A Study of Regulatory Challenges of Pediatric Oncology Phase I/II Trial Submissions and Guidance on Protocol Development.

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient-facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time-consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided.

New paradigm for expediting drug development in Asia.

Some Asian regulators currently require Phase I data in Asians before joining global Phase II/III trials. Here, we discuss inherent limitations of Phase I ethnic sensitivity studies (ESS) to identify potential interethnic differences. We review recent new drug applications (NDAs) for Japan and China to critically assess the value of separate ESSs in Asian populations. Given that the observed value of ESS was limited, we propose a new global drug development paradigm: if relevant safety, pharmacokinetic (PK), and pharmacogenetic (PG) data are available from the original Phase I study population, it might be possible to extrapolate those data to Asian populations for their inclusion in Phase II/III trials, without an ESS. This could help to streamline drug development in Asia while still addressing regulatory requirements.

Pediatric microdose and microtracer studies using 14C in Europe.

Important information gaps remain on the efficacy and safety of drugs in children. Pediatric drug development encounters several ethical, practical, and scientific challenges. One barrier to the evaluation of medicines for children is a lack of innovative methodologies that have been adapted to the needs of children. This article presents our successful experience of pediatric microdose and microtracer studies using (14) C-labeled probes in Europe to illustrate the strengths and limitations of these approaches.

Microdosing Studies in Children: A US Regulatory Perspective.

Microdosing studies in children are used to obtain pharmacokinetic information, to study the ontogeny of metabolic enzymes, or to study drug disposition.

Toward clinical application of tissue-engineered cartilage.

Since the late 1960s, surgeons and scientists envisioned use of tissue engineering to provide an alternative treatment for tissue and organ damage by combining biological and synthetic components in such a way that a long-lasting repair was established. In addition to the treatment, the patient would also benefit from reduced donor site morbidity and operation time as compared with the standard procedures. Tremendous efforts in basic research have been done since the late 1960s to better understand chondrocyte biology and cartilage maturation and to fulfill the growing need for tissue-engineered cartilage in reconstructive, trauma, and orthopedic surgery. Starting from the first successful generation of engineered cartilaginous tissue, scientists strived to improve the properties of the cartilaginous constructs by characterizing different cell sources, modifying the environmental factors influencing cell expansion and differentiation and applying physical stimuli to modulate the mechanical properties of the construct. All these efforts have finally led to a clinical phase I trial to show the safety and feasibility of using tissue-engineered cartilage in reconstructive facial surgery. However, to bring tissue engineering into routine clinical applications and commercialize tissue-engineered grafts, further research is necessary to achieve a cost-effective, standardized, safe, and regulatory compliant process.

Early phase clinical trials in pediatric hematology and oncology.

Pediatric oncology is an unrivaled success story in the recent history of medicine. This success is mostly based on a persistent refinement of evidence based therapeutic concepts. With that regard physicians and their staff are highly experience in the conduct of prospective evidence based trials and are therefore competent partners for the pharmaceutical industry. In times of personalized medicine the individual target population is diminishing and the borders of indications are not more disease based. A situation that requires new concepts from the industry. Therefore children with cancer could benefit early from the current developments as well as the pharmaceutical industry could benefit from the legislative incentives through highly recruiting and well conducted prospective trials. Pivotal is a functional platform of communication in order to maintain a close dialogue between academia and pharmaceutical companies.

Current status of phase I clinical trials in Asia: an academic perspectives.

Clinical trials increasingly occured in Asia during the past years as pharmaceutical industries embraced globalization in the clinical research fields. The trend is true with phase III clinical trials but not for early stage/phase I clinical trials in Asian countries is still under-represented. The conduct of phase I clinical trials is considered more sophisticated and difficult than the later stage clinical trials. There are continuing concerns from the pharmaceutical industries about the capacity of Asian countries in conducting this type of clinical trials. We highlighted several problems concerning the ethical and scientific issues, the implementation of ICH-GCP and local regulations, investigators and clinical trial subjects. The purpose of this paper is to give some perspectives addressing the problems in conducting phase I clinical trials. Improving collaboration and capacity building among the Asian countries is a solution that we proposed in order to increase the quality and quantity of phase I clinical trials in Asian countries.

Regulatory and ethical issues for phase I in utero gene transfer studies.

Clinical gene transfer research has involved adult and child subjects, and it is expected that gene transfer in fetal subjects will occur in the future. Some genetic diseases have serious adverse effects on the fetus before birth, and there is hope that prenatal gene therapy could prevent such disease progression. Research in animal models of prenatal gene transfer is actively being pursued. The prospect of human phase I in utero gene transfer studies raises important regulatory and ethical issues. One issue not previously addressed arises in applying U.S. research regulations to such studies. Specifically, current regulations state that research involving greater than minimal risk to the fetus and no prospect of direct benefit to the fetus or pregnant woman is not permitted. Phase I studies will involve interventions such as needle insertions through the uterus, which carry risks to the fetus including spontaneous abortion and preterm birth. It is possible that these risks will be regarded as exceeding minimal. Also, some regard the probability of therapeutic benefit in phase I studies to be so low that these studies do not satisfy the regulatory requirement that they "hold out the prospect of direct benefit" to subjects. On the basis of these considerations, investigators and institutional review boards might reasonably conclude that some phase I in utero studies are not to be permitted. This paper identifies considerations that are relevant to such judgments and explores ethically acceptable ways in which phase I studies can be designed so that they are permitted by the regulations.

The role of the Istituto Superiore di Sanità as the competent authority for Phase I trials in the translation of advanced therapies.

Advanced therapy medicinal products (ATMP) can offer new, effective therapeutic options for the treatment of severe illnesses, including cancer, neurodegenerative and cardiovascular diseases. Translation of advanced therapies to the clinic has been slow despite significant academic research from academia and foundations. The implementation of 2001/20 Directive in Italy established that the development of an ATMP should follow the GXP rules - good manufacturing practice (GMP) for production, good laboratory practice (GLP) for non clinical safety studies and good clinical practice (GCP) for clinical trials. The high costs of GCP application and the needs for GMP facilities are perceived as the most important bottlenecks for the development of ATMP. Here it is pointed out that a strategic cooperation between different actors (academia, industry and experts in regulatory issues) is strongly needed. In particular, it is highlighted that the Istituto Superiore di Sanità, as the competent authority for the authorization of Phase I clinical trials, has a specific responsibility in fostering the translation of safe and effective therapies for human diseases.

TRICARE; coverage of National Cancer Institute (NCI) sponsored Phase I studies. Final rule.

This final rule adds coverage of National Cancer Institute (NCI) sponsored Phase I studies for certain beneficiaries. The NCI sponsored clinical treatment trials are conducted in a series of steps called phases. Phase I trials are the first studies conducted in people. They evaluate how a new drug should be given (by mouth, injected into the blood, or injected into the muscle), how often, and what dose is safe.

Ethical, legal, and social implications (ELSI) of microdose clinical trials.

A "microdose clinical trial" (microdosing) is one kind of early phase exploratory clinical trial, administering the compound at doses estimated to have no pharmacological or toxicological effects, aimed at screening candidates for further clinical development. This article's objective is to clarify the ethical, legal, and social implications (ELSI) of such an exploratory minimum-risk human trial. The definition and non-clinical study requirements for microdosing have been harmonized among the European Union (EU), United States (US), and Japan. Being conducted according to these regulations, microdosing seems to be ethically well justified in terms of respect for persons, beneficence, justice, human dignity, and animal welfare. Three big projects have been demonstrating the predictability of therapeutic dose pharmacokinetics from microdosing. The article offers suggestions as how microdosing can become a more useful and socially accepted strategy.

Approaches using molecular imaging technology -- use of PET in clinical microdose studies.

Positron emission tomography (PET) imaging uses minute amounts of radiolabeled drug tracers and thereby meets the criteria for clinical microdose studies. The advantage of PET, when compared to other analytical methods used in microdose studies, is that the pharmacokinetics (PK) of a drug can be determined in the tissue targeted for drug treatment. PET microdosing already offers interesting applications in clinical oncology and in the development of central nervous system pharmaceuticals and is extending its range of application to many other fields of pharmaceutical medicine. Although requirements for preclinical safety testing for microdose studies have been cut down by regulatory authorities, radiopharmaceuticals increasingly need to be produced under good manufacturing practice (GMP) conditions, which increases the costs of PET microdosing studies. Further challenges in PET microdosing include combining PET with other ultrasensitive analytical methods, such as accelerator mass spectrometry (AMS), to gain plasma PK data of drugs, beyond the short PET examination periods. Finally, conducting clinical PET studies with radiolabeled drugs both at micro- and therapeutic doses is encouraged to answer the question of dose linearity in clinical microdosing.

Comparative requirements for exploratory clinical trials -- eIND, eCTA and microdosing.

Exploratory clinical trials provide a strategy for rapid human entry of investigational drugs. Such clinical studies are typically conducted during early clinical development in phase I as first-in-human studies, have no therapeutic intent, are not intended to examine clinical tolerability and involve a small number of human subjects at limited dose/exposure. Early decision data derived from such clinical studies may include PK, PD and/or biomarker-based translational medicine endpoints as well as PK/PD modeling approaches. This review critically discusses the various exploratory clinical trial strategies, their advantages and disadvantages as well as the regulatory safety requirements. In this respect, strategies for exploratory Investigational New Drugs (eIND), exploratory Clinical Trial Applications (eCTA) and microdosing are highlighted and compared in view of the new ICH M3(R2) guideline including options for biotechnology-derived pharmaceuticals such as monoclonal antibodies.

Microdosing in early lead discovery.

Microdosing provides a tool to enhance drug development by initiating human studies prior to Phase I studies. The purpose is to assist in the go versus no-go decision-making process and to eliminate early ineffective compounds from the drug pipeline. Selection of multiple potential leads can be performed at the clinical stage instead of in preclinical studies. The microdosing approach can be easily used for a molecularly targeted potential drug compound with a known mechanism of action. It provides useful data regarding accessibility and biodistribution that can be used in many estimations benefiting the development of the molecule. In addition, steady state and genetic investigations are becoming possible. Microdosing has a sparing effect on timelines and costs, however, the real importance is not yet known because, although it is known to be widely performed, only a few original reports have been published.