# Presentation: 061140

## The Pursuit of Better Medicines through Genetic Research 

- The Pursuit of Better Medicines through Genetic Research

- Terri Arledge, DVM
- US Department Head
- Drug Development Genetics

**Notes:**
Thank forum hosts for soliciting views from diverse groups involved in research on the important topic of family consent.

The informed consent process is central to the obligation to protect the rights and welfare of research participants

The integrity of the informed consent process, whether the issue is family consent or some other aspect of informed consent, is a shared interest and responsibility of researchers, ethics committees, regulators and study sponsors.

## Genetic research goals and initiatives at GSK

- Industry group addressing ethical, legal and regulatory issues with genetic research into drug response (pharmacogenetics)
- Research sponsor’s perspectives on family consent and suggested points to be considered

**Notes:**
Asked to provide a brief overview of genetic research initiatives at GSK and the timing for this information could not be more opportune.  The recent publication of human genome sequence has justifiably sparked tremendous interest in human genetics. The sequencing efforts represent an extraordinary technological feat. GSK shares the optimism of the international research community that the best is yet to come as information from the human genome sequence is translated into a better understanding of good health and disease, and ways to improve our health.

For our purposes today, there is an intrinsic connection between certain types of ongoing genetic research, for example research into disease susceptibility genes, and family medical histories.

Discuss a pharmaceutical industry working group formed to address ethical, legal and regulatory issues associated with pharmacogenetics – a type of genetic research looking at drug response – and its activities involving protecting the confidentiality of research data

Finally, I’ll offer perspectives of a research sponsor on issues of family consent and suggested points to consider in the deliberative process

## Genetic Research Goals at GSK

- Identify susceptibility genes for common diseases
- Use results of genetic research to discover new medicines acting on new targets (e.g., new genes associated with human disease pathway)
- Improve safety and efficacy of medicines by understanding the genetic basis for +/- drug response in individuals
- Promote education and informed discussion about genetic research

**Notes:**
While I can specifically speak only to GSK’s research objectives, it is worth noting that ours are not necessarily unique as many researchers are similarly engaged in efforts to understand the genetic basis for disease and response to medicines

Bullet 3 – We envision this research leading to the development of medicine response tests to predict the “right medicine for the right patient”

Bullet 4 – To this end, we employ a certified genetic counselor who interfaces with health care providers and patient groups. We also have personnel dedicated to overseeing and monitoring ethical, legal and social issues related to our genetic research

## Primary Genetic Research Initiatives

- Genetic Research

- Understanding
- diseases

- Understanding
- drug response

- New
- treatments

- Targeting
- treatments

**Notes:**

Our research can be divided into two branches.  On the left is the search for disease susceptibility genes to better understand diseases for the purpose of developing new medicines. On the right, represents research into the genetic basis for drug response for the purpose of identifying those patients who are likely to experience a positive therapeutic outcome (efficacy) from a medicine. Or, in the alternative, identifying patients who are not good candidates for a particular medicine due to safety concerns.

## Identification of Disease Susceptibility Genes

- Susceptibility genes confer a risk of - but do not cause - disease
- GSK Clinical Genetics Networks
- 	Large, international studies among academic institutions, 			genome screening centers and genetic epidemiology centers
- 	Protocols with well-characterized, standardized patient 			assessment criteria
- 	Detailed family history, clinical information and DNA from affected and 	unaffected siblings and parents
- 	Informed consent and information coding
- 	Identify gene loci responsible for disease susceptibility
- 	Examples -- Asthma, Depression, COPD, Early Onset Heart Disease, 		Osteoarthritis

**Notes:**
Many common diseases such as migraine, asthma, and cardiovascular disease result from interactions between susceptibility genes and environmental factors

GSK has launched large, international studies involving collaborations among academic institutions, genome screening centers and genetic epidemiology centers.

Clinicians and genetic epidemiologists develop protocols with well-characterized, standardized patient assessment criteria.  

Investigators then collect detailed family history, clinical information and blood samples for DNA analysis from affected siblings and unaffected siblings, and their biological parents if available.

Informed consent is obtained from all participants in the study and medical information and blood samples are coded before they leave the clinical site.

The goal is to identify gene loci responsible for disease susceptibility that will lead to the identification of new targets for medicines

## Pharmacogenetic Research

- Pharmacogenetics:  How genetic differences among patients influence their responses to medicines
- GSK’s Pharmacogenetic research in drug development trials
- 	Participation is voluntary - separate consent for 		genetic research
- 	Blood sample for DNA analysis and information 		coding
- 	Correlate drug response with genotype information 	using pooled data

**Notes:**
Participants in drug development trials are offered the opportunity to provide a blood sample for DNA analysis

Participation in the genetic research is voluntary and a separate informed consent is obtained

Family history information is typically limited to whether the subject’s biological parents, siblings and children have been diagnosed with the disease related to the drug study and the parents’ ethnicity and country of birth

The goal is to correlate drug response (phenotypic information) with genotypic information using pooled data from study participants exposed to a particular drug.  This genotypic information would be used to develop medicine response tests to better match patients to medicines.

## Patients without a 

- Patients **without **a

- side effect

- Section of SNP profile

- Section of SNP profile

- side effect

- Patients **with** a

- side effect

- Predictive of **no**

- side effect

- Predictive of **a**** **

- side effect

- SNP Print:

- Pharmacogenetic research:

**Notes:**
A promising avenue of pharmacogenetic research involves the use of Single Nucleotide Polymorphisms. So called SNPs are single base pair variations and are the most common  polymorphism.

While SNPs may not be involved directly in drug response, their relatively even and frequent distribution along the human genome makes them useful landmarks.

It is likely that SNPs are close to or within genes affecting medicine response

Patterns of SNPs could be the basis for developing medicine response tests – called a SNP print here – used by health care providers to screen patients for their likely response before prescribing.  The desired outcome would be ascertaining a medicine that is likely to be efficacious or ruling out a medicine that is likely to cause a serious adverse event in a particular patient.

It is important to note that the SNP print is not intended to yield any genetic information other than drug response.

## Pharmacogenetics Working Group

- Mission:  To advance the understanding and development of pharmacogenetics  by openly addressing and disseminating information on non-competitive topics such as ethical, legal and regulatory issues.
- Proposed Activities:  Sponsor symposia, prepare publications, interface with US and European regulators and address elements of pharmacogenetic research protocols and consents

**Notes:**
The pharmaceutical industry recognizes that the promise of pharmacogenetic research will not materialize with first addressing important ethical, legal and regulatory considerations

12 companies (GSK, Roche, Merck, BMS, Abbott, etc.) have formed a working group to address, in an open and inclusive forum, issues around pharmacogenetic research – Mission statement

Their proposed activities include facilitating symposia, publications, interface with US and European regulators, and addressing elements of pharmacogenetic research protocols and consents

The group’s first promising undertaking was the drafting of terminology and definitions for data and biological specimens – anonymous, coded, de-identified -- which have direct implications on data confidentiality and privacy interests of study participants. Their goal is to bring clarify and standardization to these terms used for example in protocol and consent forms for the benefit of patients, researchers, ethics committees and regulators.

NIH’s Pharmacogenetic Research Network recently agreed to support and adopt the group’s terminology.

## A Sponsor’s Perspectives on Family Consent

- Distinction among types of research
- Implications for Study Participants
- Implications for the Feasibility of Research

**Notes:**
With this backdrop of ongoing research and industry initiatives in mind, I’ll raise some family consent considerations from the research sponsor’s perspective.
With regard to consent considerations and genetic research, it is critical to distinguish carefully the psychosocial issues and sensitivities for subjects and family members. The objectives of genetic research, and thus the associated impact on subjects, their families and their medical information, vary dramatically as seen when the scenarios of research on serious monogenic disease (Huntington’s), disease susceptibility genes for common conditions (asthma, heart disease) and pharmacogenetics (drug response) are compared.

Subject’s privacy and autonomy could be compromised by requiring family consent and therefore lead to a reduction in research participation.

Depending on the nature of the research, it is not difficult to conceive of ways that family members could use information about study participation against the subject (custody, competency and employment contexts) 

Cost or inconvenience associated with obtaining family consent is not a sufficient justification for trampling on legitimate privacy interests. That said, irrational or overzealous applications of family consent requirements will render potentially beneficial research logistically or economically impractical.

The reality is that the research dollar only goes so far and difficult decisions about what  promising research to fund must be made everyday. 

How the issue of family consent is approached, in the final analysis, is influenced by a number of competing interests (the subject’s, the family, research logistics). Our goal must be to make sure that however the balance is struck, it reflects a full and fair consideration of these interests.

## Points to Consider regarding Family Consent

- Scientific rationale for collecting family history data
- Justification for the degree of detail
- Degree of confidence that subject is a credible source of family history
- Implementation of safeguards (data collection environment, access and release of data)

## Recommendations regarding Family Consent

- Responsibility for assessing family consent issues should remain with local investigators, ethics committees and research sponsors
- Education and guidance materials - not prescriptive, sweeping measures - should be developed for use by researchers, ethics committees and sponsors