The Exploratory IND (Phase 0) Concept

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1 The Exploratory IND (Phase 0) Concept Joseph C. Hung Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA In recent years, the costs for drug research and development (R&D) have escalated despite the fact that new technology is evolving and has greatly accelerated the R&D process for new drugs. To aid in the drug R&D process, FDA, as part of their critical path initiative, released a guidance for Exploratory IND studies (or Phase 0 clinical trials) which are intended to provide clinical information for a new drug candidate at a much earlier phase of drug R&D process. Microdose is a primary tool in exploratory IND to allow the collection of human pharmacokinetic and pharmacodynamic data earlier in the drug R&D process. Since microdosing approach is designed not to induce any pharmacological effects, these studies are safe to the participating human subjects. Microdosing studies also can be initiated with fewer preclinical safety studies, as well as require lesser resources and time for selecting promising drug candidates for further evaluation. Key words: exploratory IND, phase 0 clinical trials, FDA, microdosing Ann Nucl Med Sci 2009;22: Introduction The path that a medical product takes from development to mass-production and availability to the public Critical Path as referred by the U.S. Food and Drug Received 2/23/2009; revised 3/18/2009; accepted 3/18/2009. For correspondence and reprints contact: Joseph C. Hung, Ph.D., BCNP. Division of Nuclear Medicine, Department of Radiology, Mayo Clinic, 200 First Street SW, Rochester, MN , USA. Tel: (507) , Fax: (507) , E- mail: jhung@mayo.edu Administration (FDA) has become increasingly challenging, inefficient, and costly. In a move to speed up the development of new medicines, the FDA announced in January 2006 the creation of the exploratory Investigational New Drug (IND), the so-called Phase 0 clinical trials (the term exploratory IND rather than Phase 0 will be used throughout this article as it is used by the FDA) in a guidance titled Exploratory IND Studies [1]. The new rules were developed in response to an important report entitled Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products [2] which was released in March 2004 that urged the FDA to overhaul the national clinical trials system. In an attempt to better explain this relatively new concept, key aspects of the exploratory IND approach are presented in a format of frequently asked questions (FAQs). FAQs about Exploratory IND (Phase 0) What are specific shortcomings of the current drug evaluation and approval process? In recent years, there has been an explosion of scientific discoveries made possible through technologies such as genomics, advanced imaging, nanotechnology, and robotics. These scientific advances can help produce more and better medical products not just drugs, but biologics such as vaccines, and devices such as pacemakers. But the efficiency for scientific discoveries being translated into medical products is very low in fact, it s worse than it was 10 years ago. For example, new drugs go through three phases (i.e., Phases 1, 2, and 3) of progressively rigorous testing, or clinical trials, to show their safety and effectiveness before FDA will consider allowing them on the market. Today, new compounds that make it through Phases 1 and 2 of clinical trials fail 50% of the time in Phase 3 com-

2 Hung JC pared to a 20% failure rate 10 years ago. A new medical compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8% chance of reaching the market [2]. Typically, during new drug development, large numbers of molecules are generated with the goal of identifying the most promising candidates for further development. These molecules are generally structurally related, but can differ in important ways. Promising candidates are often selected using in vitro testing models that examine binding to receptors, effects on enzyme activities, toxic effects, or other in vitro pharmacologic parameters; these tests usually require only small amounts of the drug. Candidates that are not rejected during these early tests are prepared in greater quantities for in vivo animal testing for efficacy and safety. These basic efficacy and safety tests are most often performed in rats and dogs. The studies are designed to permit the selection of a safe starting dose for humans, to predict pharmacokinetic (PK) and pharmacodynamic (PD) parameters*, to gain an understanding of which organs may be the targets of toxicity, and to estimate the margin of safety between a clinical and a toxic dose. These early pre-clinical tests are usually resource intensive, requiring significant investment in product synthesis, animal use, laboratory analyses, and time. Commonly, a single candidate is selected for an IND application and introduction into human subjects, initially healthy volunteers in most cases. However, many resources are invested in, and thus wasted on, candidate products that subsequently are found to have unacceptable profiles when evaluated in humans. One of the reasons for drug failures during development is suboptimal PK/PD. While safety, efficacy, and toxicity failures dominate the reasons for drug * PK is a study of what the body does to the drug, whereas PD explores what a drug does to the body. PK includes the study of distribution, localization, duration, metabolism, and excretion of the administered drug. PK is usually studied in conjunction with PD which is the study of the mechanisms of drug action and the relationship between drug concentration and effect. development termination, drug metabolism could well play a role in all of these. Efficacy failures could arise through too low a concentration of drug reaching the target for an inappropriate amount of time. Safety failures could arise through the wrong concentration reaching the wrong target for too long a time period. Toxicity failures may be through metabolic routes or pathways that do not occur in humans. It is estimated that PK/PD data obtained from animal model incorrectly predict human PK/PD in approximately one in three occasions. Since animal testing does not always predict performance in humans, the value of animals in drug development is frequently challenged. Thus, understanding the PK/PD of a new molecular entity (NME) in humans during the early phase of the drug development is a key to determining whether a new NME is druggable. The creation of the exploratory IND mechanism by the FDA allows the NME to be evaluated in a limited human clinical trial so that potential drug candidate(s) that would work in humans can be identified early in the process. What is an exploratory IND clinical trial? According to the FDA, an exploratory IND study is designed to take place early in Phase 1, involves very limited human exposure, and has no therapeutic or diagnostic intent (e.g., screening studies, microdose studies please refer to the questions and answers related to microdosing concept in the latter part of this paper.) Such exploratory IND studies are conducted prior to the traditional dose escalation, safety, and tolerance studies that ordinarily initiate a clinical drug development program (i.e., Phases 1, 2, and 3 clinical trials). In exploratory IND studies, the duration of dosing is expected to be limited (e.g., 7 days). For escalating dose studies done under an exploratory IND, dosing should be designed to investigate a pharmacodynamic endpoint, not to determine the limits of tolerability [1]. How can exploratory IND approach help bring new drug products to patients faster and cheaper? Exploratory IND studies can expedite the drug development process as it can help the IND sponsors to obtain the following valuable information from a limited number of Ann Nucl Med Sci 2009;22: Vol. 22 No. 2 June

3 Exploratory IND studies subjects with a limited range of doses (i.e., microdose) for a limited period of time: * Explore a product s biodistribution characteristics using various imaging technologies * Determine whether a mechanism of action (e.g., a binding property or inhibition of an enzyme) defined in experimental systems can also be observed in humans * Provide important information on PK/PD * Select the most promising lead product from a group of candidates designed to interact with a particular target of interest in humans, based on PK or PD properties As a result, exploratory IND studies could prevent drug developers from spending unnecessary time and money to continue studying a compound that will not act as expected in humans. The exploratory IND study is not an attempt to help the drug developers cut corners. It is an innovative approach to really make it possible to achieve the abovementioned goals very early on, so that a wider variety of individual drugs in the pipeline can be screened; and increasingly scarce resources and more attentive efforts can be focused on those more promising NMEs that should be moved forward for further clinical evaluation. What are microdose and microdosing approach? Microdose is a technique that is used in exploratory IND clinical trials whereby sub-pharmacological doses of prospective drug candidates are administered to human subjects (healthy volunteers or patients) in order to obtain basic PD information (e.g., mechanisms of a drug action) or PK parameters such as clearance, volume of distribution, t 1/2, etc. A microdose is defined as less than 1/100 th of the pharmacological dose of a test substance (or predicted pharmacological dose based on animal data) or a maximum dose of < 100 µg (this latter criterion applies to imaging agent). Due to differences in molecular weights as compared to synthetic drugs, the maximum dose for protein products is 30 nanomoles. What methods have been used to detect and evaluate minute quantity of the test substance administered to human subjects in a microdose study? Microdose is dependent on the availability of ultrasensitive analytical methods able to measure drug and metabolite concentrations in the low g range. Two nuclear physics techniques have been applied to conduct analyses at these concentrations accelerator mass spectrometry (AMS) [3,4] and positron emission tomography (PET) [5,6]. Both techniques rely on the analysis of radioisotopes incorporated into the drugs under study. It is only PET and AMS that have the sensitivity to guarantee that drug and/or metabolite concentrations can be determined at these ultralow doses. In the case of AMS, 14 C is the most useful isotope for drug metabolism studies whereas for PET 11 C is proving to be the most useful. It is worth noting the huge contrast in radioactive half-life of the two radioisotopes. 14 C has a half-life of 5,740 years whereas 11 C has a half-life of 20 minutes. For PET, a radiosynthesis facility (e.g., a PET drug production center with an in-house cyclotron) must be in very close proximity to the normal volunteer or patient enrolled in the exploratory IND study. In contrast the longer physical half of 14 C means that provided no significant radiolytic or chemical decomposition occurs, the synthesized radioactive compound is stable for many years. AMS is used for determining PK data by taking body samples over time, processing the samples in the laboratory and then analyzing their drug content. PET provides primarily PD data through real-time imaging and some limited PK data 2 hours (i.e., six decay half-lives) after drug administration. With AMS technique, PK data can be obtained for up to 100 days after drug administration. Both PET and AMS quantify the total number of radiolabeled atoms present in a sample rather than distinguishing between parent drug and metabolite(s). In general, researchers wish to know the relative proportion of both in a particular sample or study. This information can be obtained through chromatographic separation of an extract of blood or plasma followed by analysis of collected chromatography fractions. How can microdose studies specifically help in the new drug development and evaluation processes? The conducting of microdose studies in parallel way is 2009;22:

4 Hung JC most appropriate when several NMEs are available, perhaps with a common structural core where the radiolabel can be introduced into the core portion of the molecule. These parallel studies are best conducted on several NMEs using parallel human subject groups. If during the drug discovery process, a number of molecules are identified which have good pharmacological activity but similar or differing animal PK, comparative human microdose studies can be conducted to establish human PK. Armed with this information, the human PK data can then be used to (1) assist in the candidate selection process, (2) determine the first dose for the subsequent Phase 1 study on the selected candidate, (3) establish the likely pharmacological dose, and (4) calculate the likely cost of goods. Another example of the microdosing approach is when microdose studies are performed compound by compound in an iterative manner. Through each microdosing round, the PK and bioavailability properties of the molecule can be improved to, in the end, provide a molecule with the optimal desired PK properties. In some cases, the drug discovery process might only yield a single molecule. Microdose study can still be useful in such circumstances as it can quickly establish if it is worth taking the molecule forward prior to committing large-scale resources to a full Phase 1 study. Sometimes a metabolic pathway is identified in human hepatocytes or liver microsomes, which is not seen in animals. Microdosing approach can be used to establish if the pathway occurs in vivo. For a drug that is expensive to manufacture, the pharmacological dose may be so great that the drug becomes uneconomic to manufacture. Since microdose study only uses less than 1/100 th of the pharmacological dose, the usefulness of this expensive NME can be explored and evaluated in a few human subjects via exploratory IND process before the manufacturer commits significant financial resource to move forward the larger scale of the traditional 3-phase clinical trials. Is microdose approach safe to the human participants of exploratory IND studies? A microdose is less than 1/100 th of a typical drug dose that would have a pharmacologic effect. As such, microdose studies are designed not to induce pharmacologic effects. Because of this, the potential risk to human subjects is very limited and is less than for a traditional Phase 1 study that, for example, seeks to establish a maximally tolerated dose. What are possible limitations of the microdosing technique? There are three potential weakness areas associated with the microdosing technique. First, the database for microdose studies is still very small. This is partly due to the length of time required to get new approaches adopted, the lack of validation programs, scientific inertia, and a failure to recognize the potential benefits of microdose studies. However, the adoption of microdosing approach is accelerating due to the facts that the regulatory climate in Europe and the U.S. has changed and small to medium size biotech companies are conducting microdose studies earlier than big pharmaceutical companies. Second, PET assay has disadvantages of short tracer half-lives. For both PET and AMS, test drug substance must be radiolabeled at metabolically stable site and both assays have limited specificity (assays may contain metabolites). Third, a microdose may not predict the behavior of clinical doses, although there is a body of evidence that linearity or near-linearity is approached for many test drugs. Does the initiation of an exploratory IND study require the completion of safety studies in animals? Yes, nonclinical safety studies must be carried out in order to support the initiation of the limited human studies in exploratory IND stage. However, the preclinical testing requirements for exploratory IND studies can be less extensive or different than is required for traditional IND studies. This is because the exploratory IND approach involves administering sub-pharmacologic doses of a candidate drug compound or compounds. The potential risks to human subjects are less than for a traditional Phase 1 study that looks for dose-limiting toxicities. For clinical studies of PK/PD or imaging, the FDA currently accepts the use of extended single-dose toxicity stud- Ann Nucl Med Sci 2009;22: Vol. 22 No. 2 June

5 Exploratory IND studies ies in animals to support single-dose studies in humans [1]. A single mammalian species (both sexes) can be used if justified by in vitro metabolism data and by comparative data on in vitro PD effects. The route of exposure in animals should be by the intended clinical route. In these studies, animals should be observed for 14 days post-dosing with an interim necropsy, typically on day 2, and endpoints evaluated should include body weights, clinical signs, clinical chemistries, hematology, and histopathology (high dose and control only if no pathology is seen at the high dose). The study should be designed to establish a dose inducing a minimal toxic effect, or alternatively, establishing a margin of safety. To establish a margin of safety, the sponsor should demonstrate that a large multiple (e.g., 100X) of the proposed human dose does not induce adverse effects in the experimental animals. Scaling from animals to humans based on body surface area can be used to select the dose for use in the clinical trial. Scaling based on PK/PD modeling would also be appropriate if such data are available. Because microdose studies involve only single exposures to microgram quantities of test materials and because such exposures are comparable to routine environmental exposures, routine genetic toxicology testing is not needed. For similar reasons, safety pharmacology studies are also not recommended. How about the good laboratory practice (GLP) compliance when conducting a preclinical safety? It is expected that all preclinical safety studies supporting the safety of an exploratory IND application will be performed in a manner consistent with good laboratory practices (GLP). The GLP provisions apply to a broad variety of studies, test articles, and test systems. Sponsors are encouraged to discuss any need for an exemption from GLP provisions with the FDA prior to conducting safety related studies, for example, during a pre-ind meeting. Sponsors must justify any nonconformance with GLP provisions. What is required to be submitted in an exploratory IND submission? The major information that must be submitted in a traditional IND application includes: * Information on a clinical development plan (Clinical Information) * Chemistry, manufacturing, and controls information (CMC) * Pharmacology and toxicology information (Preclinical Safety Testing) * Previous human experience with the investigational candidate or related compounds, if there is any (First in Human [FIH] Studies) The following sections discuss the different requirements of these four major contents between a traditional IND and an exploratory IND submission. The common theme throughout is that, depending on the study, the informational requirements for exploratory IND studies are more flexible and abbreviated than for traditional IND studies. Clinical Information A traditional IND application describes the rationale for the proposed clinical trial program and discusses the potential outcome of the clinical investigation. The exploratory IND studies focus on a circumscribed study or group of studies, and plans for further development cannot be formulated without the results of these studies. Therefore, an exploratory IND application should articulate the rationale for selecting a compound (or compounds) and for studying them in a single trial or related trials, as this represents all that is known about the overall development plan at this stage. This section should also make it clear that the IND is intended to be withdrawn after completion of the outlined study or studies. CMC The regulations stated in the Code of Federal Registrations Title 21 Part (a)(7)(i) [7] emphasize the graded nature of CMC information needed as development under an IND application progresses. Although in each phase of a clinical investigational program sufficient information should be submitted to ensure the proper identification, strength, quality, purity, and potency of the investigational candidate, the amount of information that will provide that assurance will vary with the phase of the investigation, 2009;22:

6 Hung JC the proposed duration of the investigation, the dosage form, and the amount of information already available. For the purpose of an exploratory IND application, the sponsor must state in the beginning of the exploratory IND application whether it believes the chemistry or manufacturing of the candidate product presents any potential for human risk (e.g., specific findings in preclinical studies associated with known risks of related compounds). If so, these potential risks should be discussed, and the steps proposed to monitor for such risks should be described. The FDA is in the process of developing guidance explaining the stepwise approach to meeting current good manufacturing practice (CGMP) regulations. Once finalized, that guidance will be useful to persons seeking to manufacture, or prepare, products intended for use in an exploratory IND study. In the interim, the identification, strength, quality, purity, and potency of the investigational drug compound(s) should meet the CMC requirements as described in the FDA guidance titled Exploratory IND Studies [1]. Preclinical Safety Testing The toxicology evaluation recommended for an exploratory IND application is more limited than for a traditional IND application. The basis for the reduced preclinical package is the reduced scope of an exploratory IND clinical study. Although exploratory IND studies in some cases are expected to induce pharmacologic effects, they are not designed to establish maximally tolerated doses. Furthermore, the duration of drug exposure in exploratory IND studies is limited. The level of preclinical testing performed to ensure safety will depend on the scope and intended goals of the clinical trials (i.e., clinical studies of PK or imaging, clinical trials to study pharmacologically relevant doses, or clinical studies of mechanisms of actions related to efficacy). There are a number of study objectives for which the preclinical safety programs may be tailored to the study design. Examples include: confirming that an expected mechanism of action can be observed in humans; measuring binding affinity or localization of drug; assessing PK and metabolism; comparing the effect on a potential therapeutic target with other therapies. FIH Studies Because the exploratory IND studies will be FIH studies, previous human experience is not pertinent to the submission of an exploratory IND application. Conclusion The FDA has undertaken a number of efforts to reduce the time spent in early drug development on products that are unlikely to succeed. The guidance entitled Exploratory IND Studies [1] issued by the FDA describes some exploratory approaches that are consistent with regulatory requirements currently exist in the U.S., but that will enable sponsors to move ahead more efficiently with the development of promising candidate products while maintaining needed human subject protections. The microdose study will become an accepted approach in drug development and that eventually all first in human studies will commence with an exploratory IND clinical trial. Is it ethical to expose human subjects unnecessarily to a pharmacological dose of potential drug that has poor PK/PD properties, whose development is terminated as a result, when the same information could have been obtained in a microdose study? Has there not been an unnecessary use of animals, including dogs and primates, on the terminated compound? Microdose approach used in the exploratory IND trial will make a contribution to smarter drug development by enabling early human data to be obtained. Drug selection as a result will become more human based and therefore more predictive. References 1. Guidance for Industry, Investigators, and Reviewers. Exploratory IND Studies. Center for Drug Evaluation and Research, Food and Drug Administration, U.S. Department of Health and Human Services. Washington, DC, USA, Innovation/Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products. U.S. Food and Drug Administration. Washington, DC, USA, Lappin G, Garner RC. Big physics, small doses: the use of AMS and PET in human microdosing of development drugs. Nature Rev Drug Discovery 2003;2: Ann Nucl Med Sci 2009;22: Vol. 22 No. 2 June

7 Exploratory IND studies 4. Lappin G, Garner RC. Current perspectives of 14 C-isotope measurement in biomedical accelerator mass spectrometry. Anal Bioanal Chem 2004;378: Aboagye EO, Price PM, Jones T. In vivo pharmacokinetics and pharmacodynamics in drug development using positron-emission tomography. Drug Discovery Today 2001;6: Bergström M, Grahnén A, Langström B. Positron emission tomography microdosing: a new concept with application in tracer and early clinical drug development. Eur J Clin Pharmacol 2003;59: Code of Federal Registrations Title 21 Part (a)(7)(i) IND Content and Format - Chemistry, Manufacturing, and Control Information. U.S. Food and Drug Administration. Washington, DC, USA. CFRSearch.cfm?fr= (accessed on March 13, 2009) 2009;22:

8 Hung JC (Exploratory IND ) Mayo Clinic (FDA) (Exploratory IND) ( ) (microdose) Exploratory IND Exploratory IND 2009;22: Mayo Clinic (507) (507) : jhung@mayo.edu Ann Nucl Med Sci 2009;22: Vol. 22 No. 2 June