It's the Children Again

No apologies for returning to the subject of pediatric medicines yet again. It's the subject that's largely monopolizing the attention of the European pharmaceutical industry at the moment, and the proposed new European Union rules reached yet another critical point on September 7.

Peter O'Donnell

That was the date the European Parliament completed its first reading of this contentious proposal,¹ which will both impose new clinical trial obligations on companies applying for marketing authorizations in Europe and offer them some incentives or rewards for extra studies in pediatric populations.

After an extensive—and occasionally heated—debate, there was a wide consensus on the need for the new measure when the Parliament actually voted. The motion the Parliament adopted urged improvements in the proposal to accelerate the development of medicines for children, faster authorization procedures and shorter administrative delays, and more transparency and exchange of information about what trials are underway to prevent unnecessary clinical trials.

The Parliament backed the idea of a research program—bizarrely entitled "MICE" (for "medicines investigation for the children of Europe")—to adapt existing substances no longer covered by patents for use in children, and it wanted tougher terms for the proposed Paediatric Committee. This committee, which will be located within the European Medicines Agency in London, should be set up within six months of the entry into force of the new rules, the Parliament said, and should independently evaluate scientific investigation plans put forward by companies wishing to benefit from the incentives created by the regulation.

Controversy over incentives

The most controversial aspect of the debate was the nature of the incentives to pharmaceutical companies to invest more in pediatric research—as expected, in the light of the energetic lobbying that had taken place on all sides prior to the Parliament debate. For many members of the Parliament, the proposal for an extra six months of patent protection was too generous: they wanted a shorter period, or a period fixed in light of the size of the company.

Key amendments passed by Parliament

Françoise Grossetête, the French Christian Democrat who had drafted the report for the Parliament, defended the fixed-period approach—the position that was firmly favored by the European pharmaceutical industry too. A system with too many variables would, she said, "lead us from the logic of health to the logic of the market." Since research is unpredictable, she maintained, "we should not add to that by introducing an unstable regulatory framework"—accusing critics of resorting to "arguments of carpet salesmen." She was backed by her UK Christian Democrat colleague John Bowis.

But strong opposition came not only from the Greens and extreme left-wing and right-wing groups, but also from some sections within all three of the largest political groups in the Parliament—the Christian Democrats, the Socialists, and the Liberals, who shared the view that shorter extensions would avoid citizens financing the industry through inflated prices. French Socialist Anne Ferreira urged a fixed protection period of just three months, with a possible further three months for companies with a turnover of under €100 million. "This is an important question for our social security systems and for all citizens," she said, "as it is public money which will end up paying for all of this."

The intensity of the debate was demonstrated by interventions such as German Socialist Dagmar Roth-Behrendt's: she backed the six-month term and criticized lobbyists for Poland and Hungary who wanted to see shorter periods of patent protection in order to benefit their generic pharmaceuticals producers. These disagreements reflecting national special interests were turning the discussion into "a pitiful, cheap debate," she said. "Parents of sick children will not understand it. We must think about the interests of patients, not national interests."

The European Commissioner responsible for industry affairs, Gunter Verheugen, told Parliament during the debate that the six-month fixed period was essential: "This system would be simple to use, is predictable, will produce less bureaucracy and is compatible with existing patent law. The Commission is not prepared to accept any compromise on this point...I ask Members to think of the interests of children, which are far more important than one lobby or another."

Fixed extension wins—for now

In the end, the majority of the Parliament voted to support a fixed extension of six months—but with the addition of a revision clause which would require a re-evaluation of how incentives were functioning six years after the new rules enter into force.

The main European drug industry lobby, the European Federation of Pharmaceutical Industries and Associations, acknowledged the Parliament vote as "an important step towards the quick adoption of crucial EU legislation on medicinal products for children's use" and "a further important step towards better medicines for Europe's children." It viewed the outcome as a broad show of support for a balance between the obligations for pharmaceutical companies to conduct often complex, costly, and lengthy pediatric research and the need to stimulate pediatric research in Europe. Brian Ager, EFPIA director general, hailed the vote as "a key opportunity for Europe's children and for Europe's pharmaceutical science base."

Ferreira was just as critical after the vote as she was during the debate. "The outcome does not amount to an acceptable balance between the interests of pharmaceutical companies and those of society: it is only a limited response to the need to define a public health policy that takes full account of the needs of children." She dismissed the arguments about the complexity of an incentive system customized according to each company's position: "And giving them six months additional monopoly on their sales, regardless of the turnover or the therapeutic value of the medicines, is not very reasonable," she said, accusing her Parliamentary colleagues of conniving at hypocrisy.

The next step (in Europe there is invariably another step to be taken!) is for national ministers to give their view on the proposal. "Member states will now have the opportunity to take this regulation forward" over the coming months, said EFPIA, which urged them to do so "without delay." And, as the European Parliament debate clearly showed, divisions still rack Europe over the best way to promote pediatric medicines.

EMEA action, too

To prove that pediatric medicines are not just an obsession of this columnist, nothing more is needed than to shift the focus from Brussels to London, where the European Medicines Agency is now consulting on a draft guideline on pharmacovigilance for medicines used in children.² The EMEA (and when will it stop using its old acronym, derived from its initial title of European Medicines Evaluation Agency, and switch to the more logical EMA in line with its new designation?) launched a six-month consultation period on its draft guideline in August. This is the first guideline to focus exclusively on the issues of safety of medicines in children, and covers not only reporting of adverse drug reactions (ADRs) in children, but also the possible need for studies designed to follow the long-term safety of medicines in children. It applies to "off-label" and unlicensed as well as approved use of medicines—but it does not address the pediatric use of vaccines, for which a separate guideline is being developed.

As the EMEA explains, while differences in age and the stage of growth and development during childhood make children prone to ADRs that vary in nature, type, and severity from those seen in adults, "the systems for detecting adverse drug reactions in children may not be as effective as for adults." For a start, children may be unable to communicate ADRs, or may not even be aware that they are experiencing an adverse event. And in addition to under-reporting of reactions, off-label use may increase the occurrence of ADRs. So the guideline aims at strengthening the pharmacovigilance system for all medicines used in children, whether specifically authorized for such use or not. Looking ahead to the proposed new pediatric rules the Parliament has just voted on, the EMEA also points out that its guideline will serve as preparatory work for implementing the pharmacovigilance provisions the new rules will contain.

Clinical safety

Specifically in relation to clinical safety and pharmacovigilance before authorization of a pediatric indication, the draft guideline urges that pharmacovigilance measures should be assessed "at all stages of a product life cycle." It remarks that pediatric pharmacovigilance assessment may be rather limited before authorization as there are often relative deficiencies in pre-authorization clinical trials of medicines for pediatric use. Sample sizes in Phase I and II trials are usually low, and even in Phase III trials sample size calculations are nearly always based on efficacy assumptions. "That means that the sample size limits the ability to observe anything less than common reactions," it warns, with the consequence that serious adverse events "are generally not observed in the paediatric clinical trial programme." Given the limitations, "every opportunity should be taken to maximize the information obtained from the occurrence of an ADR"—such as freezing a blood sample for drug and metabolite measurement if an ADR occurs.

The pharmacovigilance assessment should highlight areas where data to demonstrate safety are lacking, reflecting duration of use, patient numbers—both overall and in the different age categories—and indications studied. It should highlight potential risks for using the medicines in the pediatric population and suggest both postauthorization safety data collection mechanisms (such as postauthorization safety studies) and risk reduction strategies.

Special consideration should be given to the need for long-term follow up, for example through treatment registries, including possible effects on skeletal, neural, behavioral, sexual, and immune maturation and development. Mutagenicity and carcinogenicity data are also relevant. And consideration should be given to the use of pharmacogenomic/pharmacogenetic methodology to predict risk and to monitor adverse reactions prospectively.

Whenever a medicinal product is likely be used in the pediatric population, specific pediatric issues should be addressed in the risk management plan that should form part of the application for marketing authorization. A pediatric plan should be included in the pharmacovigilance plan and, where appropriate, specific pediatric risk minimization activities should be included in a risk minimization plan, says the draft guideline.

Comments from any interested party on the draft guideline are being sought by the EMEA until 31 January 2006.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

References

1. Proposal for a regulation of the European Parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004 (COM(2004)0599), European Commission, Brussels, September 2004, http://

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2. Guideline on conduct of pharmacovigilance for medicines used by the paediatric population, European Medicines Agency, London, August 2005, http://www.emea.eu.int/pdfs/human/phvwp/23591005en.pdf)