Oncology Products Benefit Most From Informal Scientific Advice By EMA-FDA Pediatrics 'Cluster'
This article was originally published in SRA
A relatively new collaboration - under which the European Medicines Agency and the US Food and Drug Administration join forces to issue informal parallel scientific advice to developers of selected pediatric medicines that are under review at both agencies - has so far benefited oncology and gastroenterology products the most.
Under the collaboration, the pediatric "cluster" of EMA and FDA officials hold monthly teleconferences to discuss product-specific or general pediatric topics of interest, and in some selective cases issue a "common commentary" to inform drug sponsors of the discussions they have had in relation to their products1. Regulators from Canada, Japan and Australia also participate in these teleconferences.
Only medicinal products that address life-threatening or serious diseases and have no, or few, treatment options or where there are major differences between the EMA and the FDA in relation to clinical trial design or endpoints are eligible for common commentaries. This should explain why most of common commentaries issued till now concern oncology drugs, said Dr Irmgard Eichler, senior scientific officer (pediatric medicines) at the EMA.
The strict criterion also means that only a few products qualify for informal parallel scientific advice. Since 2013, when the two agencies started issuing common commentaries, 165 topics have been discussed at the cluster, of which only 15 were selected for common commentaries (one common commentary was issued in an earlier pilot phase bringing the total figure to 16).
In all, seven common commentaries have been issued in relation to oncology drugs, six in relation to gastroenterology medicines and one each for cardiology and neurology products. In addition, the process has resulted in a "general" common commentary on the development of pediatric drugs for Gaucher disease2, said Eichler.
Eichler presented these figures at a conference in London on Better Medicines for Children, which was jointly organized by the EMA, the Drug Information Association and the EU Forum for Good Clinical Practice on Oct. 1 and 2.
She explained that common commentaries are somewhat different from formal EMA-FDA parallel scientific advice, which companies can request in relation to any type of product. Unlike the formal parallel scientific advice procedure, common commentaries can only be initiated by the regulators in relation to selective pediatric products and they are non-binding in nature. Common commentaries can also be issued more quickly than formal parallel advice and they do not involve participation by the product sponsor.
"Sometimes there is a need to have more than one discussion on the issues and products that are identified for a common commentary," said Eichler. Following the conclusion of a discussion, the views of the EMA and FDA in terms of where they concur or diverge are summarized in one or two pages, agreed on by the two agencies and then sent to the concerned sponsor. "This document clearly states that it is not a replacement for scientific advice… and is not binding on either agency, but we do hope that the information that we provide and the summary of our discussions are helpful for sponsors to proceed with their [pediatric development] programs," she added.
Simultaneous Submissions: Timing Is Not A Big Issue
In order to be considered for the common commentary process, the sponsor's pediatric research plan (ie the pediatric investigation plan (PIP) in the EU and the pediatric study plan (PSP) or written request in the US) should be under review at both the EMA and the FDA "preferably very early on in the regulatory process to really benefit from this exchange," said Eichler.
This means that theoretically, companies should aim to submit their pediatric research plans to the two agencies simultaneously to maximize the possibility of achieving "regulatory consensus". However, this may not be easy as there are differences in the EU and US legislation on when such plans should be submitted – the EU Paediatric Regulation requires submission upon completion of pharmacokinetic studies in adults (ie, around the end of Phase I), whereas the US Pediatric Research Equity Act mandates this at the end of Phase two.
In practice, though, "the difference in timing is not really a major hurdle in global pediatric development programs," Eichler said.
An analysis of delayed PIPs shows that over the past five years, there has been no change in the average time lag between the EU legislative deadline and the actual submission of PIPs – companies continue to submit PIPs around two and a half years after completing their adult PK studies. "What has changed is the significant decline in the number of unjustified late submissions," said Dr Eichler.
Jean Temeck, supervisor (international team) at FDA's Office of Pediatric Therapeutics, also emphasized the need for simultaneous submissions to support the harmonization process. Speaking at the London conference, Temeck said there have been instances in the past where companies have submitted their pediatric research plans to the EMA but not "looped in" FDA until a year later, by which time the EMA may have already finalized their opinion on the pediatric plan. This poses extra challenges on the system, when aiming for harmonization.
An industry representative at the conference, however, pointed out that EMA-FDA pediatric cluster meetings should not be regarded as the final word on regulatory consensus. The representative shared an instance of a drug that was discussed at the cluster and on which consensus was achieved between the two agencies, "but the FDA later asked for substantial modifications to the approach agreed with the EMA".
There Are No Secrets Between Agencies
The pediatric cluster was set up in 2007 to allow the EMA and the FDA to resolve, to the extent possible, differences in pediatric research plans under review at both agencies to avoid duplicative trials in children (see table 1 for details).
"Though we are able to harmonize [our requirements] around three quarters of the time, it's very challenging to achieve harmonization in all cases due to various reasons, such as differences in scientific practices and standards of care in the EU and the US," said Temeck.
Nearly 500 topics have been discussed at the cluster, to date, of which most (382) have been product-specific, while others (116) have focused on general issues. There is an elaborate process to ensure that both agencies are made aware of all products being submitted for review. "There are no secrets between the two agencies," said Eichler.
Specifically, the process involves the EMA sending monthly lists of all the pediatric investigation plans it has received. The two agencies then jointly identify products or scientific issues for joint discussion (also, Japan or Canada can propose a topic). Possible triggers for selecting a product/topic include: sponsors not sharing the same information with both agencies; safety concerns; differences in endpoints or indications; timing of initiation of pediatric studies; differences in age subsets of pediatric populations to be studied; and pre-clinical issues.
Once the products/issues for joint discussion are identified, the FDA receives a summary report of what the EMA's pediatrics committee (PDCO) has discussed in relation to these submissions "so that the FDA is fully aware of what has been discussed at the EMA". The FDA then develops a spreadsheet and inserts its own data for the products to be discussed. The final step involves the EMA and FDA selecting their respective experts to participate in the cluster meeting.
The EMA's head of pediatric medicines, Paolo Tomasi, said that significant effort is involved in conducting these meetings, which last for two to three hours. In terms of timing, for example, Tomasi said that the cluster meetings have to begin sharp at 12.30 pm (UK time).
They can't be held any sooner or later because 12.30 pm (UK time) means it is around 7.30 am in the US and Canada, around 8.30 pm in Japan and 10.30 pm in Australia, which means regulators in other countries have to either wake up very early or work till late to participate in these meetings. The EU gets the "nicest deal" on these meetings, Tomasi remarked.
Table 1. Examples of issues resolved through discussions by the pediatric cluster
Product | Issue | Outcome |
Oncology product to treat a specific type of brain tumor | Patient population Sponsor submission in EU proposed studies with newly diagnosed and relapsed/refractory patient populations, while in US sponsor proposed studies with relapsed/refractory patients only. | Following EMA's assertion that newly diagnosed patients could also benefit from studies, FDA too asked for studies in both patient populations. |
Products to treat children with Gaucher disease | Multiple products in pipeline for this ultra-rare disease, but limited patient pool. EMA proposed multi-arm, multi-company trials to reduce number of subjects as the same control arm could serve more than one product. | After initial concerns regarding the feasibility of such an approach, the FDA agreed with EMA's proposal. Agreement also reached on the extent of extrapolation possible, choice of endpoints, trial duration and non-clinical aspects. |
Drug in class X; adjunct to insulin to treat Type 1 diabetes mellitus (T1DM) | Timing for initiation of pediatric studies as product was first in class. EMA favored waiting until efficacy and safety data in adults became available. FDA pointed to the significant unmet need and favored initiation of pediatric studies after getting interim data from adult studies. | The two agencies aligned their approach and agreed on the need to initiate pediatric studies earlier rather than later.
|
Drug in class Y; adjunct to insulin to treat T1DM | Study design and primary endpoint. EMA agreed with sponsor's proposal of treat-to-target trial design with co-primary endpoints, but FDA found the trial design unacceptable for many reasons. | Sponsor agreed with FDA's proposal to use an insulin-capped trial design. Sponsor sought EMA's concurrence to submit a revised PIP. |
Two recombinant human products to treat rare diseases
| Choice of endpoints EMA accepted sponsor's proposal of surrogate endpoint as primary endpoint, whereas FDA insisted on clinically meaningful endpoints to assess efficacy. | EMA and FDA agreed that the totality of the evidence should be considered in the assessment of efficacy of these products, and that clinical benefit must also be demonstrated.
|
Products for treatment of ulcerative colitis | Extrapolation, dose-finding, study design and endpoints.
| FDA, EMA, Japan's Pharmaceuticals and Medical Devices Agency, and Health Canada agreed on: partial extrapolation from adult studies; conducting initial pediatric dose-finding study before starting of pediatric efficacy trial; no need for fully powered efficacy studies due to partial extrapolation; and that mucosal healing should be the ultimate endpoint. Outcome published as two-part article in the Journal of Pediatric Gastroenterology and Nutrition. |
References
1. Patient input latest issue US and EU drug regulators put heads together over, Scrip Regulatory Affairs, July 15, 2015
2. Gaucher disease: A strategic collaborative approach from EMA and FDA (EMA/44410/2014), May 12, 2014, www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2014/05/news_detail_002102.jsp&mid=WC0b01ac058004d5c1#