I recently wrote about Sickle Cell Disease (SCD) highlighting racial disparities in healthcare in terms of funding and access to care. One of the other frustrating issues is the lack of FDA approved medications for infants, forcing physicians to treat children “off-label.” I find this inexplicable and inexcusable. Enter the regulatory quagmire for more of the bizarre tales from the FDA and the NIH’s National Heart, Lung, and Blood Institute (NHLBI).
First, the good news is that sickle cell disease meets the criteria for orphan drug status, which would provide financial incentives for drug development. Gayatri Rao, MD, JD, FDA’s Director for The Office of Orphan Products Development (OOPD), explained that their office supports research as well, and that their grant program “has awarded more than $15.3 million to fund clinical research for sickle cell disease therapies, including a total of $1.2 million to support three clinical studies this past year (FY14) alone.” Ironically, however, SCD does not meet the strict definition to qualify for additional incentives through the Pediatric Priority Review Voucher program, as kids are now living too long—the statute specifies that the disease has to primarily (defined now by the FDA as greater than 50% of the population living with the disease) affect people < 18 years old and the median age is now well above that. SCD advocates have challenged this definition, as the disease has devastating effects often beginning in infancy. Dr. Rao said, “We are evaluating the comments…there has to be some interpretation and a line that is drawn. …We’re doing our best” as they revise their guidance and reconsider their interpretation of the legislation, which is rather at odds with patients’ experiences and needs. I was happy to see that their plans included meeting with patients through the Patient-Focused Drug Development Initiative.
Hydroxyurea is being studied in pediatric patients under the National Institute for Child Health And Human Development’s (NICHD) program, under the Best Pharmaceutical for Children Act which helps with pediatric drug development and testing of off-patent drugs.
Trying to understand this morass better, I next turned to Anne Zajicek, MD, PharmD, Chief, Obstetric and Pediatric Pharmacology and Therapeutics Branch of NICHD. She provided the best glimmer of hope for children regarding hydroxyurea. The NICHD worked with the National Heart, Lung, and Blood Institute (NHLBI) to make a liquid formulation of hydroxyurea for a clinical trial in infants aged 9 to 17 months, known as “BABY HUG.”
This trial began in 2000 and was completed in 2009, finding “significantly fewer acute sickle cell–related complications than those taking placebo. The lower rates of complications were associated with fewer hospitalizations and transfusions. There were no clinically important AEs (adverse events) or SAEs (serious adverse events) that were related to hydroxyurea.” Clinical and safety data are being performed in the BABY HUG Follow-up Study, due to be completed next year. I’m unclear why the wheels are still turning so slowly on this approval.
The good news? The data should go to the FDA by the end of this year and, if all goes well, there will be a pediatric indication after their review (which can take six months). But for now, and for past years, this lack of FDA approval forces physicians to treat “off-label.” Sickle cell treatment guidelines have hydroxyurea as a mainstay of therapy, yet pediatric formulations have languished without FDA’s blessing. I hate having physicians (and patients) placed unnecessarily in this kind of regulatory double bind, with following procedures taking years and years.
The Pediatric Priority Review Voucher is due to expire in March 2016; it’s unclear whether it will be reauthorized. The Advancing Hope Act of 2015 would modify the definitions to specifically include any form of sickle cell, but the outlook for enactment of this bill is not encouraging.
#SCDForum15
Last week the NIH/NHLBI hosted a two-day forum on sickle cell. I compiled a Storify of Day 1 here and Day 2 here. The videos are also available and the webcast was well done.
One talk I enjoyed was that of Dr. Wayne A.I. Frederick, President of Howard University. I can’t imagine how he managed to complete surgical training while suffering from this disease and sickle crises, as well as “the indignities that someone with chronic disease suffers.
Dr. Wanda Whitten-Shurney, of Children’s Hospital of Michigan, spoke of the need to address patients’ invisible pain. She also urged countering fears of clinical trials and the understandable fear of participating and being a “guinea pig,” noting that there is a fair amount of experience with a drug by Phase 3 of clinical trials.
There were some consistent themes, particularly the frustration and anger of patients whose pain is inadequately treated. There is an urgent need for better ways of assessing and treating pain. With the lack of general awareness about SCD, even among health care workers, patients are incorrectly often labeled as drug-seeking, especially since the cause of their pain is invisible. Emergency Room staff must be educated in identifying and responding appropriately to pain. One patient advocate, Larry Allen (@sicklebear) commented that emergency room visits might spark a PTSD type response in patients, which is misinterpreted as anger. He observed, “When the one place you can go for help and to feel safe treats you like a criminal anyone would develop PTSD triggers.”
Dr. Wally Smith, Scientific Director of the VCU Center on Health Disparities, gave a good overview on pain, emphasizing that most episodes of acute pain are treated at home. (Slides for many of these talks are in my Storify). He also emphasized the huge impact of fatigue and how that interferes with school, work, and normal activities. Dr. Smith noted that he is required to do humiliating toxicology screens on his SCD patients who use chronic opioids, and the additional risk to him, as a prescriber, if they use cannabis as well for better pain control.
One proposed solution for patients is to have their health records readily accessible to hospitals, health providers, so that there is ongoing documentation of what treatments work for an individual patient. This sort of registry is a great idea, but no two hospital systems seem to have electronic records that communicate with each other.
In the meantime, the struggles patients have being believed was a common and recurrent theme voiced by patients.
“Sickle cell disease is complex and expensive, with major barriers to healthcare delivery," observed Lewis Hsu, MD, Director of the Sickle Cell Center at University of Illinois. He raised the benefits of and need for specialized community health workers or patient navigators.
Dr. Jeffrey Glassberg, an Emergency Room physician at Mt. Sinai (NYC) who also has a sickle cell clinic, gave one of the most exciting talks. His focus is on developing evidence-based protocols for managing SCD.
Transitions in care from pediatrics to adults was a focus of Day 2, with the difficulties “normal” teens have navigating the path to adulthood safely magnified in teens with chronic illnesses like SCD or diabetes. Dr. Kanter-Washko of @MUSChealth discussed some of these problems. The life expectancy of someone with SCD used to be just 14 years, but is 40-45 today, with some even living into their 60s. Again, several patients voiced being ill-prepared for adulthood, as they (and their physicians) expected them to die before age 30. Brooke Allemang, SW at Toronto's Hospital for Sick Children gave (for me) another one of the top talks, explaining how they structure their clinic transitions. She also referred to the nifty “MyHealth Passport” wallet card, which patients can (and should) have to summarize their health information. The social work patient navigators are quite innovative in communicating with their patients and easing the transition, as well as making it safer.
Unanswered questions included mine, above, and that improved survival means that SCD now doesn’t qualify for pediatric priority review vouchers. Dr. P Mimi Poinsett MD@yayayarndiva (who has been hosting informative #sicklecellchat series on twitter) asked:
Comment: who will address implicit bias and lack of cultural competence in community #SCD care? #SCDForum15. She also noted that insomnia and fatigue can cause depression and that “Comment: Mental health and well-being seems to be the giant elephant in the room.”
There is no national registry for SCD, as public funding is lacking, and patients lack the strong, vocal advocacy groups that have been so effective for cystic fibrosis and some other rare diseases.
It is both unfortunate and frustrating that, more than 15 years after a study was begun, that there is still no liquid formulation of hydroxyurea for infants and young children. I tweeted a question about this situation, but my question was not addressed by the forum speakers. Some forum sessions focused on new drugs in clinical trials and on bone marrow transplants. While this may be a curative therapy, it has great risks and expenses. I’d like to see focus on the basics, and low-hanging fruit. There are huge disparities in access to care, so this emphasis on high tech solutions seems misplaced. As another example, Dr. Poinsett asked about the U of Illinois Sickle Cell Clinic being on the chopping block for budget cutbacks. She got no response.
The NIH/NHLBI forum was useful and I particularly welcomed that it was webcast live (as well as archived), and that they entertained some questions from social media (twitter), albeit selectively. Good format and positive first step.
It is clear from the forum and from other sources, however, that much remains to be done for these patients. In particular, there is a great need for a treatment form for infants and young children, we need to ease the transition of these patients from adolescence to adulthood, the portability of records needs attention, and there needs to be a concerted effort to educate caregivers – especially E.R. personnel -- about the needs of these patients for adequate pain control. Maya Angelou said it best: "I’ve learned that people will forget what you said, people will forget what you did, but people will never forget how you made them feel."
Selected resources:
#SickleCellChat monthly hosted by @yayayarndiva, @bloodborn, and @sicklecelldoc
Transitions: Good 2 Go and Shared Management Model
