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Drug development (an overview)

45 important questions on Drug development (an overview)

What are the total costs of a drug development?

10-13 years from idea to marketable drug and the financial costs for these years are 650-1300 million dollars. Therefore most companies try to do the preclinical work and sell the clinical work to bigger companies.

What are the top 5 big pharma's in 2013?

1) Johnson and Johnson
2) Pfizer
3) Novartis
4) Roche
5) Sanofi

In what kind of area are most drugs developed?

oncology.

The costs to develop a single new drug increased the last decades.

How does the circular model of drug development go?

1) mechanism of disease: pathophysiology + target finding
2) Drug discovery: lead finding+ mechanisms of action
3) Characterization: toxicological evaluation
4) Formulation: Large-scale production + clinical trials + registration
5) Use: economical evaluation+ safety + side effects+ drug utilisation studies

Which terms play a role during the first phase of the preclinical stage (Drug discovery)?

- (Molc.) Pathology
- Pathophysiology
- Pharmacochemistry
- Pharmacodynamics
plus molecular cell biology, molecular biology

Which areas are involved in the target ID?

- It combines bioinformatics, proteomics, genomics, disease models, internal assays, and literature searches.
- It integrates basic therapeutic research, basic test and assay methodologies, informatic tools and models.
- It is strongly influenced by corporate business policy as to which disease areas represent the best return on investment for research and development.

How is a target found?

via:
- genomics ( which genes are involved in a given disease)
- proteomics (which proteins are involved)
- 3d structure receptor
- is there a clear difference between patients and healthy persons?

Nowadays it is more focused on genomics compared to earlier days.

How is a target selected?

1) Human genes
2) The disease is found with DNA arrays. (involved proteins are characterized)
3) An animal model is found (this is not always as easy as it sounds)
4) Therapeutic targets

What is target based screening? ( in sillico and in vitro)

An insillico targeted screen:
There is a known target protein structure from a virtual chemical library, After computational docking analysis a predicted target inhibitor is found.

An in vitro enzyme based screen:
There is purified targeted enzyme together with a chemical library. During an in vitro enzyme inhibition assay an identified target inhibitor is found.

What is phenotypic screening?

Often animals like the zebrafish are used for it.
Compounds are sreened in in vitro or in vivo models to identify the compound. Basically, it is just, waiting and see what happened,

First in class drugs are mostly based on...

1: target based or system based
2) target based can be diveded into small molecules or biologics
3) system based can be diveded into chemocentric approaches and phenotypic screening.

Other possibilities are also possible.

What is a chemocentric approach?

- Identification of an active ingredient from a plant or microbial extract with known pharmacological activity.
- The derivatization of a pharmacological active natural product.
- synthetic chemical often based on random findings made decades before.

Which discoveries were used for first-in-class medicines during 1999 and 2008?

1) phenotypic screening: consist of random findings (memantine and intentional targeting (daptomycine) of specific phenotypes.
2) synthetic natural substances (verteporfin)
3) biologicals (vb. cetuximab)
4) Target based screening (aliskiren)

What is the definition of a hit compound?

It is a small molecule that serves as the starting point for developing a lead compound and shows some desired pharmaceutical activity but could nog used as therapeutic agent.

What is the definition of a lead compound?

It is the first drug (prototype) in the class and shows desired pharmaceutical activity. The level of activity may not be very great and there may be undesirable side effects, but the lead provides a start for drug development process.

How is a lead compound being found?

- There are syntheses and pharmacological screening for 100000 compounds a year.
- Syntheses are focused on: quantitative structure activity relationship (QSAR), analogs of receptor ligands, variations of known structures, analogs of endogenous compounds.
- It is performed by combinatorial chemistry.

What is combinatorial chemistry?

The synthesis of chemical compounds libraries and the screening of those libraries for compounds with desirable properties.
It is a technique invited in the late 1980's and 1990's.
it's a fast route.

How occurs pharmacological screening?

- via HTS
- with animal models
- with tissue cultures
- organ models
- biotechnology receptor models
- primary toxicology screening

What is high throughput screening?

In the beginning it starts with 10^7 different compounds. Via filtering 10^5 remain due to Lipinski rules, chemical feasibility etc. Via high througput screens 10^2 compounds remain. The active compounds are validated and 10 hit compounds remain. Due to screening and profiling up to 3 leads remain.

Which factors play a role in the development of dosage forms?

- biopharmaceutics
- route of administration (ADME)
- pharmacological properties
- desied plasma profile -> dose
- process development
- packaging, stability

quality control occurs via validated analytical methods.

When 3 lead compounds are obtained, how does the drug development go further?

The 3 leads are evaluated. The preclinical development starts in which only 1 compounds remains due to the best pharmacokinetic and pharmacodynamic characteristics.

How is a lead compound optimized?

It occurs in depth understanding and insight into the mode of action of new lead.
- modification of the active site of the molecule occurs to improve the balance of therapeutic effects and side effects.
- The results are a new compound for further development and a back-up compound for if the development of the first compound is stopped.

What things are special in the preclinical development?

- synthetic route of development
- salt selection studies
- development of analytical methods

drafting specifications
- chemical and physical properties
--purity
-- contaminations
-- crystal form

production of drug for toxicity

What is the aim (and the characteristics) of the pharmacological toxicology studies?

- demonstration of the safety of the new compound and its metabolites
- the extrapolation to man is very important
- Approximately 30 guidelines
- Usually two species (rodent and non-rodent)
- 14 days to 6 months of drug dosing

What are the advantages of toxicokinetics in animal safety studies?

- supports interpretation of repeated dose toxicity studies
- proof of absorption and exposure time
- Determination of exposure-effect relationship rather than dose-effect relationship
- Interpretation of quantitative differences in toxicity between species
- establishing dosages for humans in clinical phase 1

Which three kind of characteristics are mandatory to be tested in animal studies?

- reproduction
- short term
- long term

What things are necessary to develop a formulation of a drug?

- route of administration
- pharmacokinetics
- stability
- production process
- packaging

What is the investigational new drug application (IND)?

It is a formal process by which a sponsor requests approval to start with clinical trials.
It includes information of the preclinical phase regarding safety and effectiveness
It includes an investigational brochure for clinicians who are conducting a trial.
It includes a national regulatory evaluate (where will the clinical trials take place.

What were the consequences of the softenon scandal?

- More sensitive safety testing
- Intensifying the extent of preclinical testing
- A strengthening of drug regulatory bodies (FDA,EMA, CBG)

What is the international conference on Harmonisation (ICH)?

Within this organ all the drug regulatory bodies harmonize on various guidelines for the registration of drugs.

What are topics and guidelines of the ICH?

Q = quality
S = safety
E = efficacy
M = multidisciplinary

Think about carcinogenicity, genotoxicity, toxicokinetics for S

What is good laboratory practice?

GLP. In the early 70t's there was a lack of scientific integrity and quality. therefore in the late 70's GLP was introduced. It was about:
- to demonstrate the validity of the results
- To ensure that the quality of the results is under control
- To keep procedures for identification, collection, indexing, access, storage, maintenance, and disposal of all significant/ important records.
- The records for each analysis shall contain sufficient information.
- Traceability

What is characteristic for a phase 1 clinical study

- The aim is to determine what the drug's most frequent side effects are and often, to determine how the drug is absorbed, distributed and excreted.
- Usually only healthy volunteers are involved.
- The number of participants is 20- 80
- costs are about 10 million dollars

What kind of studies are carried out in phase 1?

- Single rising dose
- Multiple rising dose
- IV/ PO (orally) study

What is monitored during phase 1?

- screening patho/ physiological parameters
- toxicokinetics and ADME
- Sometimes effect meassurements
- biomarkers

What is the aim of phase 2?

In contrary to phase 1, phase 2 is more focused on effectiveness rather than safety.
The aim is then to obtain preliminary data on whether the drug works in people who have a specific disease or condition

What are characteristics of phase 2?

- placebo controlled. (placebo or other drug)
- safety continues to be evaluated and short-term side effects are studied.
- the number of subjects ranges from a few dozen to about 300

How is the distinction in phase 2 visible?

phase 2a: study in limited group of patients to determine the indication and the corresponding dose regmens.
phase 2b: Evidence of clinical efficacy of the disease indications and final dosage selection

What are other things that are central during phase 2 of the clinical development?

- process development
- upscaling
- Validation
- technical transfer

What are characteristics of phase 3?

- are usually placebo-controlled
- gather more information about safety and effectiveness
- may test different dosages
- may test the drug in different populations
- usually include several hundred to about 3000 subjects
- are often multi-centre trials

What are the considerations during phase 3?

- There are 3 positive studies needed (often more)
- it has to be compared to competitors
- are the clinical parameters relevant?
- big scale statistics, epidemiology
- extreme costs (100 euro untill 150 million euro for each study)

How are toxicity studies divided in the drug development?

During preclinical development more exploratory (Non GLP) studies are performed.
During clinical development more regulatory GLP studies are performed.

What is the duration of repeated dose toxicity studies in rodent and non-rodent studies?

It varies in rodent studies between 2 weeks and 6 months. In non-rodents it varies between 2 weeks and 9 months.

How are the authorizations convinced?

The registration file has to convey:
- The medicine is safe
- It is (more) effective
- We can produce it with good and constant quality

What does the registration file to FDA or EMA contain?

- All toxicological and pharmacological outcomes
- clinical documentation
- summary
- pharmaceutical documentation

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Drug development

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