If after days the FDA has communicated that there is no objection to the proposed clinical study, the IND is considered active and the clinical study can commence Table This section of the guidelines outlines an alternative approach to accelerating novel drugs and imaging molecules to humans employing a Phase 0, exploratory IND strategy exploratory IND. The exploratory IND strategy was first issued in the form of draft guidance in April, Following a great deal of feedback from the public and private sectors, the final guidance was published in January, Phase 0 describes clinical trials that occur very early in the Phase I stage of drug development.
Phase 0 trials limit drug exposure to humans up to 7 days and have no therapeutic intent. There is some flexibility in data requirements for an exploratory IND. These requirements are dependent on the goals of the investigation e. Exploratory IND studies provide the sponsor with an opportunity to evaluate up to five chemical entities optimized chemical lead candidates or formulations at once.
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When an optimized chemical lead candidate or formulation is selected, the exploratory IND is then closed, and subsequent drug development proceeds along the traditional IND pathway. This approach allows one, when applicable, to characterize the human pharmacokinetics and target interaction of chemical lead candidates. Exploratory IND goals are typically to: Exploratory IND or Phase 0 strategies must be discussed with the relevant regulatory agency before implementation.
These studies are described below. Microdosing studies are intended to characterize the pharmacokinetics of chemical lead candidates or the imaging of specific human drug targets. Microdosing studies are not intended to produce a pharmacologic effect. Exploratory IND-enabling preclinical safety requirements for microdosing studies are substantially less than the conventional IND approach.
In the US, a single dose, single species toxicity study employing the clinical route of administration is required. Animals are observed for 14 days following administration of the single dose. Routine toxicology endpoints are collected. The objective of this toxicology study is to identify the minimally toxic dose, or alternatively, demonstrate a large margin of safety e. Genotoxicity studies are not required.
The EMEA, in contrast to the FDA, requires toxicology studies employing two routes of administration, intravenous and the clinical route, prior to initiating microdosing studies. Genotoxicity studies bacterial mutation and micronucleus are required. In this case, doses would be separated by a washout period of at least six pharmacokinetic terminal half-lives. Fourteen-day repeat toxicology studies encompassing the predicted therapeutic dose range but less than the MTD have also been proposed to support expanded dosing in microdosing studies.
Exploratory IND clinical trials designed to produce a pharmacologic effect were proposed by PhRMA in May , based on a retrospective analysis of drugs that supported the accelerated preclinical safety-testing paradigm. In Phase 0 studies designed to produce a pharmacologic effect, up to five compounds can be studied.
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The compounds must have a common drug target, but do not necessarily have to be structurally related. Healthy volunteers or minimally ill patients may receive up to 7 repeated doses in the clinic. The goal is to achieve a pharmacologic response but not define the MTD. Preclinical safety requirements are greater compared to microdosing studies. Fourteen-day repeat toxicology studies are required and conducted in rodents i. In addition, a full safety pharmacology battery, as described by ICH S7a, is required. In other words, untoward pharmacologic effects on the cardiovascular, respiratory, and central nervous systems are characterized prior to Phase 0.
In addition, genotoxicity studies employing bacterial mutation and micronucleus assays are required. In addition to the day rodent toxicology study, a repeat dose study in a non-rodent specie typically dog is conducted at the rat NOAEL dose. The duration of the non-rodent repeat dose study is equivalent to the duration of dosing planned for the Phase 0 trial. If toxicity is observed in the non-rodent specie at the rat NOAEL, the chemical lead candidate will not proceed to Phase 0.
Dose escalation in these studies is terminated when: Early phase clinical trials with terminally ill patients without therapeutic options, involving potentially promising drugs for life threatening diseases, may be studied under limited e. As with the Phase 0 strategies described above, it is imperative that this approach be defined in partnership with the FDA prior to implementation. The reduced preclinical safety requirements are scaled to the goals, duration and scope of Phase 0 studies.
Phase 0 strategies have merit when the initial clinical experience is not driven by toxicity, when pharmacokinetics are a primary determinant in selection from a group of chemical lead candidates and a bioanalytical method is available to quantify drug concentrations at microdoses , when pharmacodynamic endpoints in surrogate e.
The authors concluded that the merits of exploratory INDs continue to be debated, however, this approach provides a valuable option to advancing drugs to the clinic. There are limitations to the exploratory IND approach. Doses employed in Phase 0 studies might not be predictive of doses over the human dose range up to the maximum tolerated dose. Phase 0 studies in patients raises ethical issues compared to conventional Phase I, in that escalation into a pharmacologically active dose range might not be possible under the exploratory IND guidance.
Perhaps one of the most compelling arguments for employing an exploratory IND strategy is in the context of characterizing tissue distribution e. Development programs for cancer drugs are often much more complex as compared to drugs used to treat many other indications. This complexity often results in extended development and approval timelines. In addition, oncology patient populations are often much smaller by comparison to other more prevalent indications. To help manage and expedite the commercialization of drugs used to treat rare diseases, including many cancers, the Orphan Drug Act was signed into law in This law provides incentives to help sponsors and investigators develop new therapies for diseases and conditions of less than , cases per year allowing for more realistic commercialization.
A sponsor, investigator, or an individual may apply for orphan drug designation prior to establishing an active clinical program or can apply at any stage of development e. If orphan drug designation is granted, clinical studies to support the proposed indication are required.
A drug is not given orphan drug status and, thus marketing exclusivity, until the FDA approves a marketing application. Orphan drug status is granted to the first sponsor to obtain FDA approval and not necessarily the sponsor originally submitting the orphan drug designation request. There is no formal application for an orphan drug designation. However, the regulations e. The orphan drug designation request generally includes:.
The official response will typically be provided within 1 to 3 months following submission. Upon notification of granting an orphan drug designation, the name of the sponsor and the proposed rare disease or condition will be published in the federal register as part of public record. The complete orphan drug designation request is placed in the public domain once the drug has received marketing approval in accordance with the Freedom of Information Act. Finally, the sponsor of an orphan designated drug must provide annual updates that contain a brief summary of any ongoing or completed nonclinical or clinical studies, a description of the investigational plan for the coming year, any anticipated difficulties in development, testing, and marketing, and a brief discussion of any changes that may affect the orphan drug status of the product.
While many authors have described the general guidelines for drug development 4,5, etc. It is well known that the propensity for late stage failures has lead to a dramatic increase in the overall cost of drug development over the last 15 years. It is also commonly accepted that the best way to prevent late stage failures is by increasing scientific rigor in the discovery, preclinical, and early clinical stages. Where many authors present drug discovery as a single monolithic process, we intend to reflect here that there are multiple decision points contained within this process.
An alternative approach is the exploratory IND Phase 0 under which the endpoint is proof of principle demonstration of target inhibition 6. This potentially paradigm-shifting approach might dramatically improve the probability of late stage success and may offer additional opportunities for academic medical centers to become involved in drug discovery and development.
Behind each Decision Point are detailed decision-making criteria defined in detail later in this chapter. Any altered, transformed, or adapted form of the work may only be distributed under the same or similar license to this one. Turn recording back on. National Center for Biotechnology Information , U. Early Drug Discovery and Development Guidelines: Abstract Setting up drug discovery and development programs in academic, non-profit and other life science research companies requires careful planning. Background Medical innovation in America today calls for new collaboration models that span government, academia, industry and disease philanthropy.
Purpose The purpose of this chapter is to define: Three practical drug discovery and early development paths to advancing new cancer therapies to early stage clinical trials, including:. Within each of the three strategies, decision points have been identified along the commercial value chain and the following concepts have been addressed:. Key data required at each decision point, targets and expectations required to support further development.
Opportunities available to outsource activities to optimally leverage strengths within the institution. Integration of these activities with the intellectual property management process potential decision points which:. Offer opportunities to initiate meaningful discussions with regulatory agencies to define requirements for advancement of new cancer therapies to human evaluation.
Afford opportunities to license technologies to university start-up, biotechnology and major pharmaceutical companies. Define potential role s the National Institutes of Health SBIR programs may play in advancing new cancer therapies along the drug discovery and early development path. Definitions At Risk Initiation — The decision by the project team to begin activities that do not directly support the next unmet decision point, but will instead support a subsequent decision point.
Decision Point 1 - Target Identification Target-based drug discovery begins with identifying the function of a possible therapeutic target and its role in the disease 2. Previously published peer-reviewed data on a particular disease target pathway or target, OR. Target Identification and Target Validation. Decision Point 2 - Target Validation Target validation requires a demonstration that a molecular target is directly involved in a disease process, and that modulation of the target is likely to have a therapeutic effect 2. Known molecules modulate the target.
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Type of target has a history of success e. Ion channel, GCPR, nuclear receptor, transcription factor, cell cycle, enzyme, etc.
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Decision Point 3 - Identification of Actives An active is defined as a molecule that shows significant biological activity in a validated screening assay that represents the disease biology and physiology. Acquisition of screening reagents. Primary HTS assay development and validation. Decision Point 5 - Identification of Chemical Lead A chemical lead is defined as a synthetically feasible, stable, and drug-like molecule active in primary and secondary assays with acceptable specificity and selectivity for the target.
Characteristics of a chemical lead are: Identification of a Chemical Lead. Acceptable in vivo PK and toxicity.
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Selection of an Optimized Chemical Lead. Decision Point 7 - Selection of a Development Candidate A development candidate is a molecule for which the intent is to begin Phase I evaluation. The following criteria should be minimally met for a development candidate: Acceptable PK with a validated bioanalytical method.
Selection of a Development Candidate. Decision Point 8 - Pre-IND Meeting with the FDA Pre-IND advice from the FDA may be requested for issues related to the data needed to support the rationale for testing a drug in humans; the design of nonclinical pharmacology, toxicology, and drug activity studies, including design and potential uses of any proposed treatment studies in animal models; data requirements for an IND application; initial drug development plans, and regulatory requirements for demonstrating safety and efficacy 1.
Pre-IND preparation will require the following: The book is highly recommended to all process chemists. An Industrial Perspective Matthew L. Added to Your Shopping Cart. Description This book focuses on the drug discovery and development applications of transition metal catalyzed processes, which can efficiently create preclinical and clinical drug candidates as well as marketed drugs.
The authors pay particular attention to the challenges of transitioning academically-developed reactions into scalable industrial processes. Additionally, the book lays the groundwork for how continued development of transition metal catalyzed processes can deliver new drug candidates. Attrition in the Pharmaceutical Industry. Success in Academic Surgery: Translating Molecules into Medicines. Molecular Pathology in Cancer Research. Progress in Medicinal Chemistry. Microarrays in Diagnostics and Biomarker Development.
Safety Evaluation of Pharmaceuticals and Medical Devices. New Approaches to Drug Discovery. From Morphological Imaging to Molecular Targeting. Genotoxicity and Carcinogenicity Testing of Pharmaceuticals. Global Approach in Safety Testing. Jan Willem van der Laan. Metabolic Phenotyping in Personalized and Public Healthcare. Cancer Systems Biology, Bioinformatics and Medicine.
Textbook of Personalized Medicine. Drugs in Palliative Care. Predictive Toxicology in Drug Safety.
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