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Stages of Drug Development Discovery

Stages of Drug Development Discovery

In this section, specific biological agents and devices will not be discussed, although a lot of the content applies to them because biological agents and devices are regulated in the same way as drugs. Biological agents are defined as substances made from living organisms. Examples of biological agents used in cancer care include antibodies, interleukins, and vaccines. Examples of devices used in cancer care include CT-scans, magnetic resonance imaging (MRIs), PET scans, surgical tools, and subcutaneous ports for intravenous access.

The content below focuses on drugs, but the model for devices and biologic is similar.

  • Target Identification
  • Lead Identification (find the best drug candidate)
  • Lead Optimization
  • Candidate Drug Nomination
  • New biological Information


Target Identification

The goal in the first stage of drug development is to identify a target for a potential therapy. Targets include some of the following components shown in this image that are involved in cancer development and proliferation. This ratio can change as new basic research is integrated into the drug development process.


Image courtesy of the Institute of Medicine, National Academies

The definition of "target" itself is something debated within the pharmaceutical industry, however, the distinction between a new and an established target can be made without a full understanding of just how a target is defined. This distinction is typically made by pharmaceutical companies engaged in discovery and development of small molecule therapeutics.

Established targets are those targets for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. Established targets relate directly to the amount of background information available on a target, in particular functional information.

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In general, new targets are all those targets that are not "established targets" but which have been or are presently the subject of drug discovery campaigns. These typically include newly discovered proteins, or proteins whose function has been revealed as a result of basic scientific research.


Lead Identification

The focus in the second stage is to identify a chemical or series of chemicals that will interact with the target and have the potential to impact the disease studied. After screening many compounds, researchers focus on whether or not the molecule binds to a target protein.

  • Attempt to confirm a target
  • Attempt to determine DNA and protein sequence
  • Attempt to elucidate structure and function of protein
  • Prove therapeutic concept in animals
  • Develop assay for high-throughput molecular screen
  • Mass screening and/or directed synthesis program
  • Select one or more lead structures

Every year pharmaceutical companies identify tens or hundreds of thousands of compounds that may be useful new drugs. The process of finding a new drug that affects a chosen target for a particular disease usually involves high-throughput screening (HTS), in which large libraries of chemicals are tested for their ability to modify the target. This process enables researchers to conduct millions of biochemical, genetic or pharmacological tests and rapidly identify those that modulate a particular biomolecular pathway.

These screening tests are usually simple binding assays (asking does the molecule bind to a target protein?). Testing is done in two stages: chemical similarity is important in both these stages

  • Lead Identification (find a compound that binds to the target)
  • Lead Optimization (find a compound that binds better)


Lead Optimization

When a "lead" has been identified, the next stage is to find compounds that are similar to it, that might bind even better (optimization). This can involve 'similarity searching' to find compounds previously made, or available commercially for purchase. To assess similarities, the following properties are analyzed: absorption, distribution, metabolism, excretion, toxicity (ADMET).

In later stages, medicinal chemists make specific changes to the lead compound, which they hope will improve its binding affinity. When testing a large number of compounds in order to identify a new "lead", it is best to have compounds that are as different from each other as possible.

Pharmaceutical companies purchase large numbers of compounds from third-party suppliers. They also synthesize combinatorial "libraries" of compounds. Chemical "diversity" is an important feature of such compound collections and libraries hoping to cover as much "chemical space" as possible.


Candidate Drug Nomination

The third stage of drug development is used to identify a candidate drug that meets most criteria and passes additional evaluations including safety assessment, pharmaceutical pre-formulation and process chemistry studies.


Fundamental Questions in Cancer Drug Development

1. Is this the right target?

Is the biological process targeted directly implicated in the development and progression of the disease?


2. Is this the right drug?

Does the new drug hit the target with sufficient potency to affect the underlying biology? Can this be measured in the laboratory and also in humans with the disease?


3. What is the right dose and schedule?

Can an optimal biological effect dose and schedule be defined based on the measurement of the target either directly or indirectly?


4. What is/are the right tumor(s)?

Has the new drug been tested in the right setting? What is the rationale for choosing a particular tumor as a target?


5. Issues in the development of Phase III clinical trials launch phase:

  • Phase III trials often require thousands of patients as participants
  • How to choose the appropriate drug to compare the new one too
    • Different treatment paradigms in different parts of the world
  • Choosing the appropriate endpoint
    • Clinical trials may take years to complete due to the choice of long term endpoints such as survival
  • The 'comparator' drug chosen may no longer be relevant by the time the trial is completed due to a rapidly changing environment.


6. Criteria for determining clinical benefit in oncology patients:

  • Should have direct effects on the disease
    • Overall survival is the most important, but there are also others such as:
    • Objective response rate (disease shrinks or disappears after treatment)
    • Duration of response
    • Time to progression
    • Disease-free survival
  • Should have effects on other clinical consequences of disease or treatment
    • Reduction in symptoms (e.g. pain, anorexia)
    • Reduction of treatment toxicities (e.g. nausea, vomiting, diarrhea, mucositis, fever, bleeding)
  • List of problems with many current drugs on the market:
  • Poor biopharmaceutical properties - 39%
  • Lack of efficacy - 29%
  • Toxicity - 21%
  • Market reasons - 6%
  • Other - 5%


The success rate of developing new drugs needs to be improved. The chart below shows some of the new technologies that may enable this to happen.

Criteria Old New
Patient Selection Histology Molecular Profile
Treatment High dose, intermittent Low dose, chronic
Endpoints Response, survival Same, with biomarker
Goal Disease eradication Diesease control


New biological Information

Pharmacogenomics - the branch of pharmacology which focuses on the influence of genetic variation on drug response in patients - offers great potential for identification of new targets for therapeutic intervention:

  • Genomic profiling of individual diseases will help identify many potential targets
  • Genomic profiling of individual diseases will help identify subgroups of patients that will benefit from a targeted therapy and others that may not - responders and non-responders.




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