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Review Article

Role of pharmacogenomics in drug discovery and development

A. Surendiran, S.C. Pradhan, C. Adithan

ABSTRACT
Pharmacogenetics and pharmacogenomics are two major emerging trends in medical
sciences, which influence the success of drug development and therapeutics. In current
times, though pharmacogenetic studies are being done extensively for research, its
application for drug development needs to get started on a large scale. The major
determinants of success of a new drug compound, viz safety and efficacy, have become
more predictable, with the advent of pharmacogenetic studies. There is a need felt for
Department of Pharmacology, pharmacogenomic studies, where the effects of multiple genes are assessed with the study
JIPMER, Puducherry, India of entire genome.
Pharmacogenetic studies can be used at various stages of drug development. The effect
Received: 12.03.2008 of drug target polymorphisms on drug response can be assessed and identified. In
Revised: 13.05.2008 clinical studies, pharmacogenetic tests can be used for stratification of patients based
Accepted: 22.08.2008
on their genotype, which corresponds to their metabolizing capacity. This prevents the
occurrence of severe adverse drug reactions and helps in better outcome of clinical
Correspondence to:
trials. This can also reduce attrition of drug compounds. Further, the variations in
Dr. C. Adithan
drug response can be better studied with the wider application of pharmacogenomic
E-mail: [email protected]
methods like genome wide scans, haplotype analysis and candidate gene approaches.
The cost of pharmacogenetic testing has become very low, with the advent of newer
high throughput genotyping systems. However, the cost of pharmacogenomic methods
continues to be very high. As the treatment with several drugs is being more and more
pharmacogeneticaly guided (e.g. warfarin and irinotecan), the FDA has laid down
guidelines for pharmaceutical firms regarding submission of pharmacogenetic data for
their drug products in labelling.

KEY WORDS: Drug, genotype, pharmaceuticals, pharmacogenetics, pharmacogenomics

Introduction in therapeutics, can also be utilised in drug discovery and

development.
In the process of drug discovery, most drug compounds
that act on the target during the early phases fail to emerge as Genetic Factors in Drug Effects
therapeutic agents. This could be due to unexpected failure of
efficacy or occurrence of adverse events. Pharmacogenetics The genetic factors that can affect the drug response
involves the study of single gene mutations and their effect include variations in the genes coding for drug metabolizing
on drug response. The term pharmacogenomics is much enzymes, receptors and transporters. A classic example of
broader and it involves surveying the entire genome to assess genetic polymorphism affecting drug metabolism would be
several determinants of drug responses.[1] The current status that of the enzyme CYP2C9, which is coded by the polymorphic
of pharmacogenomics is restricted to the areas of medical gene CYP2C9. Its variant alleles namely *2 and *3 are poor
research and epidemiological studies. metabolizers, with only 12% and 5% respectively of enzyme
Many treatment regimens like that of oral anticoagulants and activity, as compared to normal allele *1.[4] Variations in drug
cancer chemotherapy are now guided by the pharmacogenetic response due to polymorphism of receptors can be illustrated
status of the patient, to avoid toxicity as well as treatment with β2 adrenergic receptor polymorphisms, where homozygous
failures.[2,3] The traditional method of trial and error in selecting mutants with decreased expression of β2 adrenergic receptors
a drug dose is gradually being replaced by pharmacogenetic do not have a predictable response to the use of drugs
methods. Pharmacogenetics, which is being utilised currently like salbutamol in asthma.[5,6] Similarly, polymorphisms of

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Surendiran .: Pharmacogenomics and drug development

transporters affect drug effects. The promoter region of the or failure of a compound is lack of efficacy, which is followed
serotonin transporter gene exists in two forms: short form (sl by safety concerns.[1] This occurs mostly in phase II and phase
and ss) and long form (ll). The short form of this polymorphism III of clinical trials. Phase III study, being done on a larger
(ss) is associated with decreased clinical response to citalopram scale and on a larger study population, utilises a very large
in children or adolescents with depression or anxiety.[7,8] The share of the resources. When a trial is thus ended, the loss
variant allele 5HTTLPR-S coexisting with the CYP2C9*3 variant incurred financially as well as in terms of time is unacceptable
allele is found to be associated with an even greater risk of major for a pharmaceutical firm. Figure 1 shows the financial losses
depressive disorder.[9] incurred by termination of clinical trial in each phase.
Depending upon the nature of the drug being tested, Before the advent of pharmacogenetic studies and
these genetic variations can cause either toxicity or failure of proteomics, efficacy and safety concerns were poorly predictable
treatment in a clinical trial. Pharmacogenetic methods can in a clinical trial. In current times, the predictability of safety
be used to identify these genetic factors.[10,11] When a large and efficacy of a drug has increased to a significant level, as
number of patients are to be genotyped, as in a clinical trial, both are influenced by the genetic status of the individual, which
high throughput genotyping methods like Amplifluor® and can be assessed by pharmacogenetic studies.
TaqMan®[12] can be used at a reasonable cost. Methods like
Pharmacogenomics and its Application in Drug
haplotype mapping, where more than one genetic variation
Development
in a single chromosome is studied together, can identify the
genetic basis of diseases, as well as newer targets for drug The applications of pharmacogenomics in drug development
development.[5] process are briefly given in Table 1. It can be seen that it has a
vital role at every key stage of the drug development process.
Current Scenario in Drug Discovery and Development
Drug target and pharmacogenomics
Time factor in drug development The process of drug discovery starts with the identification
Drug discovery and development is an elaborate and time of a potential target at which the drug can act. The target can be
consuming process. The average time taken from synthesis of an enzyme in a vital pathway, a receptor, a transporter, a protein
a new chemical entity (NCE) to its marketing has increased in signal transduction or any protein produced in a pathological
from an average of 7.9 years in 1960 to an average of about 9 condition. After sequencing of the human genome, the number
to 12 years in 1990.[13] It includes two major phases, phase I of drug targets was estimated to be around 8000, out of which
being the discovery of the drug compound, which is the most 4990 could be actually acted upon - 2329 for antibodies and
crucial stage in drug development, and phase II being animal 794 for drug proteins.[15] Based on ligand binding study, 399
and clinical studies followed by marketing. The increase in molecular targets belonging to 130 protein families have
time duration can be attributed to the complexity of the clinical been identified.[16] However, currently, the number of targets
trials and rigid regulations. Out of five thousand compounds ranges only around 218, though the estimated numbers are
evaluated initially during the drug screening process, only five very high.[17] These targets are known to exhibit variations
of them enter clinical trials. Of these five drugs, only one gets owing to genetic polymorphisms. Drugs which are based on
approved for marketing. targets showing wide polymorphisms can have variations in
The process of drug development includes pathway
identification and target selection, screening of chemical
Figure 1: Potential financial loss with premature termination of a
compounds, drug development, preclinical and clinical studies
clinical trial
and, finally, drug marketing.
Cost factor in drug development
70
The total expenditure involved in a drug development and
its launch is very high. A study on the cost of drug development 60.6
60
done by DiMasi et al., in 2003, gave an estimate of US $ 802
million in the year 2000, for an NCE development, right up 50
to its marketing. This indicates the resource cost for a firm,
and not the effective cost. The capital investment has also
Million USD in 2000 dollars

been addressed by DiMasi et al. in this study. The estimated 40

capitalised phase cost for an NCE was given as US $ 1.6 million 33.5

for animal model testing, 15.2 million for phase I trial, 16.7 30
27.1

million for phase II and US $ 27.1 million for phase III trials.
[14]
In a majority of the cases, the termination of a clinical trial 20 16.8 16.7

occurs during phase II and phase III and the loss of financial
15.2

resources are high, since millions of dollars have already been 10

utilised. DiMasi has shown that by reducing the clinical phase 1.6 1.6
duration and increasing the success rates, the expenditure for 0
development per NCE is also reduced.[13] P.Cl* Phase I Phase II Phase III

Implications of termination of a clinical trial Cost Invested (DiMasi et al. 2003) Potential loss with termination of trial

The most common reason for termination of a clinical trial *Preclinical study

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Surendiran .: Pharmacogenomics and drug development

Table 1

Application of pharmacogenetic/pharmacogenomic methods in various stages of drug development

Stage Application of pharmacogenetics/pharmacogenomics

Drug target Identification Identification and characterisation of the gene coding for the drug target and to assess the variability
Phase I clinical trial Patient selection – Inclusion/Exclusion criteria
Dose range selection
Phase II clinical trial
Dose modification
Phase III clinical trial Interpretation of trial results based on pharmacogenetic test results
Phase IV clinical trial Analysis of reported adverse events with pharmacogenetic tests
Regulatory issues Requirements for submission of pharmacogenetic data during development by FDA
Patient therapeutics Personalization of drug therapy
Pharmacogenetic data in drug labelling
Identification of responders and non responders
Identification of high risk groups of adverse events

their effect. For example, polymorphism of β2 adrenoceptor drug compound during clinical trials. In current times, the
gene, as discussed earlier, has produced responders and non scenario has changed and with the availability of sophisticated
responder phenotypes. [7] This can lead to inconsistent results pharmacogenetic tools, the attrition rate can be significantly
in the preclinical and clinical studies that would follow if such reduced. This translates into reduction in loss of financial
a drug compound is pursued. Such targets can be avoided for resources for drug development. With in vitro methods, it can be
drug compounds and other suitable targets can be selected. identified during preclinical studies, if the drug is metabolized by
Thus, at an early stage, the targets can be characterised based polymorphic enzymes,[19] and a decision regarding continuation
on pharmacogenetic studies combined with proteomics and of the trial can be made. Also, this information can help in
suitable drug compounds selected for further investment. selecting appropriate patients with normal metabolizing
In most cases, variation in drug response in a disease is enzymes in phase I clinical trial; it can also help prevent adverse
attributed to many genes rather than a single gene mutation. events.[20] It must be noted that pharmacogenetic principles
The results of pharmacogenetic study do not apply when can be used for inclusion or exclusion criteria only when the
used clinically, as only single gene mutations are studied metabolic pathway of the drug is known. In cases of exploratory
when in fact multiple genes are involved. In such cases, studies, where knowledge regarding the metabolism of the drug
more than pharmacogenetic study, it would be appropriate is not known, pharmacogenetic principles cannot be applied for
to do pharmacogenomic study comparing single nucleotide selection of subjects in the early phases of studies. However,
polymorphism (SNP) maps and gene expression between the acquisition of pharmacogenetic data in the early phases of
normal and affected individuals. This can identify the genetic clinical trial can be useful for the later phases.
factors associated with the disease and thus provide newer Prediction of efficacy of drug
targets to characterise and evaluate, for the purpose of drug In contrast to the conventional methods where preclinical
development. Those that could be potential future drug targets and clinical studies are done with the purpose of determining
can be called as “tractable” or “drugable” targets.[1] With the efficacy, drugs designed with pharmacogenomic support
availability of advanced human genome sequences, the genes have a predetermined efficacy status. The chance of a drug
can now be analyzed in silico for coding regions of the tractable failing in preclinical and clinical studies due to the absence of
targets. Polymorphisms of P2Y12 receptors in platelets have efficacy is minimized. The efficacy of a drug, to a great extent,
been identified to be associated with increased risk of coronary is determined by appropriate target selection, which can be
artery disease by haplotype analysis. In the future, this can guided by pharmacogenomic methods. To cite an example, the
be a potential target for a drug compound produced against drug trastuzumab, an anti-HER2 monoclonal antibody against
coronary artery disease.[18] Selection of the right target for metastatic breast cancer, was found to be effective only in
development of a drug is vital and pharmacogenomics can women who were over expressing the HER2 protein during early
play a vital role in it. clinical trials. In the subsequent trials, studies were done only
Pharmacogenomics and clinical trials on women found to be over expressing the HER2 protein.[21,22]
Pharmacogenomics in clinical trials is a relatively new area The drug got approval for marketing with the requirement of
in which considerable hesitation is shown by pharmaceutical testing for HER2 over expression, before starting therapy. Had
companies. Incorporation of pharmacogenomic testing with this drug been tested in a whole population without genetic
clinical trials has multiple advantages. stratification, the efficacy of the drug would not have been
The two most important concerns for new drug development brought out.
are efficacy and safety. Before the advent of pharmacogenetic Pharmacogenomics can also be used to identify the target
tools, the predictability of both these factors was very low. population that would benefit the most from the drug. A typical
This translated into heavy financial loss due to attrition of the example would be association between polymorphisms in the

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Surendiran .: Pharmacogenomics and drug development

apolipoprotein E (APOE), cholesteryl ester transfer protein from genetic polymorphism, constitutes only a minor segment,
CETP, stromelysin-1 and β-fibrinogen with progression of with very low frequency distribution. In the event of an enzyme
atherosclerosis, cardiovascular events and death. It was shown polymorphism occurring in a larger population, the development
that people with such polymorphisms derived the maximum of such a drug is avoided by the pharmaceutical firm.
benefit from HMG-CoA inhibitors, as compared to those without Another concern would be the cost that the patient would
the polymorphisms.[23-26] have to endure for pharmacogenetic testing before starting
Prediction of safety of drug therapy, as the drug has been approved for marketing, based
The second major concern in a clinical trial is the safety on pharmacogenetic results. The cost of genotyping for single
profile of the drug. Data provided by preclinical studies can be nucleotide polymorphisms may not be affordable in many
applied to humans only to a certain extent. During a clinical developing and underdeveloped countries. However, with
trial, the occurrence of a serious adverse event could jeopardize advancements in technology, this price may come down in the
the drug status. Usually, such an event would culminate in the near future. As mentioned earlier, the cost for genotyping 1000
termination of the trial. DNA samples would be at the rate of 0.3 USD per genotype.
Drug toxicity occurs mainly due to increased plasma levels of But when the cost is calculated for a single patient sample, it
the drug, which may be the result of poor metabolizing capacity amounts to more than 130 USD, as the price for assay marker
owing to genetic polymorphisms. Many of the genes (CYP2C9, setup is fixed.[27] Thus it seems, genotyping is cost effective only
CYP2C19, CYP2D6, etc) have been intensely studied in various if it is done on a larger scale, which would be the case if it is
populations and characterized for various drug groups. The role used for therapeutic testing.
of pharmacogenetics in predicting the efficacy of most drugs Pharmacogenetics in patient care
is limited, as they are usually dependent on more than one The most commonly applied pharmacogenetic testing for
gene. In contrast, the safety of many drugs is, to a great extent, patient care is detection of polymorphisms of genes coding
determined by the plasma drug levels, which in turn depends for drug metabolizing enzymes and assisting in dosage
upon the drug metabolizing capacity. The drug metabolizing selection or modification. A recent study has shown that
enzymes have been identified to exhibit single nucleotide 59% of the drugs that cause adverse effects are metabolized
polymorphisms and hence pharmacogenetic approach has a by polymorphic enzymes. [29] There have been reports of
better predictability of the safety of a drug. accentuated action of warfarin in patients with increase in
The cost of genotyping for SNPs has come down drastically. INR (International Normalized Ratio) at normal doses and on
The estimated cost for analyzing 1000 DNA samples for a subsequent pharmacogenetic testing, they were found to be
single marker for SNP is 300 USD. This amounts to 0.3 USD per poor metabolizers with *3/*4 and *1/*3 polymorphisms of
genotype.[27] With the availability of high throughput genotyping CYP2C9.[2,30,31] As a result of significant association between
methods, pharmacogenetic testing can be incorporated into CYP2C9 polymorphisms and warfarin toxicity, the FDA has
inclusion criteria for selecting a subject for the trial. Those who approved inclusion of pharmacogenetic data in the product
are identified as poor metabolizers of the drug tend to attain a label for warfarin and the warfarin product label now carries
higher plasma concentration of the drug, and hence the higher the genetic information.[32] This makes warfarin therapy safer
incidence of toxicity. When poor metabolizers are avoided in the during initiation and maintenance of treatment.
study, the occurrence of serious adverse events is reduced. For Another potential use of pharmacogenetics is identification
example, polymorphisms of UGT1A1 determines the toxicity of population with risk factors not directly related to the
response to irinotecan due to its effect on the plasma levels of drug. It has been found that patients with prothrombin gene
irinotecan.[28] Thus, the study population can be stratified into mutation have a risk of developing cerebral vein thrombosis
groups based on their drug metabolizing capacity and those and when these patients are on oral contraceptive pills, they
with diminished capacity can be avoided in the study or given run an even higher risk.[33] This information, when made
lower doses of the drug. The drugs can be thus marketed with available, could prevent the occurrence of adverse events
pharmacogenetic details along with the product. with oral contraceptives in high risk patients having a genetic
Concerns with pharmacogenomics in drug development susceptibility. The reduction in adverse effects reflects upon the
protocols safety profile of the drug and in its marketing value. There is
When drugs are tested, based on pharmacogenetic profile always a persistent hesitation among pharmaceutical industries
of patients and their categorization, it gives the impression to base their drug products on pharmacogenetic testing. This
that those with poor metabolizing capacity are being left out. is due to various factors like segmentation of the market based
Seen in a broader aspect, it may be noted that this method only on genetic profile and increase in the product and health care
brings to light what has not been realized in the pregenomic costs. These factors keep the pharmaceutical industry in a
period, where the occurrence of serious adverse events in “wait and see” stance for producing pharmacogenetic data for
clinical trials and in clinical practice has been poorly explained. their products.
By utilizing pharmacogenetic tools and understanding the Challenges in inclusion of pharmacogenetics in a clinical
cause for adverse effects, the drug induced morbidity in poor setting
metabolizers can actually be prevented when pharmacogenetics The inclusion of pharmacogenetic data in health care
gets linked with clinical practice and drugs are prescribed with delivery poses many more challenges. The knowledge regarding
appropriately guided doses. It must also be realized that the the influence of genetics on specific drug response and dose
subset of population with poor metabolizing capacity, arising modulation is yet to be imparted to many of the clinicians.

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Surendiran .: Pharmacogenomics and drug development

This is, in fact, a more complicated and challenging issue. approach starts with identification of candidate genes. For a
The drug dosage is likely to become complicated with the drug response, candidate genes could be the genes coding for
involvement of genetic data. Moreover, the fact that most of the the drug metabolizing enzyme, the proteins involved in the drug
patients receive more than one drug for a single disease and transport, the proteins involved in the cellular mechanisms,
that many combination therapies exist are likely to make the the receptor proteins etc. The candidate gene is studied for
task enormous. Adjustment of drug dosage based on clinical allelic variants. A candidate gene can have more than one
parameters like liver and renal function test is well accepted allelic variant or SNP. Candidate gene effects can be studied in
and practiced. However, there is hesitation among clinicians case (people with altered drug response) and controls (people
to modulate the dose on the basis of the genetic status of the with normal drug response). Candidate gene studies are less
individual and they prefer to rely on the clinical parameters. expensive than linkage disequilibrium studies and genome wide
This could be due to the hesitation to give up the “trial and scans.[39] A limitation of candidate gene studies is that spurious
error” method or unfamiliarity with the genetic principles of association can occur if the case and controls are not adequately
drug response.[34] matched. Further, variants in other genes, which are remotely
Drug response variability and pharmacogenomics influencing the drug response, cannot be identified. Moreover, a
The factors affecting the drug response for a disease level of understanding of the drug response pathway is required
are multiple. They can be categorized as unpredictable to identify the candidate genes unlike genome wide scans.
(environmental influence, compliance and genetic profile Genome wide scan
of the patient) or predictable factors (age, sex, race, body Genome wide scan is a very extensive and elaborate
weight, disease state, nutritional status etc). With the advent of study method for effects of various allelic variants occurring
pharmacogenetic testing and the human genome breakthrough, throughout the genome and the drug response in a disease
the genetic makeup of the patient can now be considered a condition. This method involves identification of all the allelic
predictable factor for drug response. However, the predictability variants in the entire human genome and the creation of an
based on pharmacogenomic testing may not be absolute, SNP map. This is tested for association with drug response
as there are other unpredictable factors also. Yet, with the variation. [40] The advantage of genome wide scan approach,
application of pharmacogenomic testing, the drug can be made as compared with the other methods, is that, it can identify
relatively more efficacious and safer. The scope of determining the polygenic determinants of drug response. In contrast to
drug response variability based on pharmacogenetic testing candidate gene approach, genome wide scan approach does
is very limited, as compared to pharmacogenomics. A study not require prior information regarding the drug response
done on the polymorphisms of promoter and coding regions pathway in question. This approach increases the translation
of β2 adrenoceptors has shown association between the level of genetic testing in clinical response. It is estimated
haplotypes and bronchodilator response to salbutamol, whereas that the human genome has approximately three million SNPs
no association was seen between individual genotypes of β2 and it is not cost effective to screen all the SNPs. As a result,
adrenoceptor and bronchodilator response.[35] Another example only representative SNPs that are distributed evenly across
would be the variation in drug response to ACE inhibitors. the genome are selected for testing. This may be in the range
Different studies have shown different association between of 200000 to 300000 SNPs per human genome.[41] The SNP
the genotypes ACE I/I, ACE I/D and ACE D/D and response maps can be studied for linkage disequilibrium and disease
to ACE inhibitors.[36] As per the study done by Cannella et al. or drug response associations. The disadvantages of genome
(1998), the genotype of ACE does not predict the effectiveness wide scan approach is that it is very expensive to perform and
of ACE inhibitor therapy in reducing the left ventricular mass since a large number of SNPs are mapped, they need to be
in chronic uremic patients.[37] Hernandez et al. (2000) have further evaluated, as it is not hypothesis driven like that of the
shown a significant reduction in left ventricular mass index in candidate gene approach.
renal transplant patients with LVH on treatment with lisinopril Haplotype analysis
with ACE D/D genotype.[38] Kohno et al. (1999) have shown Haplotype analysis for drug response variation involves the
that patients with ACE D/D genotype are less likely to have study of clusters of SNPs occurring in linkage disequilibrium in a
regression of LVH, when treated with ACE inhibitors.[36] Thus, chromosome and their association with the drug response. This is
a broader study involving multiple genes or allele variants is different from genome wide scan approach in that only selected
needed to understand the intricacies of drug response variability haplotypes are analyzed and not the entire genome. Haplotype
and to identify the factors affecting it. The methods which can blocks are created by clustering selective SNPs and their linkage
be used for this purpose are candidate gene approach, genome disequilibrium is tested with family studies. The haplotype blocks
wide scan approach and haplotypes analysis. are then tested for association with clinical outcomes.
Methods of Studying Genetic basis of Drug Response Haplotype analysis provides more information than
Variations pharmacogenetic study of single nucleotide polymorphisms and
is cost effective. Based on these studies, the various genetic
Candidate gene approach determinants of a drug response can be identified and drug
Candidate gene approach for identifying genetic determinants development can be customized accordingly. The same methods
of drug response variability involves identifying association can be used in clinical trials, to identify high risk groups for
between various allelic variants or SNPs within the candidate adverse effects and to derive an explanation for the outliers in
gene and the drug response.[39] The method of candidate gene the study group for lack of efficacy.

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Pharmacogenomic data in labeling and their limitations development is advantageous for all sectors, drug industries
Pharmacogenomic data may be integrated in the labeling tend to have a difference of opinion among themselves on this
of a product. Such data might be useful in identifying patients issue.[45]
who require dose adjustments for the prevention of adverse As mentioned above, a well-established pharmacogenetic
effects or lack of efficacy. The FDA has approved inclusion of test is required as a valid biomarker for making regulatory
pharmacogenetic data in the labelling of drugs like warfarin[32] decisions by the FDA. For a pharmacogenetic test to be accepted
and irinotecan,[42] mainly for safety concerns. The inclusion of as a valid biomarker, the test should have a sound scientific
pharmacogenetic data for improving the efficacy of a drug is a framework and well established characteristics. An example
difficult task to achieve, owing to reasons like low predictability for a valid biomarker in pharmacogenetic tests would be those
with pharmacogenetic testing involving single gene mutations for drug metabolizing enzymes as a marker for drug efficacy
and the potential compromise of marketing for the product. and safety. Patients with variant alleles of the gene CYP2C9
However, this change in labelling can be productive only if there and VKORC1 require lower doses of warfarin, as compared to
are genotyping facilities available, which is yet to happen in patients with normal wild type alleles. This is a valid biomarker
many developing countries. It is, however, recommended by and pharmacogenetic data has been incorporated in the drug
the FDA that while labelling with pharmacogenetic data, the label for warfarin.[2,30,32]
industry should also develop methods of pharmacogenetic The FDA has made submission of a complete pharmacogenetic
testing for that biomarker and give complete information about data report mandatory, if these results have been used for
the test and its interpretation, and the dose modulation.[43] decision making in the animal study, to support the safety of
Although the FDA encourages inclusion of pharmacogenetic the drug, or in clinical trials, for the selection of subjects, dose
data in product labels, there are certain limitations of range or its modification. The complete data is also required
application of pharmacogenetic methods. The variability in the in cases where the sponsor uses the pharmacogenetic test
drug response due to non genetic factors cannot be predicted. results to validate safety, efficacy, dosage selection and
Data obtained by genetic testing must be taken only with the mechanism of action in the clinical trials. However, in cases
limitation that there are also other factors determining the where such pharmacogenetic test results are not being used
response. by the sponsor to support the results of the trial, but the test
Ethnic diversity of human population has made it necessary is a valid biomarker for that drug, an abbreviated report of
for pharmacogenetic testing to be done in every ethnic group the pharmacogenetic test has to be submitted to the FDA. In
for the product to be utilized by that group.[44] In addition to cases where the pharmacogenetic testing has been done as an
pharmacogenetic data of various ethnic groups, it is required exploratory study or for research, it is not mandatory to submit
that there are pharmacogenetic testing centers in countries such data, as they cannot be considered as valid biomarkers.
where the drug is intended to be marketed. This also requires However, the FDA encourages voluntary submission of such
that a standard pharmacogenetic testing method is adopted exploratory pharmacogenetic test data. In future, as more
uniformly to avoid variation in test results. The cost of testing information becomes available, exploratory pharmacogenetic
must be substantially low for the general public. Moreover, the test data will also need to be submitted to the FDA.
extent of usage of product labels by clinicians is insufficient to Submission of pharmacogenetic data is beneficial for both
make an impact on patient therapeutics. Clinicians may hesitate the sponsor as well as the FDA. This can help in familiarizing
to use a product that requires pharmacogenetic testing, as it the FDA with pharmacogenetic principles and thus reduce
would incur additional cost for the patient. This highlights the unnecessary delay in reviewing future submissions where
need for imparting relevant knowledge to the clinicians on how pharmacogenetic testing has been used as an integral part of the
to modulate therapeutics based on pharmacogenetic data. Until drug development. Also, sponsors get to meet the FDA experts
this goal is achieved, a pharmaceutical firm would restrain itself informally, discuss scientific data and get their peer opinion. The
from using pharmacogenomics in drug development. sponsor can use the pharmacogenetic test results to support
FDA, Pharmacogenomics and drug development the safety and efficacy of the drug compound.[46]
The FDA has provided certain guidelines for submission of Conclusion
pharmacogenetic test data by the pharmaceutical industries, as
a part of drug development.[43] As most of the pharmacogenetic Pharmacogenomics in pharmaceutical industry is a
test results are not well-established scientifically, such potential tool, awaiting use for the maximum benefit. Currently
studies cannot be used by the FDA for regulatory decisions. pharmacogenetic methods are being used worldwide,
Currently, the FDA has made submission of pharmacogenetic particularly for assessing the safety profile of drugs. Translation
data mandatory for specific cases and supports voluntary of the pharmacogenetic test results into clinical practice has
submission for other specific cases, which are described below. been possible only for a small fraction of the total number
Guidelines have also been released pertaining to the time when of pharmacogenetic studies done. As the need for analysis
a complete pharmacogenetic report is to be submitted and when of multiple genes has been realised, haplotype analysis and
an abbreviated report is to be submitted. Further, there are genome wide scan methods were designed. However, with
separate guidelines for submission of pharmacogenetic data the current cost of analysis for one SNP, haplotype analysis
for investigational new drug applications and unapproved and and genome wide scans will not enter clinical practice for
approved marketing applications. However, even though the testing in patients. Yet, these methods can be utilized by the
FDA is of the opinion that pharmacogenomic integration in drug pharmaceutical industry for their drug development process.

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Surendiran .: Pharmacogenomics and drug development

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