Wednesday, August 28, 2013
Ask2Pharma
Getting the Drug
Three main issues are involved in getting the drug to the market.
First, the drug has to be tested to ensure that it is not only safe and effective, but can be administered in a suitable fashion. This involves preclinical and clinical trials covering toxicity, drug metabolism, stability,
formulation, and pharmacological tests.
Second, there are the various patenting and legal issues.
Third, the drug has to be synthesized in ever-increasing quantities for testing and eventual manufacture. This is a field known as chemical and process development.
Preclinical and clinical trials
Toxicity testing
One of the first priorities for a new drug is to test if it has any toxicity.
This often starts with in vitro tests on genetically engineered cell cultures and/or in vivo testing on
transgenic mice to examine any effects on cell
reproduction, and to identify potential carcinogens. Any signs of carcinogenicity would prevent the drug being taken any further.
The drug is also tested for acute toxicity by administering sufficiently large doses in vivo to produce a toxic effect or death over a short period of time. Different animal species are used in the study and the animals are dissected to test whether particular organs are affected.
Further studies on acute toxicity then take place over a period of months, where the drug is administered to
laboratory animals at a dose level expected to cause toxicity but not death. Blood and urine samples are analysed over that period, and then the animals are killed such that tissues can be analysed by pathologists for any sign of cell damage or cancer.
Finally, long-term toxicology tests are carried out over a period of years at lower dose levels to test the drug for chronic toxic effects, carcinogenicity, special toxicology, mutagenicity, and reproduction abnormalities.
It should also be borne in mind that it is rare for a drug to be 100% pure. There are bound to be minor impurities present arising from the synthetic route used, and these may well have an influence on the toxicity of the drug.
The toxicity results of a drug prepared by one synthetic route may not be the same for the same drug
synthesized by a different route, and so it is important to establish the manufacturing synthesis as quickly as possible
Drug metabolism studies
The body has an arsenal of metabolic enzymes that can modify foreign chemicals, in such a way that they are
rapidly excreted.
The structure and stereochemistry of each metabolite has to be determined and the metabolite tested to see what sort of biological activity it might have. This is a safety issue, since some metabolites might prove toxic and others may have side effects that will affect the dose levels that can be used in clinical trials. Ideally, any metabolites that are formed should be inactive and
quickly excreted. However, it is quite likely that they will have some form of biological activity.
In order to carry out such studies, it is necessary to synthesize the drug, labeled with an isotope such as
deuterium (2H or D), carbon-13 (13C), tritium (3H or T), or carbon-14 (14C). This makes it easier to detect any metabolites that might be formed.
Once a labelled drug has been synthesized, a variety of in vitro and in vivo tests can be carried out. In vivo tests are carried out by administering the labeled drug to a test animal in the normal way, then taking blood and urine samples for analysis to see if any metabolites have been formed.
For radiolabeled drugs, this can be done by using high-performance liquid chromatography (HPLC) with a
radioactivity detector. It is important to choose the correct animal for these studies, since there are significant metabolic differences across different species. In vivo drug metabolism tests are also carried out as part of phase I clinical trials to see whether the drug is metabolized differently in humans from any of the test animals.
In vitro drug metabolism studies can also be carried out using perfused liver systems, liver microsomal fractions or pure enzymes. Many of the individual cytochrome P450 enzymes that are so important in drug metabolism are now commercially available.
Clinical trials
Usually, this will happen if the drug has the desired effect in animal tests, demonstrates a distinct
advantage over established therapies, and has acceptable pharmacokinetics, few metabolites, a reasonable half-life, and no serious side effects.
Clinical trials involve testing the drug on volunteers and patients, so the procedures involved must be ethical and beyond reproach. These trials can take 5-7 years to carry out, involve hundreds to thousands of patients, and be extremely expensive.
There are four phases of clinical trials.
Phase I studies
Phase I studies take about a year and involve 100-200 volunteers. They are carried out on healthy human
volunteers to provide a preliminary evaluation of the drug's safety, its pharmacokinetics and the dose levels that can be administered, but they are not intended to demonstrate whether the drug is effective or not.
Phase II studies
Phase II studies generally last about 2 years and may start before phase I studies are complete. They are carried out on patients to establish whether the drug has the therapeutic property claimed, to study the pharmacokinetics and short-term safety of the drug, and to define the best dose regimen.
Phase II trials can be divided into early and late studies (IIa and IIb respectively). Initial trials (phase IIa) involve a limited number of patients to see if the drug has any therapeutic value at all and to see if there are any obvious side effects. If the results are disappointing, clinical trials may be terminated at this stage.
Later studies (IIb) involve a larger numbers of patients. They are usually carried out as double-blind placebo- controlled studies. This means that the patients are split into two groups where one group receives the drug, and the other group receives a placebo. In a double-blind study neither the doctor nor the patient knows whether a placebo or drug is administered. Most phase II trials require 20-80 patients per dose group to demonstrate efficacy.
Phase III studies
Phase III studies normally take about 3 years and can be divided into phases IlIa and Illb.
These studies may begin before phase II studies are completed. The drug is tested in the same way as in phase II, using double-blind procedures, but on a much larger sample of patients. Patients taking the drug are compared with patients taking a placebo or another available treatment. Comparative studies of this sort must be carried out without bias and this is achieved by randomly selecting the patients—those who will receive the new drug and those who will receive the alternative treatment or placebo.
Nevertheless, there is always the possibility of a mismatch between the two groups with respect to factors such as age, race, sex, and disease severity, and so the greater the number of patients in the trial the better.
Phase IIIa studies establish whether the drug is really effective or whether any beneficial effects are
psychological. Any side effects not previously detected may be picked up with this larger sample of patients. If the drug succeeds in passing phase IIIa, it can be registered. Phase IIIb studies are carried out after registration, but before approval.
They involve a comparison of the drug with those drugs that are already established in the field.
Phase IV studies
The drug is now placed on the market and can be prescribed, but it is still monitored for effectiveness and for any rare or unexpected side effects. In a sense, this phase is a never-ending process as unexpected side effects may crop up many years after the introduction of the drug. For example, the beta-blocker practolol had to be withdrawn after several years of use because some patients suffered blindness and even death. The toxic effects were unpredictable and are still not understood, and so it has not been possible to develop a test for this effect.
Ethical issues
In phases I—III of clinical trials, the permission of the patient is mandatory. However, ethical problems can
still arise. For example, unconscious patients and mentally ill patients cannot give consent, but might benefit from the improved therapy. Should one include them or not? The ethical problem of including children in clinical trials is also a thorny issue, and so most clinical trials exclude them. This means that most licensed drugs have been licensed for adults, and that around 40% of medicines given to children have never actually been tested on children. When it comes to prescribing for children, clinicians are left with the problem of deciding what dose levels to use, and simple arithmetic mistakes made by tired health staff can have tragic consequences.
Furthermore, children are not small adults. It is not a simple matter of modifying dose levels based purely on the relative body weight of an adult and a child. The pharmacodynamic and pharmacokinetic properties of a drug are significantly different in a child compared with an adult. For example, drug metabolism varies considerably with the age and development of a child. Adverse side effects also differ.
First, the drug has to be tested to ensure that it is not only safe and effective, but can be administered in a suitable fashion. This involves preclinical and clinical trials covering toxicity, drug metabolism, stability,
formulation, and pharmacological tests.
Second, there are the various patenting and legal issues.
Third, the drug has to be synthesized in ever-increasing quantities for testing and eventual manufacture. This is a field known as chemical and process development.
Preclinical and clinical trials
Toxicity testing
One of the first priorities for a new drug is to test if it has any toxicity.
This often starts with in vitro tests on genetically engineered cell cultures and/or in vivo testing on
transgenic mice to examine any effects on cell
reproduction, and to identify potential carcinogens. Any signs of carcinogenicity would prevent the drug being taken any further.
The drug is also tested for acute toxicity by administering sufficiently large doses in vivo to produce a toxic effect or death over a short period of time. Different animal species are used in the study and the animals are dissected to test whether particular organs are affected.
Further studies on acute toxicity then take place over a period of months, where the drug is administered to
laboratory animals at a dose level expected to cause toxicity but not death. Blood and urine samples are analysed over that period, and then the animals are killed such that tissues can be analysed by pathologists for any sign of cell damage or cancer.
Finally, long-term toxicology tests are carried out over a period of years at lower dose levels to test the drug for chronic toxic effects, carcinogenicity, special toxicology, mutagenicity, and reproduction abnormalities.
It should also be borne in mind that it is rare for a drug to be 100% pure. There are bound to be minor impurities present arising from the synthetic route used, and these may well have an influence on the toxicity of the drug.
The toxicity results of a drug prepared by one synthetic route may not be the same for the same drug
synthesized by a different route, and so it is important to establish the manufacturing synthesis as quickly as possible
Drug metabolism studies
The body has an arsenal of metabolic enzymes that can modify foreign chemicals, in such a way that they are
rapidly excreted.
The structure and stereochemistry of each metabolite has to be determined and the metabolite tested to see what sort of biological activity it might have. This is a safety issue, since some metabolites might prove toxic and others may have side effects that will affect the dose levels that can be used in clinical trials. Ideally, any metabolites that are formed should be inactive and
quickly excreted. However, it is quite likely that they will have some form of biological activity.
In order to carry out such studies, it is necessary to synthesize the drug, labeled with an isotope such as
deuterium (2H or D), carbon-13 (13C), tritium (3H or T), or carbon-14 (14C). This makes it easier to detect any metabolites that might be formed.
Once a labelled drug has been synthesized, a variety of in vitro and in vivo tests can be carried out. In vivo tests are carried out by administering the labeled drug to a test animal in the normal way, then taking blood and urine samples for analysis to see if any metabolites have been formed.
For radiolabeled drugs, this can be done by using high-performance liquid chromatography (HPLC) with a
radioactivity detector. It is important to choose the correct animal for these studies, since there are significant metabolic differences across different species. In vivo drug metabolism tests are also carried out as part of phase I clinical trials to see whether the drug is metabolized differently in humans from any of the test animals.
In vitro drug metabolism studies can also be carried out using perfused liver systems, liver microsomal fractions or pure enzymes. Many of the individual cytochrome P450 enzymes that are so important in drug metabolism are now commercially available.
Clinical trials
Usually, this will happen if the drug has the desired effect in animal tests, demonstrates a distinct
advantage over established therapies, and has acceptable pharmacokinetics, few metabolites, a reasonable half-life, and no serious side effects.
Clinical trials involve testing the drug on volunteers and patients, so the procedures involved must be ethical and beyond reproach. These trials can take 5-7 years to carry out, involve hundreds to thousands of patients, and be extremely expensive.
There are four phases of clinical trials.
Phase I studies
Phase I studies take about a year and involve 100-200 volunteers. They are carried out on healthy human
volunteers to provide a preliminary evaluation of the drug's safety, its pharmacokinetics and the dose levels that can be administered, but they are not intended to demonstrate whether the drug is effective or not.
Phase II studies
Phase II studies generally last about 2 years and may start before phase I studies are complete. They are carried out on patients to establish whether the drug has the therapeutic property claimed, to study the pharmacokinetics and short-term safety of the drug, and to define the best dose regimen.
Phase II trials can be divided into early and late studies (IIa and IIb respectively). Initial trials (phase IIa) involve a limited number of patients to see if the drug has any therapeutic value at all and to see if there are any obvious side effects. If the results are disappointing, clinical trials may be terminated at this stage.
Later studies (IIb) involve a larger numbers of patients. They are usually carried out as double-blind placebo- controlled studies. This means that the patients are split into two groups where one group receives the drug, and the other group receives a placebo. In a double-blind study neither the doctor nor the patient knows whether a placebo or drug is administered. Most phase II trials require 20-80 patients per dose group to demonstrate efficacy.
Phase III studies
Phase III studies normally take about 3 years and can be divided into phases IlIa and Illb.
These studies may begin before phase II studies are completed. The drug is tested in the same way as in phase II, using double-blind procedures, but on a much larger sample of patients. Patients taking the drug are compared with patients taking a placebo or another available treatment. Comparative studies of this sort must be carried out without bias and this is achieved by randomly selecting the patients—those who will receive the new drug and those who will receive the alternative treatment or placebo.
Nevertheless, there is always the possibility of a mismatch between the two groups with respect to factors such as age, race, sex, and disease severity, and so the greater the number of patients in the trial the better.
Phase IIIa studies establish whether the drug is really effective or whether any beneficial effects are
psychological. Any side effects not previously detected may be picked up with this larger sample of patients. If the drug succeeds in passing phase IIIa, it can be registered. Phase IIIb studies are carried out after registration, but before approval.
They involve a comparison of the drug with those drugs that are already established in the field.
Phase IV studies
The drug is now placed on the market and can be prescribed, but it is still monitored for effectiveness and for any rare or unexpected side effects. In a sense, this phase is a never-ending process as unexpected side effects may crop up many years after the introduction of the drug. For example, the beta-blocker practolol had to be withdrawn after several years of use because some patients suffered blindness and even death. The toxic effects were unpredictable and are still not understood, and so it has not been possible to develop a test for this effect.
Ethical issues
In phases I—III of clinical trials, the permission of the patient is mandatory. However, ethical problems can
still arise. For example, unconscious patients and mentally ill patients cannot give consent, but might benefit from the improved therapy. Should one include them or not? The ethical problem of including children in clinical trials is also a thorny issue, and so most clinical trials exclude them. This means that most licensed drugs have been licensed for adults, and that around 40% of medicines given to children have never actually been tested on children. When it comes to prescribing for children, clinicians are left with the problem of deciding what dose levels to use, and simple arithmetic mistakes made by tired health staff can have tragic consequences.
Furthermore, children are not small adults. It is not a simple matter of modifying dose levels based purely on the relative body weight of an adult and a child. The pharmacodynamic and pharmacokinetic properties of a drug are significantly different in a child compared with an adult. For example, drug metabolism varies considerably with the age and development of a child. Adverse side effects also differ.
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