What does SIPPET mean to the Hemophilia community?
Sippet was a term more commonly used in the 18th century, whose mention has waned today. The word 'sippet' refers to a small piece of bread or toast used in a soup or sauce as a garnish. In modern times its known as a crouton. But that's not what it means to the hemophilia community. Here its been a buzz word for the past 7 months. It's an international study comparing inhibitor development in PUPs (previously untreated patients) treated with plasma-derived (pD) or recombinant (Re) Factor VIII. In a previous post on the SIPPET study I have simplified the study and its results.
The aforementioned buzz started when an abstract on the SIPPET study was presented at the ASH (American Society of Hematology) meeting in early Dec 2015. The abstract was released in advance of this meeting, in Nov 2105, and both NHF and HFA released a statement on their websites. Things were quiet over the holidays. I, a patient with Hemophilia A on recombinant FVIII, heard the word SIPPET for the first time in Feb 2016. Not much more information was available than just the term, and that there was a higher incidence of inhibitors in recombinant FVIII treated patients. So I asked around. The only additional information I got was the study was conducted primarily in Asia and Africa. Hence, the results are less relevant to us in the US. I have never had an inhibitor and so I remained satisfied with that answer.
My next encounter with SIPPET was in Laurie Kelley's PEN magazine article "The SIPPET Bombshell". This was a well-written article with a lot of detail of the clinical trial, the strategy, the results and shortcomings. Note that the article was published in May 2016 and so was likely written in March or April. Why this is important is that the SIPPET specific information available was only the abstract at ASH. There were some important questions raised by Paul Clement, the author of the PEN article.
Paul asked: The results are from an abstract and have not been peer-reviewed and published. Are the results relevant? The study was funded by plasma-derived product manufacturers. Is there a conflict of interest? Is the sample size large enough to come to a conclusion? Why was long-acting factor not used? How will MASAC respond to these results? These are very relevant questions based on what was known at the time the article was written. Well, the peer-reviewed paper on SIPPET was published in The New England Journal of Medicine (N Engl J Med 2016; 374:2054-2064 May 26, 2016).
Me being a researcher in the past helped understand the study some and look at the data, the population studied, other parameters, the results and conclusions more closely. I knew that NEJM was a top caliber journal (Impact Factor 59) to publish in and the manuscript would have gone through a thorough peer-review. On the product manufacturers' conflict of interest question, the authors of SIPPET have provided full disclosure statements of all conflicts. Its obvious that all research studies need funding from one or more sources. At times its a private foundation, sometimes its a state or federally funded agency ( such as the NIH in the USA).
Patients from India ( ~40), Egypt (~38), Iran (~16), USA (9), Italy (5) and other countries (in smaller numbers) were included. This answered one question- yes, the study was done not only in Asia and Africa. Yes, the number studied was small. My thoughts on this are, if the peer-reviewers had found the sample small they would have commented on this and sent the manuscript back for a greater enrollment or outright rejected the paper. Sample size is very important in any clinical trial.
To explain the statistical modeling I recruited a good friend. He designs clinical trials for a large pharmaceutical and has a PhD in Pharmacy. He would know about the technical appropriateness of the SIPPET study and interpret the results for me. According to him since the difference between the plasma-derived vs. recombinant population was so significant and the variability in the data was within acceptable limits (lots of statistical jargon simplified) the population studied would be sufficient. I expect the peer-reviewers held similar views. On why long-acting Factor was not tested, the answer is quite simple: It was not available when the study started in 2010.
On, are the long-awaited MASAC recommendations, based on the SIPPET study, in? Patrick James Lynch did an interview with Dr. Glenn Pierce. Dr. Pierce sits on the board of MASAC. Patrick, a hemophiliac with a tolerized inhibitor himself, questioned Dr. Pierce on why/how inhibitors form in 20-30% of the patients. He asked Dr. Pierce on the SIPPET study but did not press him because the interview was conducted soon after the NEJM paper appeared and too early to comment.
Good news, readers! MASAC released their recommendations ( # 243) today- June 28, 2016. I will offer my take on it in my next post. Meanwhile here is Patrick Lynch's interpretation of the MASAC recommendations.
Sippet was a term more commonly used in the 18th century, whose mention has waned today. The word 'sippet' refers to a small piece of bread or toast used in a soup or sauce as a garnish. In modern times its known as a crouton. But that's not what it means to the hemophilia community. Here its been a buzz word for the past 7 months. It's an international study comparing inhibitor development in PUPs (previously untreated patients) treated with plasma-derived (pD) or recombinant (Re) Factor VIII. In a previous post on the SIPPET study I have simplified the study and its results.
The aforementioned buzz started when an abstract on the SIPPET study was presented at the ASH (American Society of Hematology) meeting in early Dec 2015. The abstract was released in advance of this meeting, in Nov 2105, and both NHF and HFA released a statement on their websites. Things were quiet over the holidays. I, a patient with Hemophilia A on recombinant FVIII, heard the word SIPPET for the first time in Feb 2016. Not much more information was available than just the term, and that there was a higher incidence of inhibitors in recombinant FVIII treated patients. So I asked around. The only additional information I got was the study was conducted primarily in Asia and Africa. Hence, the results are less relevant to us in the US. I have never had an inhibitor and so I remained satisfied with that answer.
My next encounter with SIPPET was in Laurie Kelley's PEN magazine article "The SIPPET Bombshell". This was a well-written article with a lot of detail of the clinical trial, the strategy, the results and shortcomings. Note that the article was published in May 2016 and so was likely written in March or April. Why this is important is that the SIPPET specific information available was only the abstract at ASH. There were some important questions raised by Paul Clement, the author of the PEN article.
Paul asked: The results are from an abstract and have not been peer-reviewed and published. Are the results relevant? The study was funded by plasma-derived product manufacturers. Is there a conflict of interest? Is the sample size large enough to come to a conclusion? Why was long-acting factor not used? How will MASAC respond to these results? These are very relevant questions based on what was known at the time the article was written. Well, the peer-reviewed paper on SIPPET was published in The New England Journal of Medicine (N Engl J Med 2016; 374:2054-2064 May 26, 2016).
Me being a researcher in the past helped understand the study some and look at the data, the population studied, other parameters, the results and conclusions more closely. I knew that NEJM was a top caliber journal (Impact Factor 59) to publish in and the manuscript would have gone through a thorough peer-review. On the product manufacturers' conflict of interest question, the authors of SIPPET have provided full disclosure statements of all conflicts. Its obvious that all research studies need funding from one or more sources. At times its a private foundation, sometimes its a state or federally funded agency ( such as the NIH in the USA).
Patients from India ( ~40), Egypt (~38), Iran (~16), USA (9), Italy (5) and other countries (in smaller numbers) were included. This answered one question- yes, the study was done not only in Asia and Africa. Yes, the number studied was small. My thoughts on this are, if the peer-reviewers had found the sample small they would have commented on this and sent the manuscript back for a greater enrollment or outright rejected the paper. Sample size is very important in any clinical trial.
To explain the statistical modeling I recruited a good friend. He designs clinical trials for a large pharmaceutical and has a PhD in Pharmacy. He would know about the technical appropriateness of the SIPPET study and interpret the results for me. According to him since the difference between the plasma-derived vs. recombinant population was so significant and the variability in the data was within acceptable limits (lots of statistical jargon simplified) the population studied would be sufficient. I expect the peer-reviewers held similar views. On why long-acting Factor was not tested, the answer is quite simple: It was not available when the study started in 2010.
On, are the long-awaited MASAC recommendations, based on the SIPPET study, in? Patrick James Lynch did an interview with Dr. Glenn Pierce. Dr. Pierce sits on the board of MASAC. Patrick, a hemophiliac with a tolerized inhibitor himself, questioned Dr. Pierce on why/how inhibitors form in 20-30% of the patients. He asked Dr. Pierce on the SIPPET study but did not press him because the interview was conducted soon after the NEJM paper appeared and too early to comment.
Good news, readers! MASAC released their recommendations ( # 243) today- June 28, 2016. I will offer my take on it in my next post. Meanwhile here is Patrick Lynch's interpretation of the MASAC recommendations.
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