Phase zero clinical trials: A new era in regulatory approach

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1 Review Article Phase zero clinical trials: A new era in regulatory approach Y. K.Divya, V. Balamuralidhara*, M. P. Venkatesh ABSTRACT Microdosing or phase zero clinical trial is a breakthrough in drug development, where subtherapeutic dosage of various investigational products is administered under necessary safety condition to minimal number of volunteers to obtain an early pharmacokinetic profile of the product. It is an important bioanlaytical tool which benefits the patients as well as the pharmaceutical industry by bringing out new effective molecules faster and reducing the attrition rates at later clinical trial phase. Microdosing appears as a new concept in the toolbox of the drug development activity. It appears that microdosing strategy could complete standard animal to human scaling redefining the exiting concept of phase one clinical research. In future, when research methods and technology involved in phase zero studies become more sophisticated, human microdosing may be applied to a number of drugs developed subsequently. The drug and dose of the trial too small and reliable biomarkers are too thin on the ground despite great sum of money being spent to find and validate them. Phase zero clinical trials can decrease the cost and time and could improve the process of drug development in future. This review emphasis the development and impact of phase zero trial in clinical research. KEY WORDS: Clinical trials, Investigational new drug, Microdosing, Phase 1, Phase zero INTRODUCTION The concept of microdosing in human subjects has long been an experimental technique that has promised much but has not quite lived up to its potential. The advantages of human microdosing are clear. It is also called as exploratory investigational new drugs (IND) or microdosing method. Microdosing is conducted early in phase 1, involves very limited human exposure, and has no therapeutic or diagnostic intent (e.g., screening studies and microdose studies). Such exploratory IND studies are conducted before the traditional dose escalation, safety, and tolerance studies that ordinarily initiate a clinical drug development program. [1,2] WHAT IS A MICRODOSE? Guidelines define a microdose to be at 1/100 th of the expected pharmacological dose provided, and it is no more than 100 g or 30 nmol. Studies using Access this article online Website: jprsolutions.info ISSN: such a microdose are called microdosing studies. It helps to determine the safety and efficacy of new drug and devices. Human drug development is a dynamic process that keeps pace with the recent advances within the pharmaceutical analytical laboratories, combined with a precise understanding of the integrated pharmacokinetic pharmacodynamic, pharmacogenomic drug profile. New drugs are a great need for many clinical conditions but, unfortunately, development costs are rising and the number of drugs receiving marketing approval has fallen. Further, drug development is a long, complex, and expensive activity. It typically involves a total cost of US$ 500 million to 1 billion per marketed drug and is spread over years. [3] In the past decade, attrition was the highest (62%) during Phase II, 45% during phase III, and significant (23%) at the time of registration. [4] The situation has become so serious that the Food and Drug Administration (FDA) published the document critical path, highlighting the problems in drug development and encouraging novel approaches to be incorporated into the current drug development paradigm. [5] The major objectives of phase zero trials are to interrogate and refine a target or biomarker assay for Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Mysuru , Karnataka, India *Corresponding author:v. Balamuralidhara,Department of Pharmaceutics, JSS College of Pharmacy, Jagadguru Sri Shivarathreeshwara University, Mysuru , Karnataka, India. baligowda@jssuni.edu.in Received on: ; Revised on: ; Accepted on: Journal of Pharmacy Research Vol 12 Issue

2 drug effect in human samples implementing procedures developed and validated in preclinical models. Data gleaned from a phase zero trial are beneficial not only in prioritizing promising compounds but also in allowing the modification of phase I study design before initiation. MICRODOSING AND THE REGULATORY GUIDELINES This paper address the concept of micro dosing was published in 10 years ago [6] but the maximum dose that defines a microdose was not proposed at the time. The regulatory authorities followed with a position paper from the European Medicines Agency 2004, [7] guidelines from the FDA in 2006, [8] Japan in 2008, [9] and now the current definitive international guideline in [10] A microdosing is defined in all regulatory documents as being a dose of 100 μg. The latest ICH M3 guidelines now universally accepted allows a microdose to be administered to human subjects based on a single-dose toxicity study (usually in the rat), followed by 14 days observation, using the intended route of administration (or through the intravenous route), plus some in vitro target receptor data. The safety data obtained can be used to justify the administration of maximum of 100 μg of the drug, either as a single dose or as a series of divided doses to humans (for example, a two-way crossover study of 50 μg each). The ICH M3 regulatory guideline offers other possible scenarios such as the administration of up to 500 μg in a maximum of five different administrations (a maximum of 100 μg each with a period of six half-lives between doses), based on a 7-day repeat toxicity study, [10] but this review will focus on the situation where the total dose is limited to 100 μg. This review covers microdosing used to acquire traditional concentration-time pharmacokinetic data. The changes observed in the recent guidelines also stimulate the micro-dosing which is a mandatory requirement for clinical trials. [11] DESIGNING OF MICRODOSING Phase zero trial portends to human subject than traditional phase 1 trials. As such, fewer preclinical supporting data are required to conduct a phase zero trial. The initial agent dose depends in part on stated trial objectives but should not be >1/50 th of the noobserved-adverse-effect level estimated from animal toxicity testing. Validated pharmacodynamic assay, ideally with a low variable in the molecular target, is suitable for application to phase zero trial if the investigational agent can be reasonably expected to demonstrate target modulation at a non-toxic dose. Phase zero trials are designed primarily to evaluate the pharmacodynamic and/or pharmacokinetic properties of selected investigational agents before initiating more traditional phase 1 testing. One of the major objectives of phase zero trials is to interrogate and refine a target or biomarker assay for drug effect in human samples implementing procedures developed and validated in preclinical models. Thus, close collaboration between laboratory scientists and clinical investigators is essential to the design and conduct of phase zero trials. [12] MICRODOSING APPROACH IN PHASE ZERO CLINICAL TRIALS Microdosing approach is adopted for evaluating PD (mode of action) and PK (volume of distribution, binding, and clearance) in the human being for predicting or selecting the most promising drug candidate in the analog for further study. Very small amount of drug can be used to conduct the phase zero trial. This test can be conducted using special animals and models for toxicological studies mainly for long-term studies. There are two methods which have abilities of evaluation of microdose. These techniques rely on radioisotopes incorporation. [4] Two methods used and this technique was explained by Hung, Rani, and Naidu. [13] Accelerator Mass Spectrometry (AMS) This technique is used for the evaluation of pharmacokinetic data mainly. In this technique, radioisotope C14 is used for the evaluation of drug or microdose. The half-life of this radioisotope is 5740 years. Positron Emission Tomography This is mainly used for the evaluation of PD data. For evaluation of PD data, C11 radioisotope is used which having 20 min half-life. Phases of Clinical Trials There are four phases of clinical trials and medicine development exist and are defined below: Phase I Researchers test a new drug or treatment in a small group of people (20 80) for the first time to test its safety, identify the maximum tolerated dose, find a safe dosage range, and identify side effects. Phase I trials sometimes conducted in severely ill patients (e.g., in the field of cancer). Trials should be conducted on human healthy volunteers. Pharmacokinetic trials are usually considered phase I trials regardless of when they are conducted during a medicine s development. [14] The comparison of phase zero/ micro dosing with traditional phase 1 approaches is depicted in Table 1. Phase II Once the initial safety of the study has been confirmed in phase I trials, phase II trials are performed on a Journal of Pharmacy Research Vol 12 Issue

3 Table 1: Comparison of phase zero/microdosing with traditional phase 1 approaches Key components Phase zero/microdosing Traditional phase 1 Therapeutic intent None Possible Study of systemic tolerability None Yes Proof of mechanism of action Possible (e.g., PET receptor binding and Possible displacement) Pre clinical package Limited, variables Full requirements In vitro models Full requirements Full requirements Toxicology Limited, variable Full requirements Genotoxicology None or limited Full requirements GMP Flexible, depending on available Full requirements preclinical information and route of administration (e.g., sterility ensured for IV route) Regulatory review 30 day 30 day Studies Size Duration Number of study sites Maximal dose Exposure population 4 10 participants 1 14 days Single<MTD Limited Healthy volunteers or patients vulnerable populations Usual duration of program 4 12 months months Cost of program $ M $ M 6 30 participants 6 60 day Single/multiple MTD Multiple doses allowed Usually healthy volunteers (unless toxicity risk is high, e.g., in oncology studies) larger group of people ( ) to see the safety of the drug and to gather additional information regarding safe dose range. Phase II studies are sometimes divided into phase IIA and phase IIB. Phase IIa: It is specifically designed to assess dosing requirements (how much drug should be given). Phase IIb: It is specifically designed to study efficacy (how well the drug works at the prescribed dose(s)). Phase III The drug or treatment is given into a large number of people ( ) to confirm its effectiveness and monitor side effects. In this trial, phase IIIa and phase IIIb are carried out. Phase IIIa: Trials were conducted after the efficacy of the medicine is demonstrated but before regulatory submission of a new drug application (NDA) or other dossier. In this, trials generate safety and efficacy in a relatively large number of patients both in controlled and uncontrolled trials. Phase IIIb: Clinical trials were conducted after regulatory submission of an NDA or other dossier but before the medicine s approval and launch. Phase IV Phase IV trials are known as post-marketing surveillance. This trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold and to provide a additional details about safety or efficacy profile. Trials may be conducted to determine better dosing guidelines, new formulations, effects on different populations, or new indications. [15] MICRODOSING IN ONCOLOGY STUDIES In oncology studies compared to micro-dosing studies, phase 1 trials place a important role in clinical trials. Molecular targeted agents (MTA) differ from traditional cytotoxics in terms of both efficacy and toxicity profiles. Recent reports suggest that higher doses are not essential to produce the optimal antitumor effect. MTA could achieve clinical benefit at much lower dose than traditional cytotoxics in dose-seeking phase 1 trials. Phase 1 oncology trials plays an important role in translating laboratory science into effective therapies. These trials enroll patients with advanced cancer that has mostly exhausted all available standard care, to evaluate the safety profile and the pharmacokinetic properties of new therapeutic regimens. The primary aim of the study is to establish the optimal recommended dose for further trials. Traditional phase 1 oncology trials consist of the administration of increasing doses of the experimental compound to successive cohorts of patients until the maximum tolerated dose is reached. This design was developed in the context of the conventional cytotoxic agents, which exhibit dose-efficacy and dose-toxicity relationships. [16,17] 416 Journal of Pharmacy Research Vol 12 Issue

4 PEDIATRIC CLINICAL TRIALS Rationale for Conducting Clinical Trials The children s right to the highest attainable level of health enunciated by the convention on the rights of the child [18] cannot be realized if they are provided therapy based on evidence generated through studies carried out in adults. [19,20] This is essential as children and adults differ in physiological capabilities, pharmacokinetic profile, and pharmacodynamic characteristics. Their metabolic pathways, organic functions, and metabolic rates differ widely. In addition, age, growth, and development influence side effects, [21,22] and the dose of medications is dependent on body weight or surface area. Furthermore, age influences the severity and type of disease and pathological agents. [23] WHEN SHOULD PEDIATRIC TRIALS BEGIN? This is a crucial issue. Majority of molecules that enter phase one trials in adults never receive regulatory approval because of lack of efficacy or safety concerns; in general, it is not reasonable to enroll children in drug trials till the sufficient proof of safety and significant information about pharmacokinetics and efficacy in adults are available. Hence, generally speaking, it is appropriate to defer pediatric testing until adult testing has reached phase three or beyond. [24] This may be relaxed, if the disease exclusively occurs in children. For understanding, they are classified as follow:- Medicinal products for diseases that affect children exclusively (e.g., surfactant used for the treatment of hyaline membrane disease [HMD] in neonates). Here, it is logical that the entire drug development program is conducted entirely in children. Medicinal products to treat diseases that mainly affect children or are of particular gravity in children or have a different natural history in children. Medicinal products intended to treat diseases occurring in adults and children, for which there is currently no treatment. Medicinal products to treat a disease occurring in adults and children for which treatments exist but where there is insufficient knowledge of efficacy or toxicity in children. The development program can be conducted early in pediatric population after safety and tolerability data have been obtained in adults. For other products, pediatric studies can be initiated once efficacy and safety have been studied and proved in adults. GERIATRIC CLINICAL TRIALS Typically, clinical trials conducted in adult populations include patients between the ages of 18 and 65. However, drugs should be studied in all age groups, and trial participants should be representative of the patient population receiving the therapy in daily medical practice. Elderly patients are poorly represented in clinical trials. Hence, there is inadequate evidence and knowledge about responses of geriatric patients to medications. Regulatory authorities in developed countries urge to avoid arbitrary upper age limits and advise researchers and industry not to exclude elderly people from clinical trials without a valid reason. The central drugs standard control organization will be doing a great contribution to the researchers if it changes its view on stipulating upper age restrictions in clinical studies. Geriatric patients can respond differently from younger patients to drug therapy. [25] Age-related physiological changes can affect pharmacokinetics and pharmacodynamics of the drug. Geriatric patients are more prone to adverse effects due to comorbidities and concomitant drugs. BENEFITS OF ELDERLY POPULATION PARTICIPATE IN CLINICAL TRIALS Researcher can learn more about the new drugs, medical device, therapies, surgical procedure, or tests. Different dosage of the drugs to have the right results and appropriate in the elderly could be established. Risk association with exposure of large population could be predicted. Adverse drug reaction specific to the elderly could be established. Demonstrate fairness and equity in research population. ROLE OF THE FDA IN PHASE ZERO CLINICAL TRIALS According to the FDA, a phase zero is designed to take place very early in phase I and involves very limited human exposure receiving only sub-therapeutic dose, and this means, the patients (study subjects enrolled) produce a pharmacologic response than the toxic effect, and the risk involved is less than conventional phase I trials in which administration continues if there is a evidence of clinical benefit and thus phase zero trials lack even therapeutic intent (Marchetti and Schellens, 2007). Ultrasensitive AMS has made it possible to undertake clinical studies in man using extremely low drug doses to obtain early PK and ADME data. [26] REGULATIONS Regulatory experts may not make microdosing an obligatory requisite as the information can be acquired by other methods. However, the regulatory agencies Journal of Pharmacy Research Vol 12 Issue

5 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. ETHICS The FDA supports the conduct of phase zero trials. Phase zero trials in oncology-related studies raise an important ethical concerns that have received little attention in recent years. The question arises that it is ethical to enroll a subject in human microdosing that offers them no potential clinical benefit, and further concern focuses on the inclusion of terminally ill and the consequently vulnerable cancer subjects in this type of trial. The aspect was discussed in recent years by Abdoler et al., [27] ADVANTAGES Microdosing trials have several advantages before starting the phases of clinical trials. Vijayaragavan and Kumar [28] and Lappin and Garner [6] explained these advances as follows: The time period gets reduced with the help of earlier testing of pharmacological action of a new test candidate. The help in overall acceleration in the process of drug development by focusing only the promising compounds. They avoid unnecessary exposure of the participants in the trial to the not so promising compounds. They possess less risk of human toxicity with low doses of the test candidate and less time duration for exposure. Moreover, a very limited number of subjects are involved. Furthermore, such trials mostly involve a single dose administration as compared to a dose escalation study in the traditional phase I trials, thereby further minimizing risk. Pre-clinical safe site compared to conventional phase I clinical trials. Less number of animals are used. Overall time of drug development is reduced. Small quantity of the test drug is required. This methodology helps in early selection of the smarter and more promising lead molecules, and hence, the more effective drug reaches to the market earlier. All test drug prepared according to principles and procedure of Good Laboratory Practice (GLP) as well as Good Manufacturing Practice for conventional phase I clinical trials. Any route of administration is possible. The drug can be studied in sensitive patient such as renal impairments, women in their reproductive age, and cancer patients. This approach can help in studying the test drug for its modulator effect on the targets in a tumor. This approach is useful in the discovery of endogenous biomarkers for evaluating the quantitative effects of the test drug. The not so molecules can be eliminated earlier, thereby saving costs. They are helpful in obtaining the nearby therapeutic dose so determining the first dose for further phase I study. The PK data can be obtained in only near about 6 months as compared to nearby 18 months in cases of conventional phase I studies. They may help in selecting the best animal species for the long-term toxicological studies based on the inference drawn from the microdose metabolite profiling data. DISADVANTAGES Vijayaraghavan and Kumar [28] and Eliopoulos et al. [29] had explained disadvantages of microdosing trials: There is a lack of any therapeutic as well as diagnostic intention. It may be difficult to motivate the volunteer to become a part of the trail because of no therapeutic intent. Very few validated biomarkers are available for predicting the anticancer activity. Participation in the phase 0 trials may reduce the overall load of the subjects who become a part of the conventional phase 1 trials having therapeutic intention. There is a requirement of ultrasensitive and high tech equipments such as AMS and PET which are scarcely available. Since the technique of microdosing is still in its infancy, before applying this methodology, precaution needs to be exercised to the drug showing complex/non-linear kinetics. Since certain drugs dissolve readily at low dose but exhibit limited solubility at higher doses, it may be difficult to predict the absorption characteristics at microdose levels. Phase one still needs to be done, and hence, phase zero unnecessarily prolongs the process and inflates the expenditure. CONCLUSION Human microdosing clearly holds significant promise as an analytical tool. In the coming years of research, method and technology involved in phase zero trials became more sophisticated, human microdosing may 418 Journal of Pharmacy Research Vol 12 Issue

6 be applied to a number of drugs that could potentially be administered consecutively. It helps to both the patient and pharma industry with earlier availability of new test medication and reduced attrition of compound at later stages of drug development. Microdosing allows not only the selection of drug candidates more likely to be developed successfully but also helps in determination of the first dose for the subsequent phase 1 clinical trials. REFERENCES 1. Garner RC. The phase 0 micro-dosing concept. Br J Clin Pharmacol. 2006;61: Gutierrez M, Collyar D. Patient perspectives on phase 0 clinical trials. Clin Cancer Res 2008;14: Kola I, Landis J. Can the pharmaceutical industry reduce attrition rates? Nat Rev Drug Discov 2004;3: Boyd RA, Lalonde RL. Non-traditional approaches to first-inhuman studies to increase efficiency of drug development: Will micro-dose studies make a significant impact? Clin Pharmacol Ther 2007;81: Garner RC. Less is more: The human microdosing concept. Drug Discov Today 2005;10: Lappin G, Garner RC. Big physics, small doses: The use of AMS and PET in human microdosing of development drugs. Nat Rev Drug Discov 2003;2: EMEA Position Paper on Non-clinical Safety Studies to Support Clinical Trials with a Single Microdose. CPMP/ SWP/2599; Food and Drug Administration US Department of Health and Human Services Guidance for Industry Investigators and Reviewers. Exploratory IND Studies; (January 2006). 9. Pharmaceutical and Medical Safety Bureau, Tokyo. Microdose Clinical Studies. Japan: Ministry of Health, Labor and Welfare; Lappin G, Wagner CC, Langer O, van de Merbel N. New ultrasensitive detection technologies and techniques for use in microdosing studies. Bioanalysis 2009;1: Wagner CC, Simpson M, Zeitlinger M, Bauer M, Karch R, Abrahim A, et al. A combined accelerator mass spectrometrypositron emission tomography human microdose study with 14C-and 11C-labelled verapamil. Clin Pharmacokinet 2011;50: Limburg PJ. Phase 0 Study Design: Coming of Age? ): AACR (American Association of Cancer Research) International Conference on Frontier in Cancer Research; p Rani PU, Naidu MV. Phase 0 micro-dosing strategy in clinical trials. Ind J Pharm 2008;6: Web Site Editor. Clinical trials-what your need to know. Am Cancer Soc 2007;129: Chow SC, Liu JP. Design and Analysis of Clinical Trials: Concepts and Methodologies. Hoboken, NJ: Wiley- Interscience, John Wiley & Sons, Inc.; Von Hoff DD, Turner J. Response rates, duration of response and dose response effects in phase I studies. Invest New Drugs 1991;9: Itoh K, Sasaki Y, Miyata Y, Fujii H, Ohtsu T, Wakita H, et al. Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in japan. Cancer Chemother Pharmacol 1994;34: General Assembly of the United Nations. Convention on the Rights of the Child, 20 November Available from: www. unicef. org/crc/crc. htm.[ Sep. 19. Bavdekar SB, Sadawarte PA, Gogtay NJ, Jain SS, Jadhav S. Off-label drug use in a pediatric intensive care unit. Indian J Pediatr 2009;76: Jain SS, Bavdekar SB, Gogtay NJ, Sadawarte PA. Off-label drug use in children. Indian J Pediatr 2008;75: Williams K, Thomson D, Seto I, Contopoulos-Ioannidis DG, Ioannidis JP, Curtis S, et al. Standard 6: Age groups for pediatric trials. Pediatrics 2012;129:S Benjamin DK Jr., Smith PB, Sun MJ, Murphy MD, Avant D, Mathis L, et al. Safety and transparency of pediatric drug trials. Arch Pediatr Adolesce Med 2009;163: Smith PB, Benjamin DK Jr., Murphy MD, Johann-Liang R, Iyasu S, Gould B, et al. Safety monitoring of drugs receiving pediatric marketing exclusivity. Pediatrics 2008;122:e Shaddy RE, Denne SC. The Committee on Drugs and Committee on Pediatric Research. Clnical Report-Guidelines for the Ethical Conduct of Studies to Evaluate Drugs in Pediatric Populations. Available from: org/cgi/doi/ /peds [ on Sep 05]. 25. Hutchins LF, Unger JM, Crowley JJ, Coltman CA Jr., Albain KS. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999;341: Marchetti S, Schellens JH. The impact of FDA and EMEA guidelines on drug development in relation to phase 0 trials. Br J Cancer 2007;97: Vijayaraghavan R. Animal models in pre-clinical research and bio-medical research: SOP and GLP compliance. Book: Emerging Trends in Modern Biology p Vijayraghavan R, Kumar GR. Impact of phase 0 trials (microdosing) in clinical trial research. Int J Appl Bio Pharm Tech 2010;1: Eliopoulos H, Giranda V, Carr R. Phase 0 trials: An industry perspective. Clin Cancer Res 2008;14: Journal of Pharmacy Research Vol 12 Issue