Medical innovation in America today calls for new collaboration models that span government, academia, industry and disease philanthropy. Barriers to translation and ultimate commercialization will be lowered by bringing best practices from industry into academic settings, and not only by training a new generation of 'translational' scientists prepared to move a therapeutic idea forward into proof of concept in humans, but also by developing a new cadre of investigators skilled in regulatory science.

As universities begin to focus on commercializing research, there is an evolving paradigm for drug discovery and early development focused innovation within the academic enterprise. The innovation process -- moving from basic research to invention and to commercialization and application -- will remain a complex and costly journey. New funding mechanisms, the importance of collaborations within and among institutions, the essential underpinnings of public-private partnerships that involve some or all sectors, the focus of the new field of regulatory science, and new appropriate bridges between federal health and regulatory agencies all come to bear in this endeavor.

We developed these guidelines to assist academic researchers, collaborators and start-up companies in advancing new therapies from the discovery phase into early drug development, including evaluation of therapies in human and/or clinical proof of concept. This chapter outlines necessary steps required to identify and properly validate drug targets, define the utility of employing probes in the early discovery phase, medicinal chemistry, lead optimization, and preclinical proof of concept strategies, as well as address drug delivery needs through preclinical proof of concept. Once a development candidate has been identified, the guidelines provide an overview of human and/or clinical proof of concept enabling studies required by regulatory agencies prior to initiation of clinical trials. Additionally, the guidelines help to ensure quality project plans are developed and projects are advanced consistently. We also outline the expected intellectual property required at key decision points and the process by which decisions may be taken to move a project forward.

The purpose of this chapter is to define:

The scope of drug discovery and early drug development within the scope of these guidelines spans target identification through human (Phase I) and/or clinical (Phase IIa) proof of concept. This chapter describes an approach to drug discovery and development for the treatment, prevention, and control of cancer. The guidelines and decision points described herein may serve as the foundation for collaborative projects with other organizations in multiple therapeutic areas.

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. At Risk Initiation is sometimes recommended to decrease the overall development time.

Commercialization Point – In this context, the authors use the term to describe the point at which a commercial entity is involved to participate in the development of the drug product. This most commonly occurs through a direct licensing arrangement between the university and an organization with the resources to continue the development of the product.

Counter-screen – A screen performed in parallel with or after the primary screen. The assay used in the counter-screen is developed to identify compounds that have the potential to interfere with the assay used in the primary screen (the primary assay). Counter-screens can also be used to eliminate compounds that possess undesirable properties, for example, a counter-screen for cytotoxicity (1).

Cumulative Cost – This describes the total expenditure by the project team from project initiation to the point at which the project is either completed or terminated.

Decision Point¹ – The latest moment at which a predetermined course of action is initiated. Project advancement based on decision points balances the need to conserve scarce development resources with the requirement to develop the technology to a commercialization point as quickly as possible. Failure to meet the criteria listed for the following decision points will lead to a No Go recommendation.

False positive – Generally related to the ‘‘specificity’’ of an assay. In screening, a compound may be active in an assay but inactive toward the biological target of interest. For this chapter, this does not include activity due to spurious, non-reproducible activity (such as lint in a sample that causes light-scatter or spurious fluorescence and other detection related artifacts). Compound interference that is reproducible is a common cause of false positives, or target-independent activity (1).

Go Decision – The project conforms to key specifications and criteria and will continue to the next decision point.

High-Throughput Screen (HTS) – A large-scale automated experiment in which large libraries (collections) of compounds are tested for activity against a biological target or pathway. It can also be referred to as a “screen” for short (1).

Hits – A term for putative activity observed during the primary high-throughput screen, usually defined by percent activity relative to control compounds (1).

Chemical Lead Compound – A member of a biologically and pharmacologically active compound series with desired potency, selectivity, pharmacokinetic, pharmacodynamic and toxicity properties that can advance to IND-enabling studies for clinical candidate selection.

Incremental Cost – A term used to describe the additional cost of activities that support decision criteria for any given decision point, independent of other activities that may have been completed or initiated to support decision criteria for any other decision point.

Library – A collection of compounds that meet the criteria for screening against disease targets or pathways of interest (1).

New Chemical Entity (NCE) – A molecule emerging from the discovery process that has not previously been evaluated in clinical trials.

No Go Decision – The project does not conform to key specifications and criteria and will not continue.

Off-Target Activity – Compound activity that is not directed toward the biological target of interest but can give a positive read-out, and thus can be classified as an active in the assay (1).

Orthogonal Assay – An assay performed following (or in parallel to) the primary assay to differentiate between compounds that generate false positives from those compounds that are genuinely active against the target (1).

Primary Assay – The assay used for the high-throughput screen (1).

Qualified Task – A task that should be considered, but not necessarily required to be completed at a suggested point in the project plan. The decision is usually guided by factors outside the scope of this chapter. Such tasks will be denoted in this chapter by enclosing the name of the tasks in parentheses in the Gantt chart, e.g. (qualified task).

Secondary Assay – An assay used to test the activity of compounds found active in the primary screen (and orthogonal assay) using robust assays of relevant biology. Ideally, these are of at least medium-throughput to allow establishment of structure-activity relationships between the primary and secondary assays and establish a biologically plausible mechanism of action (1).

The Gantt chart (Table 1) illustrates the scope of this chapter. The left-hand portion of the chart includes the name of each decision point as well as the incremental cost for the activities that support that task. The black bars on the right-hand portion of the chart represent the duration of the summary task (combined criteria) to support a decision point as well as the cumulative cost for the project at the completion of that activity. A similar layout applies to each of the subsequent figures; however, the intent of these figures is to articulate the activities that underlie each decision point.

The submission of regulatory documents, for the purpose of this example, reflects the preparation of an Investigational New Drug (IND) application in Common Technical Document (CTD) format. The CTD format is required for preparation of regulatory documents in Europe (according to the Investigational Medicinal Product Dossier [IMPD]), Canada for investigational applications (Clinical Trial Application) and is accepted by the United States Food and Drug Administration (FDA) for INDs. The CTD format is required for electronic CTD (eCTD) submissions. The advantages of the CTD are that it facilitates global harmonization and lays the foundation upon which the marketing application can be prepared. The sections of the CTD are prepared early in development (at the IND stage) and are then updated, as needed, until submission of the marketing application.

Drug repurposing and rediscovery development projects frequently seek to employ the 505(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 505(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 11.

Historically about 40% of NCEs identified as possessing promise for development, based on drug-like qualities, progress to evaluation in humans. Of those that do make it into clinical trials, about 9 out of 10 fail. In many cases, innovative drug delivery technology can provide a “second chance” for promising compounds that have consumed precious drug-discovery resources, but were abandoned in early clinical trials due to unfavorable side-effect profiles. As one analyst observed, “pharmaceutical companies are sitting on abandoned goldmines that should be reopened and excavated again using the previously underutilized or unavailable picks and shovels developed by the drug delivery industry” (SW Warburg Dillon Read). 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.g., through improvement in convenience, tolerability, safety, and/or efficacy); expand their use (e.g., through broader labeling in the same therapeutic area and/or increased patient acceptance/compliance); or transform them by enabling their suitability for use in other therapeutic areas. 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.

The plans outlined previously in these guidelines describe advancement of novel drugs as well as repurposed or reformulated, marketed drug products to human and/or clinical proof of concept trials using the traditional or conventional early drug development, IND approach. 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, 2005. Following a great deal of feedback from the public and private sectors, the final guidance was published in January, 2006.

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. Phase 0 studies are viewed by the FDA and National Cancer Institute (NCI) as important tools for accelerating novel drugs to the clinic. There is some flexibility in data requirements for an exploratory IND. These requirements are dependent on the goals of the investigation (e.g., receptor occupancy, pharmacokinetics, human biomarker validation), the clinical testing approach, and anticipated risks.

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 studies are broadly described as “microdosing” studies and clinical studies attempting to demonstrate a pharmacologic effect. 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. Doses are limited to less than 1/100th of the dose predicted (based on preclinical data) to produce a pharmacologic effect in humans, or a dose of less than 100 μg/subject, whichever is less. 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.g., 100x). 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. Exploratory IND workshops have discussed or proposed the allowance of up to five microdoses administered to each subject participating in an exploratory IND study, provided each dose does not exceed 1/100th the NOAEL or 1/100th of the anticipated pharmacologically active dose, or the total dose administered is less than 100 mcg, whichever is less. 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 2004, based on a retrospective analysis of 106 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.e., rats), with full clinical and histopathology evaluation. 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 14-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. The starting dose for Phase 0 studies is defined typically as 1/50th the rat NOAEL, based on a per meter squared basis. Dose escalation in these studies is terminated when: 1) a pharmacologic effect or target modulation is observed, 2) a dose equivalent (e.g., scaled to humans on a per meter squared basis) to one-fourth the rat NOAEL, or 3) human systemic exposure reflected as AUC reaches ½ the AUC observed in the rat or dog in the 14-day repeat toxicology studies, whichever is less.

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.g., up to 3 days dosing) conditions employing a facilitated IND strategy. 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.g., blood) or tumor tissue is of primary interest, or to assess PK/PD relationships (e.g., receptor occupancy studies employing PET scanning).

PhRMA conducted a pharmaceutical industry survey in 2007 to characterize the industry’s perspective on the current and future utility of exploratory IND studies (3). Of the 16 firms who provided survey responses, 56% indicated they had either executed or were planning to execute exploratory IND development strategies. 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. The Phase 0 strategy is designed to kill drugs early that are likely to fail based on PK or PK/PD. Should Phase 0 lead to a “Go” decision, however, a conventional IND is required for subsequent clinical trials, adding cost and time. Perhaps one of the most compelling arguments for employing an exploratory IND strategy is in the context of characterizing tissue distribution (e.g., receptor occupancy following PET studies) after microdosing.

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. These factors (e.g., limited patent life and smaller patient populations) often complicate commercialization strategies and can, ultimately, make it more difficult to provide patient access to important new therapies.

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 1983. This law provides incentives to help sponsors and investigators develop new therapies for diseases and conditions of less than 200,000 cases per year allowing for more realistic commercialization.

The specific incentives for orphan-designated drugs are as follows:

A sponsor may request orphan drug designation for:

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.g., Phase 1 – 3). 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.g., 21 CRF 316) identify the components to be included. An orphan drug designation request is typically a five- to ten-page document with appropriate literature references appended to support the prevalence statements of less than 200,000 cases/year. The orphan drug designation request generally includes:

Following receipt of the request, the FDA Office of Orphan Product Development (OOPD) will provide an acknowledgment of receipt of the orphan drug designation request. 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.), no one has outlined the process of developing drugs in an academic setting. 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.