The US pediatric legislation was introduced with high clinical expectations. The FDA mused in 2001: “Superior drug treatment information is expected to permit quicker recoveries from childhood illnesses, with fewer attendant hospital stays, physician visits and parental work days lost.”40 These were clear clinical endpoints. In depression, however, the FDA-rewarded separate “pediatric” studies and their intellectual processing achieved the contrary. It took decades for the recognition that depression exists in young persons. When the existence of depression in young persons was recognized, the children-are-therapeutic-orphans concept and the intellectual conceptualization of “pediatric” study data unfortunately resulted in the denial of effective antidepressants to young persons.
There is high merit in the FDA’s success in keeping dangerous compounds such as thalidomide from being sold as medicines. However, with the imposure of the on-label/off-label framework on the administratively created “pediatric” population, the FDA has laid the foundations for a development that increasingly withholds effective medicines from young patients. This was taken up and augmented by the EMA.17,18,20,22
The first US pediatric legislation of 1997 did not further advance pediatric oncology. It produced in single-agent-studies pharmacokinetics/pharmacodynamic data for many chemotherapy agents that had already been in clinical use for decades. Most studies were performed in heavily pretreated young patients that had already undergone several rounds of chemotherapy and were either refractory or relapsed. These studies provided regulatory coverage in hindsight for chemotherapy agents already known to be effective. Some got pediatric labels, others did not.17,18,20,22,41 They provided publications, networking, and funds for the involved researchers, patent protection for the sponsoring companies, and offered to the clinical pediatric research networks a new platform to discuss pediatric oncology that provided them easier access to pharmaceutical companies. A new decisive breakthrough in acute lymphoblastic leukemia (ALL) came not through pediatric legislation, but through successful involvement of the immune system in destroying malignant ALL cells by re-programmed leukocytes.42
Juvenile idiopathic arthritis (JIA) is not one disease, but an umbrella term for seven distinct diseases. They start in patients up to 16 years old, but they do not end at the 17th or 18th birthday. For the JIA clinical research networks, US and EU pediatric legislation provided many FDA-rewarded and then numerous EMA-demanded “pediatric” studies to study various JIA subtypes, subsequently documented in numerous academic publications.43,44 However, these studies were not “pediatric.” A disease that starts before the 16th year of age is not automatically “pediatric” or “juvenile,” as it can persist into adulthood. Juvenile idiopathic arthritis often continues into adulthood. Biologics and monoclonal antibodies (MABs) allow effective treatment, while steroids and methotrexate allowed symptom relief, but often with heavy side effects. Biologics, MABs, steroids, and methotrexate work before and after the 17th/18th birthday. Canakinumab, a human antibody against interleukin-1-beta (IL-1β), was first targeted against rheumatoid arthritis. It failed, but proved highly successful in cryopyrin-associated periodic syndrome (CAPS), systemic-onset JIA, and other disorders caused by overproduction of IL-1β.45 The pediatric rheumatology research networks Pediatric Rheumatology Collaborative Study Group (PRCSG) and Paediatric Rheumatology International Trials Organisation (PRINTO) praise US/EU pediatric legislation as responsible for today’s massively improved treatment of JIA.43 The reality is more complex. These groups started with commendable, legitimate studies in young patients when only limited treatment options were available. Several JIA sub-diseases are fundamentally different from adult rheumatoid arthritis. Many clinical JIA studies in young patients helped to improve treatment. However, this is not an issue of “pediatric” studies, but of the biology and the characteristics of the respective disease and the efficacy of newly developed medicines. The first pivotal CAPS studies were performed in patients of all ages, because CAPS is extremely rare. In other JIA sub-diseases, there are enough patients for large international trials.
When depression was recognized to exist also in young persons, treatment became jeopardized by the children-are-therapeutic-orphans concept and the imposure of the on-label/off-label framework in the administratively created “pediatric” population. The regulatory authorities demanded separate proof-of-efficacy studies in young patients despite the fact that, for example, there is no difference in post-partum depression between a 17- and an 18-year-old young mother. This represents an artificial separation (Table 1, study 3). The children-are-therapeutic-orphans concept led to the first 23 FDA-rewarded “pediatric” studies in antidepressants,2 followed by seven further studies,14 with the ongoing studies listed in Table 1, and contributed to psychiatrists’ and family doctors’ hesitancy to prescribe effective antidepressant treatment in young patients.
Depression in young patients is not fundamentally different from adult depression. Both represent an imbalance of feelings, based on an imbalance of receptors, transmitters, and connections in a brain that has reached some maturity and struggles to cope with reality. There are not two different types of depression, an adult one in patients ≥17/18 years, and a “pediatric” one in patients <17/18 years, nor two different types of antidepressants, those for patients <17/18 years old, and those for patients ≥17/18 years old. All depressed patients have the same receptors, transmitters, and imbalances. The suicidality discussion was triggered by the children-are-therapeutic-orphans concept, became a strong deterrent against effective treatment, and is probably responsible for many suicides that could have been avoided.
The controversy of alleged suicidality in young patients with MDD reflects complex societal challenges. The APA and AACAP concerns against the FDA black-box warning were appropriate,3 but they were expressed at a time when the FDA enjoyed a peak in administrative power and societal reputetion, supported by high enthusiasm about “pediatric drug development” in the medical world, the general public, the US congress, and in the pharmaceutical industry. This situation was further augmented by the EU pediatric legislation.17,18,20,22 Now, 15 years later, it is time to re-consider.
Apart from the “children-are-therapeutic-orphans” concept, the FDA developed and expressed additional concepts regarding different childhood diseases. Malignancies in “children” were declared to be fundamentally different from adult malignancies, with the exception of chronic myeloid leukemia.41 Chronic myeloid leukemia (CML) was the first malignancy for which a successful precision medicine, imatinib, had been developed; imatinib works in CML patients of any age. Separate “pediatric” studies in antidiabetic drugs were FDA-rewarded. Type 2 diabetes mellitus (T2DM) occurs in young persons, but is rare. One risk factor is obesity. All patients in the “pediatric” T2DM studies were massively overweight. All tested drugs reduced glycemia, but not all received a “pediatric” label.17,18,20,22 The FDA/EMA-triggered separate “pediatric” studies showed efficacy of insulin in type 1 diabetes mellitus.46 No chronological switch changes insulin receptors overnight at the 17th/18th birthday. Comparable “pediatric” studies were performed in dermatology, cardiovascular diseases, hypertension, and other diseases.17,18,20,22
Childhood depression, childhood cancer, and JIA are very different, but have in common that all new drugs need FDA/EMA approval; the submitted clinical studies must meet the authorities’ expectations. Underage patients in these three disease areas have very different needs. Treatment of cancer and JIA are straightforward once they are diagnosed, while depression is more complex. Psychiatrists and family doctors, insecure about the risks of antidepressants in young patients and in fear of being sued, hesitated to prescribe them, resulting in an increase of completed suicides.2,4 Why did the FDA not retract its black-box warning? Why could the APA not increase public pressure that would have forced the FDA to do so? And why is childhood cancer more discussed in the public than suicide?
Suicide, often resulting from depression, is a much more frequent cause of death than childhood cancer,30 but pediatric oncology attracts more public attention and funding. From 2020 on, the RACE for Children Act will give the FDA the authority to demand pediatric studies for new anticancer compounds.47 Today, the FDA recommends “basket” studies for pediatric cancer,48 but from 2020 on it will mandate studies—a mandate so far only given to the EMA.17,18,20,22
Clinical trials as the basis for drug approval have acquired an enormous weight in medical decision-making. Clinicians, however, are not guided only by the principles of “evidence-based medicine.” Clinicians do not execute regulatory authorities’ commands or recommendations, but are guided by codes of conduct that include their professional training, their being exposed to scientific, commercial, and other non-scientific influences, including real-life issues. Common sense is part of this background.
The exaggerated trust in clinical studies is ridiculed by Smith and Pell who demanded double-blind placebo-controlled studies to prove the efficacy of parachutes.49 Establishing a sound balance between clinical training, trials methodology, and common sense is demanding. It is time for the medical profession to re-establish a common-sense approach towards the regulatory authorities, in treating depression and other disorders.
The studies listed in Table 1 plan to recruit >2,000 young patients worldwide. All these studies, maybe with the exception of study 1, are unethical in our opinion and should be suspended by the responsible institutional review boards/ethics committees. In several clinical disciplines, critical voices have been published against regulatory-demanded “pediatric” placebo-controlled studies, including in multiple sclerosis50 and allergic rhinitis.51
Many FDA/EMA-demanded “pediatric” studies expose patients to substandard treatment and can potentially harm them. Furthermore, FDA/EMA positions provide an insufficient framework to treat depression and to prevent suicide in young patients. To improve treatment of depression and to prevent suicide will require us to overcome hidden conflicts of interest that have evolved in the past half century and are not yet recognized sufficiently.17,18,20,22
In dealing with depressed young patients, a common-sense approach and regulatory recommendations are divergent. Gradually, common sense has guided the clinical world to the conclusion that young patients also need effective antidepressant treatment, but the “suicidality” dilemma is not intellectually resolved. To resolve it, we propose to consider abandoning the children-are-therapeutic-orphans mantra.
The physicians that started to prescribe combination therapy for adolescents with conventional melanoma did so (and had to do so) off-label. Until these studies were terminated, precious time passed, and two “pediatric” melanoma studies recruited patients that would have deserved better treatment.20,22 We will never know how many young patients died of completed suicide because the regulatory authorities’ “suicidality” concept increased physicians’ hesitance to prescribe effective antidepressant treatment.
Institutional review boards/ethics committees should consider suspension of the studies listed in Table 1, and APA and AACAP should re-express their concerns against the FDA’s black-box warning of “suicidality” in young patients. Finally, US and EU pediatric legislation need revision.