Offit: RotaShield Conflict Of Interest Allegations
Sources
"The First Rotavirus Vaccine and the Politics of Acceptable Risk": [[1]]
What Happened?
Intussusception is an uncommon condition in which a portion of the intestine descends, or telescopes, into a distal segment. Most common among infants in the first year of life, it can result in severe abdominal pain and a risk of intestinal blockage and compromised blood flow to the affected area. If diagnosed promptly, intussusception can often be resolved without surgery. But in severe cases not promptly diagnosed or treated, surgical resection of the affected portion of intestine may be required, and the condition can be fatal.
In the first year of life, the background rate of intussusception hospitalizations in the US has been estimated to be approximately 34 per 100,000 infants - about 1 in 30,000.
Wyeth's "RotaShield" was approved for use as a rotavirus vaccine - but intussusception for 1 in 5,000 was detected post-release. It was pulled from the market. About 100 cases came up during "RotaShield"'s brief licensing carrer that are attributed to the vaccine: 50 operated on, 1 died.
Intussusception was detected among some subject in the pre-licensing trials. Whether this should have caused a delay or rejection of the license is the main factual point at issue.
Offit was a member of the ACIP committee - part of the CDC, and one of the two main bodies making decisions on vaccine approval (the other being the VRBPAC, part of the FDA).
In his capacity as a member of the ACIP committee Offit voted in favour of Rotashield, while developing a rival vaccine - Merck's "RotaTeq".
Nowadays both "RotaTeq" and another rotavirux vaccine, GSK "Rotarix", are in use. They have around 1/10 of the "RotaShield" risk, eg about 1 in 50,000, and this is viewed in health policy as an acceptable risk/reward tradeoff.
Offit has profited to the tune of tens of millions of dollars from his share of the patent rights on "RotaTeq".
What's The Problem?
Offit's vote in favour of RotaShield. There is a conflict of interest if you vote on someone else's vaccine in the same category you're working on - for instance approval for their vaccine can ease the way for approval of yours. This is now not allowed in ACIP procedures.
Was The Wrong Decision Made On RotaShield, Given The Evidence At The Time?
Not according to any official judgements.
The Supreme Court's February 2011 opinion in favor of Wyeth—thereby limiting civil claims against vaccine manufacturers—was viewed as a victory by advocates of vaccination, including the American Academy of Pediatrics and twenty-one other medical organizations that had jointly filed an amicus curiae brief supporting Wyeth's position.
Nevertheless, vaccination in the United States remains a frequent source of controversy, with critics alleging failures by public health officials to adequately identify, monitor, and respond to risks associated with vaccines.
In response to these charges, the RotaShield story is regularly invoked as evidence of the effectiveness of vaccine safety activities in the United States. Synopses similar in approach and scope to the account in the Supreme Court amicus brief can be found throughout the medical literature, in congressional testimony, and in public health planning documents. In each of these tellings, the experience of RotaShield offers a clear, singular lesson: that the systems established to detect and respond to vaccine safety concerns are effective.
What Did People Know At The Time Of Approval?
FDA / VRBPAC
Similar to pharmaceuticals and medical devices, vaccines require approval from the Food and Drug Administration (FDA) in order to be marketed in the United States. The agency's Center for Biologics Evaluation and Research receives guidance in this work from the Vaccines and Related Biological Products Advisory Committee (VRBPAC), a group of experts in vaccine science and related disciplines, as well as representatives from industry and consumer groups.
In December 1997, a nearly twenty-year period of basic and clinical research contributing to the development of RotaShield was concluding, and Wyeth presented the results of this research at a six-hour meeting of VRBPAC in Bethesda, Maryland. Results regarding the efficacy of the vaccine were highly favorable. At its final dosage, the vaccine was 49 to 68 percent efficacious against all rotavirus-related disease and 69 to 91 percent efficacious against severe diarrhea, the cases most likely to result in hospitalization or death. These levels of efficacy were comparable to those of most routinely administered vaccines in the United States. The vaccine's safety profile was similarly positive, limited primarily to minor concerns such as mild fevers observed in some vaccine recipients shortly after administration.
Midway through the day, Dr. Carolyn Hardegree, director of the Office of Vaccines Research and Review at the FDA, asked about cases of intussusception observed during clinical testing. Dr. Margaret Rennels, a professor at the University of Maryland, led the multicenter clinical trial of RotaShield and was a lead presenter on behalf of Wyeth throughout the meeting. Responding to Dr. Hardegree's inquiry, she noted that five cases of intussusception had been found among the recipients of the vaccine, compared with none among the placebo groups. (A single case was later identified in the control group.) The cases occurred following the final two doses of the three-dose vaccination series, but the difference in the rates of intussusception between vaccinees and controls was not statistically significant, due to the size of the study populations.
“I was concerned that with larger numbers perhaps a causal relationship might emerge,” Dr. Rennels told the committee. Asking for five minutes to elaborate on her follow-up work in response to this possibility, she was informed by the committee chair that only “a minute or two maximum” was available. In that time she summarized a literature review regarding estimates of the general frequency of intussusception (known as the “background rate”) and concluded that “the intussusception was probably due to chance temporal association”.
There were no follow-up questions regarding Dr. Rennels's comments on intussusception and no further discussion regarding these data during the remainder of the meeting. The VRBPAC voted unanimously that RotaShield was safe and effective. Upon its licensure by the FDA on August 31, 1998, the following statement was included in the nineteen-page package insert: “Intussusception was noted in 5 of 10,054 (0.05%) vaccine recipients compared to 1 of 4,633 (0.02%) placebo recipients. These rates of intussusception were not statistically significantly different and the rate observed among vaccinees was similar to that seen in comparison populations”. Identical text appeared in the small-print information included in advertisements for RotaShield published in pediatric journals beginning that fall, and a brief report published by Dr. Rennels and colleagues (1998) presented the same findings. Intussusception was not among the adverse reactions listed in an FDA press release issued upon the vaccine's licensure, nor was it among the specific focus areas for postmarketing studies that Wyeth was instructed by the FDA to conduct.
CDC / ACIP
Vaccines are unique among medical interventions because of the equally important role of a second federal agency, the Centers for Disease Control and Prevention (CDC), in contributing to their success or failure. Whereas the FDA licenses vaccines for use in the United States, thereby approving them for marketing, the CDC issues recommendations regarding which populations should receive each licensed vaccine. It does so primarily through the work of its Advisory Committee on Immunization Practices (ACIP), a panel of external advisers that includes members with expertise similar to that of the members of VRBPAC, as well as others with backgrounds in pediatrics and public health practice. A “recommendation” may imply only a modest statement of best practices for the medical and public health communities, but a broad CDC recommendation for a vaccine—an endorsement of its routine administration to all individuals at a certain age—is seen as essential to its medical and commercial success.
While the review by the Food and Drug Administration was taking place, the CDC and the ACIP were developing draft recommendations regarding RotaShield. Their aim was to have guidance available to physicians as soon as possible following the vaccine's increasingly likely approval. The vaccine had been discussed at every meeting of the ACIP for several years preceding its licensure. Information about RotaShield and intussusception was presented to the committee in June 1997, also by Dr. Rennels, and it was reviewed by its rotavirus working group in February 1998. The panel concluded then that the condition was not associated with vaccination, consistent with statements from senior CDC staff that “the safety of the vaccine is fairly well established”. The committee thus voted in favor of recommending routine immunization for all infants with three doses of RotaShield at ages two, four, and six months, pending continued deliberation at subsequent meetings. The discussions at those meetings focused on the cost-effectiveness of rotavirus vaccination programs and potential concerns related to minor fevers among the vaccine's recipients. Intussusception was not revisited.
The ACIP's recommendations become official upon approval by the CDC and publication in its Morbidity and Mortality Weekly Report (MMWR). For RotaShield, these recommendations were still being reviewed and amended at the February 1999 ACIP meeting, and they were not published until March 19, 1999, more than seven months after licensure.
Did Offit Recklessly Approve A Vaccine In His Commercial Interests Despite Knowing Of Dangers?
I don't think the evidence demonstrates any such thing. The VRBPAC approval was based on the same evidence as the ACIP approval.
But clearly the Conflict-Of-Interest policy in the ACIP committee was far from ideal. Presumably the point of ACIP is to act as an independent point of verification. If its COI policy is not optimal, then this carries obvious risks for its effectiveness in this role.
One could certainly say that Offit displayed behaviour typical of general ACIP culture at the time, and that this culture suffered from defects in the strength of its COI policies and policy enforcement.
However many in the vaccine sceptic community would go much further. At its bluntest, the narrative is that Offit knowlingly voted through the RotaShield vaccine, in full knowledge that it carried significant insussusception risk, in order to prepare the way for his own Rotateq vaccine - a market would be created and then the vaccine would be withdrawn, to a huge commercial benefit: Offit has made tens of millions of dollars from his share of the patent rights. This "Age of Autism" article ("Voting Himself Rich: CDC Vaccine Adviser Made $29 Million Or More After Using Role to Create Market") sets out the charges in detail.
Summary
The history of the Wyeth/RotaShield vaccine's approval while Offit was on the ACIP panel is a crucial issue. It is certainly at the heart of disagreements around Offit himself, but I believe that it also operates as a key part of a negative feedback loop that poisons discussion across the pro-vaccine/vaccine-sceptic divide. I will explain why.
The pro-Offit position is that everyone made decisions around Wyeth/RotaShield in good faith, and that the decisions made remain perfectly understandable based on the evidence available at the time the decisions were made, and that there is no evidence to support the notion that there was wrongdoing involved.
I believe that this position is true.
I simultaneously believe that the ACIP process at the time needed improvements to its conflict-of-interest policy. The very fact that people can accuse Offit over RotaShield in the way they do surely proves that there is an issue here. I do not think there is any inconsistency in holding these two beliefs at the same time: you can believe that a COI policy needs improvement, without believing that people in any given situation in fact acted badly.
But Offit's hard-line critics see a very different picture. They see someone who joined the ACIP panel primarily to enrich himself - using the influence of his position to create a vast and open market for his own (Merck/RotaTeq) vaccine by rushing through the approval of a competitor (Wyeth/RotaShield) vaccine with known safety issues. At its strongest, the narrative is that Offit was fully expecting RotaShield to be withdrawn, leaving the pre-established market wide open just as his own vaccine was available to fill the gap. The consequence of this was the suffering of around 100 children, of which 1 actually died and 50 had to have surgery. In return for this, he has profited to the tune of tens of millions of dollars.
In other words, the essential narrative for many of Offit's opponents is that he has killed a child for money - that Paul Offit is literally a baby-murderer.
Everything else in people's views of Offit flows from their interpretation around the RotaShield episode. To call this an "interpretation gap" is a huge understatement: it is a gulf, a chasm. It is impossible to reconcile the views. Offit is a medical researcher who has saved hundreds of lives. He has killed a child for money. He campaigns energetically to save lives in the face of death threats. He schemes endlessly to further his own interests, while children suffer and die as a direct consequence. He is a good man who is doing is best to do good things. He is "the devil's servant" (whale.com).
And standing on the other side of the divide is Offit's dual, the closing half of the feedback loop - Andrew Wakefield. The anti-Offit characterisation is echoed in many of the accusations that are flung at Andrew Wakefield by the more intemperate pro-vaccine parties. Truly, many from each side honestly believe that the other side's prophet is a baby-murderer. This is such a deeply unpleasant thing to consider that the more decent among those on each side rarely articulate it openly - they don't even like to call the thought fully to mind - but the thought is there on both sides all the same.
Both Offit and Wakefield give a lot of speeches, but they don't use this kind of rhetoric directly about their opposite number, and there is a good reason for this. It is a deeply primal, a tremendously powerful thing to accuse someone of being a baby-murderer - there is so much energy to be tapped from the sense of revulsion that results. But it never ends well, because the energy is diseased, tainted at its source. Once you believe someone is a baby-murderer it is hard to even think of them as fully human. Discussion turns ugly even if the underlying accusation is never fully brought to the surface - the unspoken thought poisons everything that it touches, killing respect and goodwill.
More generally, it is healthy for all of us to reject accusations like this wherever they crop up, whoever they are aimed at. No monsters here - only us.