Financial conflicts of interest during meetings of the cardiovascular and renal drugs advisory committee

Methods

We derived our study methodology from previous work in other fields of medicine, which involved utilizing publicly accessible transcripts from the FDA to explore the prevalence of an FCOI in CRDAC meetings over a 10-year span [6], [7], [8], [9], [10]. Our research did not utilize human subjects, therefore this was not subject to oversight by the Institutional Review Board. Between June 2018 and March 2021, we investigated the publicly available transcripts, and meeting minutes, of all CRDAC meetings (n=31) that occurred between February 2009 and December 2019 (January 2009 was not included because there were no publicly available transcripts archived). We excluded meetings that did not have any public speakers present (n=11). From the meeting minutes, we identified all public speakers and the organizations they represented. We then recorded the following information from each transcript utilizing a pilot-tested Google form: speakers’ names, the organization they represented, whether the speaker reported having the condition for which the drug was indicated, whether the speaker had taken the drug in question, whether the speakers reported an FCOI, and if so, the company name that provided the payments. For speakers with an FCOI, we recorded the type of COI they incurred (Table 1). We then classified the speaker’s statement as positive, neutral, or negative regarding drug approval. Three researchers (CC, HG, NK) extracted this data and classified the statements in an independent, blinded fashion. Consensus meetings were held to resolve any differences found within the data. A third author (MV) was available for third party adjudication but was not needed.

The speaker’s statement regarding each drug was then compared with their reported FCOI or lack thereof. This data set was further stratified by analysis of whether each speaker had the illness that each drug was intended to treat and whether they had received said drug. This study utilized odds ratios, 95% confidence intervals, and significance levels to interpret this information. The data were placed into a Google sheet for gathering, and Stata was utilized for the statistical analysis, utilizing odds ratios to determine significance. An ordered logistic regression was performed utilizing the speaker’s testimony regarding the drug (positive, negative, or neutral) as the dependent variable. The independent variables analyzed include: conflict of interest, whether the speaker has ever taken the drug in question, the number of speakers present at the meeting, meetings with a conflicted speaker present, and whether the speaker had the disease the drug is targeted to treat. Because there was a limited number of neutral responses (n=16), neutral answers were included as “no” answers. Because all speakers who took the drug in question provided positive testimony, we chose to exclude this independent variable from our analysis. In addition, there were no speakers who had taken the drug that did not have the disease, so these two questions were combined into “drug or disease.” All responses were included, even those who reviewed multiple drugs. This was done in part due to the limited sample size, and speakers with multiple testimonies provided variable answers during these meetings.

Lastly, we took a closer look at two specific drugs, Northera (droxidopa) and Kengreal (cangrelor), which both followed the pattern of approval following a second FDA committee review and had an increase in the number of speakers with FCOI present at the second meeting. For these examples, the number of speakers present at both meetings were recorded, along with the number of speakers with an FCOI, and the final committee voting results.

Results

After excluding those meetings with no public speakers, our final sample included 20 CRDAC meetings. There were 88 public speakers during these CRDAC Open Public Hearing sessions held between February 2009 and December 2019, with a mean of 4.4 speakers per meeting (Table 2). Of the 88 speakers represented in our sample, 35 (35/88, 39.8%) disclosed an FCOI (Table 1). The most commonly disclosed FCOI was travel cost associated with attendance at the meetings, which were paid for by either the sponsor or another company (22/35, 62.9%). Furthermore, among the public speakers with an FCOI, 30 (30/35, 85.7%) made positive comments regarding the drug in question, whereas only two (2/35, 5.7%) provided negative testimony. By contrast, only 54.7% (29/53) of public speakers without an FCOI gave positive testimony. Thirty-one speakers (31/88, 35.2%) reported having the condition for which the drug was indicated, and 15 of those with the condition (15/31, 48.4%) reported taking the medication or intervention under review. Among those with the disease, 15 speakers (15/31, 48.4%) reported an FCOI. Of those taking the medication, 15 (15/15, 100%) indicated a positive review of the drug and recommended it for approval. Speakers who indicated having the condition for which the drug was intended to treat overwhelmingly provided a positive recommendation, with 29 (29/31, 93.5%) recommending approval, one (1/31, 3.2%) recommending against approval, and one (1/31, 3.2%) providing a neutral statement.

Speakers who divulged an FCOI were found to be nearly five times more likely to give a positive statement than those who did not disclose an FCOI (OR=5.0, 95% CI 1.7–14.8, p<0.004). In addition, those speakers who had the disease, or had taken the drug, were also more likely to provide a positive testimony (OR=13.1, 95% CI 2.8–59.9, p=0.001), which is consistent with previous work investigating FDA committee meetings (Table 3) [9]. There was no association found between the meeting having a single conflicted speaker present and approval of the drug (OR=2.1, 95% CI 0.3–13.8, p=0.4), or between having multiple speakers present at the meeting and drug approval (OR=1.5, 95% CI 0.2–14.4, p=0.7) (Table 4). An odds ratio could not be performed for comparing the likelihood of providing a positive statement in those who took the drug, vs. those who did not, as all who took the drug provided a positive recommendation.

Of the 20 included CRDAC meetings between February 2009 and December 2019, 11 drugs (11/20, 55.0%) were granted approval of at least some form of recommendation. Of the 11 approved drugs during this time, eight (8/11, 72.7%) had at least one speaker with an FCOI, and seven of those meetings with a speaker having an FCOI (7/8, 87.5%) also had at least one speaker with an FCOI and positive testimony (Table 2). The meetings for drugs such as telmisartan, rivaroxaban, and Northera (droxidopa) had 100% of all speakers with an FCOI provide positive testimony, and garnered approval (Table 2).

In addition, among the drugs under consideration for approval during this time, Northera (droxidopa) and Kengreal (cangrelor) were brought up twice, with approval being granted after the second committee meeting. At the initial meeting for Northera (droxidopa capsules), six (6/10, 60.0%) of speakers had an FCOI, and 100% of the speakers with an FCOI provided positive testimony. The drug was granted conditional approval with 7/13 yes votes. After further studies, Northera (droxidopa) was then brought in front of the CRDAC committee once more, this time with more than twice the number of speakers having an FCOI (13), all 13 of whom provided a positive testimony. This time, the committee voted 16–1 in favor of approval of Northera (droxidopa, Appendix A). Other drugs, like Kengreal (cangrelor), also were brought before the CRDAC committee on more than one occasion. The first meeting had no speakers with an FCOI (n=2 speakers), and the committee voted 0–9 for disapproval of the drug. At the second meeting, a speaker with an FCOI was present and provided positive testimony. This time, Kengreal (cangrelor) was approved with nine votes in favor, two votes against, and one vote abstaining.

Discussion

After systematically analyzing CRDAC meetings that occurred between February 2009 and December 2019, our investigation demonstrated that those with reported FCOIs are nearly five times more likely to provide positive testimony about drugs presented at the CRDAC meetings. Such a substantial variance in positive testimony in those with an FCOI vs. those without becomes particularly vital in circumstances where drugs are garnering approval through a second meeting in which there is an increase in speakers with an FCOI. Most strikingly, our data shows that 85.7% of speakers with an FCOI provided positive testimony, in contrast to just 54.7% of speakers without an FCOI. Likewise, studies in the Oncology Drug Advisory Committee (ODAC), Bone, Reproductive, and Urologic Drugs Advisory Committee (BRUDAC), Pulmonary-Allergy Drugs Advisory Committee (PADAC), and Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) have shown this relationship to be consistent [6], [7], [8], [9, 11, 12]

In addition, even though speakers with an FCOI were found to be nearly five times more likely to provide positive testimony, there was no association found between having a certain number of speakers present at a meeting and drug approval (Appendix B). However, this association becomes a gray area when considering drugs where the committee decision may not be unanimous. By including speakers who may receive financial compensation by virtue of travel reimbursement, grants, or other ways, pharmaceutical companies were much more likely in this study to receive a positive testimony on their behalf. By coupling this with the fact that all speakers who took the drug in question and had an FCOI provided a positive testimony (15/15), public speakers with an FCOI play to the benefit of the drug companies that recruited these speakers (Table 1). This voting behavior particularly plays a role in meetings for drugs with limited evidence or drugs in which 100% of all speakers providing testimony disclose an FCOI.

Overall, more than one-third of public speakers at the CRDAC sessions had an FCOI involving the sponsor of the drug. These individuals with an FCOI were far more likely to support drug approval, and in some instances like Northera (droxidopa), all speakers with an FCOI provided positive testimony. Open Public Hearing speakers provide an important and unique perspective on the drugs or devices in question. However, these valuable perspectives can potentially be compromised by the presence of conflicts of interest. Currently, the FDA does not require an FCOI disclosure for speakers at open public hearings, such as funding for travel, lodging, and meals, along with financial interests in each company such as stock and employment [2, 5]. Drugs such as Northera (droxidopa) and Kengreal (cangrelor) had an increase in speakers with an FCOI in comparison to the first meeting, and there was a drastic sway in the number of committee members voting for approval.

We suggest that CRDAC should require full disclosure of an FCOI instead of simply encouraging it, because this requirement would allow the committee members to consider the possible influence of an FCOI on public speakers’ testimonies, as well as allowing the committee members to focus on the safety and efficacy of the drug in question, instead of the potential bias in testimonies [9]. Although the data available in the public transcripts do not indicate the extent of transparency among public speakers regarding their disclosure, such a requirement as this may help ensure that speakers are more transparent regarding their FCOI and testimonies. We also recommend a randomization to the selection process, such as randomly picked video diaries, in an attempt to limit the amount of influence that these conflicts have on the approval of drugs during the CRDAC meetings, as mentioned by Roberts et al. [10]. Similarly, if speakers decline to disclose their FCOI, there should be limitations on whether they should be allowed to give statements, which have been shown in previous studies examining 379 and 385 meetings, respectively, to have the potential to sway the outcome of drug approval voting [4, 13]. In addition, committee members may also have conflicting interests. A study by Pham-Kanter [4] found that between 1997 and 2011, committee members with an FCOI, with sole interests in the drug or device companies and with products up for vote, were more likely to vote in favor of approval than those with no financial ties (OR=1.5, p=0.03).

Beyond public speaker influence on voting outcomes, previous studies have shown that committee voting members also often have an FCOI with industry [7, 9], [10], [11], [12]. Lurie et al. [5] found in their 2006 study that of the 221 meetings by 16 FDA advisory committees between 2001 and 2004, one or more committee members in over 70% of the meetings (73.0%) disclosed an FCOI. Among those advisory members who disclosed an FCOI, only 1% were asked not to vote or chose to abstain. Among the disclosed conflicts, the most common included consulting, grants or contracts, and personal investments. They found that 19% of consulting conflicts were valued over $10,000, 23% of grants and contracts were for more than $100,000, and 30% of the investments exceeded $25,000 [3, 5].

Furthermore, an analysis by Herder [14] in 2019 noted a trend toward the above management of the drug approval process, in which pharmaceutical companies were provided initial approval of drugs, with the stipulation of additional postmarketing requirements. Herder [14] noted that these postmarketing requirements frequently lack transparency and ultimately may fail to address the questions of most clinical significance [14]. This becomes important when one considers that, despite the flaws noted in the postmarketing requirement process, drugs are often approved when coupled with the trend of increased positive, public testimony at the second hearing. These studies provide further evidence that a more robust process is needed for evaluating the relationships among committee and voting members and their potential conflicts. Transparency and objectivity are paramount when making decisions to recommend approval of new therapies for the public, and such action is needed to address this, and the other concerns, that we have raised in our study.

Conclusions

The process of drug approval through the FDA is highly regulated and specialized into subcommittees based on specific fields of medicine. The CRDAC specifically reviews the safety and efficacy data for cardiovascular and renal drugs. This team of 11 expert, core committee members ultimately will vote for, or against, approval after hearing recommendations from public speakers [1]. Sometimes, additional voting members will also be present. The CRDAC then makes recommendations for approval or disapproval to the Commissioner of Food and Drugs. Public speakers often play a role during these approval meetings, and they may also have an FCOI, with the most common FCOI being related to travel expenses. Our study has shown that speakers with an FCOI are also more likely to provide a positive testimony regarding the drug. Having an FCOI does not prevent these speakers from providing testimony, which may sway voters in favor of approval for a drug that may not have otherwise been approved, due to factors such as limited efficacy or trial data [15]. This research is particularly important for scenarios in which drug evidence may not be as clear or as beneficial. In addition, a large percentage of speakers do not disclose their conflict of interest, and more transparency in the drug approval process will help to ensure that only drugs meeting the correct guidelines will be approved. Although our data showed that there was no statistically significant association found between the meeting having a single conflicted speaker present and approval of the drug, the overwhelmingly positive testimonies given by speakers with an FCOI has the potential to influence committee members’ objectivity. FDA committee members ultimately make independent decisions in spite of situations with overwhelmingly positive testimony; however, an adjustment made to counter the proportion of speakers present at meetings with an FCOI and positive testimonies might help eliminate a confounding variable and prevent excess subjectivity. Further stipulations, such as requiring the disclosure of an FCOI and randomizing the process of selection for speakers, can help to ensure that the integrity of the drug approval process is maintained.