Primary Phase-0 Microdosing Applications

Human Based Selection Among Multiple Preclinical Candidates

Phase-0 including microdosing applications enable human-based selection of the lead candidate. Typically, the lead candidate that progresses into expensive human clinical development is selected from multiple preclinical candidates. The selection is usually done based on animal (in-vivo), tissue (in-vitro), and modeling data. These data lack in-vivo human input. The more human-specific modern drug development becomes, with human-specific target, mechanism of action and outcomes, the greater the relevance of human-based testing to confirm selection of the lead compound among a range of preclinical candidates.

Patient Testing in First-in-Human (FIH) Studies

The safety profile of Phase-0 including microdosing approaches enables their application in patient trials right at the very first-in-human (FIH) stage. Typically, patient studies are done in late Phase-1 or early Phase-2 after healthy volunteer FIH studies have provided information about tolerance and safety of the drug under study. Being inherently safe, Phase-0 approaches address the 2 main concern regarding testing in patients. The first is the vulnerability of patients to potentially toxic interventions. The second is the potentially methodological confounding effect of interactions with concomitant medications, or alternatively, the ethically challenging option of discontinuing patients off their medications. With Phase-0, and especially with microdosing approaches, the low doses of the test article are not expected to impact (i.e., be perpetrators of) concomitant medications. In addition, any impact of concomitant medications on the test article (i.e., the test article being a victim of Drug Drug Interaction [DDI]) is not expected to lead to clinically meaningful effects. Using Phase-0 in patients in FIH studies is encouraged in the regulatory guidelines.

Cassette Microdosing: A Unique Methodological Advantage of Microdosing Approaches

With cassette microdosing, multiple drug candidates can be given simultaneously at microdose exposures to the same research participant. The reason this can be done with microdose but not therapeutic-level doses is that at such low doses the compounds are not expected to impact each other. The operational convenience and savings in resources are obvious. If the drugs are chemical analogues they can be submitted under the same regulatory Exploratory Investigational New Drug (eIND) application. In addition, simultaneous testing considerably reduces the variability inherent in clinical comparator studies. This increases the power of the studies and reduces the number of research participants required.

Facilitating Drug Development in Pediatric and Other Vulnerable Populations

The inherent safety of microdosing approaches makes them attractive as drug development tools for vulnerable populations. Such groups include pediatric, women (including pregnant women), frail elderly, hepatically- and renally-impaired, and patients with comorbidity, and polypharmacy. In other words, the list includes most populations excluded from early-phase trials and often from primary drug development programs altogether. Phase-0, and especially microdosing approaches offer the promise of including these populations earlier in development of novel drugs. Phase-0/Microdosing approaches also provide a tool for the development of drugs that have long been approved in adults but only available off-label in those aforementioned vulnerable populations. The most extensive use of microdosing in vulnerable populations has been in pediatric drug development. Some studies have been conducted in frail elderly.

Administering an Oral Drug Intravenously

One of the attractive applications of microdosing, again due to its inherent safety, is the ability to administer oral drug intravenously. This can be done without change in formulation. It is specifically noted by the regulations as one of the unique features of microdosing approaches (ICH M3 Section 7). This is similar to the use often made by industry in microtracer absolute bioavailability (AB) studies. In such studies an oral dose is given concomitantly with a 14C-labelled microtracer IV dose. In fact, an AB trial can be done entirely with microdose exposures. For example, where the oral dose is given at 99 micrograms and the IV at 1 microgram for a total of 100 microgram (the microdose definition). Multiple studies, including by industry in actual drug development, have taken advantage of this feature of Phase-0 trials.

Phase-0 Microdosing Network - Quicker Developmental Decisions

Current and Emerging Applications of Phase-0 Microdosing Approaches

‘Current applications’ refers to Phase-0 including Microdosing studies that were used in new drug development, or those used to obtain information on existing drugs in new populations or circumstances. ‘Emerging applications’ denotes new and theoretical Phase-0 Microdosing applications that are in the early stages of development and/or validation.

The following table was adapted from Burt T, Yoshida K, Lappin G, Vuong L, John C, et al. 2016. Microdosing and other Phase-0 Clinical Trials: Facilitating Translation in Drug Development. Clinical and Translational Science 9:74-88.

Current Phase-0 Microdosing applications Examples
PK  and BA Study of drug disposition (e.g., absorption, distribution, metabolism, excretion, bioavailability [ADME], TMDD); effectiveness-related PK (i.e., PK parameters that directly impact on safety and efficacy).
DDI Cocktail and cassette DDI studies.
PD/Localization/Proof of mechanism Phosphorylation in PBMCs. DNA adducts in PBMCs. Target tissue localization.
Vulnerable populations Pediatric studies of drug disposition. Future applications may apply also to women (including pregnant women), patients with hepatic impairment, renal impairment, poly-pharmacy, co-morbidity, and frail elderly patients.
Diagnostic radiopharmaceuticals Due to lack of appropriate animal models, Phase-0 used for selection among four 18F-labelled PET amyloid imaging agents for assessment of b-amyloid plaques in brains of patients with Alzheimer’s Disease.
Emerging Phase-0 Microdosing applications  
PBPK, M&S Modeling and simulations incorporating in-silico, in-vitro, PBPK/PD and economic parameters can all enhance the predictive value and feasibility of Phase-0 studies.
Biologics Small antibody (PET). Large protein (AMS).
Adaptive design Phase-0/Phase-1 Microdosing/Phase-1 adaptive design.
Intra-Target Microdosing (ITM) – drug development in target. Intra-Target Microdosing (ITM) proof-of-concept. Insulin injected intra-arterially caused local effect (18F-FDG uptake into muscle) while systemic exposure was at microdose levels with no effects.
Extreme environments Space (micro-gravity, radiation, altered chronobiology), north/south poles (cryo-environments, altered chronobiology), hyper/hypobaric environments (e.g., high altitudes). Altered physiology and pharmacology may have drug efficacy and toxicity implications and requires testing of pharmaceuticals in the extreme environment setting. Lack of emergency facilities favors Phase-0 approaches.
Individualized therapy phenotyping Prediction of DDI in healthcare settings by using microdose probes prior to initiation of therapy.
Environmental toxins Describing the disposition of potential carcinogens (e.g., PAH) using nontoxic microdoses in humans.
PK – pharmacokinetics; BA – bioavailability; PD – pharmacodynamics; TMDD – target-mediated drug disposition; DDI – drug-drug interactions; PBPK – physiologically-based pharmacokinetics; M&S – modeling and simulation; PBMCs – peripheral blood mononuclear cells; FDG – fluorodeoxyglucose; PAH – polycyclic aromatic hydrocarbon

Phase-0 Microdosing Network - Accelerating Clinical Development

Consensus Statements on Phase-0 Microdosing Applications from the First International Phase-0/Microdosing Stakeholder Meeting (March 12, 2019, Washington D.C.) and Network Discussions

Statement validity grading system:
♦♦♦  -  Supported by multiple controlled trials
♦♦  -  Supported by one controlled trial or multiple uncontrolled trials
♦  -  Supported by personal observations and/or theoretical/policy considerations (e.g., expert opinion not directly supported or refuted by evidence, or theory-based information)

Session A – Phase-0 Microdosing Applications and Research Directions (Moderators: Ilan Rabiner, Tal Burt)
A.1.1  Unique data – The following are scenarios where Phase-0 approaches can produce data not obtainable with traditional approaches at the same stage of development:
♦♦♦ A.1.1.1  First-in-patient data at the first-in-human stage (Bauer, Langer et al. 2006, Heuveling, de Bree et al. 2013, Bal, Arora et al. 2016)
♦♦♦ A.1.1.2  Parenteral data with drugs administered enterally (e.g., IV data with drugs given PO) (Lappin, Kuhnz et al. 2006, Okour, Derimanov et al. 2017)
♦♦♦ A.1.1.3  Cassette microdosing – Multiple test articles administered simultaneously (Maeda, Ikeda et al. 2011, Yamashita, Kataoka et al. 2015, Kusuhara, Takashima et al. 2017)
♦♦♦ A.1.2  Multiple preclinical candidates - When pre-clinical data cannot satisfactorily separate two or more preclinical candidates. In such cases Phase-0 Microdosing applications could be used to choose the lead candidate (Madan, O’Brien et al. 2008, Carpenter, Pontecorvo et al. 2009, Zhou, Garner et al. 2009, Wang, Aston et al. 2010, Sun, Li et al. 2012, Jones, Butt et al. 2016, Kusuhara, Takashima et al. 2017)
♦♦♦ A.1.3  Contradictory preclinical data – e.g., contradictory inter-species data; in-vivo-in-vitro data inconsistencies, contradictions between models and empirical data (Cahn, Hodgson et al. 2013, Okour, Derimanov et al. 2017)
♦♦♦ A.1.4  Vulnerable populations and other situations with narrow therapeutic index (Bauer, Langer et al. 2006, Vuong, Ruckle et al. 2008, Kummar, Kinders et al. 2009, Kummar, Anderson et al. 2013, Gordi, Baillie et al. 2014, Mooij, van Duijn et al. 2014, Turner, Mooij et al. 2015, Mooij, van Duijn et al. 2017, van Groen, Vaes et al. 2019)
♦♦♦ A.1.5  Potential to contribute pharmacodynamic and other proof of mechanism data (e.g., target engagement) (Bauer, Langer et al. 2006, Carpenter, Pontecorvo et al. 2009, Henderson, Kimmelman et al. 2013, Heuveling, de Bree et al. 2013, Wang, Zimmermann et al. 2017, Zimmermann, Wang et al. 2017, Sanai, Li et al. 2018)
♦♦♦ A.2  All 4 pillars of clinical development decision-making: PK, tissue PK, target engagement, post-receptor modulation, can be identified using Phase-0 Microdosing applications (Bergstrom, Grahnen et al. 2003, Lappin, Kuhnz et al. 2006, Vuong, Ruckle et al. 2008, Carpenter, Pontecorvo et al. 2009, Heuveling, de Bree et al. 2013, Burt, Yoshida et al. 2016, Zimmermann, Wang et al. 2017, Sanai, Li et al. 2018)
♦♦♦ A.3  Microdose administered near-infra-red (NIR) fluorescent molecules targeting tumor receptors can provide biomarkers useful in diagnosis, during surgery, and potentially in development of targeted chemotherapeutics, though is limited by the superficial detection of the fluorescent signal (Elliott, Dsouza et al. 2016, Pogue, Paulsen et al. 2016, de Souza, Marra et al. 2017, Koch, de Jong et al. 2017, Lamberts, Koch et al. 2017, Samkoe, Gunn et al. 2017)
A.4  Phase-0 Microdosing applications offer the potential for safer, faster, cheaper, higher throughput of candidate drugs through clinical development (Bergstrom, Grahnen et al. 2003, Lappin and Garner 2003, Rowland 2006, Kinders, Parchment et al. 2007, Kummar, Kinders et al. 2007, Rowland 2007, Kummar, Rubinstein et al. 2008, Rowland and Benet 2011, Rowland 2012, Burt, John et al. 2016)
A.5  The definitive utility of Phase-0 Microdosing applications will be determined on a case by case basis by identifying specific hypotheses that can be answered by the eIND approaches with sufficient confidence and quicker than with traditional approaches, taking into account scenario-specific characteristics, assumptions, and thresholds (e.g., for economical and ethical viabilities)(Yamane, Igarashi et al. 2013, Burt, John et al. 2016)
A.6  The potential of Phase-0 Microdosing applications to detect biomarkers and obtain pharmacodynamic data relevant to mechanism of action of the test articles should be considered a priority research target covering methodologies and applications of Phase-0/Microdosing approaches
A.7  Technology and methodological advances such as total-body PET (better sensitivity and dynamic capabilities than whole-body PET), Cavity Ring-Down Spectroscopy (CRDS), Intra-Target Microdosing (ITM), and modeling and simulations, have the potential to expand the utility of Phase-0 Microdosing applications (Cherry, Jones et al. 2018, Kratochwil, Dueker et al. 2018, Badawi, Shi et al. 2019)
A.8  The science of detecting drug and biomarker and metabolite concentrations in human tissues is agnostic to the notion of therapy and therefore is not bound by the need to have therapeutic-level concentrations.  In other words, while therapeutic-level exposures will always be at least 100 times higher, microdose-level exposures could produce concentrations of drug, biomarkers, and metabolites in tissues of interest, whose detection is restricted only by the limit of detection of the analytical modality utilized (Madeen, Ognibene et al. 2016)
A.9  Microdosing can be used to improve prediction of disposition of drugs affected by Target-Mediated Drug Disposition (TMDD) in a Phase-0/Phase-1 adaptive design approach that uses data from microdose exposures to improve predictions of therapeutic-level drug disposition
♦♦♦ A.10  Intra-Target Microdosing (ITM) allows for brief (seconds to minutes) exposure to therapeutic-levels of the test article in a limited target, while simultaneously exposing the rest of the body to microdose-levels (Burt, Rouse et al. 2015, Burt, MacLeod et al. 2017)
♦♦♦ A.10.1  ITM allows collection of biomarkers, other PD data from therapeutic-level exposure in targets of interest and simultaneously collecting systemic microdose-level PK data, thus providing information useful for ‘proof of mechanism’, ‘right tissue’ (Morgan, Brown et al. 2018) and the ‘pillars of drug development decision-making’ (Morgan, Van Der Graaf et al. 2012, Burt, Noveck et al. 2017)
♦♦ A.10.2  ITM administered into a symmetric organ (e.g., hand, eye, kidney, brain hemisphere) allows the simultaneous testing of therapeutic-level exposures in one and microdose-level exposures in the other. Comparison of the two allows for intra-individual estimates of extrapolation across the microdose-to-therapeutic-level exposures and whether it is linear or not and if not, what are the characteristics of the extrapolation model. Example: Wada Test (aka ‘Intracarotid Amobarbital Test’) (Wada and Rasmussen 2007, Kundu, Rolston et al. 2019)

Session B – Stakeholder Perspectives (Moderators: Elizabeth Baker and Malek Okour)
B.1  Value of Phase-0 Microdosing applications:
♦♦♦ B.1.1  Safety of first-in-human testing. Society gradually increases the value of safety of human and animal testing and becomes less tolerant of risk. Such dynamics will favor the use of safety and animal-sparing procedures.
♦♦ B.1.2  Earlier and cheaper human data for developmental decisions including the benefit of early termination of non-viable compounds (i.e., ‘fail-early’ benefit) and the associated benefit to the patent life of potentially successful backup compounds (because they are developed earlier and waste less of their patent life)
♦♦♦ B.1.3  Unique data not available with traditional approaches (e.g., first-in-human = first-in-patient, administration of enteral drugs parenterally, cassette microdosing) (see Section A.1)
B.1.4  Better design of Phase 1, 1b, and 2a studies
♦♦ B.1.5  Better predictability of human PK than preclinical models alone, therefore better pre-clinical candidate selection prior to entry into Phase 1
♦♦ B.1.6  Potential, in selected cases, to predict human PD and/or proof of mechanism data in healthy volunteers and/or patients and therefore better pre-clinical candidate selection than Phase 1, 1b, and/or 2a
B.1.7  For small companies – human data will exponentially increase the value of the asset
B.1.8  Less animal testing for human drug development – but not elimination of animal testing entirely
B.2  It is important to let every stakeholder group have a voice, not just industry, because drug development is a wide-ranging societal enterprise with direct interest, investment, and engagement of large sectors of the population
B.3  Challenges include:
B.3.1  Technical (analytical) – e.g., PET radioisotopes with short half-lives need to be produced in proximity to the imaging center and the clinical research site; PET measures total radioactivity in tissues and cannot distinguish parent drug from radiolabeled metabolites
B.3.2  Methodology – extrapolation – there is room for tolerance of error and variance, but these need to be taken into account along with the risk/benefit when considering the application of Phase-0/Microdosing; the benefit should be described as the product of an effort to increase confidence to move the drug to the next stage of development or a confident termination of development
B.3.3  Regulatory - Good Manufacturing Practice (GMP):
B.3.3.1  Generation of a white paper to highlight that full GMP standards are not always essential for microdose studies (UK & Austria don’t require GMP), though clearly there will still be a need for qualification of the batch of material to meet certain specifications of purity, pyrogenicity, sterility etc.;
B.3.3.2  In the UK PET-microdosing studies can be done using a regulatory pathway that considers the test article as a ‘challenge compound’ that does not require production under full GMP standards
B.3.3.3  There are efforts underway within the nuclear medicine societies (e.g. EANM) to come up with simplified GMP requirements for radiotracers which take into account the specific requirements of radiochemistry
B.3.4  Culture – changing the culture of drug development is a challenge; convincing decision-makers about the overall advantages of the approaches in the face of institutional inertia, i.e., current developmental processes and budgets need to be adjusted to accommodate Phase-0/Microdosing otherwise program managers will find themselves in conflict with budget and goals; perception that introducing new methods may threatening to existing job (“this will cause me to lose my job”)
B.4  Regulators see the value of Phase-0 Microdosing applications as the ability to obtain data in relative safety to humans on mechanism of action, PK, PD, and select most promising lead candidates based on these data
B.5  Financial challenges include assessing the value that microdosing and other Phase-0 approaches bring by saving time to meaningful developmental decisions and costs of traditional development saved by those earlier decisions
B.6  A comprehensive economic analysis is needed to show microdosing is cost effective in a range of developmental scenarios (e.g., drug classes, drug targets, therapeutic indications, and competitive environments)
B.7  Future directions, actions and responsible parties:
B.7.1  Outreach strategies
o Accessing industry high-level decision makers; highlight industry successful applications
o Influence regulatory and policymakers
Discussions with FDA
Offering training to industry and policy decision-makers
Policy is there, maybe need a policy statement to encourage use such as “Agency believes sponsors should consider Phase-0 Microdosing applications 2 years before going into clinical”
o White/position papers
o Review papers covering the regulation, applications, and use by industry
o Booth, happy hour or workshops at conferences such as ASCPT, ACCP, ISOP
o Annual stakeholder meeting
o Use consortia such as IQ Consortium to partner and disseminate information
B.7.2  GMP flexibility
o Identify the Phase-0 Microdosing study characteristics that enable reducing GMP criteria (e.g., not being pharmacologically or therapeutically active concentrations)
o See what arguments are used by countries which don’t require full GMP
B.7.3  Don’t call these approaches ‘Phase 0’
o It creates the perception of adding another phase to already lengthy and established process
o Alternatively, calling it another step to a Phase 1 may be easier to accept
o Or, alternatively, emphasizing the fact that adding a phase actually has the potential to increase efficiency, just as Phase 1 and 2 were added to the definitive Phase 3 trials in order to allow efficient triaging of drugs and economic de-selection of non-viable drugs

Session C – Special Populations (Moderators: Saskia de Wildt and Marie Croft; summaries by Bianca van Groen)
C.1  General considerations
C.1.1  Identify in the early stages of program development what kind of questions needs to be addressed and where best to implement Phase-0 Microdosing applications (e.g., dose selection for therapeutic-level studies)
C.1.1.1  Some microdosing approaches may generate data of scientific but not commercial value. It is important to identify study hypothesized conclusions in advance to determine whether they justify the investment in Phase-0 Microdosing applications
C.1.2  Consider the full-range of study designs, methodologies (e.g., modeling that uses microdosing to increase the confidence in model predictions), and technologies available, to obtain not only PK but also PD data (e.g., tissue penetration, target engagement, biomarkers, proxy endpoints, PET-imaging, biopsies) (Sugiyama 2009)
C.1.3  Often there are new metabolites in humans than preclinically seen in animals. Metabolite profile of drugs may be different in pediatrics, or renally/hepatic impaired populations and Phase-0 approaches may be used to identify them
C.1.4  Sponsors try to avoid special populations because of the ethical and recruitment challenges. Use trial networks (e.g. pediatric trial network) to overcome this
♦♦♦ C.1.5  Phase-0 Microdosing trials could help with dose selection for therapeutic-level studies (Carpenter, Pontecorvo et al. 2009, van Groen, Vaes et al. 2019)
C.1.6  Practical challenges include:
o Logistics (e.g., Timelines)
o Costs – need to be justified by the potential for early termination of development
o GMP – need clarification on the GMP standards required for microdosing (e.g., Non-GMP compound 14C ->dissolved in saline -> GMP compound; Microtracing: non-GMP because levels are so low) as apparently there is no harmonized application of them world-wide, e.g., EU is more flexible than USA
o Patients, caregivers, and study team should be familiar with the approaches, including the operational, ethical, regulatory, and logistic implications
C.1.7  Microdose and microtracer are treated differently. With a microtracer the subject receives also therapeutic-level doses. The distinction may have ethical implications with a microdose being, by definition, a novel, first-in-human (FIH) compound and not having a therapeutic potential (but neither a toxic potential)
C.1.9  Regulators should play a pivotal part in influencing industry
o Some regulators embrace Phase-0/Microdosing approaches while others less so. Currently, there is a ‘recommendation’, which industry is not obliged to follow
o Need to ensure regulatory positions are transparent, evidence-based, and comprehensive in that they represent all available information
C.2  Important research questions and future directions
C.2.1  Microdosing studies for transporter activity and other disposition parameters (e.g. clearance)
C.2.2  Drug-Drug Interaction (DDI) studies
C.2.3  Orphan diseases and special conditions with PET for tissue disposition, receptor binding, and biomarkers of response (as proxy endpoints and/or proof of mechanism)
C.2.4  Use of microdosing for pediatric new and legacy drug development
C.2.5  Phase-0/Microdosing are particularly attractive when there is a narrow therapeutic window
C.2.6  It is crucial to expand research to other special populations (e.g., women, pregnancy, frail elderly, hepatically/renally-impaired, comorbidity/poly-pharmacy) and extreme environments (extreme cold/heat, hypo/hyper-baric, space) to encourage sponsors to use Phase-0/Microdosing for development of old and new drugs for these scenarios
C.3  Pediatric population
C.3.1  There is great value in microdose applications in pediatrics.
C.3.1.1  Microdosing for younger ages is the most interesting because information is limited in that age range (especially within PBPK)
♦♦♦ C.3.1.2  Microdosing is useful for the study of metabolism ontogeny (Vuong, Ruckle et al. 2008, Gordi, Baillie et al. 2014, Mooij, van Duijn et al. 2014, Turner, Mooij et al. 2015, Mooij, van Duijn et al. 2017, van Groen, Vaes et al. 2019)
C.3.1.3  An adult microdosing study could be done before or in parallel to the pediatric microdosing study to enhance the validity and feasibility of the pediatric study
C.3.2  Blood sampling may be a problem. It is allowed to take 3-5% of the circulating blood volume in 30 days and no more than 1% per time (guidelines EMA/FDA/WHO, though each guideline gives different numbers). This hurdle may be potentially overcome by using a microdialysis catheter for blood sampling in children (microdialysis may be also applied in combination with 14C microdosing to assess soft tissue penetration of a compound (e.g. antibiotics), maybe not in children but in adults)
C.3.3  AMS with radioactive labelled compounds is possible in pediatrics. However, LC-MS/MS is also possible, but requires larger blood volume
C.3.4  From an academic point of view it would be interesting to take extra blood samples for a biobank during clinical care or during blood withdrawal in the context of a trial
C.3.5  Use simcyp PBPK models to test new data and see if the data is predicted well.
C.3.6  There are a lot of new papers with new models (PBPK, pop-PK) coming out, but these are not validated. It would be useful to supplement new models with new data generated using Phase-0/Microdosing
C.3.7  First-in-Child studies using Phase-0/Microdosing approaches are possible in not-too-distant future, and today in orphan diseases that are unique to children
C.3.7.1  However, it is likely that such applications will constitute only a minority of pediatric drug development.  Additional information is needed to support this statement, e.g., what are the alternative approaches? What is the validity, specificity, and sensitivity of the alternative approaches? What is the value (complementary and/or synergistic) of combining microdosing with the alternative approaches? What are the economic and/or ethical liabilities that may offset the scientific value of adding microdosing studies to pediatric drug development? (Vuong, Blood et al. 2012, Roth-Cline and Nelson 2015, Roth-Cline and Nelson 2015, Turner, Mooij et al. 2015)
C.3.8  Legacy compounds are still under- and overdosed in pediatrics but microdosing provides little value since therapeutic-level dosing is already being used and can inform full-dose study design
o However, microdosing may be considered if the use of the legacy drug is limited because of risks (e.g., narrow therapeutic index) and/or because concomitant polypharmacy introduces uncertainty about drug PK/PD/toxicity in these open-label, uncontrolled scenarios – and therefore conducting full-dose studies may be considered more than minimal increase over minimal risk (the standard the FDA uses for ethical threshold of inclusion of pediatric patients in clinical trials) (Roth-Cline and Nelson 2015, Roth-Cline and Nelson 2015)
C.4  Renally/hepatic impaired population
C.4.1  Phase-0 Microdosing studies may be useful for the study of difference between healthy individuals and renally-/hepatically-impaired patients
C.5  Oncology patients
C.5.1  Microdosing studies are ethically challenging as studying PK is not the main research objective but rather PD is the main research question
♦♦♦ C.5.2  Alternatively, Phase-0 Microdosing studies have been used successfully to study PK and PD effects in oncology patients (Kummar, Kinders et al. 2007, Kummar, Rubinstein et al. 2008, Murgo, Kummar et al. 2008, Kummar, Kinders et al. 2009, Henderson and Pan 2010, Kummar, Anderson et al. 2013, Kummar, Williams et al. 2015, Wang, Zimmermann et al. 2017, Zimmermann, Wang et al. 2017)
♦♦ C.5.3  Target tissue exposure using (PET or biopsies) would be very useful to support/refute proof of mechanism (Heuveling, de Bree et al. 2013)
C.6  Pregnancy
C.6.1  There is considerable regulatory interest in safe studies (and hence and potential for microdosing) in pregnant women since this populations notoriously lacks evidence-based support of drug administration as they are routinely excluded from clinical trials
C.6.2  One potential application is to administer a microdose (labeled or unlabeled) right before or during labor to measure exposure in fetal tissues
C.7  Alzheimer’s patients
C.7.1  Phase-0/Microdosing studies in Alzheimer’s patients face ethical challenges especially in incapacitated patients where the absence of a therapeutic potential may shift the ethical benefit/risk considerations against the approaches
♦♦♦ C.7.2  Alternatively, microdosing studies in Alzheimer’s patients may be used both for termination of development of non-viable compounds and for selection of optimal pre-clinical candidates to proceed to clinical development (Bauer, Langer et al. 2006, Carpenter, Pontecorvo et al. 2009)
C.7.3  Studies to study the blood brain barrier passage with PET microdosing could be useful if benefits surpass the challenges of developing the PET ligand
C.8  Intensive-care patients
C.8.1  Drugs specific for intensive care patients would be of interest for microdosing because of the vulnerability of the population and the often polypharmacy involved with considerable potential for DDI
C.8.2  One approach is to administer a drug intra-arterially and look at local effects first, followed by systemic PK studies
C.8.3  Metabolomics would be of interest in this population but currently would need to use Phase-0 approaches that use therapeutic-level exposures of the drug under study due to limitations of the analytical tools used to detect metabolites
2.8.3.1  However, it is possible that improvement of analytical tools’ sensitivity will enable detection of metabolites after microdose exposures and therefore could possibly also enable microdose MIST studies
C.9  Extreme environments such as space, extreme cold or heat, hyper-hypo-baric environments, and in general, any environment that would be expected to change physiology and pharmacology to an extent that necessitates the study of drugs for human living in these environments where the environments are be remote from emergency care facilities to impact adversely the risk/benefit of clinical trials (Burt, Yoshida et al. 2016)

Session D – Culture and Strategy (Moderator: Graeme Young)
D.1  Phase-0/Microdosing approaches are consistent with the ‘truth-seeking’ and ‘early-termination’ cultures being advocated to increase the efficiency of drug development (Peck 2007, Cook, Brown et al. 2014, Peck, Lendrem et al. 2015, Morgan, Brown et al. 2018)
D.2  General comments and discussion:
D.2.1  Non-predictivity of pre-clinical data and the potential to save time in developmental decision-making are topics that will resonate with industry leaders
D.2.2  At the very least, the option to conduct Phase-0 should be considered by program teams at a sufficiently early point in pre-clinical development (~ 1.5 – 2 years prior to anticipated IND application submission) (Burt, John et al. 2016)
D.2.3  Reduction in use of animals for ADME/IND package is to be encouraged (Burt, Vuong et al. 2018)
D.2.4  There is a mindset that for successful candidates, Phase-0 just adds time – awareness increase is required; perceived need for clarifications on terminology, misperceptions, and strategies (Kummar, Rubinstein et al. 2008, Burt, Yoshida et al. 2016)
D.2.5  Question raised as to whether there is an opportunity in China regarding development of the field and, specifically, whether there is interest in low-dose 14C use
D.2.6  Availability of Phase-0/Microdose clinical study data to inform application considerations, is perceived to be limited
D.3  Future Directions
D.3.1  Need for harmonization of GMP requirements
D.3.2  There are opportunities for combining technologies e.g. AMS/PET, e.g., combining 89Zr labelling of mAb with 14C labelling of the generic chelator (desferrioxamine)
D.3.3  Shift of focus is required, from focus on the weakness of the approach (i.e., ~20% of microdose studies do not extrapolate well) to the 80% that do
D.3.4  Possibly establishing comfort with I.V. microtracer approach may be a precursor to standalone microdose
D.3.5  Venture capitalists may be a captive audience as they have interest to terminate development of non-viable compounds early and before the expensive clinical development
D.3.6  Add microdose cohort to traditional Phase 1 study (i.e., use adaptive Phase-0/Phase-1 design) to build a database of controlled microdose-full-dose studies in a range of therapeutic areas, drug classes, drug targets, and competitive environments
D.3.7  Clearer guidance from regulators that indicates they are advocates of Phase 0 including, possibly, incentives for industry sponsors as with pediatric studies of novel drugs
D.3.8  A comprehensive effort to understand adoption concerns by industry needs to be undertaken with industry representatives together with other stakeholders, regulatory, academia, CROs, patient advocacy groups and non-profit organizations

Phase-0 Microdosing Applications

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Phase-0 including Microdosing applications