medication approval voting details.

Characteristic Number of votes
n (%) N = 476
GIDAC membership status
Chair 34 (7.1)
Standing member 106 (22.3)
Temporary member/expert consultant 222 (46.6)
Patient representative 27 (5.7)
Consumer representative 28 (5.9)
Other committee † 57 (12.0)
Federal employee 2 (0.4)
Degree
MD/MBBS/DO 360 (75.6)
PhD 46 (9.7)
Pharm D 18 (3.8)
Not stated 40 (8.4)
Other ‡ 12 (2.5)
COI 74 (15.5)
Direct (with sponsor) 33 (6.9)
Competitor 41 (8.6)
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† From meetings which involved other committees, such as the Pediatric Drug Advisory Committee

‡ Includes BA, MPH, and JD

GIDAC, Gastrointestinal Drug Advisory Committee; COI, conflict of interest

Conflicts of interest

There was at least one voting member with a COI in 24 (71%) of the 34 meetings. Twelve (35%) meetings had at least one sponsor COI and 18 (53%) had at least one competitor COI. Of the 476 individual votes, 74 (15.5%) involved a committee member with COI, comprised of 33 (6.9%) COI with sponsors and 41 (8.6%) with competitors. Ten of the 74 COI were among committee chairs. All members who had COI received waivers and were able to participate in voting. When stratified by time period, the number of votes that involved COI as a proportion of all votes cast in that time period were as follows: 24 (32.0%) in 1996–2000, 25 (32.8%) in 2001–2005, 5 (7.8%) from 2006–2010, 10 (6.5%) from 2011–2015, and 11 (10.2%) from 2016–2020 (Fig 1). Among the 74 COI, 31 (42%) were equity, 12 (16%) were general payments, three (4%) were research payments, and 28 (38%) were not stated. Payment values were most commonly 10,000–49,999 USD (28, 38%), not stated (22, 30%), or less than 10,000 USD (16, 21%) (Fig 2).

Fig 1. Percentage of votes at Gastrointestinal Drug Advisory Committee meetings with member conflict of interest, stratified by 5-year time intervals.

Fig 1

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Fig 2. Value of payments for the 74 votes that involved conflicts of interest.

Fig 2

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There was a significant difference with respect to the proportion of votes with COI between the different time periods (p<0.01). On pairwise comparisons, the 1996–2000 and 2001–2005 time periods each had significantly more votes with COI compared with the 2006–2010, 2011–2015, and 2016–2020 time periods (p<0.01). There were no differences when comparing the 1996–2000 and the 2001–2005 time periods, or when comparing the 2006–2010, 2011–2015, and 2016–2020 time periods (p>0.05).

Predictors of committee recommendation and votes of approval

There were no significant associations between our a priori defined predictor variables and recommendations. For committee-level recommendation, none of disease type, number of trials, sample size, endpoint type, efficacy, origin of sponsor, type of application, COI of trial author, COI for any committee member, and COI for any committee member with the sponsor were associated with the GIDAC recommending a medication for approval for the proposed indication (Table 5). Additionally, GIDAC membership status, degree, any COI, COI with sponsor, and COI with competitor were not associated with an individual vote of approval (Table 6).

Table 5. Predictors of receiving a GIDAC recommendation.

Variable GIDAC recommendation
OR (95% CI) P value
Disease (inflammatory bowel disease vs. other) 4.91 (0.86–27.88) 0.07
Number of trials (1 vs. >1) 1.25 (0.20–7.75) 0.88
Sample size (<500 vs. ≥500) 0.55 (0.11–2.73) 0.46
Endpoint (clinical vs. surrogate) 2.33 (0.28–19.24) 0.43
Efficacy (primary endpoint achieved vs. not) 3.94 (0.55–28.12) 0.12
Sponsor (US vs. other) 2.72 (0.62–12.04) 0.19
Type of application (new drug vs. biological licensing 0.35 (0.06–1.98) 0.23
COI present for trial corresponding author 4.32 (0.92–20.27) 0.06
COI present for any committee member 0.86 (0.17–4.23) 0.85
COI present for any committee member with sponsor 0.92 (0.22–3.92) 0.914
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GIDAC, Gastrointestinal Drug Advisory Committee; OR, odds ratio.

Table 6. Predictors of votes in favour of approval.

Variable Vote of approval
OR (95% CI) P value
GIDAC membership (chair or standing vs. temporary) 1.50 (0.98–2.30) 0.06
Degree (medical vs. other) 1.03 (0.66–1.59) 0.90
Any COI 1.06 (0.63–1.79) 0.83
COI with sponsor 1.18 (0.56–2.39) 0.66
COI with competitor 0.94 (0.47–1.91) 0.87
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COI, conflict of interest

Discussion

We report the first study to systematically analyze FDA GIDAC meetings using both meeting- and vote-level data. Of the 34 meetings in our sample, we found that the majority of these received recommendations of approval from the both the GIDAC and FDA. Additionally, most proposals involved review of more than one primary study, with a median sample size of 263 and the use of clinical, rather than surrogate outcomes. In terms of COI, approximately 15% of voting members reported industry payments, wherein these payments decreased over time. Finally, we did not find any significant predictors for GIDAC recommendations or individual votes.

There are several findings that warrant discussion. First, the GIDAC recommended approval for 68% of proposals, with the FDA later approving 74% of those same proposals, in keeping with previous analyses highlighting the crucial role of advisory committees in determining approval [1, 4]. Second, the number of studies used to demonstrate efficacy, dichotomised to 1 or >1, was not associated with recommending a medication for approval. This finding is discordant with FDA’s recommendation that two or more well-controlled studies, each convincing on its own, be conducted to demonstrate efficacy [22]. This result may be due to the relatively few patients available for recruitment in the clinical areas certain drugs are aimed at, such as short bowel syndrome, Barrett’s esophagus, and hepatic encephalopathy. Flexibility in methodological requirements for rare diseases has been shown for oncologic drug approvals [23].

One area that merits further exploration is that of COI among GIDAC members. Previous studies have established the high prevalence COI are common in other areas in gastroenterology, with previous studies showing a high prevalence of industry payments related to GI guidelines and point-of-care articles on IBD [15, 24, 25]. In this study, 12 (35%) of 34 meetings had at least one member who had a COI with a sponsor and 33 (6.9%) of 476 votes involved COI with a sponsor. Though the FDA has been criticized for poor oversight and regulation of advisory committee interactions with pharmaceutical companies [26, 27], there have been considerable efforts to curb undue industry influence. Prominent examples include the 2002 revision of FDA disclosure guidelines [28], the 2007 FDA Amendments Act [29], and open-access publication of committee members’ financial ties [30]. The 2002 FDA guideline revision mandated that any voting members who received waivers for COI would need to disclose whether the COI involved the sponsor or competitor of the product being voted on [28]. In the 2007 Amendments Act, the FDA chose to limit the waivers (for COI) granted to only cases where the waiver is necessary to afford the committee essential expertise [29]. Additionally, voting members would generally be disqualified if they, their spouse, or their minor child, had more than $50,000 in financial interests that could affect the meeting, regardless of need for their expertise [29]. Such changes have likely reduced COI burden, as demonstrated by decreasing COI over time among GIDAC members and no COI with sponsors from 2006 onwards.

In addition to a temporal decrease in COI prevalence, the COI that did exist in our study were not associated with pro-sponsor voting in meetings. Two previous studies, however, which evaluated FDA drug advisory meetings from 2001 to 2004 [17] and 1997–2011 respectively, both found an association between COI and pro-sponsor voting [16]. Our results may discordant for two reasons. First, we only included GIDAC meetings. In studies that include all meetings, it is possible that committees that review and approve more drugs, such as the cardiovascular and renal drug committee and the oncologic drug advisory committee [16], can skew the analysis. Additionally, we had an expanded timeline, with meetings spanning from 1998 to 2018. The implementation of policy changes during this time may have mitigated industry influence. Studies with more updated timelines, including an analysis of Oncology Drug Advisory Meetings from 2000 to 2014 [31] and another of COI among all FDA advisory committee members from 2008–2014 [18], showed results similar to ours, in that there were no associations between COI and voting.

We note the study limitations. COI data are based on self-declarations and may be underestimated [32]. Use of a systematically maintained database, such as the Centre for Medicare and Medicaid Services Open Payments Database [33], may identify additional undisclosed COI. We also had a relatively small sample size and imprecision for some analyses, as evidence by several instances of wide confidence intervals. Our analysis was further limited by an inability to evaluate for factors such as rarity of certain diseases and voting member expertise. Finally, our use of dichotomization of predictor variables may have introduced bias into our analysis [34].

Conclusion

The GIDAC reviewed 34 proposals for unique indications from 1998 to 2018. The majority received a recommendation for approval and subsequent approval from the FDA, highlighting the GIDAC’s prominent role in the regulatory process. We did not identify any predictors for meeting-level recommendations or individual votes in favour of approval. COI are present among GIDAC panelists, though they have decreased over time and have not been associated with recommendations or votes. Future studies should include an objective assessment of COI among FDA panelists by using resources such as the Open Payments database and search for predictors of approval in a larger sample of meetings.

Supporting information

S1 Checklist

(DOCX)

Click here for additional data file. (31.7KB, docx)
S1 File. Raw data on drug advisory meeting characteristics, voting member characteristics, and financial conflicts of interest.

(XLSX)

Click here for additional data file. (58.5KB, xlsx)

Abbreviations

FDA

Food and Drug Administration

GIDAC

Gastrointestinal Drug Advisory Committee

GI

gastrointestinal

COI

conflict of interest

USD

United States Dollar

IQR

interquartile range

Data Availability

The data underlying the results presented in the study are available from S1 File as well as on the public domain of the United States Food and Drug Administration Gastrointestinal Drug Advisory Committee site: https://www.fda.gov/advisory-committees/human-drug-advisory-committees/gastrointestinal-drugs-advisory-committee.

Funding Statement

The authors received no specific funding for this work.

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  • 31.Tibau A, Ocana A, Anguera G, Seruga B, Templeton AJ, Barnadas A, et al. Oncologic Drugs Advisory Committee recommendations and approval of cancer drugs by the US Food and Drug Administration. Jama Oncology. 2016;2: 744–750. 10.1001/jamaoncol.2015.6479 [DOI] [PubMed] [Google Scholar]
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Decision Letter 0

Claudio Gentili

10 Feb 2021

PONE-D-20-36649

Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings

PLOS ONE

Dear Dr. Khan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Mar 27 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Claudio Gentili

Academic Editor

PLOS ONE

Journal requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

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We will update your Data Availability statement on your behalf to reflect the information you provide.

3. Thank you for stating the following in the Competing Interests section:

"Rishad Khan has received research grants from AbbVie and Ferring Pharmaceuticals and research funding from Pendopharm. Samir C. Grover has received research grants and personal fees from AbbVie and Ferring Pharmaceuticals, personal fees from Takeda, education grants from Janssen, and has equity in Volo Healthcare. All other authors have no relevant disclosures."

Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to  PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors http://journals.plos.org/plosone/s/competing-interests).  If there are restrictions on sharing of data and/or materials, please state these. Please note that we cannot proceed with consideration of your article until this information has been declared.

Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

Please know it is PLOS ONE policy for corresponding authors to declare, on behalf of all authors, all potential competing interests for the purposes of transparency. PLOS defines a competing interest as anything that interferes with, or could reasonably be perceived as interfering with, the full and objective presentation, peer review, editorial decision-making, or publication of research or non-research articles submitted to one of the journals. Competing interests can be financial or non-financial, professional, or personal. Competing interests can arise in relationship to an organization or another person. Please follow this link to our website for more details on competing interests: http://journals.plos.org/plosone/s/competing-interests

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This manuscript investigates conflict-of-interest among members of the FDA’s Gastrointestinal Drug Advisory Committee and whether that affects how the committee votes. The study is well done and the results are not terribly surprising given the previous work on this topic that has been done recently. That said, this is still a topic that continues to deserve to be investigated.

1.I would suggest that the authors look at the number of COI waivers per meeting to see what percent of the people had a level of conflicts than would normally be allowed and how those people voted? Similarly, given the influence that committee chairs can have over the process, it would be interesting to look at whether the chairs had a COI and how they voted.

2.Were there any committee meetings where a majority of the members had a conflict?

3.The authors should describe what level of COI disqualifies someone from sitting on a committee and give more detail about how those criteria changed with the 2002 revision of the disclosure guidelines and the 2007 FDA amendments.

4.Lines 187-189: I'd like to see a bit more detailed analysis of these numbers, i.e., out of x instances where the advisory committee recommended approval, the FDA approved y but did not approve z. Out of x studies where the committee did not recommend approval the FDA did not approve y but approved z. This could be done in the form of a 2x2 table.

5.How were discrepancies between people who extracted data resolved?

6.Line 157: What was the basis for dichotomizing sample size between <500 and ≥500. Also, I think that for the number of clinical trials the authors mean 1 vs >1, not 1 vs 12.

7.In the Methods under the Sample subheading the authors said that they also looked at votes for whether a medication had demonstrated safety and efficacy and whether a medication had a favorable risk-benefit profile. Were there no votes on these two questions at any of the committee meetings?

8.Why didn't the authors use multiple linear regression to examine whether the various factors that they analyzed determined a negative versus positive vote?

Reviewer #2: The study is a potentially relevant contribution, even if, as the authors acknowledge, there are important limitations, and the scope is somewhat narrow.

My major concern regards data sharing. Indeed, the GIDAC meetings are public, so the raw data are accessible. However, to ensure reproducibility, given that the authors made several coding and extraction decisions, curated datasets of all extracted information from the GIDAC meetings for each application and indication should be included, along with all extracted information about the individual voting members. Synthetically, the readers need to have access to the entirety of the data supporting their findings and be able to re-run the analyses, without necessarily having to extract everything ab novo.

This information should be included as supplementary material, for example in several tables, or deposited in a public repository such as the Open Science Framework.

Another concern is the rationale for dichotomizing all predictor variables, particularly continuous ones like sample size? There are many problems with dichotomization in general, see for example https://www.bmj.com/content/332/7549/1080.1

Also, the statistical significance threshold should be corrected for the multiple comparisons performed.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Joel Lexchin

Reviewer #2: Yes: Ioana Alina Cristea

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 26;16(5):e0252155. doi: 10.1371/journal.pone.0252155.r002

Author response to Decision Letter 0

22 Feb 2021

February 23 2021

Dr. Gentili

Academic Editor, PLOS ONE

Dear Dr. Gentili and the members of the editorial board:

Thank you for considering and giving us the opportunity to revise our manuscript titled “Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings” (PONE-D-20-36649). We would also like to thank the reviewers for their comments. Our responses are below.

EDITOR

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

a. We have made the required formatting changes.

2. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly

a. We have included the data as supplementary file 1.

3. Please confirm that this does not alter your adherence to all PLOS ONE policies on sharing data and materials, by including the following statement: "This does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in our guide for authors. Please include your updated Competing Interests statement in your cover letter; we will change the online submission form on your behalf.

a. We have included this statement in our cover page.

REVIEWER 1

4. I would suggest that the authors look at the number of COI waivers per meeting to see what percent of the people had a level of conflicts than would normally be allowed and how those people voted? Similarly, given the influence that committee chairs can have over the process, it would be interesting to look at whether the chairs had a COI and how they voted.

a. We have stated that all voting members with COI had waivers, and that ten of the chairs had COI. Both of these statements are in the Results section, Conflicts of interest subsection.

5. Were there any committee meetings where a majority of the members had a conflict?

a. There were no meetings where a majority of the members had a conflict.

6. The authors should describe what level of COI disqualifies someone from sitting on a committee and give more detail about how those criteria changed with the 2002 revision of the disclosure guidelines and the 2007 FDA amendments.

a. We have added several details regarding this legislature in the section “Discussion”.

7. Lines 187-189: I'd like to see a bit more detailed analysis of these numbers, i.e., out of x instances where the advisory committee recommended approval, the FDA approved y but did not approve z. Out of x studies where the committee did not recommend approval the FDA did not approve y but approved z. This could be done in the form of a 2x2 table.

a. We have added in a table as suggested, which is now table 2.

8. How were discrepancies between people who extracted data resolved?

a. We have stated that discrepancies were resolved by consensus in the Methods section, Data collection subsection.

9. Line 157: What was the basis for dichotomizing sample size between <500 and ≥500. Also, I think that for the number of clinical trials the authors mean 1 vs >1, not 1 vs 12.

a. We agree that the dichotomization of certain variables could have introduced bias into our analysis, and have listed this as a limitation in the Discussion section.

10. In the Methods under the Sample subheading the authors said that they also looked at votes for whether a medication had demonstrated safety and efficacy and whether a medication had a favorable risk-benefit profile. Were there no votes on these two questions at any of the committee meetings?

a. Meeting members voted on either of the above questions. In the 34 meetings we examined, there were no meetings in which both sets of questions were answered

11. Why didn't the authors use multiple linear regression to examine whether the various factors that they analyzed determined a negative versus positive vote?

a. We did not use multiple regression to avoid overfitting this small data set. We have stated this in the Methods section, Analysis subsection.

REVIEWER 2

12. My major concern regards data sharing. Indeed, the GIDAC meetings are public, so the raw data are accessible. However, to ensure reproducibility, given that the authors made several coding and extraction decisions, curated datasets of all extracted information from the GIDAC meetings for each application and indication should be included, along with all extracted information about the individual voting members. Synthetically, the readers need to have access to the entirety of the data supporting their findings and be able to re-run the analyses, without necessarily having to extract everything ab novo. This information should be included as supplementary material, for example in several tables, or deposited in a public repository such as the Open Science Framework.

a. We have included the data as a supplementary file.

13. Another concern is the rationale for dichotomizing all predictor variables, particularly continuous ones like sample size? There are many problems with dichotomization in general, see for example11/19/15 9:25:00 AM

a. We acknowledge the deficiencies with dichotomizing predictor variables. However, given the relatively small sample size and the likely lack of a normal distribution for the continuous variables, we felt it would be more appropriate to dichotomize the variables. Additionally, we based our dichotomization partially on a similar analysis on oncology drug advisory meetings by Tibau et al. (2016). We have added in statement regarding the limitation on data dichotomization in the Discussion, limitations paragraph.

14. Also, the statistical significance threshold should be corrected for the multiple comparisons performed.

a. We have added in a Bonferroni correction in the Methods section.

Thank you once again for your consideration of this manuscript. We look forward to your review and comments.

Yours sincerely,

Samir C. Grover, MD, MEd, FRCPC

Division of Gastroenterology

St. Michael's Hospital

Attachment

Submitted filename: Response to reviewers.pdf

Click here for additional data file. (180.3KB, pdf)

Decision Letter 1

Claudio Gentili

7 Apr 2021

PONE-D-20-36649R1

Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings

PLOS ONE

Dear Dr. Khan,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 22 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Claudio Gentili

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: (No Response)

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The revisions that the authors have made have dealt with all of my initial comments. There are just some minor copy editing changes that need to be made.

Line 91: Insert “presumed” between “committee’s” and “importance”.

Line 143: It should probably be “trial(s)” rather than “trial”.

Line 165: Do the authors mean >1 instead of 12?

Line 190: The start of this line does not read properly.

Reviewer #2: I cannot access the supplementary file with all the extracted data, but I assume it is an error of the system. Please make sure it is included.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Joel Lexchin

Reviewer #2: Yes: Ioana A. Cristea

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 May 26;16(5):e0252155. doi: 10.1371/journal.pone.0252155.r004

Author response to Decision Letter 1

13 Apr 2021

April 13 2021

Dr. Gentili

Academic Editor, PLOS ONE

Dear Dr. Gentili and the members of the editorial board:

Thank you for considering and giving us the opportunity to revise our manuscript titled “Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings” (PONE-D-20-36649R1). We would also like to thank the reviewers for their comments. Our responses are below.

REVIEWER 1

Line 91: Insert “presumed” between “committee’s” and “importance”.

Line 143: It should probably be “trial(s)” rather than “trial”.

Line 165: Do the authors mean >1 instead of 12?

Line 190: The start of this line does not read properly.

Response: We have made these changes in the manuscript.

REVIEWER 2

I cannot access the supplementary file with all the extracted data, but I assume it is an error of the system. Please make sure it is included.

Response: We have uploaded this file as a supplementary XLS file.

FORMATTING

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Response: We have uploaded new figures after using PACE to ensure PLOS requirements.

Thank you once again for your consideration of this manuscript. We look forward to your review and comments.

Yours sincerely,

Samir C. Grover, MD, MEd, FRCPC

Division of Gastroenterology

St. Michael's Hospital

Decision Letter 2

Claudio Gentili

11 May 2021

Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings

PONE-D-20-36649R2

Dear Dr. Khan,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Claudio Gentili

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Claudio Gentili

14 May 2021

PONE-D-20-36649R2

Characteristics and Conflicts of Interest at Food and Drug Administration Gastrointestinal Drug Advisory Committee Meetings

Dear Dr. Khan:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Professor Claudio Gentili

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Checklist

    (DOCX)

    Click here for additional data file. (31.7KB, docx)
    S1 File. Raw data on drug advisory meeting characteristics, voting member characteristics, and financial conflicts of interest.

    (XLSX)

    Click here for additional data file. (58.5KB, xlsx)
    Attachment

    Submitted filename: Response to reviewers.pdf

    Click here for additional data file. (180.3KB, pdf)

    Data Availability Statement

    The data underlying the results presented in the study are available from S1 File as well as on the public domain of the United States Food and Drug Administration Gastrointestinal Drug Advisory Committee site: https://www.fda.gov/advisory-committees/human-drug-advisory-committees/gastrointestinal-drugs-advisory-committee.

    Articles from PLoS ONE are provided here courtesy of PLOS

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