This Informational Brochure is intended for IRBs/IECs & Investigational Site Staff. The brochure was developed to address issues relevant to DNA collection and research in the context of pharmaceutical drug development.Developed by The Industry Pharmacogenomics Working Group (I-PWG) www.i-pwg.org
The cells of the body contain deoxyribonucleic acid (DNA). DNA is inherited, and carries a code (in the form of genes), which determines physical appearance and other personal features. In a process called gene transcription, DNA is cop- ied into a related molecule, ribonucleic acid (RNA), before ultimately being translated into proteins, which determine cel- lular function. Naturally-occurring variation in DNA is a major determinant of differences among people. This variation, referred to as genetic polymorphism, occurs both within genes and outside of genes throughout the entire human genome. This variation partly explains why some people develop certain diseases and others do not, why some people respond better than others to certain drugs, and why some people develop side effects while others do not.
Pharmacogenomics (PGx) is a branch of science that uses genetic/genomic information to better understand why people respond differently to drugs. The terms pharmacogenomics and pharmacogenetics are often used interchangeably, although pharmacogenetics generally refers to the study of DNA, while pharmacogenomics is a broader term encompassing the study of both DNA and RNA1 , and generally on a larger scale. Pharmacogenomic research is different from genetic testing done for the purpose of diagnosing a person with a certain disease or for risk for developing a certain disease (e.g., genetic testing for Huntington’s Disease). PGx focuses on genet- ic variability that affects response to drugs. This primarily occurs through pathways related to drug metabolism, drug mechanism of action, disease etiology or subtype, and adverse events. PGx overlaps with disease genet- ics research since different disease subtypes can respond differently to drugs.
PGx is one approach to explore whether a drug will be useful or harmful in certain people. By identifying genetic polymorphisms that are associated with drug efficacy and safety, PGx is allowing for more individualized drug therapies based on the genetic makeup of patients. This is sometimes referred to as personalized medicine. By better understanding diseases at the molecular level, PGx is opening opportunities for the discovery of novel drugs. differently to drugs.
PGx has the overarching goal of developing safer, more effective drugs, and ensuring that patients receive the correct dose of the correct drug at the correct time.
PGx is increasingly becoming a core component of drug development programs. By using PGx to determine how drugs work differently in subgroups of patients, drug developers are making better decisions about which drugs to develop and how best to develop them. Technologies are now available to simultaneously analyze over 1 million genetic polymorphisms in the human genome. This is allowing for the identification of novel genetic markers of drug response and of disease in absence of pre-existing knowledge of the involvement of specific pathways.
PGx research is currently being used in drug development to:
A number of drugs now have instructions on their labels either recommending or requiring a PGx test when pre- scribing a drug or when making dosing decisions. A well- known example is the anti-coagulant drug warfarin. The drug label for warfarin now includes a recommended PGx test to minimize the risk of excessive bleeding (US label). There are currently three categories of PGx information in drug labels according to the FDA:
i) tests required for prescribing
ii) tests recommended when prescribing
iii) PGx information for information only.
For a current list of examples of how PGx is impacting drug labeling see: http://www.fda.gov/cder/genomics/genomic_biomarkers_table.htm
Adequate sample sizes and high-quality clinical data are key to advancements in the field of PGx. Drug development programs are therefore an invaluable resource and a unique opportunity for highly productive research in PGx. Although PGx is a rapidly evolving branch of science, the complexities of the genetic code are only beginning to be understood. As scientific discoveries continue to be made, samples collected today will become a valuable resource for future research. This may lead to the future development of new drugs that are better targeted to certain individuals and to disease subtypes.
For these reasons, it is vital to systematically collect DNA samples across all centers recruiting subjects into clinical trials that include a PGx component (where local regula- tions permit). Consent for storage of samples for future research should also be obtained if maximum benefit is to be derived from DNA samples donated by subjects. The scope of the research that may be performed both during the trial and in the future should be clearly defined in the informed consent form.
Policies and regulations for legally effective informed consent vary on national, state, and local levels. There currently are no internationally recognized regulations that dictate the basic elements of informed consent for PGx research. The I-PWG has published an article on the elements of informed consent to be considered in PGx research studies2 . These elements build upon existing basic elements of informed consent for clinical research on human subjects3 .
Policies for the return of genomic results to study subjects vary among pharmaceutical companies. There are many considerations that pharmaceutical companies weigh when determining their policy regarding the return of PGx research results to study subjects. These include i) the conditions under which genomic results were generated (i.e., research laboratory environment versus accredited diagnostic laboratory), ii) whether the results will have an impact on patient medical care, iii) whether genetic counseling is necessary, and iv) international, national, and local guidelines, policies, legislation, and regula- tions regarding subjects’ rights to access data generated on them. These considerations are addressed in detail in Renegar et al. 20064 .
An issue that is generally perceived to be of relevance to clinical genetic research is the risk associated with inad- vertent or intentional disclosure and misuse of genetic data. Although coded specimens generally have been con- sidered adequate to protect patient privacy in most clinical development, companies and other institutions involved in PGx research have historically applied a variety of additional safeguards that can be used alone, or in combination, to further minimize the potential risk of disclosure and misuse of genetic data. These include:
DNA samples and corresponding clinical data can be labeled in several ways to achieve different levels of patient privacy and confidentiality. Definitions of labeling methods are pro- vided in the glossary and are described in greater detail in the ICH Guidance E151 . It is important to recognize that there is a trade-off between the level of patient privacy protection and the ability to perform actions related to withdrawal of consent, data return, clinical monitoring, subject follow-up, and addition of new data (see Table 1)1 . The Identified and Anony- mous labeling categories described in the table are generally not applicable to pharmaceutical clinical trials.
Table 1 (adapted from ICH Guidance E151 )
PGx studies in pharmaceutical development are generally conducted in research laboratories that are not accredited diagnostic laboratories. Therefore, PGx research data usually cannot be used to make clinically meaningful or reliable decisions about a subject’s health or health risks. Furthermore, confidentiality protections described above serve to guard against inappropriate disclosure of these data. For these reasons, the potential risk to a subject’s employment or health/life insurance is considered to be minimal. The measures taken to protect subjects against reasonably foreseeable risks should be addressed in the informed consent form2 .
Many countries and regions have enacted legislation to protect individuals against discrimination based on their genetic information. For example, the USA Genetic Non- discrimination Act (GINA)5 , 6 serves to protect patients against health insurance and employment discrimination based on an individual’s genetic make-up. Legislation continually evolves based on social, ethical, and legal considerations. A list of examples is periodically updated on the I-PWG website: http://www.i-pwg.org
DNA sampling in clinical trials is straightforward in most jurisdictions. However, some countries have specific laws and regulations regarding collection, labeling, storage, export, return of results, and/or use of DNA samples. Pro- cesses for the collection of DNA samples should always adhere to the regulations of the country/region in which those samples are collected. Efforts are currently under- way toward improving harmonization and standardization of regulations and practices applicable to collection of DNA samples. However, it may be well into the future before there is consensus across nations. Because country-spe- cific local and regional laws and regulations continually evolve, it is advisable to regularly verify these laws and regulations for the jurisdiction in which approval for DNA collection is being given.
The use of PGx information to improve the risk:benefit pro- file of drugs is increasingly being encouraged by regula- tory health authorities. Authorities such as the FDA (USA), EMEA (European Union), MHLW (Japan), and ICH (Inter- national) are playing a key role in advancing this scientific field as it applies to pharmaceutical development. A signif- icant number of regulatory guidances and concept papers have already been issued1 , 3 , 7-18 , and are available through: http://www.i-pwg.org . DNA sample collection has become a key component of clinical development. It is anticipated that regulatory authorities eventually may require relevant PGx data with drug submissions19 .
Several expert organizations are helping to advance the adoption of PGx in clinical development and in medical care. A vast array of educational resources related to PGx that cater to health care professionals, IRBs/IECs, sci- entists, and patients have been created and are publicly available. Many of these organizations and resources are available through the I-PWG website: http://www.i-pwg.org .
The Industry Pharmacogenomics Working Group (I-PWG) (formerly the Pharmacogenetics Working Group) is a vol- untary association of pharmaceutical companies engaged in PGx research. The Group’s activities focus on non-com- petitive educational, informational, ethical, legal, and reg- ulatory topics. The Group provides information and expert opinions on these topics and sponsors educational/infor- mational programs to promote better understanding of PGx research for key stakeholders. The I-PWG interacts with regulatory authorities and policy groups to ensure align- ment. More information about the I-PWG is available at: http://www.i-pwg.org.
Identified Data and Samples: Identified data and samples are labeled with personal identifi ers such as name or identifi cation numbers (e.g., social security or national insurance number). The use of identifi ed data and samples allows for clinical monitoring and subject follow-up and are generally not considered appropriate for purposes of clinical trials in drug development. (Not generally applicable to PGx in pharmaceutical clinical trials).
Coded Data and Samples: Coded data and samples are labeled with at least one specific code, and do not carry any personal identifiers.
Single-Coded Data and Samples: are usually labeled with a single specifi c code. It is possible to trace the data or samples back to a given individual with the use of a single coding key.
Double-Coded (De-Identifi ed) Data and Samples: are initially labeled with a single specifi c code and do not carry any personal identifi ers. The data and samples are then relabeled with a second code, which is linked to the fi rst code via a second coding key. It is possible to trace the data or samples back to the individual by the use of both coding keys. The use of the second code provides additional confi dentiality and privacy protection for subjects over the use of a single code.
Anonymized Data and Samples: Anonymized data and samples are initially single or double coded but the link between the subjects’ identifi ers and the unique code(s) is subsequently deleted. Once the link has been deleted, it is no longer possible to trace the data and samples back to individual subjects through the coding key(s). Anonymization is intended to prevent subject re- identifi cation.
Anonymous Data and Samples: Anonymous data and samples are never labeled with personal identifi ers when originally collected, nor is a coding key generated. Therefore, there is no potential to trace back genomic data and samples to individual subjects. Due to restrictions on the ability to correlate clinical data with such samples, they are generally of little use to PGx research. (Not generally applicable to PGx in pharmaceutical clinical trials).
1. ICH E15 - Defi nitions for Genomic Biomarkers, Pharmacogenomics, harmacogenetics, Genomic Data and Sample Coding Categories. April 2008.
(Accessed at: http://www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-D-0199-gdl.pdf and at: http://www.ich.org/LOB/media/MEDIA3383.pdf )
2. Anderson DC, Gomez-Mancilla B, Spear BB, et al. Elements of informed consent for pharmacogenetic research; perspective of the pharmacogenetics
working group. Pharmacogenomics Journal 2002;2(5):284-92.
3. ICH E6(R1) - Guideline for Good Clinical Practice. June 1996. Accessed at: http://www.ich.org/LOB/media/MEDIA482.pdf )
5. Genetic Information Nondiscrimination Act (GINA): 2007-2008. (Accessed at: http://www.genome.gov/24519851 )
7. EMEA CHMP Refl ection Paper on Pharmacogenomics in Oncology - Draft. 2008. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/12843506endraft.pdf )
8. EMEA CHMP Position Paper on Terminology in Pharmacogenetics. June 2003. (Accessed at:
9. EMEA CHMP Refl ection Paper on the Use of Pharmacogenetics in the Pharmacokinetic Evaluation of Medicinal Products. May 2007. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/12851706enfi n.pdf )
10. EMEA CHMP Guideline on Pharmacogenetic Briefi ng Meetings. November 2006. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/2022704en.pdf )
11. EMEA CHMP Refl ection Paper on Pharmacogenomic Samples, Testing, and Data Handling. November 2007. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/20191406en.pdf )
12. EMEA CHMP Refl ection Paper on the Use of Genomics in Cardiovascular Clinical Intervention Trials. November 2007. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/27878906enfi n.pdf )
13. EMEA CHMP Biomarkers Qualifi cation: Guidance to Applicants. 2008. (Accessed at: http://www.emea.europa.eu/pdfs/human/biomarkers/7289408en.pdf )
14. EMEA CHMP Understanding Terminology Used in Pharmacogenetics July 2004. (Accessed at: http://www.emea.europa.eu/pdfs/human/pharmacogenetics/384204en.pdf )
15. FDA Companion Guidance - Pharmacogenomic Data Submissions - draft. August 2007. (Accessed at: http://www.fda.gov/CBER/gdlns/pharmdtasubcomp.pdf )
16. FDA. FDA Guidance - Pharmacogenetic Tests and Genetic Tests for Heritable Markers. June 2007. (Accessed at: http://www.fda.gov/cdrh/oivd/guidance/1549.pdf )
17. FDA Guidance - Pharmacogenomic Data Submissions. March 2005. Accessed at: http://www.fda.gov/cder/guidance/6400fnl.pdf )
18. EMEA FDA - Processing Joint FDA EMEA VGDSs within the framework of the Confi dentiality Arrangement May 2006. (Accessed at: http://www.emea.europa.eu/pdfs/general/direct/pr/FDAEMEA.pdf )
Created by the Industry Pharmacogenomics Working Group Education Task Force
© 2008 Industry Pharmacogenomics Working Group
All rights reserved.
This document represents the current view of the I-PWG at the time of publishing. Views and company representation in the I-PWG may change over
time. The content of this document should not be modifi ed without prior consent of the I-PWG. Translations must also be reviewed by the I-PWG. Since local laws and regulations may change at any time, individuals should always ensure adherence to applicable laws, regulations, and guidelines.