The challenges of clinical trials in children
Mark Schreiner MD
Last week we discussed the difficulties of academic Departments of Anesthesiology to keep the “research flame” alive in our specialty. Indeed, our identity and stature as a specialty is largely defined by discovery and innovation. Further, very few MD/PhDs enter anesthesiology and many traditional research training grant programs like KL2 and T32 programs go unfilled.1,2 As we said in those PAADs, “We simply do not do a good job of showcasing the joys of discovery, nor do we support our successes by providing hiring packages with sufficient protected time and research funding to our physician-scientists.” (PAAD January 18 and 19, 2023).
Although this is true across the specialty in general, it is equally an important issue in pediatric anesthesiology in particular. I’ve aske a frequent PAAD contributor, Dr. Mark Schreiner to review today’s PAAD by Dr. Susan Furth which was published in the New England Journal of Medicine’s Evidence series (not indexed in PubMed). Myron Yaster MD
Original article
Furth SL. Trials and tribulations – The challenges of clinical trials in children. NEJM Evid 2023; 2 (12): 1-2.
The deaths of 107 children from elixir of sulfanilamide resulted in the 1938 Food, Drugs and Cosmetics Act which required evidence of safety prior to FDA approval prior to marketing. After the chloramphenicol-induced gray baby syndrome in the 1950s, and finally the thalidomide disaster, Congress passed the 1962 Kefaufer-Amendments to the Food, Drug and Cosmetics Act which required proof of efficacy and not just safety to gain FDA approval. Disasters involving children provided the impetus for the both laws. However, the amended law in 1962 included a requirement to add an orphaning clause to drug labels whenever there was inadequate data to support use for children or other groups. Rather than the exception, this soon became the default. By 1968, children were considered therapeutic orphans.3 A series of laws have been promulgated to provide sponsors with patent/exclusivity extension (FDAMA) and subsequently added requirements for obtaining pediatric drug labeling (PREA). Those laws have been reauthorized several times, most recently in 2012 as part of the Food and Drug Administration Safety and Administration Act of 2012 (FDASIA). For those interested in a more detailed history of pediatric drug regulation see Ward4 and the FDA’s history summary.5
Despite these laws children still have not achieved equity with adults. Susan Furth, in a recent editorial,6 updates some of the continuing challenges impeding pediatric drug development. She identifies a number of challenges impeding drug and device approvals for children. These fall into a number of familiar categories.
1. Lack of preclinical models for many childhood diseases. Some childhood diseases don’t have adult counterparts and therefore animal models are needed. For example, the animal model for Leber Congenital Amaurosis was a perfect analog of the disease in humans allowing early pediatric trials – and the first genetic therapy approved for either adults or children.
2. Challenges in creating palatable liquid formulations remain a huge challenge. Drugs are often bitter tasting and poorly soluble.
3. Dose finding/selection to identify the correct dosage for children of different ages. Dr. Furth identifies the rapid changes throughout childhood that make dose finding more than a matter of simply scaling the dose to weight or BSA.
4. Ethical and regulatory issues (more on this in a bit) that are familiar to all pediatric investigators.
5. Limited availability of patient populations mandating the need for multicenter, multinational trials. Since most pediatric clinical trials are single center and underpowered, the need for scale mandates the need for significant funding.
6. Difficulty in recruiting and retaining subjects slows enrollment and often leads to failure of promising trials.
As anyone who has served on an IRB will know, the ethical issues are complex but not insurmountable. Dose-finding and PK studies are usually considered by IRBs to lack a prospect of direct benefit. The IRB regulations prohibit such studies in children unless the risk is not more than a minor increase above minimal. For this to be the case, there must be substantial evidence of safety (and usually efficacy) from studies that enrolled adults. These studies also require the assent of the child (if old enough to fully assent) adding another challenge.
Any multi-dose dose finding (Phase II) study or pivotal (Phase III) efficacy pediatric trial has to hold out the prospect for direct benefit to the participant which is not the case for adults There has to be evidence of efficacy in adults or animal models (when there is no adult equivalent condition) before pediatric trials begin.
Given the need for safety and efficacy data, it is not surprising that pediatric studies lag behind studies in adults. Dr. Furth notes that the success of pediatric Covid vaccine trials may point the way forward for future pediatric drug trials. She notes that involvement of parents and the public helped ensure the trials were acceptable and feasible. My own experience working with many industry sponsors is that they often design studies as if the participants were adults – frequent visits and blood draws. To succeed, pediatric trials require simplicity and attention to the family needs. The Cystic Fibrosis Foundation has championed tremendous progress for the treatment of CF by using its considerable sway to affect trial design and implementation.
Pediatric Covid vaccine trials were delayed until after proof of the efficacy and safety in adults. The pediatric trials initially limited enrollment to 12 - 17 year-olds and only after proof of safety and efficacy in this age group were younger age cohorts enrolled, one younger age cohort at a time. The need for adequate safety and efficacy data in adults and older children means pediatric trials will almost always lag behind approval in adults.
To increase enrollment, Dr. Furth suggests that “local physicians should be engaged to help with recruitment”. I’m a bit skeptical that with all the pressures on overburdened practices and lack of adequate time, space, training and incentives, that this is realistic. Less common pediatric diseases will continue to require participation of specialists at pediatric institutions.
Dr. Furth points out that most drugs and devices used in children are not FDA-approved. While this is true, it reflects the fact that most drugs and devices used in pediatrics are no longer under patent or exclusivity protection. The NIH has sponsored only a handful of studies under Section 409I of the Public Health Service Act, resulting in only 14 drugs receiving one or more labeling change between 2014 and 2023.7 Since industry sponsors have no incentive to conduct these trials, academic investigators need to step up and fill some this void.
In 2002 I identified the lack of incentives for academic investigators to get involved in pediatric drug trials as a major obstacle.8 “Not all of the blame for the lack of labeling information for drugs falls on the shoulders of the pharmaceutical industry. Academic medicine and pediatric practitioners need to do more as well. Drug development must become an acceptable and rewarded pursuit for academic investigators. Department chairmen, committees on appointments and pro- motions, and peers need to recognize the value in this work. Study design, data management and interpretation, and information dissemination are important components of the trial process. Without incentives (e.g., time, space, resources) and rewards (e.g., recognition and promotion) academic physicians will not participate as investigators.”
I wish Dr. Furth had acknowledged some of the tremendous success spurred by passage of FDAMA or PREA. Thousands of pediatric trials have been conducted since 1997 with a tremendous surge in labeling changes, currently averaging over 60 per year. Compared to the pre-1997 era, this has been monumental. Lastly, as Ward2 points out, the biggest gap in knowledge and our greatest current challenge is obtaining data relevant to neonates. At present, they remain therapeutic orphans.
Send your thoughts and comments to Myron who will post in a Friday Reader Response.
References
1. Brass LF, Thalji N, Hodge DQ, Akabas MH. Physician-Scientists in Anesthesiology: The All Too Empty Pipeline. Anesthesia and analgesia 2023;137(4):725-727. (In eng). DOI: 10.1213/ane.0000000000006648.
2. Emala CW, Sr., Tawfik VL, Lane-Fall MB, et al. The Anesthesiology Physician-Scientist Pipeline: Current Status and Recommendations for Future Growth-An Initiative of the Anesthesia Research Council. Anesthesia and analgesia 2023;137(4):728-742. (In eng). DOI: 10.1213/ane.0000000000006520.
3. Shirkey H. Therapeutic orphans. The Journal of pediatrics 1968;72(1):119-20. (In eng).
4. Ward RM. Improving Drug Therapy for Pediatric Patients: Unfinished History of Pediatric Drug Development. The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG 2023;28(1):4-9. (In eng). DOI: 10.5863/1551-6776-28.1.4.
5. United States Food and Drug Administration. A brief history of the Center for Drug Evalutation and Research (CEDR). (https://www.fda.gov/about-fda/fda-history-exhibits/brief-history-center-drug-evaluation-and-research).
6. Furth SL. Trials and tribulations - The challenges of clinical trials in children. New England Journal of Medicine Evidence 2023;2(12):1-2.
7. United States Food and Drug Administration. NIH funded pediatric labeling changes for drugs studied under the 409i process. (https://www.fda.gov/drugs/development-resources/nih-funded-pediatric-
labeling-changes-drugs-studied-under-409i-process).
8. Schreiner MS. Paediatric clinical trials: redressing the imbalance. NatRevDrug Discov 2003;2(12):949-961.