Year : 2013 | Volume
: 2 | Issue : 2 | Page : 75--80
Phase 0 trials (microdosing): A new paradigm in clinical research
Prasan R Bhandari
Department of Pharmacology, S.D.M. College of Medical Sciences and Hospital, Sattur, Dharwad, Karnataka, India
Prasan R Bhandari
Department of Pharmacology, S.D.M. College of Medical Sciences and Hospital, Sattur, Dharwad - 580 009, Karnataka
Microdosing offers a technique to augment drug development by commencing human studies earlier to Phase 1 studies. A systematic search for articles in the PubMed was performed MedLine up to August 2012. The rationale is to support in the go versus no-go decision-making process and to reject early non-promising molecules from the drug pipeline. Selection of several probable frontrunners can be accomplished at the clinical stage instead of in preclinical studies. The microdosing technique can be easily utilized for a molecularly targeted promising drug compound with a known mechanism of action. It offers beneficial data concerning accessibility and biodistribution that can be used in many assessments furthering the development of the molecule. However, the use of microdose pharmacokinetic studies as a vital tool in drug development is still to catch on. While this methodology assures probable expenditure reductions and a significant increase in productivities of the drug development practice, foremost obstacles still must be overcome before the procedure becomes routine practice. Clear guidelines in Europe and the USA have had a supporting effect. The dearth of permitting requirements for microdosing studies in Indian regulation, in spite of low-risk and obvious application for the local drug development industry, is inconsistent with the nation�SQ�s hopes to be among the bests in pharmaceutical research.
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Bhandari PR. Phase 0 trials (microdosing): A new paradigm in clinical research.Int J Health Allied Sci 2013;2:75-80
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Bhandari PR. Phase 0 trials (microdosing): A new paradigm in clinical research. Int J Health Allied Sci [serial online] 2013 [cited 2023 Sep 21 ];2:75-80
Available from: https://www.ijhas.in/text.asp?2013/2/2/75/115680
Problems in Pharmaceutical Industry
With rising expenditure and reduced output of new medicines reaching the market, the pharmaceutical industry is failing in its principal function. Stagnation in new drug discovery has been documented during the last decade, notwithstanding higher investment in drug research and development related activity. A 40% decrease in the introduction of new chemical entities was evidenced during 1994-2004 despite a 70% increase in investment in research and development-related activities. Hence, investment in higher risk drugs or in therapies for uncommon diseases or diseases that predominantly afflict the poor has also been mainly limited due to rising cost and increased attrition rates. Attrition was highest during Phase 2 (62%) but still significant in Phase 3 (45%) and at the time of registration (23%). Clearly, given the high cost and time required for clinical development, these late-stage disappointments are untenable. If it continues like this, it could possibly slip into a fatal deterioration. Hence, some positive steps are imperative to avoid this problem. A systematic search for articles on microdosing/Phase 0 in the PubMed was performed MedLine up to August 2012.
The industry's continuing dependence on nonhuman biology as the source of its evaluation of potential safety and efficacy could be the cause of the problem. If the industry is to continue as a foundation of innovation in drug therapy it should appreciate that the emphasis has to be more on relevant human-based testing. Earlier clinical testing, in the form of microdosing, and development of more-powerful computational approaches based on human information can be incorporated. Fortunately, progress is being made in both approaches. However, a problem remains in the lack of functional evaluation of human tissues. The lack of commitment, and the inadequacy of the tissue resource itself, is hampering any serious developments. 
Significant suffering would be associated in laboratory animals during testing the safety and efficacy of a successful human medicine. Additionally, evidence from the tested animal species has to be extrapolated to humans. Hence, wherever possible replacement, reduction as well as refinement of animal procedures (the Three Rs) should be employed, as per UK and European legislation. There has been substantial progress with applying in vitro and in silico methods to both drug efficacy and safety testing over the last decade. 
Substantial efforts have been made towards the development and international acceptance of alternative methods to safety studies using the laboratory animals during the last two decades. The seventh Amending Directive 2003/15/EC (European Community) to Cosmetics Directive 76/768/EEC (European Economic Community) in the EU (European Union) has set challenging timelines for phasing out of many standard tests using laboratory animals. In continuation of this policy, the new European chemicals legislation favors alternative methods to conventional in vivo testing if validated and appropriate. Even alternative methods in the status of prevalidation or validation, but without scientific or regulatory acceptance may be used under certain conditions. 
The Food and Drug Administration (FDA) emphasized this problem in a 2004 white paper classified as "Critical path initiative" (CPI). Hence, it initiated steps to target stagnation and rise in attrition rates. Taking indication from CPI many new drug development projects have been initiated world-wide such as implementing microdosing, adaptive designs, and taking advantage of newly developed biomarkers under the CPI. ,
There is a pressing requisite for innovative toolkits to advance the critical development path that leads from scientific discovery to the patient, as per the US FDA way back in 2003. Given this situation, microdosing or Phase 0 (zero) trials should allow an early evaluation of pharmacokinetic as well as pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of human. Guidelines on exploratory investigational new drug studies in human have been published by the US FDA in January 2006. Currently a Phase 0 program is continuing at the National Cancer Institute to assess the influence (feasibility and utility) of Phase 0 studies on drug development. A position paper produced by the Evaluation of Medicinal Products (EMEA) in 2004 discussed the probability of a condensed preclinical safety package to support early microdose (MD) clinical studies in Europe. Recently, a concept paper on medicinal products was published by the committee for medicinal products for human use of the EMEA. Additionally, EMEA's guidelines on Phase 0 studies are expected shortly. The factual impact of Phase 0 studies on the drug development process as well as on the safety needs to be judiciously assessed. 
Performing pre-Phase 1 microscopic dose human studies (sub-toxic and below the dose threshold for measurable pharmacological or clinical activity) may allow drug candidates to be evaluated earlier for in vivo human pharmacokinetics and metabolism. Accelerator mass spectrometry (AMS), nuclear magnetic resonance spectroscopy and positron emission tomography (PET) are possibly useful spectrometric and imaging methods that can be used in concurrence with such human studies. Some limited animal tests, however, would still be required before pre-Phase 1 MD studies. This would assess the potential risk posed by entirely novel chemicals. Microdosing studies should be introduced in a way that does not compromise volunteer safety or the scientific quality of the resulting safety data. This would enhance selection of right drug candidates thereby ameliorating the potential of later candidate failure. Early submission of in vivo human ADME (Absorption Distribution Metabolism Excretion) data, especially for pharmacokinetics and metabolism, could achieve this. 
A necessity for modification in the drug development process has been generated by the convergence of numerous market factors. Some of the few major ones being public scrutiny, high failure rates for investigational agents, and concern about the use of animals in research. Certain alterations in this process are being carried out in response to confront these problems. Microdosing, administering very small, radiolabeled doses of investigational agents to human, is one change that has the potential to save time and money. It is used to determine the pharmacokinetic profile of agents. Although not all authorities approve that it will live up to its promise, but the potential is great. 
Concept and applications
The concept of microdosing has been present since the last approximately 10-15 years. During this period an increasing number of drugs documented in the literature where the pharmacokinetics at a MD has been compared with those observed at a therapeutic dose. Presently, almost 80% of the MD pharmacokinetics existing in the public purview has been demonstrated to scale to those observed at a therapeutic dose, within a two-fold difference. 
Microdosing studies using the sub-pharmacological doses provide initial understanding into the body's disposition toward candidate compounds. Extremely sensitive analytical technology is vital in microdosing studies that utilize qualitative and quantitative assays of target materials in humans. AMS has enabled the implementation of a human microdosing study in the early phase of clinical drug development. Results obtained from AMS microdosing studies using the labeled compounds can offer several categories of information for candidate selection, including pharmacokinetic characteristics and metabolic profiles of candidate compounds. Although, it remains unclear whether microdosing effectively predicts the pharmacokinetics of therapeutic doses, additional advance of microdosing studies using the AMS may help the field of new drug development and could pose a new challenge to researchers. The use of advanced technology in candidate selection will contribute to improved productivity and competitiveness in pharmaceutical research and development. 
Presently, the two bioanalytical methods commonly used for human microdosing studies are: LC-MS/MS (Liquid Chromatography Mass Spectrometry/Mass Spectrometry) and AMS. Each technique has benefits and drawbacks with the decision of instrumentation being meticulously tied to the primary objective (s) of the study. If a quick decision is essential on the relevance of a pharmacokinetic profile or if a choice is needed from a sequence of compounds, specifically before radiolabeled material is available, LC-MS/MS may be desirable. However, if extreme sensitivity is mandatory, data are necessary on all drug-related material and metabolites, or a simultaneous intravenous MD is used to determine absolute bioavailability (sometimes referred to as microtracing), AMS becomes the analytical method of choice. It is highlighted that microdosing is only one tool in the drug developer's tool box and it should be used in the context of all available data. Nevertheless, when used aptly, microdosing is a valuable tool, bridging between lead optimization and early clinical development. 
Thus, a "better" compound for new drug candidate that demonstrates required PK (Pharmacokinetic) profiles in human is selected by the MD clinical study. The threat of adverse effects to a human subject is regarded as insignificant as only a minute amount of the test compound (>100 μg) is administered. The utility of this technique is restricted since administration of low-dose could exhibit dissimilar PK profiles compared to that of the therapeutic dose. Besides, data regarding the efficacy/safety of the test compound cannot be attained from the MD clinical study. However, physiologically-based pharmacokinetic model analysis based on the data of both the MD clinical study and in vitro study on metabolism, transport, and binding assists the precise estimation of PK profiles in humans at the therapeutic dose. Furthermore, PET molecular imaging technology additionally improves the usability and applicability of the MD clinical study by contributing the data on efficacy/safety. This innovative procedure is extremely anticipated to restructure the drug development and to enhance the success probability in the clinical trial. These practices, if synchronized efficiently, are likely to revolutionize the new drug discovery and development. 
The utility of microdosing studies is presently growing into absolute bioavailability and mass balance studies. Besides purely pharmacokinetic prediction, microdosing is now being extended into areas of drug development. Drug-drug interactions are being studied by giving human volunteers a MD of the candidate drug before and after the administration of a drug known to inhibit or induce certain enzymes, such as the cytochrome P450s. Information regarding the metabolism of a drug candidate can be obtained earlier by administering a (14) C-drug to human volunteers and comparing the plasma concentration-time curves for total (14) C and unchanged parent compound. Full metabolic profiles can be produced as an early indication of the drug's metabolism in human, prior to Phase 1 clinical studies. Microdosing is also being applied to conditions where the levels of a drug in cell or tissue types are crucial to its efficacy. The application of microdosing as a tool in drug development is therefore, expanding into different and hitherto unexpected fields. 
Earlier selection and evaluation of a potential new test substance in humans reduces the time periods to Phase 1 studiesReduces the unnecessary exposure of the participants to the not so potential compounds,Non-potential molecules can be rejected earlier, hence saving costsDecreases human toxicity due to minute dose of the test substance and shorter duration of administration/exposure to the drug (since they mostly involve a single dose administration as compared to a dose escalation study in the traditional Phase 1 trials)Less number of human/animals are usedLesser preclinical safety package is necessarySmall quantity of the test drug is essentialTest drug may be prepared as per the principles of the good laboratory practices unlike good manufacturing practices compliance as required for the traditional Phase 1 studiesAny route of administration is possibleDrug can be assessed in vulnerable patients such as patients with renal impairment, women in their reproductive age, cancer patients, etc.Assessment of the test drug for its modulator effects on the targets in a tumorDetection of endogenous biomarkers for estimating the quantitative effects of the test drugAttains the likely pharmacological dose, thus, determining the first dose for the subsequent Phase 1 studyPK data for initial dose selection can be obtained in nearly 6 months as compared to nearly 18 months in case of conventional Phase 1 studiesSelects the best animal species for the long-term toxicological studies based on the inference drawn from the MD metabolite profiling dataMore effective drugs reach the market earlierReduces overall cost of conducting a MD study as compared to that of a conventional Phase 1 study.Drawbacks
Absence of any therapeutic and/or diagnostic intentMotivating volunteers to become a part of the trial is difficult as there is no therapeutic intentReduces the overall pool of the subjects who become a part of the traditional Phase 1 trials, which may have some therapeutic intent alsoVery few validated biomarkers are available for predicting the anti-cancer activityUltrasensitive and high tech equipments like AMS and PET are required, which are scarcely availableCaution needs to be maintained while administering drugs demonstrating complex/non-linear kinetics as microdosing is still in its initial stagesPredicting the absorption characteristics at the MD levels is challenging since certain drugs dissolve easily at low-doses; however, display limited solubility at higher doses,Unnecessarily extends the process and increases the expenditure as Phase 1 still needs to be carried out. Regulations
Regulatory experts may not make microdosing an obligatory requisite as the information can be acquired by other methods. However, the regulatory agencies may offer support or similar incentives for companies getting certain drugs like life-saving medications to the development and commercialization stages more quickly. The modifications witnessed in the current regulatory guidelines also encourage the more repeated use of microdosing in subjects. Further, precise characterization of the kinetics of a drug over time, after administration, is a vital regulatory condition. This can be attained by administration of radiolabeled drug to the subject and following its fate in plasma and excreta. Since, AMS studies require very minute quantities of radiolabeled compounds; it may not be a significant source of material risk by regulatory authorities. Furthermore, recently, European Medicinal Agency and USA Federal Drugs Authority have published articles and supported evaluation. 
Regulatory amendments supporting Phase 1 and microdosing studies would open the door to the science of early clinical development, setting the stage for rapid growth and scientific advancement in pharmaceutical development in the country. This could bring India into the mainstream of pharmaceutical research. Additionally, it would lay the foundation for a probable crucial role for the country in global drug development in the recent future.
While numerous Indian companies currently competing with their world-wide peers to discover and develop new drugs, there is no concept of Phase 0 or any other equivalent of an Exploratory IND (Investigational New Drug) in Indian regulation. The toxicology necessities for conventional Phase 1 studies are more challenging in India than elsewhere in the world. Hence, Indian companies will be having a drawback if and when they require microdosing studies. This could also restrict them from making choices among candidate drug molecules or to help with other aspects of decision-making in the course of running a drug development program. The unfortunate state of development of Phase 1 expertise in the country suggests that India will remain excluded from emerging scientific capability not only in advanced approaches such as microdosing but also from the prospect to make a mark in the science of early clinical development, the most interesting frontier in the journey of drug candidates from bench to bedside.
In 2007-2008, the Indian Society for Clinical Research had suggested an amendment in regulation that would permit the regulators to recognize and allow microdosing studies in India. The suggestion would align Indian regulations with the best advanced ones anywhere in the world. The Drugs Technical Advisory Board unanimously approved the proposal together with other far-reaching amendments in regulation. Unfortunately, the proposals were disregarded by the government because of non-technical sensitivities surrounding clinical research and drug development in India. Since then, regulatory reform in drug development science has stagnated. 
As reported in May 2010, Council of Scientific and Industrial Research of India has started an open-source drug discovery (OSDD) initiative, on the lines of FDA's CPI. This program has provided a collaborative platform for scientists, doctors, engineers, technical experts, software professionals and others with a wide range of expertise, to enhance the drug discovery process. This project is focused on targeting tuberculosis and is an internet-based project with no intellectual property. OSDD is now a strong community of 3200 participants from about 74 countries. 
Because of a regular escalation in time as well as expenditure of drug development and the substantial extent of resources required by the customary approach, companies can no longer afford to endure to late Phase 3 with drugs, which are unlikely to be therapeutically effective. The imminent challenge for the pharmaceutical industry would be to reduce its research and development costs by attaining a significant cut in the attrition rate for drugs entering preclinical and clinical development. It should also minimize the development period and to enhance the prospect of success in later clinical trials by restructuring the development processes. In the 100 years to 1995, the pharmaceutical industry had worked on about 500 targets with a limited number of compounds. However, now using the novel methodologies such as genomics, high throughput screening and combinatorial chemistry, drug companies should see a surge in the number of targets, and leads it can explore. Thus, a tough process for selecting candidate compounds out of research and a quick elimination procedure for the candidate, which does not measure up in advanced trials, is obligatory to avoid wasting time, energy, and money. To develop the evolution from research to development it is essential to:
Validate innovative targets,Define success standards for research,Incorporate bioinformation at each stage in drug discovery,Outline requisites for development,Recognize the "losers" and select the "winners" earlyConcentrate resources on them,Program the research and development (R and D) process to optimize resource requirements versus time lines, andConfirm an actual flow of information from drug discovery to late phase of development.In drug development, an exhaustive knowledge of a drugs' action is essential from animal models and Phase 1, 2 a studies before taking the drug further in development. Drug development process must be reorganized linking preclinical and early clinical development as an exploratory stage and Phases 2 b, 3 as a confirmatory stage rather than going sequentially. Preclinical and clinical-pharmacological studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials that require power for proof-of-safety and efficacy. Approaches to improve the quality of decisions in drug development are:
Use and incorporation of new tools such as pharmacogenomics to enhance information regarding the cause of the disease and to detect new therapeutic strategies;Modeling and replication of preclinical and clinical trials to bond the breach between the initial phases of the development of a new drug and its possible effects in humans;More refined clinical pharmacokinetics to answer the question if the drug is present at the disease location for an adequate time, andProvide data on concentration-effect-relationships;Selecting and estimating surrogates/biomarkers for safety and efficacy;Participation of the target population at the earliest;Using the information skills to make better use of existing data.Additional exhaustive studies should be performed during this exploratory stage of development. This enables an earlier decision regarding the continuation or discontinuation of further development, thus, saving development time and money. Decreasing the risk for patients and improving the success-rate of the project in the later confirmatory effectiveness trial would also be ensured. Taking responsibility as the link between research and development gives clinical pharmacology a major opportunity to assume a pivotal role in research and development of new drugs. To reach this goal, clinical pharmacology must be fully integrated in the whole process from the candidate selection to its approval. 
Thus, human microdosing evidently holds a substantial promise as an analytical tool. As research procedures and expertise involved in Phase 0 trials become further refined, human microdosing could be useful to a number of drugs that might possibly be administered consecutively. Microdosing may become an established methodology in drug development, when first in man studies may begin with a Phase 0 study. However, the true effectiveness of Phase 0 microdosing studies lies with the capability to envisage under what situations this approach will offer information within a specified and acceptable range, as compared to the therapeutic dose data. Exploiting on the on-going quick progresses in the drug development technology, without doubt, reducing the period of drug development, diminishes the cost remarkably. Until further information is available, it is presumed that microdosing strategy could supplement the customary animal-to-human allometric scaling; redefining the existing Phase 1 study designs. This strategy may help to reduce animal testing in the identification of novel drug candidates.
Further, microdosing may benefit both patients and the pharma industry with an earlier accessibility to new test medication and lesser attrition of compounds at advanced stages of drug development. Microdosing permits not only selection of drug candidates more likely to be developed successfully, but also helps in the determination of the first dose for the subsequent Phase 1 clinical studies.
In nutshell, human microdosing is an encouraging approach and notwithstanding numerous hindrances in terms of set-up, prevailing guidelines and ethical challenges, the subject is worth considering. The Drug Controller General of India has commenced deliberations on human microdosing and the prospect of commencing Phase 0 clinical trials in India. There is a necessity for systematically authenticating this new breakthrough in the field of drug development with an objective of helping the patients, the animals, the pharmaceutical industry, and the mankind as a whole.
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