Members of the bleeding disorders community came out toÂ share their experiences with bleeding disorders treatment with the FDA.
HFA worked with partners like NORD, PPTA, and NHF to ensure that our community was effectively represented.Â Patients and advocates of every age, every background, and with several different conditions came out to share with the FDA their hopes, fears, highlights, and trials in treating their conditions.
Below is the testimony of the Hon. Donald S. Goldman (Ret.), who shared hisÂ his experiences across seven decades of hemophilia treatment, from receiving whole blood to factor, while detailing his hopes for contemporary Hepatitis C therapy trials. Donald did a wonderful job of explaining that no two patients receive the same care, calling on the FDA to ensure a wide range of safe, effective, and affordable treatment options for the hemophilia community.
I will be 70 on October 10th. Over seven decades I have seen major improvements in the safety and efficacy of treatments as well as matters of storage, volume, ease of administration, and length of effectiveness. I have confidence that my great grandchildren will benefit from miraculous treatment advances and perhaps a cure.
My recommendation is that we continue to seek improvements in all these areas. Patients and their Hemophilia Treatment Centers (HTCs) should have access to new advances with a full understanding of their risks and benefits. Phase IV studies should be mandated on all novel treatments.
On December 21, 1991, I made a presentation to the FDA’s Blood Products Advisory Committee which was then considering the first recombinant factor. I was told that some physicians had urged that approval be denied because of potential inhibitor development. I decided to respond. Almost 25 years later, my advice still applies.
I explained how the first time that I received a pint of whole blood was before the Korean War.
Next, I received plasma and then fresh frozen plasma. Each transfusion carried the risk of strange sensations, stinging, unpleasant tastes, severe hives and the risk of hepatitis.
When I wanted to try out for Little League, I had to choose between the risk of injury and the risk feeling different from my peers. When I started using cryo (10 or more bags at a time), sometimes the units were tinged green, almost fluorescent, a result of the donor taking birth control pills. When we drove to Montreal on a vacation, we had to map out an itinerary that included places to buy dry ice so we could keep cryo frozen.
We used to call some of the initial attempts to lyophilize cryo, “bubble gum,” which related to the consistency of the product that resulted. Efforts to further purify factor were ridiculed, comparing such efforts to the Pepsodent toothpaste commercial, as “trying to get the yellow out.”
After an NHLBI conference entitled “Unsolved Problems in Hemophilia,” my doctor reported that there were risks of long-term usage of factor causing liver damage, kidney disease, or infectious diseases from source-paid plasma. Those risks did not deter me because before my life had been driven by painful bleeding episodes, being bedridden, and spending time in emergency rooms. Prospects for school, career, and a normal lifespan were dim. Factor and home care liberated me from pain and severe disability, and made life fulfilling.
When AIDS first reared its ugly head, some physicians said that AIDS was not even transmitted by blood products; others said that AIDS was no more of a problem than hepatitis B had been, and still others were fearful. Questions of factor versus cryo were ever-present because the voluntary sector which made cryo refused to ask blood donors about high-risk behaviors.
When heat-treated factor first appeared some thought that it might alter the molecule and cause inhibitors. Some argued that the increased cost did not justify their use. Then there were many types of heat treatment, different temperatures, different stabilizers, and different time periods.
Once there was a shortage of factor and I only had two doses left at home. It was a Wednesday night of a Thanksgiving weekend and I felt the beginning of a bleed in the knee. I had to decide whether or not I should use one of my two doses that were left when I still had four or five days of weekend ahead of me.
When solvent-detergent and monoclonal antibody products appeared on the scene, they seemed to be better choices. But I also remember learning of seroconversions in Germany and being reminded of the risk of manufacturing errors and Red Cross snafus.
I explained to the Blood Products Advisory Committee that while I did not know what choice I would make if a recombinant product were available, what I wanted was for me and my HTC to have all the options so that we could choose with knowledge of all the potential benefits and risks.
That presentation was almost a quarter century ago. When I learned about this FDA program, I re-read my 1991 statement and thought how relevant it still was.
Let me bring you up-to-date. Between 1992 and 2009, I continued to use factor and had two knee replacements which enabled me to serve as a Superior Court judge. I enjoyed that career and presiding over substantial criminal and civil trials. I now mediate part-time and spend time with my wife and 4 grandchildren and travel when possible. I am still on home care and use recombinant factor. My doctors recommend prophylaxis but I am not fully compliant. I have some breakthrough bleeds, so I use about 20,000 i.u. per month. This costs about $250,000 per year all covered by Medicare and supplementalÂ coverage.
The FDA has asked me to discuss the considerations that go into trying new products. Let me use Biogen’s new product, Eloctate, as an example. One consideration is cost. Using over $250,000 per year, even a small co-pay is far beyond my means. Currently, the product I use has no co-pay. Using factor every four days instead of 3 times a week means less wear and tear on my “old faithful” vein that I won’t let anyone else touch. On the other hand, if I develop Parkinson’s disease, finding a vein might be more difficult. In addition, longer lasting factor is important when travelling on many fronts – maintaining factor VIII levels, storage, emergencies – to name a few. Next February, I am travelling for 16 days. At every other day dosage, I need to bring 8 doses plus 4 more for emergencies, or a total of 12 doses. I would only need to bring 8 doses of a longer lasting factor, a quantity much more convenient for travelling. Fitting lots of factor and other medications into carry-on luggage is a challenge. A dosing schedule of once every four days would also help overcome the problem of adherence. On the other hand, I usually follow the adage that if current treatment is doing fine, do not change. Assuming the availability of insurance coverage and my age, I will probably switch soon but I am not sure I would urge the same to a young child facing a lifetime of treatment.
Other companies will soon have new longer lasting products which use PEGylation rather than Fusion technology. These products will be controversial. Advocates of Fusion may claim that PEGylation may lead to the accumulation of large molecular weight compounds in the liver and other organs, albeit with no known consequences. Advocates of PEGylation may point to the novelty of Fusion and its unknown consequences over the long term.
While I was able to escape infection with HIV, I did not escape hepatitis C. In 2010, a course of Interferon and Ribavirin left me with no benefit. My viral load actually increased during treatment. I developed cirrhosis, had no energy or stamina and entered a transplant list. Then in early 2014, new drugs became available, and my hepatologist suggested an off-label combination therapy. Insurers rarely cover off-label usage, particularly for an expensive drug combination costing about $2,000 per day. They agreed to cover it and within 10 days my viral load was undetectable with no side effects and has remained undetectable. When relapses were reported in persons with cirrhosis who had been null responders on prior treatment, my doctor wanted to continue medication for another 12 weeks. I am not sure what I would have done if the insurers had denied the addition $150,000 in cost, but they approved it so no hard choice was presented.
Thus, as you can see, cost is an important aspect of the balance between choices and risks. Having an effective treatment is of no importance if it is not affordable. In my travels to Latin America, I met a young man who could hardly walk and desperately needed a knee replacement but could not afford the factor needed to cover surgery.
What is important is very individual. For the child with difficult veins and a history of infections in ports, a better way of administration is key. For someone with an inhibitor, a new treatment for inhibitors is key. For those with already-damaged joints, new arthroplasty components are needed. For those who cannot afford factor, particularly in less-developed countries, biosimilars offer the hope of competitive pressure to make it more affordable. For me, with grandchildren who are carriers, an absolute cure isÂ required.
And so, I conclude with the message that there will always be choices and risks in treating a complex chronic medical condition. The decision as to which choices to make and which risks to take are highly individualized and require careful consideration by collaborative discussions between patients, their families and HTCs. While long acting factor has the potential to make adherence and effective prophylaxis attainable from birth, treatment advances did not stop with fresh frozen plasma, cryoprecipitate, lyophilization, heat treatment, solvent detergents, recombinant, Fusion or PEGylation. And it must not stop now because even incremental improvements offer improved options for persons with hemophilia today and for generations to come. There is no single answer. There is no one choice. There is no uniform risk. The job of the FDA is to maximize those choices and make sure that patients and HTCs are informed so they can choose their risks.