Early drug development strategies and routes to first in human trials pdf

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A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing.

In the fields of medicine , biotechnology and pharmacology , drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by serendipitous discovery, as with penicillin. More recently, chemical libraries of synthetic small molecules , natural products or extracts were screened in intact cells or whole organisms to identify substances that had a desirable therapeutic effect in a process known as classical pharmacology. After sequencing of the human genome allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease-modifying in a process known as reverse pharmacology.

Early Drug Development: Strategies and Routes to First-in-Human Trials

Metrics details. Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials.

Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns.

One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials.

Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines.

A wide range of commercial and government contract options are available for investigators seeking to advance their candidate s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot Program provide funding and services to assist applicants in preparing the preclinical programs and documentation for their drugs.

Increasingly, private foundations are also funding preclinical work. Close interaction with the FDA, including a meeting to prepare for submission of an Investigational New Drug application, is critical to ensure that the preclinical development package properly supports the planned phase I clinical trial.

The drug development process is typically divided into three major steps: discovery, preclinical development, and clinical trial. The transition from discovery to preclinical development is a continuum, and results of preliminary pharmacology and toxicology testing often contribute to lead drug candidate selection.

The boundary between preclinical development and clinical trial is sharply defined by the filing of an Investigational New Drug IND; Table 1 lists preclinical development acronyms application, which is required prior to initiation of the clinical trial. The activities supporting an IND application are the subject of this overview. The adage 'begin with the end in mind' is particularly appropriate for preclinical development, as the resulting IND must support the planned clinical trial design.

For example, a clinical trial involving daily chronic administration requires repeat-dose toxicity studies in preclinical animal models. These activities are seldom discrete and sequential; rather, they are interrelated and often concurrent, with results from each activity informing the other steps as the drug candidate progresses through characterization and optimization Figure 2.

Preclinical drug development stages. Following identification of a drug target and candidate compounds, several early activities, such as pharmacology, in vivo efficacy, and experimental toxicology, can contribute to the selection of a lead candidate for preclinical development. Preclinical flow diagram. The parallel and inter-related activities contributing to preclinical development are summarized with color coding to denote related components: manufacturing red , analytical grey , documentation orange , safety blue , clinical green.

Stephen Covey's advice to 'begin with the end in mind' from his bestseller The 7 Habits of Highly Effective People [ 1 ] is also applicable to drug development. Many project development teams find it helpful to develop a target product profile TPP to guide preclinical development. The TPP is a useful tool for delineating the required as well as desired features of the new drug product, critical milestones, and metrics to success.

The TPP provides a framework to ensure that the preclinical development program supports the intended clinical trial design and therapeutic use [ 2 ]. The contents of a TPP may vary from compound to compound and from team to team, but each profile generally includes therapeutic indication s ; market size, competition, and differentiators; expected clinical use, including key trial endpoints; drug target and mechanism of action; patient age range; dose route, form, and frequency of administration; bioavailability and duration of action; safety, precautions, and contraindications; chemistry, manufacturing, and controls CMC profile, including solubility, manufacturing process, formulation, storage conditions, and stability; patent status and any modifiers of exclusivity for example, orphan drug status.

In the case of chronic neurodegenerative diseases such as Alzheimer's disease, the unique medical needs of elderly patients have the potential to affect several aspects of drug design. Alleviation of Alzheimer's disease will most likely require long-term treatment and, therefore, the preclinical toxicology program must include repeat-dose administration to mimic the dosing regimen expected in the clinic.

Since Alzheimer's patients are generally well past child-bearing age, some delay in safety testing for genetic and reproductive toxicity potential is permitted. On the other hand, it may be important to evaluate the potential for drug-drug interaction much earlier in the drug development program since many elderly patients are likely to be prescribed medications to manage blood pressure, cardiovascular diseases, metabolic and digestive disorders, joint inflammation, diabetes, and other conditions associated with aging.

Project teams may select a route and frequency of dose administration that is optimal for compliance in elderly Alzheimer's disease patients. Many drugs targeting neurodegeneration such as Alzheimer's disease will need to cross the blood brain barrier to access the cellular target. Depending on the cellular mechanism, bioavailability, particularly to the brain, at or above a selected target concentration may be another required feature delineated in the TPP.

The TPP document continues to evolve as the drug development program progresses, and it should be regularly reviewed by the team to assess whether required goals are being met.

Any results indicating potential safety concerns or the inability of a given new chemical entity to fulfill stated TPP criteria should be evaluated by the team for their potential impact on project success. The prelude to IND-enabling preclinical development generally includes efficacy, pharmacology, and experimental toxicology studies to define the dose, route, and frequency required for subsequent studies. Using one or more pharmacological animal models of the disease, the initial efficacy studies demonstrate that treatment with drug candidates has the desired therapeutic effect.

Efficacy studies also help to identify the best drug candidates for further development. A number of studies are used to address the absorption, distribution, metabolism, and excretion ADME characteristics of the drug. Bioavailability studies are generally conducted in vivo on candidates intended to be administered by a nonintravenous route. Bioavailability results provide information on the percentage of drug that is absorbed by the body as defined by quantity in plasma.

Pharmacokinetics PK studies provide information on the maximum attainable plasma concentration c max , the time after dose administration to c max t max , the mean residence time in the plasma, clearance, and other information used to characterize the body's effect on the drug. Initial dose range-finding and toxicity studies include single- and multiple-dose administration protocols with varied observation times. These earliest studies are intended to determine the maximum tolerated dose MTD , identify observable signs of toxicity, and provide a rationale for setting dose levels in more complex definitive studies.

Regulatory requirements almost always call for definitive studies in at least two laboratory animal species, one rodent rat or mouse and one nonrodent rabbit, dog, nonhuman primate, or other suitable species. Preliminary toxicity, bioavailability, and PK studies should also include one or more rodent and nonrodent species, including the species to be used in the definitive studies. The group sizes for the early range-finding studies may consist of only a few animals and one sex one animal per dose level.

Once a suitable dose range is identified, group sizes are increased to at least three per sex per dose level to allow for statistical comparisons. Only a few endpoints are collected in these range-finding studies unless there are particular toxicity concerns; a larger number of required endpoints will be evaluated in the eventual definitive studies described below.

Although scientific and reporting integrity is expected for any study, quality assurance audit and review are rarely required for bioavailability, PK, and range-finding studies. According to the FDA guidance, both of these designations refer to 'any substance or mixture of substances intended to be used in the manufacture of a drug medicinal product and that, when used in the production of a drug, becomes an active ingredient of the drug product.

Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body. Ultimately, the API must be well characterized in terms of structure identity crystalline or polymorphic , counter ions salts and co-crystals, impurities, stability, chirality and enantiomer s , appearance, solubility, and other chemical and physical properties.

All preclinical drug development programs require an adequate drug supply. As development progresses, increasing quantities of higher quality APIs are required for small non-good laboratory practice non-GLP efficacy studies, early formulation activities, in vivo dose range-finding studies, and finally rigorous IND-enabling GLP toxicology studies. For small molecule drugs, milligram quantities of research grade material are usually suitable for early stage in vivo efficacy and ADME studies, as well as small PK and dose range-finding studies the latter may require gram quantities.

When a molecular entity is selected, preformulation activities commence to determine its physical and chemical properties, including counter ion salt or polymorphic form, solubility, and stability. The outcome of this stage is a recommended form, and the API portion of the project will transition to issues surrounding reaction efficiency, cost of goods, purity and control of impurities, and batch-to-batch consistency.

In most cases the original medicinal chemistry reaction must be refined to improve availability of common starting materials and reaction reproducibility and scalability to maximize both product consistency and yield for each batch. As each batch is scaled up to produce greater quantities grams to kilograms , the analytical control assays will require more stringent tolerance limits. Eventually these synthetic steps, along with control documentation, will be written into the master batch record and included in the IND package in the CMC section.

In addition, API stability and degradation, including identity of major degradation products, will be evaluated for a variety of storage conditions and documented in the CMC section.

These latter steps fall under GMP guidance and are beyond the capabilities of most investigative research laboratories. At some point in the process, the investigator may opt to transfer the synthetic process along with appropriate legal intellectual property documentation to a specialized contract research organization CRO that will produce required batches along with a Certificate of Analysis or GMP release for each batch.

Drug formulation, the mixing of API with other chemical ingredients to create the drug product DP , is often a major hurdle in drug development. At this stage, the route of administration intended for the clinic should be clearly identified.

Drugs may be introduced either enterally oral, buccal, and rectal or parenterally not through the alimentary canal including by injectable routes intravenous, intramuscular, and subcutaneous , topically, and by inhalation.

Except for imaging diagnostic agents, vaccines, and antibodies, most drugs targeting neurodegenerative diseases and their symptoms will be administered by the enteral or possibly topical routes. Drugs intended to be administered orally may be formulated as a solution, suspension, capsule, or tablet.

Any formulation intended for human use is subject to rigorous quality control manufacturing and safety testing. In addition to the clinical application, the specific physicochemical properties of a DS will influence formulation options. A number of parameters must be considered when creating the DP formulation. The components of any formulation must have physical and chemical compatibility with the DS. Formulations may incorporate components such as dissociation enhancers that are found to improve bioavailability of the active DS.

Solid formulations, particularly tablets, may be coated to improve swallowing, mask an unpleasant taste, protect ingredients during storage, improve appearance, and control drug release over time or target it to specific regions of the gastrointestinal tract.

In most instances, the clinical drug formulation is not fully optimized before submission of the IND and the initial first-in-human FIH clinical studies.

Therefore, it is customary to compose a simple formulation to be presented as the DP in the IND and used in phase1 studies to deliver the drug to human subjects. For example, an oral FIH trial design may utilize drug supplied as a powder; an appropriate quantity is weighed out by the pharmacist and placed in a gelatin capsule prior to administration.

For both oral and intravenous FIH trial designs, a specific amount of drug may be supplied in a clinical vial also known as powder in bottle, or PIB to which the appropriate volume of vehicle specific liquid component is added prior to administration. These approaches are most useful for early phase 1 trials involving relatively few human subjects.

As the clinical trials become more complex and involve more subjects, oral formulations may be prepared in tablets or capsules containing scaled quantities, or 'strengths,' of the drug for example, 50 mg, mg, and mg so that each patient can take a combination of quantities to target individual body weight.

Once the unit dose is established usually after phase 2 and before phase 3 clinical trials , a formulation is selected as the final DP for later stage clinical trials and product release. As described above for APIs, all formulations intended for human use are prepared under rigorous specifications as outlined in the GMP guidelines. Starting from the initial drug discovery phase, analytical chemistry applications are found throughout the drug development process.

These applications can be categorized into two major subdivisions: pharmaceutical analysis and bioanalysis. Pharmaceutical analysis involves the measurement of an analyte in a neat sample or formulation, whereas bioanalysis is the quantification of an analyte in a biological matrix. Reliable analytical methods are required to test and qualify in-coming materials, in-process methods, equipment, formulations, DSs, and DPs.

These methods are critical for analyzing the various formulations that may be investigated for a final dosage form and are integral to quality control in GLP and GMP settings. Therefore, analytical methods may need to be developed for a variety of materials and circumstances, each with a different intended purpose. For example, the analytical method required for formulation development may not require the same performance characteristics as those required for a stability-indicating method for DS or DP.

The research and development component includes analytical method development and analytical support for preformulation and formulation. The quality control unit is responsible for the oversight of GMP analytical work. It is essential that the validated methodology used to test the DS be used in clinical manufacturing. The developed method must satisfy two requirements: it must be accurate, requiring high specificity, good precision, and good reproducibility; and it should be practical, with the necessary ruggedness, sensitivity, and linearity.

Assay methods are verified under the ICH guidelines for reproducibility, specificity, selectivity, accuracy, linearity, precision, applicable concentration range, limit of detection, limit of quantification, ruggedness, and robustness. The specifications for DS typically include a physiochemical characterization program that generally requires determination of the composition, physical properties, and primary structure of the desired product.

Drug Discovery and Development Process

Metrics details. Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties.

The basics of preclinical drug development for neurodegenerative disease indications

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Combined integrated protocol/basket trial design for a first-in-human trial.


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