INT J TUBERC LUNG DIS 19(12):S69–S74 Q 2015 The Union http://dx.doi.org/10.5588/ijtld.15.0616

Accelerating clinical drug development for children with

S. Murray,* L. McKenna,† E. Pelfrene,‡ R. Botgros‡ *The Global Alliance for TB Drug Development, New York, New York, †Treatment Action Group, New York, New York, USA; ‡Office of Anti-infectives and Vaccines, European Medicines Agency, London, UK

SUMMARY Despite urgent need, the development, approval and following successful phase II studies, shifting from the availability of child-friendly anti-tuberculosis drugs lag current age de-escalated approach to concomitant significantly behind that of adults, with children having enrollment of children from the various age groups in been ignored in anti-tuberculosis drug development studies, and leveraging the concepts of both the Unified research. This paper outlines possible strategies for Pathway and regimen development that have helped accelerating and better integrating the development of speed the study and development of novel regimens in drugs and regimens for pediatric tuberculosis (TB) into adults. existing drug development pathways for adults: initia- KEY WORDS: trial design; formulation; ethical guide- tion of pediatric studies of new treatments as soon as lines; medicines; infectious disease; pediatric; tubercu- promising efficacy data have been generated in adults losis

ALTHOUGH IT IS CONSIDERED a productive time These development needs are further emphasized in terms of ongoing research in the field of by the increasing number of children with TB tuberculosis (TB), with new products and regimens globally;4–6 however, it will be many years before being evaluated in adults, pediatric research initia- the novel drugs and regimens now being approved tives are generally following at a slower pace.1 It is and deployed for adults will reach children. Whereas widely accepted that the treatment of pediatric drug- pediatric research needs are increasingly recognized susceptible (DS-TB) and drug-resistant TB (DR-TB) is by key documents such as the Stop TB Partnership’s hampered by factors such as high pill burden, long GlobalPlantoStopTB,7 existing funding and treatment duration, coexistent toxicities and a lack of incentives available to support these activities remain child-friendly drug formulations. As such, against a inadequate. Although children represent about a background of historical neglect, the medical need for quarter of the global TB burden,8 pediatric TB improved and appropriate pediatric TB treatment research and development (R&D) accounts for just remains unmet. 2% of total R&D funding.9 The collection of data in children is often delayed Another critical aspect further contributing to the compared to adults, and this scarcity of pediatric data delayed development of anti-tuberculosis medicines has underlined the need to address the numerous in children is the frequent lack of age-appropriate knowledge gaps in this population, including phar- pharmaceutical formulations. Following the World macokinetic (PK) and adverse effects profiles of old Health Organization’s (WHO’s) 2010 revisions to second-line and new anti-tuberculosis drugs and first-line drug FLD dose ranges,10 new, child-friendly regimens; optimal duration of treatment and follow- formulations that take into account these updated up; adequate drug combinations and relevant doses dose ranges for FLDs have only recently become for disease manifestations more common in children available. Age-appropriate formulations do not exist (e.g., osteoarthritis, meningitis); the optimal duration for most second-line agents, and some of those that of anti-tuberculosis treatment in human immunode- do exist are deemed inadequate.11 The current use of ficiency virus (HIV) positive children and character- second-line agents in children with TB is guided by ization of drug-drug interactions as well as the sparse or incomplete data;11,12 hence the current optimal duration of treatment for multidrug-resistant practice of makeshift and potentially dangerous TB (MDR-TB) in children with minimal disease dosing options in children with TB, such as crushing (uncomplicated hilar adenopathy).2,3 or partitioning tablets intended for adults.

Correspondence to: Stephen Murray, The Global Alliance for TB Drug Development, 24th Floor, 40 Wall Street, New York, NY 10005, USA. Tel: (þ1) 212 227 7540. e-mail: [email protected] Article submitted 14 July 2015. Final version accepted 15 September 2015. S70 The International Journal of Tuberculosis and Lung Disease

REGULATORY LANDSCAPE not confer protection to younger cohorts. Due to the many and significant physiological and metabolic Among opinion leaders and policy makers alike, differences between the various pediatric age groups, consensus has grown that harmonization and stream- data generated in older children do not necessarily lining of requirements and processes may help predict what will happen in younger cohorts, nor do optimize pediatric drug development.13 In the Euro- they mitigate the risks.16 In relation to the safety pean Union (EU), this entails early agreement on a aspects, differences in the adverse event profile and pediatric investigation plan (PIP) that states key drug interactions between children and adults due to binding, time-bound measures that incorporate de- existing biological differences between these groups tails on the development of age-appropriate formu- cannot be excluded. Depending on the drug under lations. As per the EU Paediatric Regulation evaluation, intense safety monitoring might therefore 14 (Regulation EC No. 1901/2006), developers are be necessary in children. Simultaneous enrolment of requested to prepare their envisaged pediatric devel- certain pediatric age groups into TB trials may prove opment program no later than upon completion of to be an alternative viable option, and could be PK studies in adults and subsequently to discuss and further discussed with regulators. It has to be agree upon it with the EU regulator. recognized nevertheless that, apart from the above, TB trials should enroll only children with con- further aspects also need to be considered and may firmed or probable TB disease, as defined according lead to a delay in conducting the agreed studies in to the published case definitions for DS- and DR- younger age groups, principal among which is the 15 TB. In particular, children aged ,5 years suffering usual lack of availability of an age-appropriate from TB disease and those with HIV/acquired pharmaceutical form at the time of conducting the immune-deficiency syndrome constitute the most pediatric studies. susceptible groups for research prioritization. In the previously mentioned age group, TB disease presents more often with extrathoracic locations, warranting PROPOSED STRATEGIES FOR ACCELERATED further examination and evaluation of treatment TUBERCULOSIS DRUG/REGIMEN outcomes, while PK in young children may differ DEVELOPMENT substantially from that of older children. Among the options available to accelerate anti- International Conference on Harmonisation (ICH) tuberculosis drug development in children, the guidelines state that: ‘[vulnerable] group should stand following could be envisaged (see Table). to benefit from the knowledge, practices or interven- tions that result from the [medical] research.’ Novel Initiate pediatric studies after successful Phase II trials therapeutic agents or regimens should therefore be in adults considered for further study and development if there It is generally accepted that efficacy can be extrap- is a prospect for improved efficacy/effectiveness over olated from adult studies. However, single- and the comparator or a better safety/tolerability profile. multiple-dose PK studies that include the collection Alternatively, new drugs or regimens may hold the of safety outcomes have to be conducted to ensure prospect of treatment shortening or simplification or that the dosing regimen used in children is adequate. obviate the need for parenteral drug administration. The determination of the optimum dose cannot be Age-appropriate formulations assuring accurate dos- achieved using simple allometric scaling based on ing, adequate tolerability and palatability should be weight and surface area.17 Prior to initiating trials in made available and should ideally be used for PK and children, an adequate preclinical safety package and safety investigations in children. juvenile toxicity studies have to be performed. For HIV co-infected patients, fewer drug-drug interactions would be considered an advantage over Concomitant enrolment existing TB regimens. Nevertheless, while it is Single- and multiple-dose PK studies conducted in all recognized that children with HIV and TB are one age groups simultaneously will help in selecting the of the groups that is among the top priorities in terms appropriate dose to be used in children. These studies of unmet need, the lack of adult drug-drug interaction could be conducted in addition to the patient’s studies between TB drugs and highly active antiret- standard treatment. roviral therapy is clearly an important limiting factor, and may further hamper the generation of pediatric Development of drug regimens for children data in this subpopulation with very limited treat- Novel strategies employed to accelerate drug devel- ment options. opment in adults can also be applied to the pediatric Although not counted as a formal regulatory drug/regimen development. One such strategy of requirement, sequential age-de-escalation is one of ‘regimen development’ is to examine new drugs the frequently used enrolment strategies for pediatric individually in animal studies and then in human studies. This conservative approach may, however, phase I and early phase II, but to subsequently Strategies for pediatric TB drug development S71

Table An overview of historical and current development strategies and the newly proposed paradigm for drug development in pediatric tuberculosis

Proposed/accelerated pediatric Historical Current development Development strategy No specific pediatric development; Pediatric development is generally Single-dose PK studies begin as children are given adult doses, or initiated once a drug or regimen soon as successful phase II adult doses are adjusted according to is approved for adults, starting studies are complete. Study weight with adolescents and gradually multiple dose/comprehensive PK moving to younger children and safety in all children (no age de-escalation) in parallel with phase III (in adults) Challenges Drugs in regimens are administered Significant delays for access to new Overcoming traditional clinical and using ad hoc methods drug or regimens for children ethical considerations of how (administering adult-sized pills, children can be studied crushing, dispersion in liquids etc.). Pediatric safe/efficient dosing often unknown

PK ¼ pharmacokinetic. evaluate these collectively within new regimens in late institutional review boards and ethics committees phase II and phase III studies.18 This regimen (Table). development strategy can greatly shorten the time to develop and register novel regimens in adults, and INCENTIVES TO INCREASE AND ACCELERATE could be applied to children’s development programs PEDIATRIC TUBERCULOSIS DRUG RESEARCH as well. If a new safety issue arises during the evaluation of a regimen, it might be necessary to do Regulatory standards on the collection of important additional animal or phase I work to determine the pediatric data for novel TB drugs have been the main cause/source of the issue. This is one of the driving force behind the development of novel anti- limitations/risks of a regimen-based approach. tuberculosis drugs in children, but may still be Similarly, the ‘Unified Pathway’ allows for parallel insufficient for ensuring timely access to treatments enrolment of both people with DS- and DR-TB into for children. The European requirement for the the same clinical trial. An example of such a trial is agreement of a PIP prior to granting marketing the recently completed NC-002 study of PaMZ authorization ensures that relevant pediatric PK and (pretomanid þ moxifloxacin þ pyrazinamide).19 This safety data will be collected and that a pediatric greatly simplifies regimen development and removes formulation will be developed.20,21 The United States the time and cost associated with developing new Food and Drug Administration (FDA) allows drugs regimens for DS- and DR-TB independently. In this for orphan diseases, i.e., those that affect fewer than strategy, patients are included in clinical trials if they 200 000 individuals per year in the United States, are infected with a strain of TB that is susceptible to such as TB, exemption from pediatric studies the drugs in the regimen, irrespective of whether they altogether.22 could be qualified as drug-susceptible or drug- Regulatory incentives, such as extended marketing resistant, according to the existing definitions. This exclusivity23 and vouchers24 offered strategy is equally applicable to both children and by the FDA, intended to encourage rather than adults. mandate investigations in pediatric populations, have To address potential challenges associated with this so far been ineffective for TB. As of March 2015, 210 approach, appropriate pediatric TB specialists should products have been granted pediatric exclusivity, be involved in drug safety monitoring boards. If none of which are indicated for the treatment of TB required, the program could include long-term in children.1 Exclusivity and other market-driven follow-up through the introduction of a drug registry incentives confer less benefit and attractiveness in the and the collection of surveillance data to detect absence of a lucrative market and competition, as is possible late effects on skeletal, behavioral, cognitive, the case for TB. Pediatric exclusivity has also left sexual, and immune developmental maturation. It is some age groups understudied, as once pediatric nevertheless recognized that the above could prove exclusivity is granted for studies conducted in older challenging in resource-poor countries. children, there is no additional incentive for conduct- In addition, there is likely a practical need for ing studies in younger age groups. Furthermore, additional capacity building for clinical trial sites and pediatric exclusivity does little for products that have investigators. This capacity building can help im- no remaining patent life, as is the case for most prove the number of sites that are qualified to second- and third-line anti-tuberculosis drugs. perform clinical trials in children, facilitate enroll- Alternative incentives, particularly those focused ment strategies, and overcome barriers posed by on creating an attractive market, may be more S72 The International Journal of Tuberculosis and Lung Disease effective for accelerating the development and avail- (TBTC), where appropriate, includes children in their ability of pediatric TB treatments. An advance market work, largely centered on the TB drug rifapen- commitment (AMC) is a legally binding agreement tine.27,28 for an amount of funds that is used to subsidize the Funders could create further incentives for both purchase, at a given price, of an as of yet unavailable public network and investigator-initiated research to drug, diagnostic or vaccine.25 AMCs attract devel- include children. For example, study protocols or opers by guaranteeing a certain volume of procure- grant proposals that include children could be ment and return on investment in the absence of a assigned a priority review status or extra points on clearly defined market. AMCs by donor agencies such scoring materials. Public funders could also mandate as the Global Fund for HIV, TB and (Global the inclusion of pediatric research components in all Fund, Geneva, Switzerland) and the US Agency for studies that follow successful phase 2 studies in International Development (USAID, Washington DC, adults. Such requirements could apply both to new USA), or even by governments with well-established drugs and regimens. Finally, the recently proposed 3P political will, such as that of South Africa, could help Project—‘Push, Pool, Pull’—combines incentives draw private-sector interest and investment in pedi- such as increased donor and public funding meant atric TB treatments. to ‘push’ promising drug candidates through earlier While AMCs may be an effective strategy for phases of development, with ‘pull’ incentives such as drawing investment to what might otherwise be an milestone prizes designed to financially reward the unattractive market, revealing the true burden of TB achievement of certain R&D objectives. While the 3P among children is a longer-term, complementary Project was conceived to address underlying issues strategy. Work to improve estimates of the global hampering the development of new TB regimens, burden of TB in children, to develop more sensitive similarly, push/pull incentives could be applied to and non-sputum based diagnostic tools, and to accelerate research and development in children, integrate TB services with those for reproductive, particularly if the mechanism could interest new maternal, neonatal and child health is critical to funders that do not currently support TB and further elucidating the true potential market for pediatric TB research.29 pediatric TB medicines and hopefully creating market Advocacy is another tool that can be used to raise incentive. awareness of the importance of timely investigation In addition to creating market incentives to attract of TB treatment regimens in children, and hold drug investment, increasing donor and public funding for sponsors, donors, and public funders accountable for pediatric research and development is absolutely ensuring its realization. Vocal reinforcement that critical. A grant from UNITAID to the Global inclusion of children in research is an expectation of Alliance for TB Drug Development (TB Alliance, the TB community will further encourage and New York, NY, USA), a not-for-profit product accelerate the development of and access to anti- development partnership with the mission of devel- tuberculosis treatment for children. oping improved TB treatments, and its project partner, the WHO Global TB Program and Depart- CONCLUSIONS ment of Essential Medicines and Health Products, is an example of a donor-initiated incentive that has The current approach to anti-tuberculosis drug successfully catalyzed the development and market development is not sufficient to rapidly address the introduction of pediatric TB treatments. The goal of urgent unmet medical needs of children with TB. the grant is to make available and improve access to Ample opportunities exist to improve today’s efforts. correctly dosed, properly formulated, affordable, Overlapping pediatric development with ongoing high-quality pediatric TB medicines meeting the adult development of anti-tuberculosis drugs and current WHO guidelines for these drugs. Thanks to regimens (Figure), and applying the approaches of this investment, revised fixed-dose pediatric formu- regimen development and the Unified Pathway to the lations of FLDs will finally be available, 5 years after development of pediatric formulations, will greatly the WHO issued the updated pediatric TB treatment accelerate the availability of new TB treatments for guidelines. The US National Institutes of Health children. These strategies can be applied without (NIH, Bethesda, MD, USA) is also contributing, compromising current safety or ethical standards. funding a number of investigator-initiated and However, it would be highly desirable that more IMPAACT (International Maternal Pediatric Adoles- adequate incentives to conduct the necessary research cent AIDS Clinical Trials Network) studies that will for children are created and implemented. Augment- fill long-standing gaps for existing anti-tuberculosis ing existing incentives, such as the funding available drugs and advance investigations of novel TB drugs in for pediatric TB drug development, and new incen- children, including children who are HIV-positive.26 tives, such as an AMC for pediatric drugs, are Furthermore, the US Centers for Disease Control and necessary to perform the clinical trials that address Prevention-funded Tuberculosis Trials Consortium this unmet public health need. Strategies for pediatric TB drug development S73

Figure Optimized anti-tuberculosis drug development: integrated adult and pediatric clinical trials. PK ¼ pharmacokinetic; DS-TB ¼ drug-susceptible TB; DR-TB ¼ drug-resistant TB; TB ¼ tuberculosis.

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RESUME En d´epit de besoins urgents, l’´elaboration, l’approbation nouveaux traitements d`es qu’ils ont g´en´er´e des donn´ees et la disponibilit´edem´edicaments antituberculeux d’efficacit´e prometteuse chez les adultes (apr`es des adapt´es aux enfants restenta ` la traˆıne par rapporta ` etudes´ r´eussies de phase II) ; passer de l’approche ceux des adultes, les enfants ayantet´ ´ e largement ignor´es actuelle limitant lesetudes ´ chez les plus jeunesa ` dans la recherche et le d´eveloppement des m´edicaments l’enrolement ˆ concomitant d’enfants de tous les groupes pour la tuberculose (TB). Cet article expose les strat´egies d’ˆage dans lesetudes ´ ; et amplifier les notionsa ` la fois possibles pour acc´el´erer et mieux int´egrer l’´elaboration d’Unified Pathway et d’´elaboration de protocoles qui de m´edicaments et de protocoles pour la TB p´ediatrique ont contribu´e`a acc´el´erer l’´etude et l’´elaboration de dans les voies de d´eveloppement des m´edicaments TB nouveaux traitements chez les adultes. pour adultes : initiation d’´etudes p´ediatriques des

RESUMEN Pese a que existe una necesidad urgente, el desarrollo, la nuevos tratamientos, tan pronto como se hayan autorizacion ´ y la puesta al alcance de los medicamentos obtenido datos prometedores de eficacia en los adultos antituberculosos adaptados a los ninos˜ no han avanzado (luego de un resultado favorable de la fase II de los al ritmo del progreso con las preparaciones destinadas a estudios cl´ınicos); la transformacion ´ de la estrategia los adultos; en la investigacion ´ sobre los medicamentos actual de escalonamiento regresivo en funcion ´ de la antituberculosos se han ignorado en gran medida los edad, en una inclusion ´ concomitante de ninos˜ de los ninos.˜ En el presente art´ıculo se describen estrategias que diferentes grupos de edad en los estudios cl´ınicos; la podr´ıan acelerar el desarrollo de medicamentos y promocion ´ de dos conceptos, a saber, la V´ıa Unificada mejorar la integracion ´ de los reg´ımenes pedia´tricos en (tuberculosis sensible y resistente en un mismo estudio) y los mecanismos existentes de investigacion ´ farmac´eutica el mecanismo de formulacion ´ de reg´ımenes que ya ha dirigida a los adultos. Se proponen las siguientes contribuido a acelerar el estudio y la formulacion ´ de medidas: la iniciacion ´ de estudios pedia´tricos con los nuevas pautas terap´euticas dirigidas a los adultos.