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The Offit Index: Tracking a Patent Owner’s Ongoing Financial Interest in One Vaccine’s Sales

Posted Jan 05 2011 12:00am
Baby bottom By Mark Blaxill

Vaccine developer Paul Offit has just published a new book, Deadly Choices, in which he turns up the volume and the rhetoric against what he likes to call “the anti-vaccine movement.” His target, he argues, has launched a dangerous assault on the public health, and its misguided disciples are everywhere, including people like you and me. Based on the advance description, I don’t plan on boosting his sales.

But my friend and colleague Dan Olmsted has read it and wrote about it  HERE . Dan found the tone mean-spirited and describes Offit’s work as “a score-settling screed against anyone who's ever criticized him or vaccine safety surveillance.” Offit isn’t alone in his name calling, it seems the public relations mavens of the medical industry have been working overtime to pin the “anti-vaccine” label to anyone they can find. The reality, however, is that the movement Offit and his industry cronies criticize so ruthlessly is really a grass-roots consumer movement, concerned about the health of children, distrustful of the “public-private partnership” that has emerged with the vaccine industry and its regulators, and is speaking out with increasing force for long-overdue improvements in vaccine safety management. This movement is good for children’s health, but not for the vaccine industry’s profits, which is why the propaganda is escalating. In his new book, Offit takes the hate speech to a new level, asking all Americans to fear this diverse community of concerned consumers because, “the anti-vaccine movement threatens us all.

Even for Offit, this new book is an escalation. He has written three books before this one, What Every Parent Should Know About Vaccines  (a standard “vaccines are always safe” propaganda piece published in 1998), The Cutter Incident (a revisionist history of one of the great breakdowns of vaccine safety, in which he offers the bizarre complaint in 2005 that fear of litigation was driving vaccine manufacturers away from the industry, even as industry revenues and profits were exploding like never before) and Autism’s False Prophets (a 2008 attack on the autism parent community for raising concerns over vaccine safety). The thread in Offit’s writing is clear, making the world safe for vaccine manufacturers.  But why would a man like Offit, so obviously concerned for his public reputation, get down and dirty on vaccine safety advocates, parents like Barbara Loe Fisher, Jenny McCarthy and our own J.B. Handley? One possible answer is the simplest one of all.

They’re costing him money.

By my count, close to $1.5 million dollars so far and rising.  That’s the cumulative sum of royalty income due to the relatively weak performance (as compared to the industry leader, Prevnar) of his patented Rotateq vaccine.

Counting Offit’s Millions.

About a year ago, Dan Olmsted and I reported in considerable detail on Offit’s financial stake in Rotateq (see  HERE ). We demonstrated that he has already made over $10 million and stands to gain much more if Rotateq is commercially successful.

But exactly how much more?

One benchmark for Offit’s Rotateq royalty earnings is Pfizer’s Prevnar vaccine, which protects against certain strains of strep bacteria. In commercial terms, Prevnar, which was introduced by Wyeth in 2000, is the most successful vaccine ever launched. In its tenth year it reached roughly $3 billion in worldwide revenues and is on a pace to exceed $3.5 billion in 2010. For any vaccine developer looking to maximize profits, Prevnar sets the standard. It was adopted rapidly, both in the United States and globally; it has no competitors in its category; with the exception of one episode of supply problems in 2003, its growth has been continuous; and its history has been remarkably free of any reputation problems due to safety concerns.

Using Prevnar’s commercial history, one can assess Rotateq’s sales performance in the period since its introduction in 2006. Setting “year one” the same for both vaccines, (Prevnar was approved in February 2000, Rotateq in March 2006), the chart below compare the annual worldwide revenues, showing clearly how Rotateq has already fallen behind Prevnar in its five years on the market (I projected 2010 revenues for both products by assuming fourth quarter revenues in 2010 were unchanged from last year and added that estimate to reported revenues for the first three quarters).

Rotateq adoption gap  
Clearly, Rotateq has a significant and rising adoption gap when benchmarked against Prevnar. There are two major reasons for that. Unlike Prevnar, Rotateq has a competitor in its category, GlaxoSmithKline’s Rotarix. But Rotarix has so far made few inroads in the US, the largest single market for any vaccine. Rotateq’s largest problem has been in international markets, where Rotarix has outperformed Merck’s offering.

But competition doesn’t explain Rotateq’s declining sales. The rotavirus vaccine category as a whole has been struggling for the last two years. Perhaps that is because diarrhea avoidance isn’t quite as compelling a value proposition in advanced markets as a vaccine that protects against rare but sometimes fatal cases of meningitis. Another reason underlying weak uptake of rotavirus vaccines is that they have long been plagued with a poor reputation for safety. These concerns go back to 1999, when an early Rotateq competitor called Rotashield was introduced and then “voluntarily withdrawn” from the market over a potentially fatal condition called intussusception (intussusception occurs when one portion of the intestine becomes inverted and telescopes within the next). When Rotashield hit the US market in 1998, a rash of intussusception reports led to its withdrawal just a year later. More recently, rotavirus vaccines have been plagued with additional safety problems, with revelations last year of contamination of both Rotarix and Rotateq with strains of pig viruses.

The Rotateq adoption gap is no academic matter for Offit; these  lost revenues have a direct impact on his pocketbook. In our analysis, “Counting Offit’s Millions” Dan Olmsted and I estimated that Wistar Institute’s deal with Paul Capital gave Offit a royalty interest amounting to an eighth of a cent on every dollar of Rotateq sales above $300 million. If Rotateq were to sell like Prevnar, Offit would stand to make well over $1 million in royalty payments this year and over $3 million in 2015. But if Rotateq’s sales continue to struggle, as they have so far, his royalty checks can drop into the low six figures. Perhaps even to zero if demand for the vaccine collapses and worldwide revenues fall below $300 million.

In order to illustrate the dynamic nature of Offit’s financial interests, I’ve constructed a simple model that I’ve christened The Offit Index. It has two elements. The first is the dollar amount of what I’ve called the “Rotateq adoption gap,” more precisely, worldwide Rotateq revenue minus the worldwide Prevnar revenue for a comparable year after launch (for simplicity’s sake, I’ve not adjusted for inflation, which would make the gap larger). The second element (see the red bars below) multiples each year’s gap by Offit’s royalty stake (an eighth of a cent per dollar of sales above $300 million) and then sums all the lost royalty income to develop a cumulative cost to Offit. Year 5 in the chart below includes all of Offit’s lost royalty income through 2010.

Offit Index  
As you can see, Rotateq’s failure to keep pace with Prevnar puts Offit about $1.4 million in the hole so far, with prospects for many millions more if current trends continue. 

The Offit Index measures something very personal for the author of Deadly Choices. It shows why he might be so unhappy with the vaccine safety movement, or at the very least why he continues to escalate his personal attacks on parents. After all, if a group of people were costing you millions of dollars, wouldn’t you be angry with them too?

Prevnar is the value standard, but who captures the value?

The Offit Index gave me an opportunity to reflect a bit on the dissonances that can emerge between private and public value. The case for the public value of Prevnar relies on its ability to prevent several form of invasive pneumococcal diseases (IPD), especially pneumonia and meningitis, caused by streptococcus pneumoniae. IPD is a serious and occasionally fatal disease, more common in children than adults, but more dangerous for the elderly. Before Prevnar was introduced in the US, CDC surveillance estimated that IPD occurred at a rate of 9.5 per 10,000 in children under five, with a mortality rate of about 1%; among adults over 65 years old, IPD rates were 6.2 per 10,000 but with a mortality rate of 23%. (Hicks et al 07) The case for Wyeth and Pfizer to reap billions in profit from this vaccine rests exclusively on Prevnar’s success in reducing the human toll of IPD.

From a public health perspective, the early returns on Prevnar were full of hope and optimism. After just a few years in the American market, initial studies of Prevnar’s impact (see Hicks et al 2007 and Hsu et al 2005) reported reductions of more than 60% in IPD cases and hospitalizations in children by 2004. But even though most studies emphasized Prevnar’s successes, this early optimism was tempered in the most comprehensive investigation, one that covered a population of 19 million people in and around 8 major cities. The study found that “the overall mortality rate among children did not change during the study period” (remaining constant at about six deaths per million children) and adult mortality decreased only slightly (Hicks et al, 2007).

The reason? Wyeth’s vaccine was proving effective at reducing IPD and associated mortality from the 7 strains of bacteria in Prevnar, but because streptococcus pneumoniae comes in many different forms, it appeared that suppression of the strains in Prevnar 7 might be promoting the survival of different pneumococcal strains.  Even worse, these surviving strains might prove to be more virulent than the strains they replaced.

Sadly, recent studies in Dallas (Techasaensiri et al, 2010), Cleveland (Jacobs et al, 2008) and Massachusetts (Hsu et al, 2010) have shown that this is exactly what happened. Dallas rates of IPD in children fell by more than half from 1998 to 2003, but as the non-vaccine strains emerged, the overall IPD rate began increasing and reached three quarters of the pre-Prevnar rate by 2008. The Cleveland study showed explosive growth rates, from 100% to as high as 900%, in the non-vaccine strains over a seven year period. In Massachusetts, the increase in IPD from non-vaccine strains completely cancelled out the reduction in IPD from vaccine strains between 2001 and 2007, with eight deaths resulting from these non-vaccine strains (which were often antibiotic resistant) and a case fatality rate of over 3% in infants.

The remarkable conclusion of these studies was never to question the wisdom of the policy to begin with (did we really need to spend billions on a Wyeth vaccine that didn’t reduce deaths in children and only temporarily reduced IPD cases?), but rather to increase the number of the streptococcus pneumonia strains contained in the vaccine. Instead of seven strains, a larger combination of “serotypes” would be needed: maybe ten, maybe thirteen, maybe more, out of a population of as many as forty known varieties.

So now we have Prevnar 13, approved by the FDA in February 24, 2010. And despite the marginal public value of the original vaccine, Wyeth’s commercial momentum never skipped a beat. From 2000 through 2010, Wyeth’s sales of Prevnar 7 added up to over $15 billion. This success paid huge dividends to Wyeth’s shareholders. When Pfizer acquired Wyeth in late 2009, they paid $68 billion. A large portion of that acquisition price was due to Prevnar, Wyeth’s #3 brand behind Effexor and Enbrel. In early 2010, Pfizer launched the new Prevnar 13 vaccine and it appears that the Prevnar brand is on track for its biggest year ever, easily topping $3 billion in sales. After fourth quarter results are in, it seems likely that Prevnar 13 will garner over $2 billion in revenue in its first year as Pfizer phases out Prevnar 7.

For a vaccine that one large population study showed had no life-saving benefits for children, isn’t that a lot of money to provide to a private corporation in a mandated government program? No one in the public health establishment seems to have asked that question.

The prospects for Rotateq

Offit and his partner Merck would certainly love to model Rotateq after Prevnar’s success, but from the beginning rotavirus vaccines have been plagued with problems. The benefits of preventing rotavirus infection have been harder to sell to both parents and pediatricians. Death from meningitis is one thing, a little baby diarrhea is another, especially in an advanced country like the US. Despite the marginal public benefits of rotavirus prevention, the CDC has consistently approved new vaccines in the category. The real obstacle to Rotateq’s success is that safety concerns have plagued the rotavirus vaccines since the first vaccine in the category was introduced.

This concern over safety would certainly help explain Offit’s publishing behavior. If safety is an obstacle to profit, why not fight back? Call the vaccine safety movement names. Call them “anti-vaccine.” And marginalize them as a movement “that threatens us all.”

But while propaganda missives might create some air cover for Rotateq, there’s still the more difficult problem of explaining away the individuals who develop adverse reactions from Rotateq. For rotavirus vaccines, intussusception has been a particularly thorny safety problem. The first rotavirus vaccine ever developed came from Prevnar’s developer, Wyeth. Wyeth’s vaccine, Rotashield was introduced in August 1998 but then abruptly pulled from the market little over a year later due to concerns over intussusception.

Offit sat on the advisory committee that in October 1999 made the decision to withdraw Rotashield. He recused himself from this vote, although he participated in the discussion, remarking, "I'm not conflicted with Wyeth, but because I consult with Merck on the development of rotavirus vaccine, I would still prefer to abstain because it creates a perception of conflict.” The commercial reality was more than a perception, and in the case of the Rotashield vote the decision to withdraw gave Offit a huge financial benefit. Because when Rotateq came to market in 2006, it had no competition and instantly took on the lead position in the rotavirus vaccine market. Rotateq’s introduction came with hopes that it would be a safer vaccine than Rotashield and it has managed so far to preserve that reputation, effectively deflecting any association with the intussusception problems that killed Rotashield. Offit has been a key part of building that reputation: in 2001, he was advancing a “unique strain” hypothesis in CDC deliberations, an argument that RotaShield was formulated in a way that did increase intussusception risk whereas other formulations (e.g. Rotateq) did not.

But are rotavirus vaccines really safe? Based on reports of intussusception to the Vaccine Adverse Event Reporting System (commonly known as VAERS, a passive surveillance system that captures only a fraction of real adverse events), the relationship between these adverse events and the introduction rotavirus vaccine, including Rotateq, couldn’t be much clearer. As the chart below demonstrates, when rotavirus vaccines have been on the market, these events have spiked, when they have been suspended or unavailable, the number of adverse events are essentially zero.

Rotavirus vaccines drive int events  
Rotavirus vaccines are listed in 95% of the 1,168 intussusception reports filed in VAERS since 1988. Of these, over 60% specifically identify Rotateq (of the remainder, Rotarix accounts for 26% and Rotashield 11%). Interestingly, whereas just a little over 100 reports of intussusception led to Rotashield’s withdrawal, nearly 700 reports of intussusception following Rotateq administration have not had the same effect. In contrast to its Rotashield decision, the CDC rose to Rotateq’s defense, claiming in a 2008 report that “the observed rate of intussusception was not higher than the age-adjusted background rate of intussusception” (Haber et al, 2008)

Intussusception is a dangerous and occasionally fatal complication of vaccination but it is not the only deadly adverse event associated with Rotateq. VAERS lists 175 deaths since 2006 with Rotateq among the listed vaccines. Of these reported deaths, six were listed with intussusception as a symptom, usually as the cause of death (scroll down past the end of this essay to read these six VAERS reports).

In a further safety problem for the rotavirus vaccine category, the FDA announced on March 22, 2010 that Rotarix would be suspended in the US after tests showed that the GlaxoSmithKline vaccine was contaminated with porcine circovirus type 1 (PCV 1). Then, in May the FDA announced that subsequent tests had shown that Merck’s Rotateq vaccine was contaminated as well, not just with PCV1 but also with another, potentially more dangerous, porcine circovirus called PCV type 2. Faced with the choice of suspending both approved rotavirus vaccines or accepting the risk that porcine circoviruses might be unsafe, the FDA chose the latter course and removed its Rotarix suspension, allowing both Rotateq and Rotarix to remain on the market, PCVs and all.

The commercial impact of the PCV problem is not yet clear, since fourth quarter revenues haven’t yet been announced. However, following the March FDA announcement, Rotarix quarterly 2010 sales were down by 43% relative to the second and third quarter sales in 2009. By contrast, Rotateq’s second quarter revenues rose in 2010, due in part to Rotarix’s suspension, but after the May announcement of Rotateq’s contamination with both PCV1 and PCV2, Rotateq’s third quarter sales were off 6%.

Any way you slice it, none of these safety problems--neither the recurring drumbeat of hospitalizations and deaths from intussusception nor the media coverage of pig virus contaminants--can be good for business. And every bit of bad news takes money directly out of Paul Offit’s pocket, reinforcing his frustration with vaccine safety advocates. Still, the long term commercial impact on Rotateq’s profits of all these safety concerns remains unknown.

And Offit's royalty income stream remains unknown as well. We’ll be following Merck’s quarterly earnings reports in the months and years ahead, calculating the Rotateq adoption gap over time and updating The Offit Index as the data comes in.

Mark Blaxill is Editor-at-Large of Age of Autism and co-author with Dan Olmsted of the new book, The Age of Autism: Mercury, Medicine and a Manmade Epidemic.

References:

1. Hicks LA, Harrison LH, Flannery B, Hadler JL, Schaffner W, Craig AS, Jackson D, Thomas A, Beall B, Lynfield R, Reingold A, Farley MM, Whitney CG. Incidence of pneumococcal disease due to non-pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998-2004. J Infect Dis. 2007;196(9):1346-54.

2. Hsu K, Pelton S, Karumuri S, Heisey-Grove D, Klein J; Massachusetts Department of Public Health Epidemiologists. Population-based surveillance for childhood invasive pneumococcal disease in the era of conjugate vaccine. Pediatr Infect Dis J. 2005;24(1):17-23.

3. Jacobs MR, Good CE, Bajaksouzian S, Windau AR. Emergence of Streptococcus pneumoniae serotypes 19A, 6C, and 22F and serogroup 15 in Cleveland, Ohio, in relation to introduction of the protein-conjugated pneumococcal vaccine. Clin Infect Dis. 2008;47(11):1388-95.

4. Hsu KK, Shea KM, Stevenson AE, Pelton SI; Massachusetts Department of Public Health. Changing serotypes causing childhood invasive pneumococcal disease: Massachusetts, 2001-2007. Pediatr Infect Dis J. 2010;29(4):289-93.

5. Haber P, Patel M, Izurieta HS, Baggs J, Gargiullo P, Weintraub E, Cortese M, Braun MM, Belongia EA, Miller E, Ball R, Iskander J, Parashar UD. Postlicensure monitoring of intussusception after RotaTeq vaccination in the United States, February 1, 2006, to September 25, 2007. Pediatrics. 2008;121(6):1206-12

VAERS reports of death listing intussusceptions as a symptom and death as the outcome 

Death #1: Location not reported

 

 

Write-up: Information has been received from a health professional concerning a 4 month old female with a history of diarrhoea and malnutrition who on 03-NOV-2006 was vaccinated with Rotateq. There was no concomitant medication. On approximately 27-NOV-2006 the patient experienced intussusception, crying, hematochezia and vomiting and was hospitalized. The reporter felt that intussusception, crying, hematochezia and vomiting were not related to therapy with Rotateq. Patient died on 27-NOV-06. Additional information is not expected.

Death #2: Oklahoma

 

 

Write-up: Pt. expired 3 days after ck-up. Parents reportedly found child dead in bed. 6/20/08 Autopsy states COD as SIDS. Report states pathological diagnosis as patent foramen ovale; lungs w/congestion & atelectasis; small bowel [intussusception]; GERD. Found unresponsive in bassinet after being placed prone approx 5 hrs earlier. CPR initiated 1/4/08 Reviewed pcp medical records & vax records which confirms vax as reported. Records indicate patient in good health on day of vax, only concern was constipation & formula changed.

Death #3: Connecticut

 

 

Write-up: Information has been received from a physician concerning an approximately 5 month old male with a history of "reflux" who in approximately October 2007, was vaccinated orally with a second dose of Rotateq. Two weeks post vaccination, on 08 NOV 2007, the patient was seen "in the office" at which time the patient was "congested with on an off vomiting". The patient presented with "a good bowel movement" and was given amoxicillin and sent home. Approximately 16 hours later the patient was taken to the emergency room (ER). "The child passed away on 10 NOV 2007". The patient''s status was not recovered. The reported cause of death was "necrotic bowel". The adverse events reported were considered to be, Disabling, immediately life threatening by the reporter. Additional information has been requested. 1/25/08 Received vax record which reveal patient also received Pediarix #2 AC21B133AA, Hib #2 Merck lot # 0436U, Prevnar #2 B54007H & Rotateq #2 0670U.. 1/29/08 Reviewed ER medical records of 11/9/07 which reveal patient arrived in cardiopulmonary arrest having been brought to hospital by parent. Had voided & had bloody stool, possibly vomited & had been lethargic prior to coding. Was in severe acidosis, shock, dehydration, hypercarbia, arrhythmia, infection. Resuscitated & transferred to higher level of care ER. FINAL Initial ER DX: abdominal castrophe; respiratory/cardiac arrest; and septic shock. 2/1/08 Reviewed hospital med records which reveal patient transferred from outlying hospital in critical shock condition. Admitted 11/9-11/10/2007 to ICU. Had 36 hour hx of poor feeding, increased crying & developed bilious emesis & bloody stools. Intubated & emergent laparotomy & ileocecectomy was performed in ICU. Finding at surgery: [intussusception] extending to hepatic flexure w/small area of necrosis in cecum & entire small bowel w/diffusely involved ischemia thought likely secondary to shock & cardiac arrest. Bowel remained dusky at end of procedure & abdomen left open w/bowel wrapped in order to visulize recovery. Develop

Death #4: Illinois

 

 

Write-up: Patient found unresponsive in crib by parents. No symptoms prior - autopsy revealed intussusception. Pronounced dead at ER. 1/23/09 Autopsy report states COD as complications of intussusception. Also states: six areas of IS of small intestine; changes of distant intestine present; early pneumonia; inflammation of lung tissue & small airways. Patient had been found unresponsive in crib after recent history of cold like symptoms with fever.

Death #5: Location not reported

 

 

Write-up: Information has been received from a physician concerning a 19 week old female with malnutrition and a history of lice infestation, scabies infestation and vaccination BCG on 21-Aug-08 who on 24-Oct-2008 received first vaccination of ROTATEQ and second vaccination on 22-Dec-2008. Concomitant vaccine therapy included the first and second doses of PENTAVALENTE and polio given on 24-Oct-08 and 22-Dec-08. On 08-Jan-2009 the patient died. The cause of death was intussusception. Infant started vomiting and nauseas within the 5 previous days (#5 a day) before visiting the hospital. Treated with oral rehydration solution at health care center two days before. Signs and symptoms registered: Diarrhea with mucus, green-colored, no blood (however mother referred bloody stools), twice a day, no abdominal pain. Treated with laxatives by non-medical personnel. Clinical symptoms remained the same for 2 days, then starts fever. Physical Evaluation: FC 160x FR 48 t 39 height 62 cm. Hypoactive, lethargic, dehydration signs, with fever, pale and showing sign of capillary fragility. Capillary refill 4 seconds; abdominal distention = 42 cm, no mass or abdominal pain. Rectum and anus: normal. On January 2009 (day unknown) patient required surgery for intestinal necrosis ileo-colic section. Surgeon stated an intestinal invagination probably associated to congenital malformation of the intestine. Additional information has been request.

Death #6: Illinois

 

 

Write-up: Intussusception (ileo-cecal) requiring bowel resection. 5/19/09-records received for DOS 1/2/09 and 3/5/09 -clinic notes for follow-up-3/13/09-seen in clinic after presenting to ED with large bloody stools times 2 days, developed respiratory distress. Transfusions. Intubated. PICU. Impression: rectal bleeding, DIC, leukocytosis. 5/21/09-operative report received for DOS 3/13/09-exploratory laparotomy with right hemicolectomy and ileocolostomy. DX: Intussusception. Presented with C/O abdominal tenderness and distended abdomen, rectal bleeding. Post operatively developed ARDS, ventialtor dependent. Subsequent surgery 5/7/09 Median sternotomy, PDA ligation, pulmonary artery banding, insertion of right femoral arterial line. 5/12/09-subsequent surgery for closure of sternal wound. Failure to wean from ventilator. 8/11/09 Hospital DC summary, ICD-9 codes received DOS 3/11/09 to 7/5/09. Assessment: Intussusception status post bowel resection, ischemic colitis - septic shock, multi organ system dysfunction. Additional clinical data abstracted: 5/28/09 Continued fever. Signs of sepsis. Parental decision to withdraw care on 7/5/09. Patient expired on 7/5/09. ICD-9 Codes: 786.05 Shortness of breath, 560.0 Intussusception, 286.6 Defibrination syndrome, 557.0 Acute vascular insufficiency of intestine, 785.52 Septic shock, 569.83 Perforation of intestine, 038.49 Septicemia due to gram-negative organism, 038.43 Septicemia due to Pseudomonas, 518.5 Pulmonary insufficiency following trauma and surgery, 745.69 Endocardial cushion defect, 747.0 Patent ductus arteriousus, 238.79 Neoplasm of uncertain behavior of other lymphatic and hematopoietic tissue, 995.92 Severe sepsis, 599.0 Urinary tract infection site not specified, 758.0 Down''s syndrome, 427.5 Cardiac arrest.

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