Project management ( Heparin: A Global Medicinal Disaster ) case study

Project Management

LYMERIX: AN UNFORTUNATE END THAT COULD HAVE BEEN AVOIDED

Lyme disease…

Lyme disease was first acknowledged in 1977 in Lyme, Connecticut, when different clusters of the town’s residents came down with cases of juvenile rheumatoid arthritis. At first, it was thought to be derived from an autoimmune disease, but that did not explain the vast outbreaks of rheumatoid arthritis continuing to pop up in abnormally young populations throughout the northeastern United States. Finally, researchers were able to identify the previously unrecognized source: the nasty, little, bacterial spirochete known as Borrelia burgdorferi. The disease is spread by Ixodes Scapularis, more commonly known as the deer tick, whose natural host is mice and deer (1).

The transmission of the bacteria to the human host occurs over several hours when the deer tick bites and remains attached. Most often, the deer tick goes unnoticed on the human due to its near microscopic size, and is left uninterrupted to transmit the bacteria. The only known indication of the disease is the unmistakable bull’s eye type rash that develops around the bite site several days or weeks after the host has been bitten. Upon being diagnosed with Lyme disease, long doses of antibiotics are prescribed. If the Lyme infection is left untreated, a variety of flu like symptoms will often develop in addition to Bell’s palsy and other neurological symptoms. In about 60% of the patients, chronic arthritis often develops (2). It is common even after treatment for the patient to exhibit periodic “flare ups” of symptoms for months or years. Every year well over 20,000 cases of Lyme disease are reported, and even as much as three times as more go unnoticed (2).

The story of LYMErix…

In 1990s, an outer-surface, 31 kDa, lipoprotein known as OspA on the B. burgdorferi was found. Although it was shown to be highly variable, it was considered to be a promising candidate for vaccination studies (1, 3). SmithKlineBeecham took the consensus sequence of OspA and developed a Lyme disease vaccination that used a recombinant OspA as their immunogen, and called it LYMErix (1). Recombinant OspA, when expressed in E. coli cells and subsequently injected into mice in preclinical studies, protected against Lyme disease; therefore, it was considered to be a highly, promising candidate for vaccination (1-3). Immunization was shown to be antibody driven, and offered protection from heterogeneous B. burgdorferi driving its candidacy as a vaccine (3). In a safety and efficacy trial in humans conducted by the University of New Mexico’s school of medicine, recombinant OspA was shown to be safe and effective. The trial was randomized, double blinded, and placebo controlled. The participants received two or three doses of the vaccine, and they were followed for one year after the final dose (1,4). The only side effects or adverse events that were reported were pain and tenderness at the injection site, which subsided after three days (4). When LYMErix underwent a similar, larger phase III, clinical trial with 10,906 subjects, in an endemic area, 76% of vaccinated individuals exhibited a reduction in Lyme disease after a year with no significant side effects shown (1). As a result, the FDA approved the three dose LYMErix vaccine for Lyme disease in December 1998 (1).

The issues arise…

As soon as the FDA approved LYMErix for marketing questions about its development began to arise. As pointed out in the review article, The Lyme Vaccine: a cautionary tale there were four major problems contributing to its market withdrawal in 2002 (1). First, the vaccine was only efficacious for 76% of the vaccinated individuals, which meant close to a quarter of the vaccinated individuals would not receive any benefit. Second, in order to maintain the titer for a year the vaccine had to be given in three doses over a course throughout a year. There were questions about the long efficacy of the vaccine, such as how often a booster would be needed (1,3), which in turn, brought up questions about the cost effectiveness of the vaccine. Third, SmithKlineBeecham never conducted studies in children: the most at risk population for Lyme disease. Fourth, LYMErix was only effective against the North American strain of B. burgdorferi eliminating the international market. Despite being aware of these issues, SmithKlineBeecham went forward with the launch.

The public view…

Lyme disease became a “hot topic” as did the LYMErix vaccine. LYMErix benefits were the main emphasis in advertisements with little regard for its potential side or long term effects. The media encouraged the public to speak to their physicians if they lived in a high prevalence area. Between 1998 and 2000 more than 1.4 million doses of the LYMErix vaccine were distributed in the United States, a mere fraction of the total number of flu vaccinations distributed every year (5).

The “glory days” for LYMErix were short lived. In the early 1990s the FDA created the Vaccine Adverse Event Reporting System (VAERS) as a way to keep post licensure surveillance of vaccines. According to the VAERS, 905 adverse events were reported during the two year time span. Of the 905 adverse events, 7.4% reported events were deemed serious, requiring hospitalization; however, these events were not necessarily caused by the vaccine, and were considered to be not significant by both the FDA and SmithKlineBeecham (5). The majority (56%) of the adverse events were the typical associated vaccine redness, swelling at the injection sites, and flu like symptoms not lasting longer than three days (5). Among these events there were also 59 reported cases of arthritis that developed within 30 days after the vaccination. There were 49 cases of arthritis were reported in the placebo recipients (6). These results translate to a reported cumulative arthritic incidence of 333 per 100,000 doses in vaccine recipients and 308 per 100,000 doses in placebo recipients (6). Since arthritis was considered to be an adverse event, it received significant attention; although, the reported cases were lower than in the estimated background population the cases were not considered to be out of the ordinary. If only half of the 1.4 million doses of LYMErix were administered, it would be expected that at least 2000 individuals would have reported arthritis. Approximately the same number of the placebo recipients would have also developed arthritis (6). Thus the number (59) reported to VAERS was far below the expected incidence rate in the background (6). Also, there was no temporal association found between the administration of LYMErix and the onset of the symptoms (5). The FDA had no reason to deem the LYMErix unsafe; however, the media refused to let the adverse events go, and hunted down these “vaccine victims” putting a human face to suffering (1).

Despite the supporting evidence that LYMErix was safe, the media focuses its attention on the fact that there were serious adverse symptoms associated with the vaccine. Lyme disease public action groups were soon publicizing the controversy. As a result, more and more allegations began to surface that were unreported adverse events associated with LYMErix (1, 5). The media began to question the credentials of physicians. Collectively this caused a public uproar leading to a class action suit against SmithKlineBeecham in December of 1999 (5). The suit claimed that LYMErix caused harmful side effects, and the SmithKlineBeecham withheld information about its potential risk (1).

FDA’s response…

With all the negative press coverage and allegations around LYMErix, the FDA was obligated to take action. The FDA reexamined the phase III clinical trial that lead to licensure. Upon examination it was found significantly more vaccine recipients than controls had minor side effects associated with all immunizations (1). Most of the side effects occurred within 48 hours of injection and were gone within a week without any treatment. The FDA followed the participants for year and concluded there were no more arthritic symptoms than in the control group (1). There were no apparent short adverse events that the FDA found justifiable to revoke licensure; although, the long term side effects remained unknown.

SmithKlineBeecham’s response…

With the rising accusations, SmithKlineBeecham launched a post licensure safety and efficacy case control study trial. Initially, they were planning on following the patients over a four year period and enrolling 25,000 LYMErix recipients and another 75,000 to serve as controls; however, due to a lower than expected recipient population, the study was only conducted for a two year time span and enrolled only 10% of what SmithKlineBeecham had anticipated (1). The results were still consistent with the prior trials; there were no significant adverse events to support the allegations.

Around the same time of SmithKlineBeecham’s post licensure trial researchers began to develop a better understanding of Lyme disease. It was found that people who genotypically expressed human leukocyte associated antigen DR4+ after being infected with Lyme disease had a greater chance of developing chronic arthritis (1). These patients produced a high level of autoantibody to OspA in their joints. These findings suggested that these genetically predisposed individuals when injected with LYMErix could develop an arthritic autoimmune response. Developing a genetic test to prescreen these individuals would have just added cost to the vaccine development potentially causing more harm than good (1).

The final Chapter…

The trial was highly publicized, and as a result an FDA advisory panel reconvened to discuss the case. After hearing compelling testimonies from both sides, the FDA finally sided with SmithKlineBeecham. The FDA believed the benefits from LYMErix outweighed the risk, and could remain on the market; although, the phase IV trial was to continue (1). At this point, SmithKlineBeecham had had enough. They were tired of being ridiculed and fighting the media. Consequently, in 2002, they pulled LYMErix off the market. Soon after in 2003 the law suit was settled. SmithKlineBeecham paid the prosecuting fees, but the alleged “vaccine victims” received no compensation (1). To this day, SmithKlineBeecham, now GlaxoSmithKline, denies their vaccine caused harm, and they insist LYMErix was taken off the market due to financial concern.

SmithKlineBeecham Project Management Analysis…

The fact of the matter was that public image was everything for SmithKlineBeecham. It did not matter that their vaccine was safe and effective in an area with high prevalence of Lyme disease. A mere 59 out the 905 patients that reported adverse events with LYMErix may have developed arthritis as the result of the LYMErix vaccine. The media took a small risk and blew it completely out of proportion which resulted in a bad public image and dwindling sales. The project managers at SmithKlineBeecham made the right decision from an economic standpoint.

The choice came down to two options: 1) Write off the losses or 2) continue to fight a losing battle and hope to win the war.

Option 1 was simple. Quit then, take LYMErix off the market to satisfy the public and prevent future losses, while hopefully saving SmithKlineBeecham’s public image. At this point SmithKlineBeecham was already in the hole, there was no point to dig it any further.

Option 2 was to continue to fight a losing battle and hope to win the war. To go with this option SmithKlineBeecham would have had to continue to invest money into studies to show LYMErix was safe, while continuing to combat the allegations and fighting with the media. Then, if the safety studies came out showing that a small subset of the population that contained a predisposed genotype had autoimmune responses after being vaccinated with LYMErix, then SmithKlineBeecham would risk more law suits. Not only would they have to spend money to settle those suits, SmithKlineBeecham would have to admit LYMErix caused harm. Then in order to keep LYMErix on the market they would have had to come up with a genetic test for screening the recipients, or started over again at the preclinical stage altering the vaccine. Millions if not billions could have been spent, which quite possibly could have ended in failure anyways. If the target population wasn’t already scared off by the media, the increase in cost because of the diagnostic test, which may or may not be covered by insurance, would surely ward off more. So with the remaining hand full of the target population, it was no longer cost effective for SmithKlineBeecham to produce it.

If SmithKlineBeecham continued the LYMErix project, not only would it require more excessively, large, monetary investments, but time as well. Time in the biotechnology/pharma world is limited. The longer a company spends on development and clinical trials the shorter the patent exclusivity becomes. All a competing company would have had to do is come out with a Lyme disease vaccine slightly better than LYMErix, that doesn’t need a diagnostic test and LYMErix would be gone.

Clearly, the project managers at SmithKlineBeecham made the right decision. The budget had its limits, and the project was not going to produce the return they had expected. There was no way to add value to the project to make it worthwhile to save. Further development would have cost millions, and the patent clock would have continued to tick away time. SmithKlineBeecham did the best thing it possibly could from the company’s standpoint and terminated LYMErix.

LYMErix was a safe vaccine, the FDA found no definitive evidence that LYMErix actually caused arthritis. Vaccines have to be designed with a strong safety profile, because they are going into healthy people to avoid future disease. Prior to licensing LYMErix, SmithKlineBeecham, could have better communicated the general risk associated with any vaccines. Vaccines are taken with a small upfront risk to avoid a serious risk later; whereas, with most pharmaceuticals the side effects have to be weighed against the disease or condition they are fighting.

The media played a huge role in the outcome of LYMErix. They constantly communicated how bad the alleged adverse events were, and nothing was stated about how people benefited from LYMErix. The media changed the risk benefit ratio, forcing the public to believe LYMErix was a horrible thing. SmithKlineBeecham should have communicated the risk better and emphasized the benefits of the vaccine. The company and FDA could have stated the facts about Lyme disease and how difficult it is to treat. Instead, they let the media turn the risk benefit ratio toward the unfavorable risk associated with the vaccine. The company should have asked physicians and FDA to emphasize the benefits of vaccines in general, and explain that there is always a small, inherent risk associated with any vaccination.

FDA Project Management Analysis…

The FDA requires vigorous preclinical studies and very in depth clinical trials with any vaccines to prove vaccines are safe and efficacious before going into the healthy individuals. In the LYMErix cases the FDA should have also communicated the benefits and risk associated with vaccines. The FDA did the right thing remaining neutral, and reporting just the facts. The facts were that the LYMErix vaccine was safe, efficacious and did not appear to cause any harmful, adverse effects. They did not see any evidence to consider removing the LYMErix licensure. They could have also explained that there is an inherent risk with anything put into the human body. They could have pushed the ill effects of Lyme disease and difficulties with treatment, and how many people the disease affects.

Implications for Today…

LYMErix was made out to be the scapegoat in the spot light. Lyme disease should have been the bad guy then, just as it is today. Today, Lyme disease continues to affect thousands of people every year, and in 2012 it was 7th on the list of CDC’s most common notifiable diseases in the United States (7). The deer tick population is booming, and yet still no vaccine has come to the market for Lyme disease. The FDA and SmithKlineBeecham let the media kill an efficacious remedy through bad risk communication. It could happen again today! Companies need to emphasize the risks associated with getting the disease, and the benefits of their vaccination. Diseases need to be put into the spot light as the bad guy, and that cannot be turned around. Today, there are diseases that were nearly eradicated making a comeback because ignorant people are refusing to get vaccinated. The burden falls not only on the company but on the FDA as well to relay the safety and benefits of vaccination to the public.

References

1. Nigrovic LE and Thompson KM. The Lyme Vaccine: a cautionary tale. Epidemiol. Infect. (2007) 135, 1-8.

2. The history of the Lyme Disease Vaccine. http://www.historyofvaccines.org/content/articles/history-lyme-disease-vaccine.

3. Nardell DT, Munson EL, Callister SM, and Schell RF. Human Lyme disease vaccines past and future concerns. Future Microbiol. (2009) 4, 457-469.

4. Keller D, Koster FT, Marks DH, Hospach P, Erdile LF, Mays JP. Safety and immunogenicity of a recombinant outer surface protein A Lyme Vaccine. JAMA. (1994) 271, 1764-1768.

5. Shen AK, Mead PS, and Beard CB. The Lyme disease Vaccine—A public Health Perspective. CID (2011) 52, S247-S252.

6. Lathrop SL, Ball R, Haber P, Mootrey GT, Braun MM, Shadomy SV, Ellenberg SS, Chen RT, Hayes EB. Adverse event reports following vaccination for Lyme disease: December 1998-July 2000. Vaccine 2002; 20:1603–1608.

7. http://www.cdc.gov/lyme/stats/