Drug Discovery and Development - E-Book: Technology in Transition

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Senanayake Boehringer Ingelheim Pharmaceuticals. Szabo Consultant in Drug Development. Chung Merck and Matthew L. Crawley Main Line Health. 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 primary rate limit among the decision criteria is the determination of the safety margin, as this can be affected by the formulation and dosing strategies selected earlier.

In this case, the authors have presented a project that includes a 7-day repeat dose in rodents to demonstrate an acceptable safety margin. 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.

We recommend that this meeting take place after the initiation, but before the completion of tasks to support decision point 7 selection of a development candidate. The feedback from the FDA might necessitate adjustments to the project plan. Making these changes prior to candidate selection will save time and money. Pre-IND preparation will require the following:.

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The advancement criteria supporting decision point 8 should be completed in 12 months. We recommend preparing the pre-IND meeting request approximately 3 to 6 months prior to selection of a development candidate provided that the data supporting that decision point are promising. The decision to submit an IND application presupposes that all of the components of the application have been addressed. The following criteria should be addressed in addition to addressing comments from the pre-IND meeting:.

The advancement criteria supporting decision point 9 are estimated to be completed in 12 months, but might be compressed to as little as 6 months if necessary. Most successful Phase I trials in oncology require months for completion, due to very restrictive enrollment criteria in these studies in some cases. The most important factors in determining the length of a Phase I study are a logically written clinical protocol and an available patient population.

Proceeding to Phase II trials will depend on:. Our estimate is based on a 25 patient outpatient study completed in 18 months. This cost is largely dependent on the number of patients required and the number of centers involved. Our estimate is based on outpatients with studies completed in 24 months.

Drug repurposing and rediscovery development projects frequently seek to employ the b 2 drug development strategy. This strategy leverages studies conducted and data generated by the innovator firm that is available in the published literature, in product monographs, or product labeling. Improving the quality of drug development plans will reduce the time of b 2 development cycles, and reduce the time and effort required by the FDA during the NDA review process.

Drug repurposing projects seek a new indication in a different patient population and perhaps a different formulated drug product than what is currently described on the product label. By leveraging existing nonclinical data and clinical safety experience, sponsors have the opportunity to design and execute novel, innovative clinical trials to characterize safety and efficacy in a different patient population.

The decision points for drug repurposing are summarized in Table For drug repurposing, actives are identified as follows Table Hits are confirmed as follows for a drug repurposing project Table When considering the b 2 NDA approach, it is important to understand what information is available to support the proposed indication and what additional information might be needed. The development path is dependent upon the proposed indication, change in formulation, route, and dosing regimen. A thorough search of the literature is important in order to capture information available to satisfy the data requirements for the IND.

Any gaps identified would need to be filled with studies conducted by the sponsor. The clinical formulation development will include the following Table Based on this assessment, as well as the intended patient population, the types of studies that will be needed to support the clinical program will be determined. It is possible that a pharmacokinetic study evaluating exposure would be an appropriate bridge to the available data in the literature Table Clinical supplies will need to be manufactured.

The list below provides some of the considerations that need to be made for manufacturing clinical supplies Table Following the pre-IND meeting with the FDA, and conducting any additional studies, the IND is prepared in common technical document format to support the clinical protocol. The IND is prepared in 5 separate modules that include administrative information, summaries CMC, nonclinical, clinical , quality data CMC , nonclinical study reports and literature, and clinical study reports and literature Table 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.

Human proof of concept may commence following successful submission of an IND i. The list below provides some information concerning human proof of concept Table Of those that do make it into clinical trials, about 9 out of 10 fail. Although this statement was made more than 10 years ago, it continues to apply. Beyond enablement of new drugs, innovative approaches to drug delivery also hold potential to enhance marketed drugs e.

These opportunities contribute enormously to the potential for value creation in the drug delivery field. Table 20 summarizes the decision points for the development of drug delivery platform technology. See Table 21 for a schematic representation of the time and costs associated with development at this stage. Preparation of a development plan allows the sponsor to evaluate the available information regarding the compound of interest whether at the development stage or a previously marketed compound to understand what information might be available to support the proposed indication and what additional information may be needed.

The development plan that is prepared will take this information into account in order to determine what information or additional studies might be needed prior to submission of an IND and initiating first-in-man studies. A thorough search of the literature is important in order to capture available information to satisfy the data requirements for the IND.

See Table 23 for a schematic representation of the time and costs associated with development at this stage. Following the pre-IND meeting with the FDA and conducting any additional studies, the IND is prepared in common technical document format to support the clinical protocol. The IND is prepared in 5 separate modules, which include administrative information, summaries CMC, nonclinical, clinical , quality data CMC , nonclinical study reports and literature, and clinical study reports and literature.

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. 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. 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.

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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.

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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.

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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.

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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. Type of target has a history of success e.

Ion channel, GCPR, nuclear receptor, transcription factor, cell cycle, enzyme, etc. 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. 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: Prepare pre-IND meeting package, which includes adequate information for the FDA to address the specific questions clinical plan, safety assessments summary, CMC plan, etc. The following criteria should be addressed in addition to addressing comments from the pre-IND meeting: Decision Point 10 - Human Proof of Concept Most successful Phase I trials in oncology require months for completion, due to very restrictive enrollment criteria in these studies in some cases.