Limitations, challenges and ethics

1. Introduction

(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)

Progress in DNA sequencing and related technologies have boosted pharmacogenomics and pharmacogenetic research. However, researchers still are challenged to bring meaningful changes to the clinic. These challenges are outlined below.

2. Resistance

Tumours can become resistant to some targeted anti-cancer medicines. This means that a tumour is treated by a medicine at first with success, but the medicine stops working later on. It is thought that further mutations in tumours can cause resistance and tumours tend to mutate frequently.

Resistance is also an issue with viral and bacterial infections, such as HIV or Tuberculosis, when the amount of medicine in the blood stream/tissues is not regular.

With the medicine ‘vemurafenib’, which is used to treat melanoma, three forms of resistance have been found so far. For example, new mutations can activate ‘new’ signalling pathways in the tumour to cause cell growth. This can ‘bypass’ the pathway that the medicine is blocking, so that the medicine can no longer stop cell growth.

Treatment with more than one medicine may be one way to avoid resistance.

3. Ethical Challenges

There are particular ethical issues for genetics in medicines development, and many of these also apply to the area of pharmacogenomics and pharmacogenetics. Some people feel that there is now plenty of agreement on some of the ethical issues, but other areas are still being debated.

Many people see genetic information as powerful and private. This is partly because it can predict the risk of a patient’s future disease, and partly because it can give information both about the patient and about family members. Others point out that researchers should consider if the genetic information has clinical significance (in other words, that it will actually affect someone’s health). Not all genetic information is significant, so perhaps not all genetic information is ‘sensitive’.

Pharmacogenomics and pharmacogenetics research needs access to blood or tissue samples (sometimes from a large number of people). Sometimes these samples are stored along with detailed personal and medical information. Biobanking is the term used for large, organised sets of samples and data.

Three important debates about the ethics of biobanking for genetic research revolve around informed consent, disclosure of findings and privacy/confidentiality of data. These are described further in the following sections.

4. Informed Consent

Informed consent is the process where people give their consent to take part in a research project or a clinical trial. Clinical study volunteers give their consent based on an understanding of what the research involves, i.e. they are informed before they give their consent.

Biobanks contain large numbers of samples and data that are extremely useful forfurther research that goes beyond the initial research project that the volunteers have participated in. So there is a question about what exactly the volunteers are consenting to.

A study volunteer can give consent only for a specific a clinical trial or research project. This means that it can be impossible to do more valuable research on the same samples and the same data for other purposes after the clinical study or research project is done. If researchers want to use the samples or data for other purposes or projects, they will have to re-contact the hundreds or thousands of study volunteers to obtain consent for such additional research. This may be difficult or impossible, if volunteers have moved, or died for example. One common solution to this problem is to ask volunteers for a general consent which is not limited to one specific research project or study.

Another important issue is ‘disclosure’, i.e. whether research results are given to study volunteers or people who have taken part in research and how these results are given. This should be clearly explained as part of the informed consent process.

5. Disclosure

There is much debate about how researchers should disclose results to individuals who take part in genetic research.

There are many publications on disclosure in genetics research. These include international ‘ethic/legal’ guidelines (that include advice on both ethical and legal issues) and policy documents from all kinds of organisations. There is also a lot published on how to disclose results specifically from pharmacogenomics and pharmacogenetics research.

A goal for a research project may be to examine how genetic differences or variations in people can affect a certain disease or treatment. Such research may have two findings, called pertinent and incidental findings. These findings may bring about results that are important to the health of the individual person (pertinent findings). Or, they may bring about results that can be important to an individual person’s health in an unexpected way (indicental findings). Incidental findings might be that the person might be at high risk of a disease that the initial project did not plan to look into (an example could be via whole genomic sequencing technology).

There may be both disadvantages and benefits to a person who takes part in research if information is disclosed about the person’s health.

There are several things that should be considered:

• A research project result is per definition ‘exploratory’. This means that the result will likely need to be confirmed by a clinical laboratory (which has strict quality standards). However, in many cases, this will not be possible. And because the results are exploratory, they need to be properly understood by individuals who take part in the research (if they are given the findings).
• Is the result clinically significant (could it actually affect health?), and how serious is the condition concerned?
• What treatments or preventive action (such as changes to diet), if any, are available?
• How should an individual’s ‘right not to know’ be protected (that is, they may not want to know about their risk of getting certain diseases, especially when no prevention or treatment is available)?(1)
• How should researchers handle results if their significance is unclear? That is, genetic variations that are not yet proven to be important to health.
• What should happen if new scientific knowledge reveals that certain genetic information becomes significant after it has been obtained?
• Should people who took part in the research be re-contacted with this new information?
• Is there a privacy problem if research information is disclosed? For example, once a genetic test result is on someone‘s medical record, might this be accessible to insurers or employers? Does the individual taking part in the research have concerns about this?

A good process of informed consent (see section 4 above) should take into account all of these points. The responsibilities of researchers must be clear, as well as the wishes of the individuals who take part in the research. Anyone who takes part in research must have accurate and clear information about what to expect.

(1) Dondorp and de Wert 2013. The “1000-dollar genome”: and ethical exploration. European Journal of Human Genetics 21:S6-S26.

6. Data handling

Safe storage of biobank data is important. With the right computing skills, it has been possible to identify individuals’ genomic data, when databases have been made freely available online.(1) In 2008 the American National Institutes of Health (NIH)had to close its open access database for this reason. (2)

Data should be properly ‘encoded’, safely stored and available only to authorised researchers. There is legislation in the EU and its member states to ensure researchers have clear standards to work from.

To encode data, they can either be:

• Anonymised (no identifying information is linked with the data)
• Pseudonymised (data are given ‘false’ names, so that genetic and clinical information can be linked, but the identity of the person that the data comes from is not stored).

The use of pseudonyms works if there are enough people in the database that share the same clinical information. But if only one or two people have a particular disease, it might be possible to identify them and their genetic data.

The design of IT systems that control and store data is very important. Researchers have sophisticated systems for clinical and genetic data in pharmacogenomics research. For example, GENOmatch is a ‘data protection concept’ which was developed in a joint project between the pharmaceutical industry, software experts and academics. It protects data but also allows researchers to disclose results to individual people.

Another approach, which can be controversial, is taken by other genomic research studies, such as the Personal Genome Project UK. This project will make its data freely available online, as the NIH previously did. Names and addresses will not appear, but individuals taking part are warned that they could easily be identified and that their privacy cannot be guaranteed.

(1)  Dondorp and de Wert 2013. The “1000-dollar genome”: and ethical exploration. European Journal of Human Genetics 21:S6-S26.

(2) Ferguson W. 2013. A hacked database prompts debate about genetic privacy. Scientific American. http://www.scientificamerican.com/article.cfm?id=a-hacked-database-prompts