What About the Kids?

Historically, drugs have been developed, tested and authorized for adults only. Most people would agree that children have a right to safe, effective medicines, suitable for their needs, but translating this into practice has been a slow process.

In most cases, developing pediatric medicines has not been financially appealing. Developing pediatric drugs is often both costly and risky, and the target market may be only a handful of children, which makes return on investment questionable. The result is that very few products have been specifically developed for children; clinicians often have to rely on off-label or unlicensed drug use, and extemporaneous preparations such as crushing tablets and mixing them with water to administer what they hope is the correct dose. However, with new directives pushing the issue into the spotlight, the last ten years have seen an increasing focus on the needs of children in the drug development process.

Indeed, regulations in the US and Europe now require pediatric plans for all new patent protected drugs, including line extensions, with incentives in the form of extended exclusivity. The regulations have certainly had a significant impact, but it is only now that we are starting to see the results, with new pediatric drugs hitting the market and the industry gaining experience and confidence. There are still major challenges, but I believe we’re going to see great advances in the coming years with the continued commitment of academia, governments and industry.

How is developing a pediatric medicine different to developing an adult drug? In fact, the general principles are exactly the same. The key differences lie in safety and acceptability. It is often said that children are not just small adults, and new research is teaching us just how true that is. During infancy and childhood there is rapid growth and changes in various organs, body composition and metabolic pathways.  There are also differences in gastric pH and gastrointestinal motility between adults and children.  This means that babies, infants and children may handle excipients and active pharmaceutical ingredients (APIs) differently, leading to potential toxicity and changes in the required dose of API.

Here, I discuss the main areas to consider when developing pediatric medicines, and look at how far we’ve come since the regulations came into effect.

Children take center stage

Recognizing the lack of pediatric formulations entering the market, and the limited availability of information on the safe use of medicines in children, both the US and Europe introduced new regulations in the late 1990s and 2000s to tackle the problem. The regulations include a ‘carrot and stick’ approach, with requirements for pediatric development plans for patent protected products offset by an extended exclusivity period. There are also incentives in place for the development of off-patent pediatric medicines. Read more in “Taking the Guesswork Out of Pediatric Medicine.”

In Europe, since 2007 all companies developing a new product, or a line extension for a patented drug, must submit a pediatric investigation plan (PIP) to the European Medicines Agency (EMA) Pediatric Committee (PDCO) no later than completion of adult human PK studies (after Phase I trials). The PIP is a plan of work and should contain preclinical information including juvenile toxicity studies, details of the proposed pediatric product and the clinical trials to be carried out in the pediatric population. Validation of the adult licence application is conditional on companies complying with the agreed PIP, which also gives them a six-month extension of their supplementary patent certificate.

Regulators are clearly keen for drug makers to consider the needs of the whole pediatric population, including neonates (newborns). However, from a company perspective, it is risky to spend time and money working on pediatric indications of a drug that may never come to market – and so some companies are delaying pediatric development. The EMA has quoted several cases where PIPs have been submitted during Phase III adult trials, and found to be totally unsuitable. The companies have then had to re-formulate the product or re-do a clinical study, causing considerable extra expense and delay. I think the message is very clear – pediatrics should not be a bolt-on, but an integral part of our drug development processes. There are several key building blocks in particular that need to be carefully considered.

Safety first

Finding excipients with appropriate safety and tolerability is a major hurdle in pediatric drug development, and we have to justify the choice of excipients in the PIP. The immaturity of organs, particularly of very young children, mean that certain excipients can’t be metabolized in the same way as an adult. A classic example is that high doses of propylene glycol, a common additive in food and medicinal products, can be toxic for babies. So it’s important to look at the absorption of these materials, how they’re broken down, and whether there is the potential for them to accumulate.

There are a lot of older medicines currently used for children that would not get approved via the current regulations. A study carried out in 2009, looking at commonly administered liquid medicines, found that levels of excipients such as ethanol and sorbitol were potentially harmful for premature infants, and were above recommended levels for adults on a weight basis (1). The authors estimated that the dose of ethanol might be equivalent to giving the babies several beers per week!

What makes our lives so difficult as drug developers is that there is limited information available about the safety of excipients for pediatric patients, especially in very young children. In general, the aim is to use as few excipients as possible and to stick to those with a well-established safety profile. Each excipient should be assessed by considering the benefit versus risk of its use, weighing up a range of factors, including the age of the patients, how long they will take the medicine for, the indication, what dose they will receive and if there is an alternative excipient. For example, if the product is for the treatment of a life-threatening condition (e.g. cancer) it might be acceptable to use an excipient that has limited safety information to increase solubility to achieve sufficient bioavailability, whereas the same excipient  might not be acceptable for use in a product for a less serious condition (e.g. a cough medicine). the European Pediatric Formulation Initiative is building a database (“STEP Database”) to act as a repository of excipient information available in the literature, to assist in the development of pediatric medicines (www.eupfi.org).

Taking the Guesswork Out of Pediatric Medicine

We have seen more studies conducted in children in the past seven years than we have in the last 30 combined. This is in part down to new rules and incentives introduced in the US and Europe in the late 1990s and 2000s to address the neglect of children in drug development, so that physicians are not forced to rely on off-label use.

United States

Pediatric medicines in the US have not one, but two specific Acts. In 2002, earlier legislation was replaced by the Best Pharmaceuticals for Children Act (BPCA), which offers an additional six months of patent protection for companies who agree to carry out pediatric studies requested by the FDA. BCPA is voluntary and acts as the carrot for drug companies. The stick comes in the form of 2003’s Pediatric Final Rule and Pediatric Research Equity Act (PREA). Under PREA, companies submitting new drug applications to FDA must include a proposed pediatric study plan, which is similar to a PIP, but generally submitted later, at the end of Phase II. In certain circumstances, the law also allows FDA to require pediatric assessments for drugs already on the market. As in Europe, it is possible to defer submission or to obtain a waiver.

PREA and BPCA were re-authorised under the FDA Amendments Act (FDAAA) in 2007 and then were permanently re-authorised under the FDA Safety and Innovation Act (FDASIA) in 2012.

Europe

The European Medicines Agency (EMA) has introduced various documents and directives concerning pediatric medicine and children in clinical trials since 2001, but most companies chose not to pursue development in this area. In January 2007, however, the Pediatric Regulation came into force, which made pediatric studies mandatory for all new medicines.

The plan must contain a full proposal of all studies and timings needed to support pediatric use in all necessary age-appropriate formulations, and must be approved by the EMA’s Pediatric Committee. Modifications can be made at a later stage as knowledge increases through development and, of course, not all new drugs are suited (or needed) for children, in which case companies can apply for a waiver from the EMA.

Companies that comply with their PIP receive an additional six months of patent protection. The EMA has also been keen to encourage drug makers to pursue pediatric formulations for off-patent drugs. This process is voluntary and also requires the submission of a PIP. Once approved, you can use the PIP to apply for a Pediatric Use Marketing Authorization (PUMA), which is a license to use a product in children only. The reward for this is ten years of regulatory data and market protection.

Can’t take, won’t take

Dosage form is a key consideration right from the start of the pediatric drug development process. Small children have difficulty swallowing conventional  tablets (especially large tablets), and there is a risk of choking. The WHO reports that four children under 36 months died from choking on albendazole tablets during a deworming campaign in Ethiopia in 2007 (2). The most common solution to this issue is an oral liquid version – along with all the formulation challenges that it can bring. Keeping potential pediatric dosage forms in mind at an early stage of development, for example when selecting the salt for the API, could save a lot of additional work later on.

An interesting development over the last two to three years is that I’ve seen more interest in solid oral dosage forms, even for very young children. Oral liquids have historically been the preferred dosage form for pediatrics – and I think there is still a very important place for them in terms of dosing flexibility – but there are concerns about the preservatives required. In resource-poor areas, stability, transport and storage of liquids may also be an issue. There seems to be an increasing trend to use powders that can be dissolved or dispersed in water just before taking, to make solutions or suspensions. The development of oral films, orodispersible tablets and mini tablets is also becoming more common.  These mini tablets are just two or three millimeters in diameter. It is generally accepted that a child would need to be about six to be able to swallow a conventional tablet, but this depends on the size of the tablet and the ability of the child. Studies published in the literature have successfully administered mini tablets to infants aged as young as six months, so this could be an exciting area in the future (3).

But of course, just because children can take their medicine doesn’t mean that they will do so willingly! Children are typically less tolerant of the bitter taste of many APIs and prefer a sweeter taste. This isn’t just children being difficult – there are subtle differences in how children and adults perceive tastes. Something that an adult might say was a slightly bitter, a child may find genuinely disgusting, and so  companies take taste of pediatric medicines seriously. Quite a few companies use an ‘electronic tongue’ as a screening tool to make an initial assessment of the bitterness of their APIs and formulations. This gives an idea of what taste-masking, if any, is required. Palatability of formulations may be assessed using  a taste panel, or during clinical trials. Clinical studies now often include a questionnaire asking participants about the taste and texture of the medication, and this is particularly important in pediatric trials, as it’s very difficult to directly extrapolate adult taste panels to children. There is currently no standard methodology for conducting palatability and acceptability studies, and this is another area of future development.

Masters of Destruction

Medicine poisoning in children is a common occurrence, particularly in children under five. In the US alone, a child is taken to the emergency room every eight minutes due to poisoning with a medicinal product. Most medicine bottles come with child-resistant (CR) caps, but to date there have been few products available to keep children away from blister packs, which make up 80 percent of drugs in Europe. Making a carton that can withstand a determined 4-year-old is no easy task. Ron Linssen, Managing Director of packaging development company Ecobliss, explains how they did it with Locked4Kids.

What are drug companies’ responsibilities with regard to CR packaging?

Legally, Europe lags behind the US. In 1970, the US introduced the Poison Prevention Packaging Act, which forced pharmaceutical companies to use CR packaging for all prescription drugs, as well as various other potentially toxic substances. EU law does not require medicines in blister packs to be supplied in CR packaging, though some member states have limited regulation. According to the WHO, the introduction of CR packaging in the US led to a dramatic decrease in child poisoning, so I think the time has come for the European Commission to review this. Medication use has only increased over the past decade, and tablets can be very appealing to children.

How do you make the carton hard for kids to get into, but easy for everyone else?

It took us almost two and a half years to develop a carton that can withstand all of a child’s ingenuity and strength, but is easy to use for adults and the elderly. It is a delicate balance; a tightrope walk. The trick with Locked4Kids is that it requires virtually no force to open. You just have to press two points on the carton and pull the tray out. But the points are spaced so that it is very difficult for young children to push both at once.

What was the toughest part of the process?

The most difficult thing is to get the product through child testing. Each test is done with 50 children aged around three or four. They initially get five minutes to do whatever they want to try to open the packaging; then the tester, without speaking, demonstrates how to open the packaging. He or she does this about two feet from the kids’ noses, so they can get a close look, and also indicates that they can use their teeth to get it open if they want. Then they get another five minutes. Now, for children this age ten minutes is a long time, and watching the tests, it’s amazing that any carton would withstand it! The children will try to poke their fingers in, pull as hard as they can, squeeze it, bite it – anything to get it open. Every time you make a change to the design, you have to go through this testing again. You may think the design is good, but it’s the kids who will have the final verdict! And if you make it too hard for the kids, it often becomes too challenging for older patients too, so it’s back to the drawing board.

What has the reaction been like so far?

Usually, when you bring out a totally new product, you expect some backlash. But people are responding very positively to this. We have tried to make it easy for manufacturers – Locked4Kids production can be easily automated, and can be used wherever you would use a normal carton. Obviously compared with an ordinary carton, Locked4Kids is more expensive. But compared with a CR bottle the costs are similar. We hope responsible drug companies will consider CR packaging even where there is no legal requirement.

Of course, there is a fine line between making a medicine palatable and making it too nice, which encourages children to view the medicine as sweets...

Delivery dramas

The delivery device can also play an important role in the safety and acceptability of children’s medicines. It is not uncommon for parents to inadvertently over or under-dose their child’s medication, as they can find measuring the right dose difficult. According to the results of a recent US study that examined 11 years’ worth of records from the National Poison Database System, a child experiences a medication error every eight minutes, and while the majority didn’t require treatment, 25 lost their lives (4). In an effort to make dosing easier for parents, several companies are now looking at fixed-dose oral syringes, with a locking mechanism that allows the dose to be set by a pharmacist, for example.

For older kids, there are some innovative designs in the area of pen injectors for insulin or growth hormone that try to make them less like medicines and more fun. For example, there are some devices shaped like cars. The idea is to make kids less embarrassed to carry them round in their pockets and to use them if needed.

In adolescents, compliance for a chronic condition is notoriously bad, so anything that makes it easier or less embarrassing for this age group to take their medication is very welcome. Teenagers are less interested in car-shaped devices, but there has been a lot of discussion around discreet packaging, such as small packs with one or two doses that can be slipped into bags or pockets. So far, though, we’ve seen few actual innovations. Things are further along in the over-the-counter market, with some of the major painkiller brands bringing out interesting small wallet packs, so it would be great to see prescription pharma use some of these platforms.

Growing up

In Europe, over 1,600 PIPs have been submitted, but there is a significant lag time before the products come to market as the majority are still in development. So, hopefully further down the line we will see a lot more pediatric products, including more off-patent products. Whilst new drugs now have to consider a pediatric formulation, many existing off-patent drugs are still being used off-label – a situation that has been difficult to remedy given the potential poor return on investment. In Europe, regulators have introduced an incentive: companies that obtain a Pediatric Use Marketing Authorization (PUMA) for an off-patent medicine receive an additional ten years’ data exclusivity. However, only one PUMA has been granted to date, and most research on off-patent drugs is being done by small companies, the European funded consortia and academia. This may be in part due to the uncertainties that companies face in the reimbursement of these medicines.

As companies and regulators gain experience and more products become available, our understanding of the unique needs of children will only grow. We will also benefit from research being carried out on the physiology and pharmacology of children in different age groups – it is encouraging to see our collective knowledge expand.

The next big challenge for researchers in this area is to address the neonatal group – babies are almost like a different entity because there are so many changes in terms of organ development, enzyme maturation and so on, in that first year. Companies need to do more research in this group, despite the caution that is natural when working with tiny babies (see “Tiny Babies, Big Challenges” for the neonatologist’s view).

Working with pediatric drugs is always a challenge, and sometimes unpredictable, but it’s that extra dimension that makes it so fascinating.

Tiny Babies, Big Challenges

We caught up with physician and researcher Mark Turner, Senior Lecturer in Neonatal Medicine at the University of Liverpool, Director of Research and Development and Honorary Consultant Neonatologist to Liverpool Women’s NHS Foundation Trust, to find out more about the unique needs of newborn and premature babies.

Other than their size, what makes children, and particularly babies, process drugs differently to adults?

There are two big reasons that babies handle drugs differently. First, their bodies are maturing and developing. In the liver, most medicines are metabolized via a number of enzymes and children and babies have different enzymes to adults. In the womb, the mother filters out most toxins, but a few make it though and need to be metabolized. So the baby is programmed to protect itself from the chemicals that get through the placenta. As they get older, children face different environmental pressures, so the liver is gradually reprogrammed. These differences in liver enzymes can have unpredictable effects. For example, some of the activity of morphine comes from specific metabolites – since young babies lack the enzymes that produce those metabolites, different doses of morphine may be needed in babies. The second reason is that the targets are different. When you give a drug that works on certain receptors, sometimes those receptors aren’t present in children.

How much do we know about those differences?

We probably only know a tenth or a quarter of what we need to know. Ethically, we can’t do studies in healthy children, so the only way to find out more is to track the medicines and metabolites in our young patients, which can be challenging. I work with babies who weigh as little as 500g and have a total circulating volume of 30 or 40 ml of blood. Clearly, we can’t take the same amount of blood as we do in adults or older children, so we have to adapt our studies.

What challenges do neonatologists face in terms of availability of drugs?

Estimates of the proportion of drugs licensed for neonates vary between 10 and 25 percent, so we often have to use drugs off-label. I describe my job as guessing which drug to give, guessing what dose to give, and hoping the team don’t make too many errors as they dilute medicines that are intended for adults. Often the drugs have to be diluted by ten times to give a dose small enough for a baby. The current regulation in Europe and the US will improve this over time for new medicines, but there are a large number of off-patent medicines that are always going to be
a problem.

What is needed to improve the situation?

Along with many of my colleagues, I think we need to change the incentives that are available to pharmaceutical companies to evaluate off-patent medicines. Many drug companies want to do the work, but at the moment it is just not economically viable. There needs to be a global discussion with companies, regulators and payers about how we can incentivize the study of commonly used off-patent medicines.

I spend half of my time looking after sick and dying premature babies. I stand at the end of the cot and I have to guess which drug to give and at what dose - the uncertainty is such a burden. That’s what motivates me to study drugs and help other people to study drugs - to try to remove some of that uncertainty.

Dangerous Drugs

49% of drug prescriptions in pediatric wards were either unlicensed or off label, in a 2012 Swedish survey (5).

3x higher rate of exposure to potential adverse drug events (ADEs) in pediatric inpatients compared with adults (6).

79% of potential ADEs in hospitalized children occurred when doctors were ordering medications (6).

Over 70,000 children attend US emergency departments every year after accidental medication poisoning, usually after getting into parents' or grandparents' medication (7).

20% increase in children under 5 visiting the emergency department for accidental medication overdoses from 2005 to 2009 (7).

2 is the peak age for accidental medication overdose (7).

63,358 calls to US poison control hotlines are made every year by concerned parents or caregivers after a medication error at home in a child under six (4).

1/4 of medication mistakes occurred in infants under one (4).

1/4 involved the child being given the same medication twice (4).