EXECUTIVE INTERVIEW - Synteract: Advances in Pediatric Clinical Research & the Promise for the Future

While the pediatric use section to the label template was established in the US as early as 1979, and the FDA began further initiatives to improve pediatric-use information on drug labeling with the first of several rules in 1994, many medications still lacked prescribing information for children and had not been tested and evaluated for them. Today, increasing legislation in the US and the EU makes pediatric development plans a requirement for all new medicines that do not have a waiver or are exempt from pediatric regulations, not just those that are specifically for children. What does this mean for drug developers, young patients, and their families?

Synteract is a CRO that has been at the forefront of working with sponsors in pediatric clinical research, with 260+ pediatric clinical projects conducted globally. In November 2018, it acquired KinderPharm, a pediatric specialist CRO, to further build out its pediatric drug development offering. Drug Development & Delivery recently spoke with Dr. Martine Dehlinger-Kremer, Vice President, Pediatric Development at Synteract to discuss current and significant challenges in pediatric clinical research, advancement of regulations surrounding them, and where the industry is headed.

A: Pediatric clinical trials are still not as well accepted by society. Even today, more than 50% of medicines administered to children have never been tested in this population, yet there is still some reluctance about involving children in trials, particularly by parents and some physicians. They fear harming young patients due to uncertain treatment effects, or that their ailing child may be administered a placebo. Investigators are apprehensive to recruit children for trials given the large amount of information they must provide to families and the trial participants. Work still needs to be done to help investigators understand families’ perceptions of trials and how to best provide support and improve recruitment.

Participation in trials is improved by having trained investigators who understand the complexities, appropriate facilities that meet the needs of children, and experienced trial coordinators to facilitate recruitment and trial conduct. It is important to have an appropriate child-friendly environment and to adapt treatments to their special needs. Trials should be as pragmatic and flexible as possible, with limited additional testing and monitoring beyond requirements of routine clinical care. Visits should be scheduled around school hours and holidays as much as possible. Having nurses go to the home of the child for some tests to avoid visits on site may help as well.

The importance of engaging families in trials design, review of protocols, and patient-facing documents cannot be underestimated. One way to help parents and children decide to participate in a trial is by improving readability of the consent and assent. Using plainspoken, clear documents that are more graphical in nature for younger age groups along with videos, infographics, or pictures to explain the clinical trial will effectively help orient families and children.

Finally, the burden of trial participation is different for children versus adults. For example, some children’s fear of needles may make obtaining blood samples challenging. To address this burden and protect children from unnecessary testing, one should consider trial designs with sparse sampling that minimize the number of required blood draws. It is also advised that the volume of blood taken be limited in children, and especially in those that are younger. Hence, the volume of blood sampling allowed in pediatric trials is less than 3% of the estimated circulating blood volume over a period of 4 weeks and should not exceed 1% at any single time. Alternative appropriate sampling techniques, such as finger or heel pricks or salivary samples, may be preferred as they minimize discomfort. Also, specific assays, such as micro-assays, are critical for pediatric trials as they allow analysis with limited blood amounts.

Q: When it comes to the pediatric population, infants obviously have different needs than toddlers, grade-school age children, or preteens. How can the industry address the different needs of pediatric age groups in clinical trials?

A: The pediatric population is indeed not a harmonized population. It is advisable to have the protocol and patient-facing documents, such as the assent form, reviewed by patients/advocacy groups before implementation to ensure they are adapted to the child’s age and maturity level.

We recommend providing tailored trial information on aspects important to parents. Parents or guardians must be allowed enough time to make a decision, taking into consideration the amount and type of information provided, organization of the consent meeting, communication style, and additional materials (e.g., illustrated booklets, videos) provided.

Although consent by parents/guardians is a legal requirement for trials, the explicit wish of children must also be respected, and investigators need to include them in decision-making as much as they are capable, depending on age and mental maturity. Information about the trial should be provided in an age-appropriate format to improve comprehension, show respect, preserve trust, and enable cooperation. Children’s dissent must be respected, particularly if it is different from their usual response to similar procedures in normal clinical care. If the child refuses to participate, the investigator cannot include them. If the investigator cannot convince him/her, regulations and ethics guidelines will not allow their inclusion.

Q: Has the industry progressed when it comes to recruitment of pediatric populations?

A: The industry and regulators are working together to improve pediatric research and ensure medicines are adequately developed. Pediatric networks are being created to facilitate clinical trials in children. International pediatric trial networks have been established to improve infrastructure and research. The US and EU created networks with specialized expertise in conducting trials in children and have dedicated funding for pediatric research and training.

The National Institute for Health Research (NIHR) Medicines for Children Research Network (MCRN) in the UK was established in 2005. This network, which benefited from government funding, has been very successful. By 2012, 25,000 children were recruited to over 300 Medicines for Children Research pediatric trials.

The US Pediatric Trial Network (PTN), sponsored by Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), was launched in September 2010 for a 7-year program, with $95 million to conduct pediatric trials on off-patent medicines. This network provides an appropriate environment for performing safe and effective trials in children as recommended by the Best Pharmaceuticals for Children Act (BPCA), a drug development program in a variety of therapeutic areas. In 2012, the network, in collaboration with the FDA, commenced pediatric studies on 30 drugs. As of today, PTN recruited over 7,000 children in 38 studies.

The Network of Paediatric Research at the European Medicines Agency (Enpr-EMA) was established in March 2011 in collaboration with research networks, investigators, and centers with recognized expertise in conducting pediatric trials. This network is working toward developing necessary competencies and avoiding unnecessary duplication of pediatric studies, educating parents or caregivers and children about trials and encouraging their participation, raising awareness about the necessity for trials in children of all ages with healthcare professionals, supporting their involvement in such studies, and engaging in dialogue with ethics committees on pediatric trial issues. (Note: Dr. Dehlinger-Kremer is an observer Member of the Coordinating Group of Enpr-EMA.)

I-ACT, the Institute for Advanced Clinical Trials for Children, established by Critical Path Institute in March 2017, was launched in the US to optimize and accelerate biomedical innovation using child-centered clinical trial networks and collaboration with like-minded institutions, trial sponsors, and other stakeholders.

The conect4children (c4c) project in the EU was launched in May 2018. It is a large collaborative pediatric network that will facilitate development of new drugs and other therapies for the pediatric population in Europe. The c4c consortium aims to enhance the competitiveness of Europe as a critical region for developing medicines for children by using existing expertise, patient access, and developing common processes to be applied to disease natural history studies, registries, studies of new therapies, and comparisons of existing therapies.

Patients and parents are also more involved in pediatric research. There are international children advisory groups, such as the International Children’s Advisory Network (iCAN). A worldwide consortium of children’s advisory groups, iCAN is dedicated to giving children and families a voice in health, medicine, research, and innovation by increasing education about the importance of children’s involvement. With chapters across the US and worldwide, iCAN (of which I am a member of the External Advisory Board since October 2018) works with CROs like Synteract and partners with local children’s hospitals to help address the needs of pediatric clinical research and healthcare and advocates for patients worldwide.

Q: When it comes to the advancements for pediatric drug development, what has been successful in moving the industry forward and what has not?

A: Pediatric regulations in the US, including BPCA, PREA, and FDASIA have been successful. In the US, drugs with Orphan Drug Designation were exempt from PREA requirements. With the FDARA from 2017, and the RACE for Children Act, this exemption will be eliminated for cancer drug development, and therefore, will improve opportunities for children by:

-Ending exemption of PREA obligations for cancer drugs with orphan designations if the molecular target of the drug is relevant to children’s cancer

-Requiring companies to evaluate their product in children when the molecular target of their drug is relevant to children’s cancer

Even though the Pediatric Regulation entered into force much later in the EU than in the US, Europe has had great success in adding new drugs approved for children as well as new indications for children. There is, however, still some room for improvement as not all PIPs are completed on time.

In the EU, the 10-year Commission report on EU Pediatric Regulation (October 26, 2017) recognized the positive impact of the Pediatric Regulation overall, though the Regulation appears most effective when adult and pediatric needs overlap. Fewer advances have been made in diseases that are unique to children. While some instances of over- or under-compensating drug developers with financial rewards exist, overall benefits appear to outweigh costs.

Therefore, the European Commission does not currently recommend re-opening the legislation. It will evaluate pediatric and orphan regulations to better understand why rewards do not seem to be driving development for rare childhood diseases. Findings are expected to be delivered in 2019, enabling the next Commission to make informed policy decisions.

Meanwhile, the European Commission and EMA have started to streamline application and implementation of the Regulation, including making changes to deferrals and revisiting PIP processes.

A revised and revoked class waivers list has been in force since July 28, 2018. Applications for new medicines or variations of marketing authorizations will be validated against it. Waivers, specifically in oncology, will no longer be automatic. Regulators will expect companies to have considered product mechanism of action and pediatric needs prior to decision.

The EU Commission and EMA held a workshop with patients, academia, healthcare professionals, and industry on March 20, 2018 to discuss potential improvements to the Regulation. An action plan, taking into account recommendations collected during the workshop was published in October 2018. The action plan is structured around five topics areas:

-Identifying pediatric medical needs

-Strengthening of cooperation of decision makers

-Ensuring timely completion of pediatric investigation plans (PIPs)

-Improving the handling of PIP applications

-Increasing transparency around pediatric medicines

The action plan, that consists of 21 actions in total, should address the challenges identified by the EU Commission and EMA and increase the efficiency of pediatric regulatory processes in the current legal framework and boost the availability of medicines for children. The completion of this action plan takes into consideration the Brexit, EMA relocation, and business continuity plan. Some actions are deferred and some deadlines are likely to be revisited. The completion of all the actions is thus not expected within the initially planned 2 years’ time frame, i.e., by the end of 2020.

Close collaboration between the US and the EU has improved pediatric clinical research significantly. We look forward to continued oversight and the resulting benefits to children, who need these medicines, and their families.

To view this issue and all back issues online, please visit www.drug-dev.com.