Pa#ent Perspec#ve FDA / ASPEN IVFE Public Workshop. Randall C. O Reilly

Transcription

1 Pa#ent Perspec#ve FDA / ASPEN IVFE Public Workshop Randall C. O Reilly

2 Goals Provide an accurate and objec#ve summary of (a subset of) pa#ent s perspec#ve on IVFE s Mainly long term pediatric TPN pa#ents Conducted anonymous survey, 75 respondents Illustrate with my personal experience (son Max) Highlight clear issues in outcomes: TPN Associated Liver Disease (TPNALD) is primary outcome measure of concern.

3 My Son Max May, 2006 very long segment Hirschsprung s (20 cm func#onal small bowel)

4 Total Bilirubin

5 Pa#ent Survey Data

6 Total Bilirubin

7 Total Bilirubin

8 Total Bilirubin 7 years

9 Pa#ent Survey Data

10 Pa#ent * Perspec#ve on IVFE: TPNALD is Primary Concern * Mainly pediatric, long- term TPN dependent pa#ents

11 Consistent with Published Data Puder et al, 2009 (N=42 FO, 49 SO) SO FO

12 Consistent with Published Data Fish Oil (N=18) Gura et al, 2008 Soy Oil (N=21)

13 Pa#ent * Perspec#ve on IVFE

14 Pa#ent * Perspec#ve on IVFE: Summary of Data and Comments TPNALD is a serious issue, with at least one available solu#on It has been a long #me (7+ years), with no clear signs of progress Due to necessary confiden#ality constraints, pa#ents are last to know Pa#ents experience a lack of control on mul#ple fronts: At mercy of companies to submit proposals to FDA At mercy of FDA s stringent, expensive, and slow approval criteria At mercy of skep#cal Dr. s to get IND s, run studies Pediatric long term TPN users are a #ny popula#on FDA orphan status = 200,000 pa#ents, this popula#on is ~2, ,000 = cutoff for economic viability of approval costs This is a classic recipe for frustra#on!

15 Pa#ents are Eager for Solu#ons! How can we help? Very excited that this workshop is taking place, and eager to hear what everyone has to say! Can we appeal to your emo#ons? Keep in mind that these are real lives are at stake (cute babies)! Brainstorm new crea#ve solu#ons? Take advantage of fact that IVFE s are mainly a food? Focus on emulsifica#on standards, not full rigorous standards applied to new drugs? Pa#ents would really appreciate geing a fuller understanding of current status and future prospects for availability of alterna#ves! Is rapid Clinolipid approval a good sign? (trials only demonstrated equivalence, but got priority review status) Understand that confiden#ality prevents any significant disclosure of the situa#on: must suppress frustra#on and con#nue to wait..

16 Pa#ent Comments Why is omegaven not FDA approved when it works so well? Omegaven saved our babies liver!! Please approve it!! If this were your child that had to undergo these treatments, wouldn't you want the best possible outcome for them? My two month old is showing liver damage from Intralipids, please help us. Omegaven could save his life but it isn't available. Please, if it was your son/daughter you would want omegaven. What is the hold up with Omegaven? Is it worth the lives of babies passing away in masses every year? Will it mamer when it finally affects one of your children? (Note: 3 month old baby died of TPNALD) What would it take to get Omegaven approved other than leing people die for the study! Possibly liver func#on studies? Fish oil based lipids, specifically Omegaven, saved my child's liver and kept us from having to have a transplant when she was just 3 months of age. No child should have to go through the horrors of liver disease. The FDA has a responsibility to keep us safe and not approving this drug because no hospitals will par#cipate in a blind study is ludicrous. Children are dying and something needs to be done about it!

17 Pa#ent Comments While there is nothing intrinsically wrong or unsafe about 100% soybean oil (my son has been on them for 9 years with no problems), some pa#ents can't tolerate the 100% soybean oil and should therefore be able to try SMOF or Omegaven. Those intralipids are approved for use in other countries with good results and should be available to American consumers as well. Omegaven saved my child's life and should be FDA approved. There has been other treatment op#ons yet approved by the FDA that are saving lives. Why allow kids to die because of red tape? Omegaven has saved the lives of many children. However, when my daughter was born missing 90% of her small intes#ne, her doctors did not even men#on it, and she was in the NICU for MONTHS so they had plenty of opportunity. I had to do internet research on my own. Because it is not FDA approved, the medical community refuses to talk about it. How is that acceptable? How many babies have died of liver failure because the FDA has delayed this life saving IV lipid? Some fortunate children in the US have gomen approval to use Omevagen through FDA's compassionate use protocol; the health of the majority of these children is as good, if not bemer, much bemer, than their cohorts receiving soy- based lipids. When is this going to be made available for all children who need it? My grandaughter was on lipids for 5 1/2 months & biopsy showed Stg 4 liver cirrhosis. She was on Omegaven for 9 months- surgery done July 2013 showed liver looks good- Omegaven stopped the liver disease & reversed it. This also saved my granddaughter from needing a liver transplant.

18 Pa#ent Comments Given the strong evidence that Omegaven does not cause TPN cholestasis in infants and children, why is Omegaven s#ll only being granted the status of compassionate use? My child was on Intralipid as an infant for seven months, the last six of which were in the ICU, with bilirubin levels reaching mid 20s, several episodes of profound bleeding, repeated infec#ons, and other liver- associated complica#ons. Within two weeks of geing Omegaven, my son was on a regular hospital floor, and came home a few weeks ater that. He never did need the mul#visceral transplant that was being considered. He was able to con#nue on TPN with Omegaven (no more Intralipid) for another six years and happily came off TPN altogether a few months ago. Without a doubt, he would not have been able to avoid transplant without the use of Omegaven. Older children and adults are suffering liver damage and failure due to lack of access to less toxic fat emulsion op#ons. Pa#ents should have open access to alterna#ve fat emulsions including fish oils for the decreased liver toxicity, cardiovascular benefits and poten#al an#- inflammatory effects these alterna#ve oils offer. My child is a long- term TPN user (two years) and our biggest fear is the damage the lipids are doing to her liver. Please expidite lipid alterna#ves - especially Omegaven and those already approved for use in Europe. This has the poten#al to save so many lives, including the one most important to me. The FDA does all it can to make our food supply safe, so why not TPN since medically fragile pa#ents deserve the best too.

19 Pa#ent Comments IntraLipids are killing babies, why is there no FDA approved alterna#ves in the US? The current "side effects and risks" for the currently available soy bean based lipids is liver failure and death - either while wai#ng for transplant due to limited availability of organs for infants and young children or post transplant due to poor outcomes for intes#nal and liver transplants. Omegaven clearly a safer choice and frankly any side effects can't be worse than liver failure and death; most children show no side effects. This is a cri#cal issue in which many children con#nue to die because omegaven is not available to them. Would you consider widening the qualifica#ons for Omegaven compassionate use so that children don't need to be in liver failure in order to qualify? Knowing that soybean based lipids destroy the liver, why is approval for Omegaven taking so long? It can prevent liver failure, liver damage and the need for some transplants if used in a #mely manner for our babies. My son is being underfed IV lipids because the level his body needs was damaging his liver. We need other op#ons. Wouldn't it be bemer to use strictly omegaven and save lives/livers of adults (and babies!) Than to use a liver damaging lipid and treat later with transplants and other drugs? If there is a bemer op#on, we should be allowed to take it. Why not omegaven it saved my grandson life and restored his liver. Off TPN for a bowel trial which failed, now he can only get soy lipids - liver profile is elevated constantly. Always having to cut back on TPN soy lipid to bring alk phos levels down. Weight energy quality of life has been diminished.

20 Pa#ent Comments With such posi#ve results on omegaven why would the FDA force children to race against a clock: liver damage vs nutri#on un#l their body can process their own. Pa#ents requiring PN and IVFE are living longer, fuller lives than ever before. We need a lipid component that will safely help facilitate that, as the only current op#on does not. If YOU personally HAD TO infuse Fish Oil, Olive Oil or Soybean Oil into a vein going directly into your heart, which would you choose? You've heard the benefits of Fish Oil and Olive Oil, and have probably changed your oral diet to include both. What benefits of Soybean Oil have you read? Have you deliberately added Soybean Oil to your family's diet? Would you infuse Soybean Oil into your own system? Into your child's? Please don't say "Whatever my Doctor tells me to. USA Physicians have no choice BUT Soybean Oil - unless your child is dying and meets the criteria to be in a trial at specialized hospitals. Soybean Oil builds up in my 10 year old's liver causing a high Triglycerol level. Instead of leing this level build up and destroy her liver, we then have to drop down in the amount of Lipids infused (50ml every 4 days rather than 50ml everyday) un#l her Triglyceride level decreases. It's a delicate balance that I have done for 10 YEARS now on her 10 year old body. Would you be willing to take this risk with your child or yourself if you had a CHOICE? FDA approval of Omegaven will be a lifesaver. Plus financially doesn't it make sense to prevent liver failure with a non- Soybean lipid rather than pay for the damage in the long- run? Why should a baby with an already compromised diges#ve tract be forced into a low or no op#on situa#on whilst figh#ng for survival? If anyone deserves the funding for more op#ons, a bemer personal 'fit', then surely it is they.

21 Pa#ent Comments We have been wai#ng for years for Omegaven for our TPN dependent son who, thru a liver biopsy has been diagnosed with Stage 3 fibrosis and level 2 Famy Liver. Because his liver func#on **blood tests** are at or near normal, he does not qualify anywhere in the US for Omegaven for liver rescue. We were encouraged last year when we were told that the FDA would soon approve Omegaven for everyone in the US. We were devastated ****again**** when our health care provider recently told us, despite their efforts, the FDA said NO. I realize that the FDA wants to protect the public against a medica#on that could be harmful, but when we do not have currently a good drug for providing IV lipid nutri#on and people are having life- threatening liver condi#ons from it, there should be a way to approve a drug that has been successful for years in other countries, ie Omegaven. In veterinary medicine, we make owners aware if a drug has not been approved for use in a specific specie, but s#ll use it and are protected by AMDUCA. Why can't we do the same for this? There is compelling evidence and over 100 children that have been on it, and the drug has not only not created liver disease it has reversed it. It is unacceptable that such a great product is not allowed to be used as ini#al therapy on people that need it the most. For certain cases, like Omegaven, it is not ethically possible to do a proper double- blinded study. Clinical evidence should be used to make a determina#on. Thank you for listening. Although IVFE treatment does have it's risks, health care providers should not be solely focusing on those. They need to make the pa#ents understand that there are benefits to the treatment and not make their pa#ents fearful of having treatment. Is this the best op#on for our children? What are other op#ons? What is withholding other TPN op#ons? Product like Omegaven has the poten#al to save lives, rather than causing further problems for TPN pa#ents. Why is there such limited knowledge or informa#on given to the pa#ent's and their families about long- term use of Lipids and TPN?

22 Pa#ent Comments My son was born at 34 weeks with no known medical anomalies at birth. At day 3 he suffered with NEC and in less than 12 hours he needed emergency surgery to remove 90% - 95% of his small intes#nes, a minimum of 25% of his colon, his appendix and ileocecal valve. He started TPN and IntraLipids right away. In three weeks he showed signs of TPN- Induced Cholestasis and by 6 weeks old, he was severely jaundiced, lethargic and had a total Bilirubin of 9.9. Like many babies and young children, my son did not do well with 100% soybean oil based IntraLipids. We were told by several doctors and specialists that he had a small chance of making it to one year old with his failing liver. We were vigilant with our son's care and sought out what could be done for his survival. We learned about Omegaven and the possibility for it to reverse the damaging effects of the IntraLipid. He became part of the clinical trials for Omegaven at Children's Hospital Boston. Ater star#ng Omegaven he started showing drama#c improvement. He became an ac#ve baby and the jaundice slowly faded away. He also no longer needed blood transfusions. His liver was healing and he was no longer needed a liver and small intes#ne transplant. He was on Omegaven for 20 months. His central line was pulled in April of 2011, two months ater weaning from both Omegaven and TPN. He is currently four years old, con#nuing to adapt with short bowel syndrome. He takes all fluids and food by mouth. His success in using Omegaven is exactly why it should be immediately FDA approved. In many cases babies and children fall short in healing, geing transplants and staying alive because of the lengthy process it can take to get Omegaven approved for Compassionate Use. Most #mes insurance won't cover it because it is considered an experimental drug. I don't see why it is not immediately used in the case where a newborn cannot take food by mouth and must be put on intravenous feedings. IntraLipid was killing my son, but Omegaven literally saved my son's life.

23 Pa#ent Comments Omegaven has been approved in compassionate use in certain cases but the requirements for qualifica#on are so narrow it knocks most out. Can that be reevaluated so we are given this safer op#on? We need more op#ons such as Topical lipids in dosing and effec#veness, etc. What can be done for us. Will be on TPN for life#me due to idiopathic intes#nal failure. Not a liver transplant candidate but is in liver failure presumably due to lipids. I am currently on TPN and have been for 3 years. Recently my blood test results showed con#nuing decreases in my magnesium levels. My schedule was changed to 4 nights of my regular TPN with lipids and two nights with no lipids. I have one night off a week. It would appear that the Omegaven might be a bemer op#on for me.

24 Pa#ent Survey Ques#ons

25 Overall Before we get into the more detailed case history data, you can provide some overall opinions about current IVFE options available in the US. Based on your experience, please rate your overall perception about the safety of the 100% soybean oil based IVFE's (e.g., IntraLipid), which are the only one's currently approved by the FDA: Perceived safety Neutral / don't Very Unsafe Unsafe know Safe Very Safe Do you think that the FDA should take aggressive steps toward facilitating the approval of alternatives to the currently approved IVFE treatment? Approve Alternatives Strongly Disagree Disagree Neither Agree nor Disagree Agree Strongly Agree If you could ask a public question or make a statement at the FDA workshop, what would it be? (Note: there will be a period for open public comment at the workshop, but it is relatively brief). Answers to this question can help shape the patient representative's presentation at the workshop. Anything entered here will be considered public information that can be widely shared.

26 Patient Information The following questions provide basic information about the patient, which is useful for analyzing the results. If you feel that any of this information is too intrusive, revealing of the patient identity, etc, then feel free to skip. Is the patient living or deceased? Living Deceased Current age of patient, or age at time of death? For example, if 4 years and 9 months old, you would enter 4 for Years and 9 for months. If more than 10 years old, you do not need to specify months. Age, Years Age, Months Age at which patient started receiving TPN, including IVFE (lipids)? Age, Years Age, Months

27 Patient Information What was the primary medical condition that led to the need for TPN, including IVFE? Short Bowel Syndrome (see next for subtypes) Chronic nausea (e.g., from chemotherapy) Bowel obstruction Microvillous Inclusion Disease Malabsorption Intestinal dysmotility Failure to thrive Radiation enteritis Crohn's disease or ulcerative colitis Intestinal infarction (blood clot) Gastroschisis Other (please specify next) Prolonged diarrhea High-output fistula Don't know For Short Bowel Syndrome cases, please specify the cause of SBS NEC: Necrotizing enterocolitis Hirschsprung's disease Volvulus Atresia Tumor Other (please specify next) Surgery for Crohn's disease Don't know Enter medical condition if not listed above, or additional relevant if multiple

28 In which country is the patient receiving IVFE? (if multiple over time, choose the longest duration one) For patients receiving IVFE in the USA, select what state the patient is receiving IVFE in (if multiple over time, choose the longest duration one) IVFE Usage The following questions ask about IVFE use and outcomes. There will be similar questions for the first, second and third type of IVFE that the patient has received (as applicable). Total duration of IVFE received -- if discontinuous, please add together all the time into one summary number. For example, if the patient has received 5 years, 2 months, and 1 week of total IVFE, you would enter 5, 2, and 1 in the sliders below. Use the most convenient unit -- if you had 8 weeks, just enter 0 years, 0 months, and 8 weeks. For longer durations (over a year or more) it is not necessary to enter weeks. Total Years of IVFE Months of IVFE Weeks of IVFE

29 IVFE1 What was the first IVFE received by the patient? (select multiple if used in combination) IntraLipid, Liposyn or other comparable 100% soybean oil emulsion (this is the only type approved by FDA in US) Structolipid, Lipofundin, Lipovenoes or other roughly 50/50 blend of soybean oil and MCT oil ClinOleic or other roughly 80/20 blend of olive oil and soybean oil Lipoplus (40% soybean oil, 50% MCT, 10% fish oil) SMOFlipid (30% soybean oil, 30% MCT, 25% olive oil, and 15% fish oil) Omegaven (100% fish oil) Don't know Total duration of first type of IVFE received -- if discontinuous, add together the time, and following the same format for years, months and weeks as the previous duration question. Total Years of First IVFE Months of First IVFE Weeks of First IVFE

30 Is the patient on a reduced level of the first type of IVFE compared to the standard dose? For many IVFE's, the standard is 2 g/kg/day, but for Omegaven, it is 1 g/kg/day, and some patients have been receiving 1 g/kg/day of soybean oil IVFE (IntraLipid). Many patients may be unaware of what dosing level they are on, in which case please enter Don't know. Standard dose Reduced dose Don't know Number of days per week receiving the first IVFE? Days per week Did the patient experience any side effects or negative outcomes that were attributed to the first IVFE? If so, select all that apply from this list, or enter Other and list if not available on the list. No side effects or negative outcomes Yellow eyes or skin (jaundice) Chills, fever, sore throat, headache, hives TPNALD -- TPN Associated Liver Disease (cholestasis, fibrosis, cirrhosis) -- enables more detailed questions next Bluish skin color Chest or back pain Difficulty breathing Essential fatty acid deficiency (EFAD) Unusual bleeding or bruising Portal hypertension (ascites, varices) Liver transplant (alone or as part of a multi-organ) Death Other (please specify next) Other side effects or negative outcomes (please list with commas separating multiple items) Were any of these side effects or negative outcomes reported for this patient on the FDA's MedWatch system? Yes No Don't know

31 For TPNALD selected above, what was the highest total bilirubin level recorded from the patient? Total Bili in mg/dl For TPNALD selected above, was a liver biopsy performed? If so, the result can be entered next. Yes No Don't know What level of cirrhosis was found in the liver biopsy? Cirrhosis Level (1-6)

32 IVFE2 Did the patient receive a second type of IVFE? Yes (details will be specified next) No (skip to next section) Don't know (skip to next section) What was the second IVFE received by the patient? (select multiple if used in combination) IntraLipid, Liposyn or other comparable 100% soybean oil emulsion Structolipid, Lipofundin, Lipovenoes or other roughly 50/50 blend of soybean oil and MCT oil ClinOleic or other roughly 80/20 blend of olive oil and soybean oil Lipoplus (40% soybean oil, 50% MCT, 10% fish oil) SMOFlipid (30% soybean oil, 30% MCT, 25% olive oil, and 15% fish oil) Omegaven (100% fish oil)

33 Total duration of second type of IVFE received -- if discontinuous, add together the time, and following the same format for years, months and weeks as the previous duration question. Total Years of IVFE Months of IVFE Weeks of IVFE Is the patient on a reduced level of the second type of IVFE compared to the standard dose? For many IVFE's, the standard is 2 g/kg/ day, but for Omegaven, it is 1 g/kg/day, and some patients have been receiving 1 g/kg/day of soybean oil IVFE (IntraLipid). Many patients may be unaware of what dosing level they are on, in which case please enter Don't know. Standard dose Reduced dose Don't know Number of days per week receiving the second IVFE? Days per week

34 Did the patient experience any side effects or negative outcomes that were attributed to the second IVFE? If so, select all that apply from this list, or enter Other and list if not available on the list. No side effects or negative outcomes Yellow eyes or skin (jaundice) Chills, fever, sore throat, headache, hives Bluish skin color Chest or back pain Difficulty breathing Essential fatty acid deficiency (EFAD) Unusual bleeding or bruising TPNALD -- TPN Associated Liver Disease (cholestasis, fibrosis, cirrhosis) -- enables more detailed questions next Portal hypertension (ascites, varices) Liver transplant (alone or as part of a multi-organ) Death Other (please specify next) Other side effects or negative outcomes (please list with commas separating multiple items) Were any of these side effects or negative outcomes reported for this patient on the FDA's MedWatch system? Yes No Don't know

35 Did the patient experience any positive outcomes from the second IVFE in relation to the first IVFE? If so, which of the following symptoms were improved by the second IVFE (please only select items selected for the first IVFE above) No symptoms were improved Unusual bleeding or bruising Chills, fever, sore throat, headache, hives Yellow eyes or skin (jaundice) Bluish skin color Chest or back pain Difficulty breathing Essential fatty acid deficiency (EFAD) TPNALD -- TPN Associated Liver Disease (cholestasis, fibrosis, cirrhosis) -- enables more detailed questions next Portal hypertension (ascites, varices) Other (please specify next) Other symptoms improved by the second IVFE (please list with commas separating multiple items) For TPNALD selected above, what was the typical total bilirubin level recorded from the patient after the maximum effect of the second IVFE was experienced? Total Bili in mg/dl

36 For TPNALD selected above, what was the highest total bilirubin level recorded from the patient? Total Bili in mg/dl For TPNALD selected above, was a liver biopsy performed? If so, the result can be entered next. Yes No What level of cirrhosis was found in the liver biopsy? Cirrhosis Level (1-6)