Clinical Research - The problems with PIPs

The problems with PIPs

Almost three years into Paediatric Regulation 1901/2006/EC, and the Paediatric Investigation Plans are proving challenging. Katrina Megget considers their impact on Marketing Authorisation Applications and looks at where the obstacles are

January 2007 saw a shake-up of the European drug approval process. With data suggesting that 50% of medicines used for European children (90% in neonates) may not previously have been tested in paediatric populations, governments and regulators decided it was imperative to ensure drugs were not only safe and effective for these age groups, but they could be administered in child-friendly formulations. It was no longer acceptable to “guesstimate” paediatric dosage based on adult treatment regimes, or continue cutting, crushing or splitting drugs to smaller sizes for lack of a suitable paediatric formulation – practices that can put children at risk of overdose, under-dose, adverse reactions and even death.

In July 2008, under the European Commission’s Paediatric Regulation, the new requirements for submitting Marketing Authorisation Applications came into force, mandating that companies include an EMEA approved Paediatric Investigation Plan (PIP) to identify all appropriate clinical studies, waivers or deferrals. The regulation includes applications for marketing authorisations of new indications of already approved drugs, a new pharmaceutical form, or a new route of administration.

Despite the obvious ethical challenges, the rationale was that children would benefit from safe and efficacious drugs, and the pharmaceutical industry from a six-month patent extension. Waivers can be granted if the medicine is only intended for adult conditions or if it does not offer significant therapeutic benefit to children.

In the first year after the Paediatric Regulation became law in all member states, the European Medicines Agency’s Paediatric Committee received 233 validated applications covering around 420 indications, the majority being in oncology.

Teething problems

However, the new requirements have had some teething problems, with reports from pharma companies of increased red tape, practical and ethical challenges with clinical trials, and difficulties with PIP compliance checks. According to a recent survey by The Organisation for Professionals in Regulatory Affairs (TOPRA), 70% of a sample of 23 pharma companies said their MAA submissions had been delayed because of the PIP requirements. The survey also found that 86% encountered difficulties with compliance checks – and this some two years after the introduction of the legislation. A recent workshop held by EMEA/European Federation of Pharmaceutical Industries and Associations (EFPIA) in conjunction with TOPRA, the European Biopharmaceutical Enterprises and members of the Paediatric Committee, discussed these issues in an attempt to clarify the PIP process.

Christine-Lise Juluo, Director of Scientific, Technical and Regulatory Affairs at EFPIA, told Clinical Discovery magazine that EFPIA was not surprised companies had experienced delays “because this reflected a concern that an increasing number of companies have been reporting to EFPIA”. But she said “any figure should be taken cautiously”, not only because the sample size of the TOPRA survey was “fairly small” but because the regulation is still new and therefore experience is limited on its impact on submissions and approval dates.

The EMEA, for its part, believes the survey figures are inflated and not indicative of a wider trend. To date, the Agency’s data indicate that only five out of a total of 68 MAAs received since July 2008 have been delayed because of non-compliance with the regulation. “This is certainly not 70% and therefore the figure is indeed surprising and inaccurate,” a spokeswoman said.

Pharma may have been unprepared

Yet some companies have clearly encountered hurdles, despite the regulation’s stated objective “to improve the health of children in Europe… without delaying the authorisation of medicinal products for use in adults”. The EMEA denies problems in implementing the regulation, instead suggesting pharma may have been unprepared. For example, the Agency says that in two of the five delayed cases, the delay was less than two months “and was due to misunderstanding of the requirement of the Paediatric Regulation on the part of the applicant”.

The other three cases are recent and still pending, it says. “The few companies that took the requirements set by the Paediatric Regulation into consideration, when it was very late to modify their plans may perceive this as a delay,” the EMEA spokeswoman told Clinical Discovery magazine. “The practical consequences of the Paediatric Regulation were clearly underestimated by the industry and some companies have been slow to anticipate additional workload and the need for additional expertise,” she added. However, with the third anniversary of the Paediatric Regulation due at the end of December, the Agency believes the requirements should now be well understood by all stakeholders.

Yet, Paediatric Research Consultant Jane Lamprill thinks differently. “There is strong anecdotal evidence that pharmaceutical companies, competent authorities and ethics committees are struggling,” she says. “It always takes time to turn an ocean-going oil tanker. The trouble is, as a result of the Paediatric Regulation, different sorts of tankers are turning at once, and sometimes in different directions. This is a much needed innovative regulation which involves a steep learning curve and requires collaboration between all players in paediatric drug development.”

Identifying the obstacles

So what are the main stumbling blocks facing the industry? Professor Tony Nunn, Associate Director (Industry Lead) at the UK’s National Institute for Health Research Medicines for Children Research Network (MCRN) – whose role is to assist pharma in conducting paediatric clinical trials – says they have seen a “large increase” in the number of trials associated with PIP applications. And the EMEA acknowledges there is “unquestionably additional work” involved in conducting clinical trials in children, and that pharma companies need to “factor in” these extra requirements when drafting any drug development programme.

In addition, clinical trials in children are more expensive than in adults, they take longer, and they have practical and ethical implications. Some companies are also inexperienced in testing medicines in children – what might work in an adult trial may not when adapted for children, particularly in terms of volume and frequency of blood samples.

The feasibility of some paediatric clinical trials can be a real issue Lamprill notes. The company regulatory departments should always check with their clinical colleagues regarding paediatric trial feasibility so that realistic recruitment timelines are included in the PIP, she says. “Otherwise delays will occur later if the PIP needs to be modified.”

Another difficulty is if the Paediatric Committee or Competent Authority requests additional tests which prove to be unacceptable to ethics committees. Indeed, Lamprill is worried that if difficult paediatric protocols are being included in the PIP companies may be forced to perform studies with families from poorer countries or where healthcare is not free at the point of delivery, and so families are incentivised for financial reasons. Moreover, she says there are financial implications for smaller companies that may not have the resources to perform the requested studies.

Any one of these issues can lead to a delay in the marketing authorisation. The EMEA gives an example where validation was delayed because the company was unable to produce the final reports of studies agreed in the PIP in time for the compliance check and so could not show compliance with the agreed PIP.

Then there is the issue of recruitment. Paediatric trials take longer to recruit, says Lamprill. “Much finance is wasted when complex protocols for trials are not acceptable to ethics committees, families, and children, and therefore result in zero recruitment. Strong anecdotal evidence suggests that some senior pharmaceutical managers may not allocate sufficient time or resources to allow for longer timelines.” This is further compounded for companies that have products with a short patent life.

Nunn takes a different view, suggesting that using a network approach is beneficial as it brings on board new study sites if others are struggling to recruit, thereby maintaining the overall rate of accrual. He adds that for most industry-sponsored studies MCRN sites have recruited the required number of patients to the agreed timeline.

A collaborative effort

The EMEA told Clinical Discovery magazine it is keen to introduce steps to simplify and accelerate the assessment of the PIP/waiver applications and says it regularly seeks and receives feedback. EFPIA’s Juluo acknowledges the complex challenges raised by paediatric research and says large-scale surveys need to be performed to identify the precise nature and origin of the problems facing applicants, so allowing appropriate solutions to be put forward.

Lamprill also suggests that many in pharma still need to be trained in the new requirements, and says there needs to be a wider understanding of the practical and ethical issues involved in conducting paediatric studies. Yet she says “green shoots” are being seen, with various meetings taking place between the stakeholders that are slowly leading to increased collaboration and decreased dysfunctionality. The Agency says industry and regulators also need to work cooperatively – although it notes the “quality” of the PIP/waiver applications “does not depend on the EMEA” – and suggests pharma must be proactive for all parties to gain maximum benefit.

“The Paediatric Regulation now provides us with an unprecedented opportunity to improve children’s access to better medicines and ultimately to a healthier and better life,” says the Agency. “The ultimate goal for the EMEA and for the industry alike is to care for them better than ever before.”

What is a PIP?

A paediatric investigation plan is a drug development plan that must be pre-approved by the EMEA’s Paediatric Committee. It includes the company’s proposed measures – including timelines for the appropriate clinical and non-clinical studies – to obtain a paediatric indication with an age-appropriate formulation for all ICH paediatric age groups. A waiver or partial waiver may be granted if the disease does not occur in children or some paediatric age group subsets – or if the medicine does not offer a significant therapeutic benefit to children. Likewise, deferrals can be requested for non-paediatric disease treatments. Once agreed, the PIP is legally binding to the applicant and a compliance check is necessary to ensure all agreed measures have been performed. If companies fail or are slow to comply with the paediatric regulation they may find themselves unable to submit, and this will delay the MAA for the adult drug.

Katrina Megget is an independent healthcare writer