Blind Trust E-Book

Klaus Rose

• Herausgeber: Hammersmith Health Books
• Kategorie: Fachliteratur
• Sprache: Englisch
• Veröffentlichungsjahr: 2022

Beschreibung

Many parents of children with serious health problems may wonder why new medicines are initially not approved for minors and, if their condition is rare, why at the same time there is such pressure to enter any young person under 18 into drug trials. So-called 'paediatric' pharmaceutical studies have become an international multi-billion business with many careers in academia, regulatory authorities and the pharmaceutical industry based on this work, yet much of this activity is founded on a series of flawed concepts that have led to immeasurable wastage of resources and serious, ongoing medical abuse. In this revelatory book, the former head of paediatric drug research at two major pharmaceutical companies provides a guide for parents and non-specialists interested in advancing the health of individual children and groups of children showing the key differences between clinically-directed and administratively-directed research, what will potentially benefit or harm children and how the law needs to change around the world so that true advances can be made.

Leseprobe

This book is dedicated to our daughter Rebecca, without whom this book would never have been written. Rebecca was our first child, born in 1994 with Sturge-Weber syndrome (SWS – see www.sturge-weber.org), a complex disease for which only symptomatic treatment is available. Rebecca was moderately mentally and physically handicapped and suffered from epilepsy, among other things. And she was always full of zest for life. Over time her epilepsy had become more stable, but in June 2021 she had an epileptic fit in the night, suffocated, and passed away. Living with a special child shapes the life of parents and siblings and gives you an insight into areas and aspects of society that would otherwise remain closed. Rebecca will always stay alive in our hearts.

Contents

Foreword

About the author

Preface

Abbreviations

Part I: Introducing the flawed concept of ‘paediatric’ research

1. Introduction

2. The business of paediatric research

3. Can ‘children’ receive ‘adult’ medicines?

4. Finding good and identifying bad studies

Part II How the flawed concept of ‘paediatric’ research affects the treatment of specific conditions

5. Cancer, leukaemia and other malignancies

6. Suicide and depression in young people

7. Diabetes

8. Epilepsy

9. Knee surgery

10. Perinatal depression

11. Pain relief

12. Attention-deficit hyperactivity disorder (ADHD)

13. Inflammatory skin diseases

14. Juvenile idiopathic arthritis (JIA)

15. Multiple sclerosis

16. Covid-19

17. Infectious diseases, antibiotics and other antimicrobials

18. Inflammatory bowel disease (IBD)

19. Rare and ultra-rare diseases

20. Cystic fibrosis: an example of a rare disease

Conclusion: How to restore public trust in science, medicine, clinical research and the regulatory authorities

End note

References

Index

Foreword

It is a great honour to be invited to write a preface for Dr Klaus Rose’s new book. He has become one of my heroes in medicine. Dr Rose has taken on the giant regulatory authorities involved in childhood drug trials – the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) – as well as pharmaceutical companies and academic physicians who have advanced their careers by advocating and participating in these trials. The best analogy for this struggle is to compare Dr Rose to a young David trying to defeat the Philistine giant in the Old Testament story in the Book of Samuel. In this analogy, the ‘giants’ are inappropriately advocating for unnecessary and potentially harmful clinical trials in ‘children’ for drugs where proof of concept has already been established.

Since 1962, pharmaceutical companies, in an effort to protect themselves from damage lawsuits, have inserted paediatric warnings into drug labels [the literature supporting a pharmaceutical]. These labels warned that the drugs had not been tested on children. As a result, children were referred to by many as ‘therapeutic orphans’. Consequently, the American Academy of Pediatricians (AAP) began to support separate paediatric clinical trials and, in collaboration with the FDA, paediatric pharmaceutical legislation was introduced resulting in patent extensions for pharmaceutical companies that undertook clinical trials in ‘children’. In Europe, the EU has been even more demanding in that the European Medicines Agency (EMA) has demanded that the company developing a drug submit a draft ‘paediatric investigation plan’ (PIP) mandating that the company would perform clinical trials in minors. The PIP negotiation with the EMA usually takes one year and must be approved and later performed for the drug ultimately to be approved and available to adults. If the PIP is rejected, the EU approval of the new drug is blocked until a new draft PIP has been submitted and has been successfully negotiated.

This has resulted in delayed availability of new drugs to our vulnerable children and grandchildren despite the fact that proof of concept has already been undertaken. Instead of expensive and lengthy clinical trials, all that is needed are dosing studies for smaller children. The resultant delay is not only unconscionable but the trials often place children in the control group at potential harm.

In this new text, Dr Rose exposes the lies, hypocrisy and false promises made by researchers and regulatory authorities and offers solutions to parents and others who are involved.

Jane M. Grant-Kels MD, FAAD

Professor of Dermatology, Pathology and Pediatrics

Vice Chair, Department of Dermatology

Director of the Cutaneous Oncology Center and Melanoma Program

Founding Chair Emeritus, Department of Dermatology

Founding Director Emeritus of the Dermatology Residency and Dermatopathology Lab

University of CT (Connecticut) Health Center Dermatology Department, Connecticut, USA

About the author

Klaus RoseMD MS is a medical doctor who worked in the pharmaceutical industry for 20 years. He was an enthusiast for pharmaceutical studies in children and became global head of paediatrics first at Novartis and then Genentech/Roche before becoming an independent advisor on paediatric studies for drug approval in 2011. Through this work he came to understand a large proportion of ‘investigations’ in children are not only unnecessary but also ethically questionable yet these problems are hidden behind the message of ‘helping children’ that is hard to challenge. His book for scientists and health professionals involved in drug trials – Considering the Patient in Pediatric Drug Development: How good intentions turned to harm – was published by Elsevier (Academic Press) in 2020.

Preface

I am a medical doctor. After clinical training I joined the pharmaceutical industry to use my languages in an international job. When in 1997 I came across paediatric clinical studies, I was intrigued, also because our eldest daughter suffered from a rare, complex disease. I became passionate about ‘paediatric drug development’, became global head of paediatrics at Novartis from 2001 to 2005, and had the same position at Genentech/Roche from 2005 to 2009. Since 2011 I have been independent, advising companies on paediatric studies that are requested/demanded by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). From early on, I saw that many paediatric studies required by the regulatory authorities were questionable, but did not investigate this further until recently. Finally, I found the answer to the riddle in historical documents from the American Academy of Pediatrics, the FDA and the EMA. Demanding separate paediatric studies began when drug toxicities were observed in newborns in the 1950s. Real dangers of drugs to babies were exaggerated into alleged risks of all drugs in all ‘children’, even those who were already physically mature. Justified early concerns for babies have since grown into a worldwide industry of pointless and even harmful ‘paediatric’ studies as the many cases highlighted in the book will show. But they make perfect sense if you look at who benefits. US lawmakers were persuaded to reward pharmaceutical companies funding ‘paediatric’ drug studies with patent extensions, allowing those companies to sell their drugs longer at a high price. All of a sudden paediatric researchers were being asked for advice and to conduct studies. ‘Paediatric’ careers emerged in academic research, the regulatory authorities and pharmaceutical companies.

The catch is that the 18th birthday, an administrative milestone, is also used as the milestone for a non-existent physical transformation. The body matures slowly during the process of puberty. A tall 16-year-old athlete is administratively still a child, but no longer physically immature. Minors do not remain as immature and vulnerable as newborns until they come of age; medicine treats the body, not that body’s legal status. This is a new challenge at the interface of medicine and the law in the context of continuing medical progress and blind trust in institutions and regulatory authorities to ‘do the right thing’ – a new challenge for the 21st century.

I publish in international peer-reviewed medical journals.1,2 My first medical textbook, Considering the Patient in Pediatric Drug Development: How good intentions turned into harm was released in 2020.3 More books are in the pipeline. Unexpectedly, I found I had come across the largest abuse in medical research since the unveiling of inhumane studies in the USA in 1966,4,5 and the termination of the Tuskegee Study in 1972.6Blind Trust aims to reveal this abuse, bringing together the many fields of paediatrics to give an overall picture of the ongoing situation, and to help parents to avoid questionable studies that will not help their children and might even harm them.

References

1. Rose K. Published research: https://pubmed.ncbi.nlm.nih.gov/?term=klaus+rose&sort=date&size=100

2. Rose K. Website: www.klausrose.net

3. Rose K. Considering the Patient in Pediatric Drug Development: How good intentions turned into harm. Academic Press; 2020.

4. Beecher HK. Ethics and clinical research: From the anaesthesia laboratory of the Harvard Medical School at the Massachusetts General Hospital. New England Journal of Medicine 1966; 274: 1354-1360. www.observatoriobioetica.org/wp-content/uploads/2016/09/Beecher_Ethics_and_Clinical_Research_1966.pdf

5. Harkness J, Lederer SE, Wikler D. Laying ethical foundations for clinical research. Bulletin of the World Health Organization 2001; 79(4): 365-366. www.who.int/bulletin/archives/79(4)365.pdf

6. Wikipedia: The Tuskegee Syphilis Study. https://en.wikipedia.org/wiki/Tuskegee_Syphilis_Study

Abbreviations

AAP – American Academy of Pediatrics

ACI – autologous chondrocyte implantation

ADHD – attention-deficit hyperactivity disorder

ALL – acute lymphoblastic leukaemia

ANS – autonomic nervous system

ATMPs – advanced therapy medicinal products

CAPS – cryopyrin-associated periodic syndrome

CAR-T – chimeric antigen receptor – T cell

CDC – Centers for Disease Control and Prevention, USA

CFF – Cystic Fibrosis Foundation

CFTR – transmembrane conductance regulator

CINCA – chronic infantile neurologic cutaneous and articular syndrome

CNS – central nervous system

CROs – clinical research organisations

DMT – disease-modifying treatment

EC – ethics committee

EMA – European Medicines Agency

Enpr-EMA – European Network of Paediatric Research at the European Medicines Agency

EuPFI – European Paediatric Formulation Initiative

FCAS – familial cold auto-inflammatory syndrome

FDA – Food and Drug Administration, USA

FDAMA – FDA Modernization Act

FDARA – FDA Reauthorization Act

FMF – familial Mediterranean fever

GIGO – garbage in, garbage out

IBD – inflammatory bowel disease

ICMJE – International Committee of Medical Journal Editors

IPMSSG – International Paediatric Multiple Sclerosis Study Group

IRBs – institutional review boards

JIA – juvenile idiopathic arthritis

MACI – matrix-assisted autologous chondrocyte implantation

MAS – macrophage activation syndrome

MHRA – Medicines and Healthcare Regulatory Agency, UK

MIS – multi-system inflammatory system

MPH – methylphenidate

NCT number – National Clinical Trials number

NIH – National Institutes of Health, USA

NORD – National Organization for Rare Disorders, USA

NSAID – non-steroidal anti-inflammatory drug

PIP – paediatric investigation plan (required by EMA)

PRCSG – Pediatric Rheumatology Collaborative Study Group

PRINTO – European Paediatric Rheumatology International Trials Organisation

T1DM – type 1 diabetes mellitus

T2DM – type 2 diabetes mellitus

TNF – tumour necrosis factor

TRAPS – TNF receptor-associated periodic syndrome

Part I

Introducing the flawed concept of ‘paediatric’ research

Introduction

The business of paediatric research

Can ‘children’ receive ‘adult’ medicines?

Finding good and identifying bad studies

Chapter 1

Introduction

The instinct to protect our children is one of the key drivers that helped mankind to survive hostile conditions during our origins in primaeval times. In those early days, we had to overcome lifethreatening dangers like prey animals, wildfires, snowstorms, flooding, hostile tribes, starvation and more. Today’s society is far more complex and is differentiated into rich and poor, educated and less educated, the stylish and the homespun, and many different ideologies. We have a government; we have institutions and laws; we have modern medicine. Nevertheless, when it comes to survival, our instincts still kick in – the family against the rest of the world. Modern ideology contends that we all are equal, but this is only correct in theory. Cynically speaking and to quote George Orwell’s Animal Farm, some people are more equal than others – they have access to more and better resources.

Parents are scared when their child gets sick. Fear is another old and powerful instinct. Many diseases that in the past were merciless child killers can today be prevented, treated, or both. But fear for our children continues to have a deep impact on our lives as parents, grandparents and members of society as a whole.

Today’s society is changing and evolving increasingly fast. Families have become smaller. When children grow up, they often move away for education or work. Social mobility has increased. With increased mobility, the immediate support from grandparents and the extended family has become less crucial than it used to be generations ago. Education has become more complex. Children are no longer dressed as little adults as was the case a century ago. In rural areas, young children used to be sent out to play with other children all day long. They returned home when they were hungry, and in the evening to sleep. This may still work somewhere, but not in our cities. And most of us now live in cities.

Healthcare has become more complex along with everything else. The list of diseases against which we can vaccinate our children is constantly growing. Also, for the healthcare of their children parents depend today more on education and modern communication and less on the advice of older generations than in the past. Child mortality has decreased with improved hygiene, housing, nutrition, clothing, education and, of course, healthcare as well as many more factors. We now have specialised healthcare professionals working in many diverse institutions. This includes direct care for the individual by a range of highly trained professionals in specialised, well-equipped hospitals supported by ongoing research at many levels.

It is with this research that this book is concerned and its interface with the medical care of children and young people. Research in both academic institutions and commercial organisations continually improves and expands available technology, drugs and medical devices. However, where this research is carried out simply for the purposes of doing research rather than to improve what is available, we have a problem as this book will show.

Clinical guidelines ensure standard treatment for those diseases where a certain level of accepted practice has been reached. Today, surgery can correct congenital malformations of the heart, the digestive system, the abdominal wall and many other organs; injuries can often be repaired; post-surgical infections can be overcome. This can be done only with the support of modern drugs – such as antibiotics and immunesuppressants – modern surgical tools that allow keyhole surgery, modern imaging techniques, electronic documentation of patient histories, and more.

A flawed concept in paediatric research

Unfortunately, despite all these advances, a flawed concept has slipped into today’s paediatric research. As long as a minor can be treated routinely with well-established medications and/or procedures, this should not concern parents, but if their child suffers an accident, or is diagnosed with a serious and/or rare disease, or the parents observe that somehow their child is not developing as s/he should, then they can suddenly be exposed to the consequences of the flawed concept.1,2,3,4 They may be asked to consent to their child being included in a study for a new drug or device or procedure. This study will be justified by explaining that we do not know if the given intervention works in children. As I will show, parents should listen to their instincts/gut feelings about such requests. They have the right to decide if their child should participate in a study and if this will be in their child’s best interests. They can and should refuse experimental treatment if they suspect anything fishy.

Medical treatment should always consider both body and soul. Prayers address the soul. Drugs are physical and treat the body though they can of course also affect the mind and emotions. The flawed concept at the heart of this book relates to the physical body and how it differs between adults and children.

So what is this flawed concept? It is the rigid separation of medical research into ‘paediatric’ – children aged 0 to 17 – and ‘adult’ (generally, over 18). The body does not change on the night of the 18th birthday, yet laws in the US, European Union (EU) and post-Brexit UK insist that individuals administratively classified as ‘children’ should receive medications that have been examined separately in extensive ‘paediatric’ clinical studies.5 This concept of separate ‘paediatric’ studies and ‘paediatric’ drug development sets an artificial barrier in the way of the clinical work of paediatricians and general practitioners to provide treatments they know to be useful, because these are subject to separate research coordinated by academic paediatric researchers and demanded by the regulatory authorities.

As we shall see, the different meanings of the term ‘child’ create an artificial semantic blur. Legally and administratively, a ‘child’ is a minor who has not reached the age of majority (18 in most countries), but physiologically and bodily, most adolescents mature long before this official age limit.2,3,6 When a young person wants to buy alcohol, they may already look like an adult and may already be physically mature. Nevertheless, they must provide a document (ID) to prove their age.

The semantic blurring of the term ‘child’, and the clinical studies the conflicting meanings trigger, may still appear to be far away from our everyday concerns. However, it is among the key tasks of research to explore the limits of what we know already and to recognise where new knowledge is needed. On what then should we be focusing ‘paediatric’ research? So much has been achieved up until now with research that has pushed back the frontiers. Seventy-five years ago, many paediatric wards were filled with children in iron lungs, as polio had taken away their ability to breathe on their own.7,8 Without iron lungs, the young patients would have died. Iron lungs became unnecessary when polio was prevented by vaccination. Without research, neither the iron lung nor the polio vaccine would have been developed.

Our concern for our children may mean we are less critical than perhaps we should be of some types of research. As an example, paediatric oncology has marketed its need for research funding very cleverly. To emphasise its importance, cancer is often described as the most frequent cause of death in children ‘by disease’.9 Well, the most frequent cause of death in children is actually accidents, followed by suicide, and only then malignancies.10 Nevertheless, parents’ fears that one day their child might develop cancer, and the overall protective instincts of human beings to help sick children, mean that paediatric oncology studies find it easy to get funding and support, be they worthwhile or not.

The appeal to further improve the healthcare of ‘children’ always sounds very noble. It is no surprise that children’s medical research charities find fund raising relatively easy. However, behind this shiny surface there is an ugly truth. Many of the ‘paediatric’ studies that are triggered by demands from paediatric researchers and the regulatory authorities are unnecessary. Others may even harm young patients.3,4 In the course of this book I aim to show how to distinguish the useful from the useless and the useless from the downright bad.

To understand the flawed concept in paediatric research and its consequences is both easy and difficult. It is difficult if you try to immerse yourself in depth in too many scientific disciplines and details, or if you deeply and blindly believe everything that medical doctors, authorities, and ‘experts’ tell you. It is easy under three conditions: you must be curious; you must be ready to ask questions; and you need some scepticism about authorities, official doctrines and official rules.

The flawed concept behind ‘paediatric’ studies has emerged over decades. Overall, drug studies in minors younger than 18 years are called ‘paediatric drug research’ which are part of ‘paediatric drug development’. Many of the researchers and healthcare professionals who were trained in this concept are acting in good faith. Parents with sick children are probably those for whom the absurdities and cruelty of unnecessary ‘paediatric’ studies are easiest to grasp. As I will show, paediatric drug research has become to a large degree a pseudo-scientific construct. The following chapters will guide you through the transition of drug development from the preserve of academic institutions to the business of for-profit pharmaceutical companies; the myth that ‘on-label’ treatment is safer than ‘off-label’ treatment; and the implications of the globalisation of drug development. Part II of this book will show, through many example clinical areas, including cancer, epilepsy, knee surgery and depression, how unnecessary research is harming young patients.

This book is intended not just to bring unnecessary and therefore wasteful research to public attention. It is meant to be of practical use to any parent considering the question ‘Should I agree for my child to take part in this research project?’ It is my hope that, through specific examples and general guidance, you will know when to say ‘Yes’ and when, without guilt despite all sorts of pressures, to say ‘No’.

Chapter 2

The business of paediatric research

This chapter aims to explain how ‘paediatric drug development’ has become a huge business worldwide. It outlines the basic processes of drug development and shows how the vast amounts of data collected in minors are driven more by legal compliance and conflicts of interest than the wish to advance knowledge about the best treatments for children. The need for parallel tracks for drug approval in adults and ‘children’ is, you will see, a misleading construct that has developed a life of its own and blinds public perception and even the perception of many of its protagonists. De-mystifying this situation is long overdue.

Drivers of drug regulation

By today’s standards, many of the drugs sold in pharmacies before World War II, though assumed to be helpful to patients at the time, were not. Many contained alcohol, cocaine, and other intoxicants. They were able to improve patients’ mood in the short term, or to help them to sleep or to cope with pain, but many were also dangerous. In those days, all products available in pharmacies were sold ‘over the counter’ (OTC) without a prescription from a medical doctor.

Two major catastrophes have since formed the way drugs are developed today. These involved the antibiotic Elixir Sulfanilamide in the US and the drug thalidomide worldwide.

The sulfanilamide disaster

In 1937 a company developed a liquid form of the antibiotic sulfanilamide, effective against streptococcal infections. The company used, as the solvent, diethylene glycol rather than alcohol (ethanol), but was unaware that this was poisonous for humans. More than 100 people died when Elixir Sulfanilamide was released in the US. No adequate records had been kept by medical doctors or pharmacists as to whom the drug had been dispensed. It required the entire field force of the Food and Drug Administration (FDA) to retrieve all leftover bottles of this product when the company’s own recall efforts proved inadequate.1

The FDA was empowered to seize Elixir Sulfanilamide bottles only because the drug’s name was misbranded. ‘Elixir’ implies that a product contains alcohol according to the United States Pharmacopeia – National Formulary (USP-NF), but instead this medication had been produced with the highly toxic diethylene glycol.

This first large national drug disaster triggered the US’s 1938 Food, Drug, and Cosmetic Act. After this companies had to submit safety data to the FDA for evaluation prior to marketing in the form of a New Drug Application (NDA).2

The thalidomide disaster

While the Elixir Sulfanilamide disaster was still local in nature, the next catastrophe was global. Thalidomide was developed and first marketed in Germany in 1957, where it was, from the very beginning, sold OTC – that is, without the need for a prescription. It was promoted as a ‘wonder drug’ for insomnia, anxiety, morning sickness and more. The promise to help combat morning sickness of course enticed pregnant women specifically. It was soon marketed in many countries.

Thalidomide resulted in a devastating range of limb deformities in the babies of women who had taken thalidomide during a specific time span of their pregnancy. It took until 1962 for the drug to be removed from the last markets worldwide. It was never approved in the US, but had been dispensed in so-called ‘clinical studies’ in which medical doctors gave the drug to anybody they thought it might help, without any documentation. The number of affected children in the US was very low, but much higher in Canada and many other countries. Worldwide, probably around 10,000 children were affected.3,4,5

Legislation to prevent further disasters

Prompted by the thalidomide disaster and in contrast to Germany, the US reacted swiftly and decisively. The Drug Efficacy Amendment of 1962 to the Federal Food, Drug, and Cosmetic Act demanded that companies from then onwards had to show efficacy and safety of new drugs before approval, demanded accurate information about side effects in drug advertising, and stopped generic copies of old drugs being sold under new trade names as new ‘breakthrough’ drugs for high prices. Worldwide, the principle of clinical studies, performed before the application for marketing approval for a new product could be submitted, was gradually introduced.2

Thus the thalidomide catastrophe shaped drug development worldwide. Effective drugs cannot now be developed and sold without competent supervision; in the US this is done by the FDA,6 in the EU by the European Medicines Agency (EMA) as an umbrella organisation over the EU member countries’ national regulatory authorities,7 and in the post-Brexit UK by the MHRA.8A new triangle of power emerged in 20th-century healthcare: traditional professions and institutions; the pharmaceutical (and medical devices) industry; and the regulatory authorities.

Out of this triangle, combined with the general public’s trust in the state and in science, emerged the business opportunity for specifically ‘paediatric’ research. In the US this involved the cooperation between the American Academy of Pediatrics (AAP) and the FDA; US ‘paediatric legislation’, was then adopted and expanded by the EU.9,10,11

Children as ‘therapeutic orphans’

In the late 1960s, the concept of children as ‘therapeutic orphans’ – an emotive term in itself – emerged. From 1962 on, following the Drug Efficacy Amendment of 1962 to the Federal Food, Drug, and Cosmetic Act, companies had been including ‘paediatric warnings’ in information about newly approved drugs to protect themselves from lawsuits in the litigious US legal framework. These warnings were triggered by toxicities that had been observed in premature newborns in the 1950s. Later, additional toxicities had also been observed in mature newborns.

It was the first chairman of the American Academy of Pediatrics (AAP) Committee on Drugs, Dr Shirkey, who claimed these warnings made children ‘therapeutic orphans’.12 His war cry was for all new drugs to be trialled in minors as well as adults and it was very successful. The AAP and the FDA became powerful allies. To cut a long story short, they convinced US lawmakers that separate ‘paediatric‘ studies needed to be performed for all new drugs.9,10,11 The mechanism to do so was to offer pharmaceutical companies the incentive of a six-month extension of the patent protection for any drug requiring such studies: so-called ‘paediatric exclusivity‘. For pharmaceutical companies, it was very rewarding to earn these patent extensions – it gave them an extra half year in which to sell their own brand drug at a high price before other manufacturers could make and market a generic copy.

Created in 1997 by the US Congress, ‘paediatric exclusivity’ was intended to incentivise paediatric research. The official story was that pharmaceutical companies typically recruited only adult patients into their regulatory studies, and that for investigation in the ‘paediatric population’ (under the age of 18) there were no incentives, as the paediatric market was smaller than the adult one.

However, the market for such medications is not in fact as small as was often claimed. In the beginning, the FDA defined ‘children’ as anybody below 17 years of age. Later, the EU used the age limit of the 18th birthday. Today, both agencies use the 18th birthday. Minors represent roughly a quarter to a fifth of the entire population. In their first years, babies and infants are sick more often than adults. This changes gradually when adults become elderly. A significant proportion of the healthcare costs of patients is spent during their last months of life. Minors represent a significant proportion of the entire population, but babies grow fast, and do not remain babies until they come of age.

Companies tried to bring their new drugs to market cost-effectively. In the early debates about ‘paediatric drug development’, the researchers wanted as many ‘paediatric’ studies as possible but, specifically in adolescents, such studies were unnecessary and superfluous. Drug efficacy had already been shown in adults. The paediatric dosing tables and formulas used at the time were, with few exceptions, sufficient for children, only not for newborns and especially preterm and/or underweight newborns. The importance of changes in the developing body during the first days, weeks and months of life was used to justify ‘paediatric’ studies in all ‘children’, blurring two different meanings of the term ‘child’. Administratively, everybody is a child until s/he comes of age. But bodily, adolescents’ bodies mature much earlier. It was not the market for children’s medicines that was too small, but rather the desire of paediatric researchers for funding that was too great.

It would be too easy to blame everything on the desire of paediatric researchers for funding. The shock of the thalidomide catastrophe had a long-lasting effect. Everyone believed that a new, safe chapter had now opened with government supervision of drug development. The reports of toxicities of modern drugs in babies, the new trust in government supervision, and the generally high trust in science led to the belief that only officially approved (‘on-label’) drugs were safe. Indeed, it was in 1988 that the term ‘off-label’ first emerged,13 showing the growing importance of regulatory authorities in healthcare. ‘Paediatric drug development’ became a movement coordinated through a collaboration between academic science, regulatory agencies and, in the US, the pharmaceutical industry. From that time on, all drugs for ‘children’, who were now defined administratively, not by their degree of physical maturity, had to be approved specifically in ‘children’ and for this, separate ‘paediatric’ studies were required.

The effects of ‘paediatric exclusivity’

‘Paediatric exclusivity’, as described in Chapter 1, holds off competition from generic versions of drugs for six months, allowing the originating company to sell its medicine for the original, higher, patent-protected price for half a year longer than allowed under patent law.

The US’s paediatric legislation in 1997 suddenly offered industry the incentive to investigate clinical questions in young patients in a dimension that had never existed before. From then on, companies needed advice as to which studies they should propose to the FDA. To get such advice companies approached leading paediatric academic clinicians, who of course liked this new attention. Once the FDA had issued a ‘written request’ for paediatric studies and the company had committed to these studies, they needed to be performed. Most diseases in minors are rare. These studies were usually not confined to one or even a few medical centres as these could not provide sufficient ‘subjects’. Instead, they were international from the very beginning.14 Participation in an international study enables many things: international networking beyond the regular academic research conferences; publication in journals of the highest reputation; invitations to give presentations; the hiring of new personnel; assistance with financing research infrastructure; access to journalists; and more. Thus the USA’s paediatric legislation was, from 1997 on, a huge business opportunity for individuals and institutions involved in paediatric research.

‘Paediatric’ clinical trials are estimated to cost two to five times more per patient than adult clinical trials.15 The costs of FDA-incentivised ‘paediatric’ studies were analysed in a paper published in 2018: the total costs of ‘paediatric’ studies into 54 drugs were estimated at $4.9 billion in 2017.16 Clinical trial costs may include:

• payments to the clinical research site

• payments for the use of the relevant research centre

• patient enrolment

• administrative trial procedures

• materials

• laboratory use

• imaging

• transport of blood samples, tissue samples and other materials

• data management

• monitoring

• administrative management by the sponsoring company or by a commercial clinical research organisation (CRO)

• the institution’s review board (IRB)/ethics committee (EC)

• transportation costs for patients

•insurance

• translation of protocols and other documents into many languages

• and more.

For every unnecessary study that is done, we must bear these costs in mind in addition to the human costs to patients and families and the opportunity costs of meaningful research not carried out.

The official version of events is that the FDA has helped to generate data to guide clinical decision-making for many drugs used in paediatric medicine. Of the 189 drugs granted ‘paediatric exclusivity’ between 1998 and 2012, more than half received new or extended approval for paediatric use, a quarter resulted in new safety concerns, and an eighth resulted in new dosing information. This sounds convincing and logical, and has been repeated as support for ‘paediatric’ studies countless times.17,18,19,20,21 How true are these claims?

Was the FDA right?

The first paediatric status report by the FDA to Congress in 2001 explained that the FDA expected ‘significant advances in pediatric medicine. 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’.19 These were clear clinical expectations. The FDA was committed to advancing child healthcare and believed that regulatory approval of the use of drugs in minors would advance child healthcare. However, in its next paediatric status report to Congress, in 2016, it did not repeat these expectations. Instead, it listed all the studies the paediatric laws had triggered and caused to be funded, and claimed that this activity had improved paediatric healthcare.22Clinical studies in young patients, however, should not be performed for their own sake.

The FDA did not repeat its clinical expectations because there were no real, measurable success stories to be reported. FDA-triggered ‘paediatric’ studies resulted in more ‘paediatric’ approvals but were mostly useless or exaggerated, or even harmed patients, as the chapters in Part II will illustrate. They did, however, advance the careers of individuals in paediatric academia, the regulatory authorities, pharmaceutical companies and commercial clinical research organisations that were happy to perform ‘paediatric’ clinical studies.

The European Union’s ‘Paediatric Regulation’

The system of ‘paediatric’ clinical studies was amplified and expanded when the EU introduced its own ‘Paediatric Regulation’ (Regulation (EC) No 1901/2006), requiring separate ‘paediatric’ studies in patients younger than 18 years. Paragraph # 2 of the preamble to the ‘Paediatric Regulation’ is a declaration to combat the market forces that were allegedly unable to provide the necessary studies for the ‘paediatric population’.23

With the exception of drugs that target diseases officially listed as not existing in ‘children’ (individuals under the age of 18), companies have had, from 2007 onwards, to submit a draft ‘paediatric investigation plan’ (PIP) to the EMA for all new drugs. This draft PIP must propose ‘paediatric measures’, with the three most important elements being:

• juvenile animal studies

• the development of child-friendly formulations (babies cannot swallow tablets)

• clinical studies.

If the EMA does not like the measures proposed by the drug company, it can reject the PIP, and the drug will be blocked from EU approval for adults as well as ‘children’ until an acceptable PIP has been negotiated. Approval of new products is the life-blood of research-based pharmaceutical companies. In September 2020, the EMA website listed more than 2000 PIP decisions, including accepted, refused, and modified PIPs, and waivers (no PIP required).24 In 2017, the number of PIPs issued surpassed 1000.25 Each PIP demands one or several ‘paediatric’ studies.

PIPs demand studies in ‘children’ that essentially repeat the regulatory studies for adult approval; often these are placebo-controlled studies to prove efficacy in this population, defined as 1 to 17 years old, 2 to 17 years old, or divided into ‘paediatric’ sub-groups, such as 6 to 11 years old and 12 to 17 years old.9,10,11

The costs for all these ‘paediatric’ studies were estimated in an EU Commission report in 2017. For the industry altogether they were estimated as €2.1 billion per year, based on the evaluation of 85 real PIPs. The total research-and-development costs per PIP were estimated at €18.9 million. On top of this come the company overhead costs of roughly €720,000.25,26 Each PIP costs the respective company on average about €20 million. If we multiply the €2.1 billion costs per year by the years since PIPs were introduced (14 x €2.1 billion),25,26 the result is €28.14 billion.

The EU also offers a patent extension at the end of patent life, the ‘Summary Protection Certificate’ (SpC). As there is no EU-wide patent law, companies must file for patent extensions in each individual EU member state, which is feasible for major companies and makes sense in larger countries. Even so, this is barely comparable with the US. In the EU ‘paediatric’ studies must be negotiated years before it is even known if the compound in question works at all. Be that as it may, these numbers show that the costs are considerable.

Has child health improved in the EU?

The EMA website claims that the EU paediatric legislation is ‘designed to better protect the health of children in the EU’.28 Its 10-year paediatric report issued in 2016 says ‘more medicines for children’ have been achieved.25 What this actually means is simply that more drugs now have EMA ‘paediatric’ approval. It concludes that the EU Paediatric Regulation has ‘had a very positive impact on paediatric drug development’. Page 14 of the report lists alleged examples of achievements in rheumatology, cardiovascular diseases, infectious diseases and oncology. However, these ‘achievements’ document only regulatory activism, not clinical improvement.

The EU Commission’s 10-year paediatric report, The State of Paediatric Medicines in the EU, released in 201726 (also published as a brochure with the same text, but additional nice colour photos of young patients and doctors, including an attractive, white female doctor with a brown baby, and some graphics),27 is based on the the EMA’s 2016 report.25 It likewise outlines alleged achievements and claims that before the EU legislation, drugs in ‘children’ were administered based on physicians’ own experience rather than on the results of clinical research; discusses past challenges like the need to crush tablets for babies and small children; and repeats the EMA position that off-label use of medicines can be dangerous in ‘children’.26,27

The EU commission report appears convincing at first glance. To decode it, we need to repeat two basic, common sense questions:

• Was there a crisis in child healthcare before 2006?

• Before the EU Paediatric Regulation had there been an increase in child mortality, that later improved as a consequence of the EU Regulation?