By Ian Schofield 26 Feb 2021
The MHRA is losing no time in getting its much heralded “new era” of medicines regulation up and running.
Most clinical trials required under EU pediatric investigation plans are medically senseless, and many cause harm to patients, argues consultant Klaus Rose. This is a challenge not only for the pharmaceutical industry but for regulators and wider society as well.
Since 2007, the European Medicines Agency recommends the marketing authorization of new drugs only if they are accompanied by a pediatric investigation plan (PIP) approved by its pediatric committee (PDCO).
Drug regulators in the EU claim PIPs are needed because of "neglect of children in the development of effective and safe medicinal products" or "lack of availability of appropriate medicines for children." Such statements are medically wrong. Pediatric medical treatment is continuously improving. How could statements in open contradiction to reality exert so much influence?
This year the European Commission is due to publish a report on how the EU Paediatric Regulation (Regulation (EC) No 1901/2006) is faring 10 years after it came into force in 2007. This provides an opportune moment to discuss why the PIP system needs a thorough revision.
The idea of running separate clinical trials in adults and children can be dated back to the aftermath of the thalidomide catastrophe that led to the 1962 US legislation that mandated clinical testing of new drugs before registration. This law also transferred control of drug advertising to the US Food and Drug Administration.
From 1963 on, US pediatrician Harry Shirkey pointed out that warnings against pediatric use were placed on drug labels, concluded that these denied the use of new drugs to children, and called children "therapeutic orphans.”
Shirkey’s view was taken up by the American Academy of Pediatrics, which claimed that the bodies of minors – from newborns to adolescents – are so different from those of adults that they need separate proof of safety and efficacy (S&E). The AAP stated in its 1995 guidelines on ethical conduct in pediatric studies: “There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents.”
But Shirkey also observed that most physicians ignored the pediatric warnings. Indeed, legally these warnings did not prohibit use in children. They prevented the advertising of medicines for pediatric use (which the FDA has controlled since 1962), and prevented damages lawsuits in the litigation-prone US.
The AAP and the FDA collaborated closely in the belief that minors needed pediatric labels based on separate S&E studies. Later, the FDA defined pediatric age as under 16 years in the Federal Code of Regulation (201.57(f)(9) CFR); in the US legal adulthood is regulated at the state rather than the federal level.
Eventually, the US pediatric legislation promised financial rewards (pediatric exclusivity, a patent extension) for pediatric regulatory studies. But the therapeutic orphan concept equated the contemporary legal term "children" with a medical/physiological term. Newborns' bodies are indeed different from those of adults; less so in the case of school-age children and even less so for adolescents.
The therapeutic orphans were/are a misleading blur at the interface of law and medicine: demands for separate S&E studies in all minor age groups were/are based on exaggerated AAP statements. In 1995, for example, the AAP "proved" in its 1995 guidelines on pediatric studies that any drug used in minors without sufficient pharmacology studies posed the risk of toxicity and death by referring to just two publications on antibiotics in preterm newborns: this was a bold extrapolation from babies to anybody under the age of 16.
The human body matures and becomes adult before the person’s 16th birthday. Why should antibiotics, cytotoxics, or creams work in adults and not in adolescents or school children? The therapeutic orphan blur reflected clinicians' uncertainty about the methodology of clinical trials: pediatric clinical pharmacology (PCP) had just started. Minors need data on dosing and safety, not separate proof of S&E. Since 2006, the FDA allows extrapolation of efficacy of anti-epileptics from adults down to four years of age and has licensed an anticancer compound down to 12 years based on adult plus additional population pharmacokinetic (PK) data. The FDA has not revised the general therapeutic orphans concept.
Pediatric use of drugs that received US pediatric exclusivity was and remains very limited. Children and adults have predominantly different diseases.
The EU Paediatric Regulation took up, intensified and expanded the therapeutic orphans/US pediatric legislation approach. It defines the "pediatric population" as everybody between birth and 18 years. PIPs demand separate efficacy, safety and other studies in minors as if they were another species. Some PIP-demanded studies lack medical sense simply upon analysis of the inclusion criteria.
For example, a number of PIPs require studies in patients with a physiologically mature body, but who are still under 18. These are not "pediatric" patients, nor are these "pediatric" studies. They reflect a “territorial” attitude, as if these patients "belong" to the PDCO. Recruitment to these studies is based on legal, not medical criteria.
In the case of dermatology, for example, one PIP (EMEA-000585-PIP01-09) demands an active controlled study on efficacy, tolerability and quality of life in 12-17 year olds for a cream against solar urticaria.
Another (EMEA-000892-PIP01-10) requires two S&E studies in 12-17 year olds with acne, while EMEA-001624-PIP01-14 demands five S&E studies for a monoclonal antibody (MAB) in 2-17 year olds with atopic dermatitis, and EMEA-000415-PIP01-08-M01 requires one S&E study with immunoglobulin in 2-17 year olds with myositis.
These efficacy/S&E studies are medically senseless. Creams, MAbs and immunoglobulin work the same before and after the 18th birthday. Dosing in <12 year olds can be assessed by PK and pharmacodynamic (PD) modeling. Most essential safety issues are already known from the adult pivotal trials. Additional safety issues in children of school age will not be detected in separate regulatory studies. For this, registries are a much more appropriate method.
EMEA-000366-PIP04-12 demands one PK-PD modeling study and one population PK modeling study for adalimumab in 12-17 year olds. Compared with the five S&E MAb studies, they may appear modest. But are they medically necessary?
The alleged need for separate S&E studies in minors is based on flawed, scientifically indefensible AAP claims, worsened by the EU legislation’s extension of the "pediatric" age range. Most PIP-demanded studies are "only" medically senseless (and therefore unethical). Even worse are studies in diseases that are so rare in minors that there are not enough patients for multiple PIP studies.
For example, 12 melanoma PIPs have been published. Two melanoma studies were terminated in 2016, while four continue recruiting minors with melanoma and other solid tumors. PIPs demand unfeasible studies in pediatric psoriasis, leukemia, multiple sclerosis and any disease frequent enough in adults to attract drug development, but rare in minors. To identify such studies, all PIPs for the same disease need to be examined. The examples above are the tip of the PIP iceberg: more research will corroborate these findings.
For allergens for specific immunotherapy, PIPs demand five-year placebo-controlled studies in tens of thousands of children and adolescents, exposing patients on placebo to the risk of progression to asthma. The EMA’s 10-year report on experience with the Paediatric Regulation claims that 238 new medicines for use in children have been authorized in the EU. But there are no 238 new medicines for children: they simply obtained pediatric labels. To what degree this improves clinical care is not even addressed. Page 14 of the report lists the "achievements" so far, saying that "many medicines have become available after PIP completion for the treatment of infectious diseases." But the products themselves existed before, i.e., they were "available". A new asparaginase product has allegedly become "available" for acute lymphoblastic leukemia (ALL). But ALL has been treated with asparaginase for decades, achieving survival rates of 90% before the PIPs started. The EMA 10-year report is misleading, at best.
The flawed AAP statements reflected concern for children's health and a wish for pediatric research, research funds, and an AAP-controlled monopoly on clinical investigations: a clear conflict of interest.
Budgets for institutions, including regulatory authorities, are assigned on the basis of their perceived value to the public. In the US, with its checks and balances, the US pediatric legislation had initial positive outcomes.
The EMA is a supranational, more insulated entity. The EMA uses the AAP's moral imperative in PIP negotiations as if the EMA represents the high moral ground and the pharmaceutical industry the opposite. An alleged lack of appropriate medicines for children is claimed by employees of the EU regulatory authorities connected to the PIP system. The EMA claims that off-label use of medicines in children is dangerous in general, in open contradiction to clinical reality: most pediatric sub-specialties developed with off-label drug use.
The AAP has a clear, pragmatic position towards off-label use. The European Academy of Pediatrics by contrast does not have a position on either off-label use or PIPs. The desire of the EMA and the EU national regulatory authorities to emphasize their role in public health, as well as clinicians' conflicts of interest, have so far been ignored in the PIP discussion.
Initial scepticism, partially based on traditional/archaic protective instincts, has given way to an enthusiastic welcome for pediatric research. But minors need reasonable studies, not as many studies as possible. The concept of drug treatment for rare, pediatric, and rare pediatric diseases has been deep-frozen since 1963 by the therapeutic orphan blur at the interface of medicine and law.
Specialists successfully used whatever medicines were available, while pediatric clinical pharmacology expanded partially through the US and EU pediatric legislation. Academia always needs money; industry funding was welcome, without considering potential conflicts of interest: for the individual academic clinician, participation in a clinical trial brings opportunities of publishing, networking, and funding. But if the trial harms patients, as is the case with unfeasible studies or studies that prevent effective treatment, this is done on the back of the patients, which is unacceptable.
Companies are tempted to accept questionable PIPs as annoying but affordable additional costs of drug development. So far, this has worked. But what about patients recruited into questionable studies? When US parents learn about the medical senselessness of such trials, they will sue. If a company cannot prove that it pushed back, US judges might hand out punitive damages, which can ruin a company, a hospital, an institutional review board (IRB) or an ethics committee (EC).
Companies should take steps to defend patients against unfeasible/unethical PIP study requests, for both ethical and long-term economic reasons. Large companies have learned to live operationally with PIPs, but at the cost of patients' health. Backlashes by parents' lawsuits are inevitable, specifically so in the US where patients' rights and the legal system allow strong damages lawsuits, including punitive damages.
Companies need more self-confidence. The EU pediatric legislation allows the EMA to enforce medically senseless studies. Companies cannot register without a PIP; during PIP negotiations they must "propose" studies. But the law doesn't coerce them to play theater, to pretend to share the EMA/PDCO's pseudo-scientific position.
Companies should express their thoughts openly. During PIP negotiations, they should "propose" studies but they should share their concerns before the study starts with the respective IRB/ECs, who mostly are not yet aware of the general danger PIPs represent for underage patients. IRBs/ECs will learn. They can and should reject unfeasible PIP studies, and suspend ongoing ones.
EMA/PDCO insist in negotiations that their position is based on science, which is often not the case. So far, some single IRBs/ECs have rejected PIP studies. Once rejections become more frequent, negotiations and modifications will become easier. EMA management is aware that prolonged confrontations with IRBs/ECs would be detrimental to its reputation.
So far, bodies representing the pharmaceutical industry have tried to alleviate the operational PIP burden, but there are limitations to what they can do. The EMA is expanding the PIP obligations by further revoking class waivers: from 2018, PIPs will be required for diseases that are extremely rare in minors, such as liver cancer. Industry bodies need to look again at the PIP system and the therapeutic orphans concept and should lobby for a fundamental revision.
Similarly, EU national professional bodies representing pediatricians and physicians should distance themselves from the PIP system and ask for it to be revised. Pediatricians who aspire to a leadership position in future need to learn about these areas. Within pediatric academia a debate needs to be started about questionable PIP studies and conflicts of interest when clinicians participate in them.
Better scientific understanding of the challenges of pediatric drug development outside of the AAP, therapeutic orphans and PIP schemes is needed. The intellectual flaws in the AAP's guidelines need to be addressed. The FDA should stop collaborating in the "pediatric cluster" with the EMA, which also involves regulatory authorities from Japan, Australia and Canada. Also, the US pediatric legislation needs a critical re-assessment.
Non-payment of minors' treatment by reimbursement institutions or menacing lawsuits because drugs are not licensed in children were two out of five arguments put forward during a conference on pediatric clinical pharmacology in 1997 as a justification why pediatric labels are necessary. These are legal, not medical challenges. They can and need to be addressed by legally allowing physicians to use their experience to assess the maturity of the patient’s body, independent of the patient’s date of birth. Regulatory authorities worldwide should reject unethical PIP studies and suspend ongoing ones.
The longer the PIPs system continues, the more the EMA's public image will be damaged. It would be desirable for the EMA to propose the immediate abandonment of the PIP system, but the chances that this will happen are remote.
We need to re-consider the role of labels in pediatric healthcare, specifically in rare diseases where large safety and efficacy trials are unfeasible, and in patients who get diseases before legal adulthood. Who in 1962 would have imagined that one day there would be effective drugs against lethal diseases such as melanoma or chronic myeloid leukemia? There are too few minors with these diseases for systematic S&E studies.
To nevertheless treat minors with such drugs does not make them therapeutic orphans. The therapeutic orphans concept, the insistence on separate S&E studies in children, and the automatic requirement for PIPs are becoming an obstacle to progress in healthcare.
Revision of the therapeutic orphans concept is a societal task. Revising the EU pediatric legislation will require a change in scientific assessment and in public opinion. Pediatricians, pharmacists, industry and authorities will need to conduct an intense dialogue on such changes, but not under the pretense that tighter regulation is necessarily good for children.
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