What this is and why I’m writing it.
In any type of community – bleeding disorders, family, Harry Potter Fan Club – strong communication is imperative. Communication bears the responsibility of carrying information from one to another so that assessment and action planning can take place. The growth of the internet has allowed for rapid and broad-reaching communication that, on the grand scale of things, has been a huge influence in the development of world events such as the Arab Spring, civil movements like Black Lives Matter, or humanitarian efforts such as those recently launched by Humans of New York for the benefit of Syrian refugees.
The speed and accessibility of online communication, however, also presents new challenges. In 1980, if you were looking to avoid “that big spoiler” from the Empire Strikes Back, you had to steer clear of a few publications and the nightly news’ coverage of new movies. In 2015, avoiding spoilers from The Force Awakens essentially means avoiding the internet entirely (I promise not to spoil a single movie in this article!). And this shift toward rapid – sometimes unwanted, sometimes incomplete – communication is far from limited to the entertainment industry.
Recently the abstract from the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) was published. I’ll get into the details of SIPPET shortly, but for those who don’t know, basically the SIPPET study was designed to learn more about possible connections between certain hemophilia treatment products and the risk of inhibitor development in minimally-treated or previously untreated people (PUPs) with severe Hemophilia A. The abstract’s results presented some potentially startling information, however and unfortunately, the study in its entirety – including final analysis – has not yet been published. In fact, projections are that it won’t be published until sometime in late January-early February, but even that appears to be a best guess.
Now, the National Hemophilia Foundation’s (NHF) Medical and Scientific Advisory Council (MASAC) is considered to be the preeminent group of physicians, scientists, and other medical professionals with a wide range of expertise on bleeding disorders, blood safety, and infectious disease. MASAC is responsible for establishing and revising treatment guidelines based on all available data, including studies. In the case of SIPPET, MASAC has driven two NHF releases to date: The first, from November 12th, stated, “The results of this study may prove to be significant to our community,” with the second on December 17th reading, “While this is potentially an important study, the data are incomplete at this time, and it will be critical to review the full study report when it is published. We do not yet know when or where the study will be published.”
It seems quite flawed to me that an abstract presenting potentially alarming information can make its way into the hands of the general public months before the full study and final analysis are published enabling experts to analyze, summarize and develop action plans accordingly. This is precisely the type of contemporary communication challenge I was referring to above, and honestly, it’s caused me some stress and anxiety, and I’m a believer that in any given group, whenever one person has a certain experience, chances are, others are having it too. So I’m guessing others are experiencing some level of stress or anxiety over what we know about this study so far, and with that in mind, I decided to do some homework and speak to an expert.
Dr. Pipe holds a few impressive professional titles, as a Professor of Pediatrics and Pathology at the University of Michigan and the Pediatric Medical Director for the University of Michigan’s Hemophilia and Coagulations Disorders Program. He has also been a member of MASAC since 2006 and Chair of the council since 2014. He’s the expert I spoke to about what the SIPPET abstract actually means. I’ll be quoting him and referring to points he made throughout this article.
Quick background on hemophilia and inhibitors.
I should quickly address that while I imagine most reading this are members of the bleeding disorders community or otherwise informed about bleeding disorders, there may be some curious outsiders amongst the readership, so two quick definitions:
Hemophilia, simply put, is a rare, hereditary bleeding disorder in which blood doesn’t clot normally. (More on hemophilia and its causes).
Inhibitors, simply put, are antibodies that the body produces in response to infused clotting factor concentrates taken for the treatment of hemophilia. This makes many standard treatment plans ineffective. (More on inhibitors).
Inhibitors are scary; I know firsthand as someone with severe Hemophilia A who battled with one for seven years (ages 5-12). I’ll never forget how radically my life changed after I completed immune tolerance therapy (ITT); I could walk around, play with friends, and live free of concern that most “normal” activities of daily life would result in yet another prolonged bleeding episode with irreversible and devastating effects.
During what could be considered a golden era of product development for the treatment of people with hemophilia, there remains a great unmet need in understanding more about inhibitor development, management, and eradication. Dr. Pipe acknowledges this discrepancy and believes that it is bringing, “more focus to [understanding] if there is product-specific or class-specific differences in the risk to developing an inhibitor.” MASAC has issued more than 400 communications since it’s 1954 inception, including many on inhibitors. They recognize the significant need despite this “golden era.”
The SIPPET study and abstract.
Fair warning: This is where things begin to get a little dense.
SIPPET was a randomized study which took place between January 2010 and December 2014 that collected data on 251 children. This winter, the abstract was released prior to the oral presentation of SIPPET at the American Society of Hematology’s (ASH) Annual Meeting.
The big, startling result reported in the abstract is that the class of recombinant FVIII (rFVIII) products resulted in a 1.87-fold higher incidence of inhibitor development than was seen in those treated with a plasma-derived product (pdFVIII) containing von Willebrand factor (VWF). In other words, those treated with a product from the recombinant class in this study were nearly twice as likely (1.87x) to develop an inhibitor than their peers taking a plasma-derived product containing von Willebrand factor.
Still with me? I told you it gets dense quickly, and again, one of the contemporary challenges with the process of how studies are published is that these dense – and sometimes alarming – abstracts can be released and widely distributed several weeks to months before the full study is available; however, credible researchers, analysts and clinicians are extremely hesitant to make any definitive statements or actionable recommendations based on abstracts because they do not present the full story, “Often times when you see the final publication, you can see that there’s been some differences,” recounts Pipe. “I can think of many studies in the past where the abstract research resulted in one conclusion, but by the time the final publication came out, the main conclusion was not the same as what was in the abstract.” Numerous articles, like this one, support his claim.
Now that being said, one could argue that SIPPET’s abstract specifically deserves more attention at this point in the study’s existence than most hemophilia-related studies at a comparable point because of how great the need is to understand more about curbing the rate of inhibitor development coupled with what appears to be alarming information stated in the abstract’s conclusion.
This is precisely why I called Dr. Pipe. As a leading clinician and the Chair of our community’s greatest authority on medical and scientific advancements, I thought he, if anyone, could provide some clarity during this waiting room-esque period between the abstract’s publication and the publication of the full study. As a someone who is most certainly not a medical expert, I was seeking a comprehensive laymen’s understanding on two things:
1) What the SIPPET abstract is actually stating, and
2) Why specifically MASAC needed to wait for the full SIPPET study to be published before it would make any recommendations.
Spoiler alert (no, not that kind – I promised!): My lengthy conversation with Dr. Pipe helped me understand both. To help communicate that understanding to you, I’m highlighting three of my big takeaways from that conversation.
Takeaway 1: Understanding Products, Product Classes, and the Complexities of Analyzing and Interpreting SIPPET’s Product-Related Data.
Given that one of the abstract’s conclusions was that PUPs using rFVIII products were 1.87x more likely to have developed an inhibitor than the PUPs using pdFVIII products containing VWF, should clinicians cease prescribing PUPs rFVIII products at this time? Dr. Pipe’s response:
One skeptical view of the appearance of this abstract is that there are products on the market that should just be taken off the market completely. Or the government should say, “They should not be prescribed to PUPs.”
Dr. Pipe is an outstanding communicator and spoke with controlled confidence and intelligence throughout the conversation, but he was notably emphatic about this next point:
There’s no way that I’ve seen any data – and this is just my personal assessment – I have not seen any data to date that would suggest any particular product should be taken off the market because of inhibitor risk. That is not what the data to date has shown. And keep in mind, the SIPPET study is not a product-specific comparison. I hope the community doesn’t lose sight of this. This is a class comparison.
He’d mentioned “class” a few times by this point and despite having read that word throughout in the abstract as well, I wasn’t clear on what “class” actually meant. He clarified:
SIPPET basically compared two comparative groups: 1) VWF-containing pdFVIII products that were approved, as well as 2) a basket of first, second, and third generation rFVIII products. As it turned out, there’s very few VWF-containing pdFVIII that were used in this study that are even available in the US. And in the recombinant class, the use of first and second generation products in the US and around the world is quite a bit lower than the third generation products. The study was not powered to look at product-specific differences, they could only compare the broad classes.
Of course, this isn’t the first study to be done on inhibitor development; there have been many, like the 10-year-long Research of Determinants of Inhibitor Development (RODIN) study, which also sought to further understand the role of product classes in inhibitor development amongst PUPs. The conclusion, “the use of recombinant factor VIII products in children with severe hemophilia A did not have a significant effect on the risk of inhibitor development, as compared with the use of plasma-derived products, nor was the von Willebrand factor content of the products or switching among them associated with the risk of inhibitor development.”
In other words, that conclusion appears to be at odds with the SIPPET abstract’s conclusion. There was, however, an unexpected and noteworthy conclusion of RODIN. To quote the study directly, “the risk of inhibitor development was 60% higher among children receiving a second-generation full-length recombinant product than among those receiving a third-generation full-length product”. Dr. Pipe referred to this finding as he continued to explain the challenge of data analysis and interpretation of any one particular study:
They [those running SIPPET] did a secondary analysis because of the results of the RODIN study on 2nd generation, recombinant products. They took those patients out and redid their analysis, and they didn’t see any impact. So this study did not confirm the 2nd generation issue that was raised during the RODIN study. It’s a good example of why, as researchers and clinicians analyzing this data, there’s competing data out there and you really need to look at the data as a whole. So I take nothing away from the fundamental results as reported here [in SIPPET’s abstract], but before there’s anything actionable done, we really have to look at the totality of the data and the full published report.
To further the point that we cannot look at this abstract and simply dismiss all recombinant products as suboptimal for reducing the rate of inhibitor development in PUPS, Dr. Pipe highlighted innovations in the recombinant class of products since 2010, SIPPET’s start date and cutoff point for product consideration. These innovations to products in the recombinant class include:
1) Human cell line-derived recombinant human FVIII,
2) Recombinant FVIII-Fc fusion protein, and
3) Pegylated full-length recombinant FVIII.
Regarding the Fc fusion development specifically, Dr. Pipe emphasized:
[There are] a multiplicity of publications that have studied the Fc fragment, which is part of the immunoglobulin molecule, and exposure to the immune system could have a tolerizing effect.
In other words, this particular innovation in the recombinant class may in fact be a step forward in curbing the prevalence of inhibitors. Regarding pegylation:
Curiously about pegylation, we do pegylation in a number of protein replacement disease areas where the primary goal of the pegylation is actually to reduce the immunogenicity of the molecule. None of these were addressed in SIPPET whatsoever. So even if the study ends up confirming some trend between the two product classes, in a sense, we have to deal specifically with the products we have and are using in this country right now.
He went on to guesstimate that perhaps as many as 30% of our population is currently using recombinant products that have been developed with one of these three innovations and how – again – none of these products were considered in the SIPPET study.
If you’re like a me, a medical layperson, you may start to be feeling overwhelmed by all this. Trust me, you are not alone! It’s complicated stuff, and the longer I spoke with Dr. Pipe, the more I came to appreciate just how complex the analysis and interpretation process is. If you’re feeling brave, let’s keep going and consider another takeaway from that conversation.
Takeaway 2: SIPPET’s Sample Size, Variables, and Patient Relevancy.
Dr. Pipe made clear that for all the mystery surrounding inhibitors, the “primary drivers” of inhibitor risk have been identified:
There’ve been some publications that, armed with about three or four pieces of information, [enable you to] be highly accurate in predicting who’s going to have an inhibitor.
Those “pieces of information,” those “drivers,” include:
1) Genotype,
2) Family history,
3) Polymorphisms of the immunoregulatory genes, and
4) Intensive exposure to FVIII at an early age.
Now in the SIPPET study, 303 patients were initially enrolled, 251 had data collected about their experience, but ultimately only 216 were fully compliant (35 of the 251 had truncated follow-ups). As mentioned earlier, the study looked at patients from 14 different countries spread across five continents, adjusted to equally divide seven different putative confounders (FVIII gene mutations, ethnicity, hemophilia family history, inhibitor family history, previous blood component exposure, therapeutic regimen, age at first treatment and country site) between the two arms of the study. I asked Dr. Pipe if all those variables and considerations were significant when interpreting the data, especially given that confounders such as genotypes and family history have been identified as “primary drivers” in assessing inhibitor risk:
This is one of the things people reviewing this study are going to have to address. You want to have balance in each group on all levels: age, ethnicity, previous exposure, in genotypes, ideally. We don’t have any granularity from this abstract and it wasn’t really addressed in the oral presentation, but what specific potential confounders did they look for and how did they demonstrate there was no difference in the two arms? And because of [those screened out, and] dropouts and all the potential confounders, is it possible that even this, the largest randomized-controlled trial (RCT), was still not large enough to answer this question [about inhibitors and specific products or classes]?
I was curious to know as well, given that we acknowledge things like genotype and family history to be “primary drivers,” how we take into consideration the number of patients studied in SIPPET that came from developing regions or countries, areas widely understood to have insufficient information about family history and accurate diagnoses:
[As a clinician,] whenever you evaluate a RCT, there’s a couple things you have to take away. Does the population that was studied in that trial apply to your particular patient? One thing that should not be lost in this study, though it was a global trial, is that there were a significant number of patients who were recruited from North Africa and India. So a clinician from the US may say, “Is the population of patients in this study really the same as patients I look after in my patient population, and can I really extrapolate from the observations of this study to the patient that I have in front of me in my clinic today?” These are important questions for clinicians to consider.
My understanding of the need for “granularity” on studies like SIPPET was becoming more and more concrete. Hypothetically, theoretically, from a certain perspective, if/then – these are all valuable frames for spitballing what an abstract like this might mean, but without being able to dig into specifics, there isn’t much of anywhere to go. I found that discovery simultaneously comforting – because I believe it to be true and I’ve always found truth at least somewhat comforting – and frustrating, because my left brain really likes concrete answers.
Last takeaway. Home stretch!
Takeaway 3: The Strength, Nimbleness, and Readiness of MASAC.
As I mentioned earlier on, MASAC has been around since 1954 with the mission to issue recommendations and advisories on treatment, research, and other general health concerns for the bleeding disorders community, and is composed of expert physicians, scientists, and other medical professionals. If you’re knowledgeable about leadership in the bleeding disorders community, you’ll appreciate MASAC’s current, impressive 30-person roster. As sitting Chair of the committee, Dr. Pipe has the unique role of being a leader amongst a group of leaders:
One of the principles that I’ve tried to move forward is the nimbleness of MASAC as a body even outside of our face-to-face meetings, that occur twice a year.
A soft chuckle with an almost ‘believe you me’ tone escaped as he said:
I can tell you that MASAC has already been discussing and deliberating this [SIPPET], even before the abstract was available. We’ve continued those deliberations at a subcommittee level, we’ve driven the communications that have gone out to the community through NHF since the ASH presentation, and we’ll continue evaluating the totality of data over the coming months in preparation to come together for our February meeting.
He expressed hope that the publication would be released ahead of that February meeting so that MASAC could fully evaluate it against the larger body of published material to date:
The good things is, we’ve been discussing and deliberating this issue [inhibitor development] for years now, as incremental data has come in, we have issued revised recommendations accordingly, and I believe that an outcome from this Spring’s deliberation is that there will potentially be a revised recommendation, if the group feels that it’s appropriate.
So, I’ve tried to articulate how I came to understand MASAC’s – and really, our greater community’s – need to wait for the study to be published before meaningful analysis and action-planning can take place. I think I’ve done alright, but still, one could very easily respond with, ‘Well what about the blood contamination crisis? NHF/MASAC didn’t act quickly enough and our community was devastated.’
In my opinion, a direct comparison between the time of uncertainty in the 80s and now is unfair, but I do recognize the argument that a lack of action in favor of information-gathering can be, depending on circumstances, far worse than action with partial information. That’s also just my opinion. Dr. Pipe and I discussed this topic as well:
There’ve been many times before where this community has had to make decisions when they weren’t necessarily armed with all the data…If we go back to to the HIV/Hepatitis C era, do you know what the primary deliberation was around heat-treatment and pasteurization around plasma-derived product? It was a concern that this might actually trigger more inhibitors; clinicians had to make decisions about embracing heat-treated plasma products with a concern that this may lead to an increase rate of inhibitors.
Quite a coincidental reveal (to me). He continued:
We didn’t have data at that time to make that decision. It can be challenging when you have to make treatment decisions without all the data in front of you. When recombinant material appeared – go back to the literature, to the late 80s and early 90s – issues about risk of inhibitors were actually raised as recombinants were coming through. People were saying, ‘Are we going to trigger more inhibitors by embracing recombinant technology?’ There were others saying, ‘No, recombinants may actually have a reduced rate of inhibitors.’ Well, fast forward 25 years later and we’re still having the same types of debates. It’s challenging. We have a rare disease population; it’s very difficult to do very large studies like you do in other diseases, which is a dilemma.
I think it’s also important to point out that there are sitting members of MASAC and community leaders at NHF and elsewhere who were personally infected during the blood contamination crisis. Some level of skepticism can be useful in analyzing a situation, perhaps even this one, but personally, I find it hard to believe MASAC or NHF leadership would have anything but sensitivity to the tension created during periods of uncertainty given both professional and personal experience in this community.
So, Now What?
I feel pretty lucky to be a young adult living in the internet age: Everyday, I read news from around the world, sourced from entities I’ve determined to be credible, not from the handful made readily available to me; I’m able to keep in touch with friends and family, and can usually work from anywhere with a Wi-Fi connection. The internet has done me right, but like most valuable developments, it’s not without drawbacks. Information, most notably incomplete or unwanted information [Note: I kept my word on the movie spoilers thing!] is made available at a pace our species has never seen before, and my biggest takeaway from my deep dive into SIPPET and inhibitor studies is this:
Science is complicated and slow, and the internet thrives on simple and quick.
Inhibitor development is the single greatest challenge facing the hemophilia community. Having spoken with Dr. Pipe, I’ve gained a much, much deeper appreciation for just how complex this problem is, and how for all we do know, there is so much we still don’t. My hope is that by expressing a few of my major takeaways, I’ve helped a few others – maybe even you! – understand the complexity of this challenge, and the complexity of analyzing and interpreting data from study abstracts such as SIPPET’s. And if questions remain, Dr. Pipe emphasized NHF’s accessibility during this uncertain time:
In response to the communications that go out, we want to hear from the community, giving them a chance to weigh in on this issue, to ask questions. We have an open invitation to community members to interact with NHF through their chapters or the foundation directly, or to talk to their clinicians. We’ve put an open letter out to the treatment community as well, summarizing the issues to date and encouraging them to communicate with us and send us their questions and concerns so that we can make sure that everyone’s voice is being heard. That’s the right approach here. There is no definitive answer staring us in the face that we need to make a decision on right this second, but going forward, I hope there is an action item, or two, or three, and we want to make sure everyone’s voice has been heard so that the issue is fully vetted.
Finally, as we wrapped up, Dr. Pipe summarized his overall view on hemophilia and inhibitors with a tone that, frankly, given our focus of our conversation, struck me as surprisingly hopeful:
I think the timing is right to include patient management decisions and product selection as part of a multi-faceted approach to try to address inhibitor risk in hemophilia. It’s not gonna be the sole answer because as the SIPPET [abstract] results showed, the plasma derived rate of inhibitors is unacceptable. We acknowledge that we don’t yet have an approved product in hand that has eliminated the risk for inhibitors in Hemophilia A, but that’s still the goal, and incrementally we want to put recommendations in place that will give the best possible outcome for the largest portion of the population. I don’t think I’ve ever been more hopeful on outcomes for hemophilia as I am today, and there’s no way that this study is a setback in anyway. If anything, it’s just going to continue to fuel the passions of clinical researchers, basic science investigators, and pharmaceutical manufacturers. And I hope in my lifetime that inhibitors have been eradicated from this population.
I’m not known for my patience, and I consider it a process flaw (albeit, from what I’m told, one we must accept) that abstracts are able to hit the internet and be widely distributed before experts have had access to complete studies enabling them to make fully-informed decisions and recommendations. Be that as it may, I encourage all community members concerned about the rate of inhibitor developments in our community to join me in heeding Dr. Pipe’s advice: Educate yourself, deepen your understanding, and prepare to have a well-informed, articulate voice on the subject once all data from SIPPET is available and revised recommendations and treatment plans are considered.
Patrick James Lynch is the President and Co-Founder of Believe Limited. He’s a producer, writer, and actor living with hemophilia.