Biopsies can be categorized as either diagnostic or research (non-diagnostic research). Genomics costs have decreased dramatically in recent years. Spurring the push for, commensurate efforts to mine minuscule tissue specimens for genomics information to identify have also increased. This in turn has increased scope and frequency of research biopsies. This answer explicates some of the overarching issues pertaining to biopsies, specifically research biopsies,
- Their risks and benefits for patients.
- Whether patients fully understand their specific cost versus benefit, as in whether they are providing meaningful informed consent, and
- Ownership of the ensuing data and safeguarding its privacy.
Risks and Benefits of Research Biopsies
Biopsies are usually used to perform diagnoses. Done and discarded. So far so good. However, the situation in terms of risk and benefits for patients changes, sometimes even drastically, where research biopsies are concerned. Research biopsies entail different purposes that constitute markedly different costs versus benefits for a given patient. For example, biopsies could be primarily for discovery or to help guide therapy, two very different purposes (see below from 1).
A patient may have a considerably different appreciation of cost versus benefit of a research biopsy depending on their understanding of whether or not they’re likely to benefit directly from its research utility (). While a biopsy taken to guide the conduct of the trial itself, say, help calibrate drug or other Rx option, is obviously beneficial to the patient themselves ( ), biopsies intended for performing correlative or purely exploratory research or even for use in some future as-yet undefined research clearly entail greater cost for a patient. Not only is a given patient unlikely to benefit directly from a research biopsy, multiple samples from the same patient increase potential risk.
Additionally, some types of biopsy are inherently risky. For example, lung biopsies entail risk of, collapsed lung in layman’s terms, ( ) while multiple consecutive liver biopsies entail risk of increased bleeding ( ). Needle-track seeding or potential to alter or spread a tumor during biopsy is another concern, with the risk being low, not absent ( , 7). For example, a systematic review of 57 clinical trials found 745 research biopsies performed on a total of 576 patients had overall and major complications of 5.2% (39 of 745 biopsies) and 0.8% (6 of 745 biopsies), respectively ( ).
Do patients fully understand their specific cost versus benefit from research biopsies? Some do, many don’t
Does the process of taking biospcecimens entail meaningful informed consent? That is the nub of the ethical dilemma about research biopsies. With a bestselling book and now a mainstream film, the widely publicized travails regarding ownership of and profits from HeLa cells derived fromhave brought the issue of informed consent center-stage in the public domain and stoked layperson interest in the issues of autonomy, transparency and ethics pertaining to the collection of human biospecimens ( ).
Where in the past the biomedical research community developed the informed consent process largely on its own behind the scenes without much public input or debate, clearly such a paternalistic approach is less likely to pass muster moving forward. However, despite such heightened awareness, data also suggest we are still in a transitional period since participants’ understanding of relative benefit and harm is highly variable across studies (, ). Since laws and regulations vary widely across countries, unsurprisingly a wide patchwork of rules and regulations apply to the issue of informed consent for human biological materials (see below from , ).
Biopsies taken under different circumstances also entail different ethical dilemmas. For example, making biopsy mandatory to get enrolled into a clinical trial creates an obvious ethical morass (). Those in favor of course argue that human biological materials are needed from every trial participant in order to understand not just who benefits from a drug but also why and that modern molecular medicine promises to do just this ( ). Those against argue linking research biopsy to clinical trial enrollment could be easily coercive since patients could perceive their loss of access to potentially beneficial, even curative, experimental therapy as actual harm ( ).
Indeed, one 2015 review () of 55 clinical trials (n = 636) found that requirement for mandatory biopsy, in this case lung biopsy for patients with advanced non-small cell lung cancer, was a barrier to trial enrollment, specifically that more patients (83 versus 55%, respectively) received study treatment and that too earlier (after 9 or 16 days, respectively) when the trial didn’t have a mandatory biopsy requirement. This dataset implies some patients indeed balk at paying the cost (a mandatory invasive biopsy) for perceived benefit (gaining access to experimental treatment).
As to the utility value of research biopsies, despite the fact that research biopsies are often a mandatory requirement for clinical trial enrollment, i.e., patient acquiesces to submitting research biopsies in return for participating in a clinical trial in order to gain to an experimental therapeutic, one 2017 review found that fully 61% (28 of 46 trials) did not report results from research biopsies (17).
Clearly the push for big data has become pervasive enough for the element of avarice to seep into the process so much so investigators seem to be collecting material just in case for some future unspecified use. Problem with such an approach is it elides not only the individual risk to patients but also sets up a much more contentious future reckoning since so many of the issues pertaining to data ownership, privacy and confidentiality from human biospecimens are far from settled and in fact are beginning to be debated only more vigorously in the wake of widespread publicizing of the Henrietta Lacks story.
Ownership, privacy and confidentiality of human biospecimen data
According to a 2015 treatise making the case for why patients should own their medical data (see below from),
‘the US legal framework is constructed in a manner to block individuals from accessing their own medical data—in 49 of the 50 states in America, these data are owned by doctors and hospitals.’
Contrast this to former president Obama saying at a February 2016 White House Summit on Precision Medicine (),
‘I would like to think that if somebody does a test on me or my genes, that that’s mine, but that’s not always how we define these issues.’
The situation is especially fraught as it pertains to reporting research biopsy results to patients. For example, two reviews (, ) report that in the US, research biopsy results can only be given to patients if they were obtained by, or verified in, a (CLIA)-certified laboratory. While (IRBs) govern the conduct of clinical research, a 2013 review (1) states reporting of results back to patients is determined by the hospitals concerned on a case-by-case basis, which merely serves to increase the burden on IRBs and individual researchers.
In the US, themandates IRB approval for US government-funded biospecimen collection but this legal requirement doesn’t apply to industry-funded research ( ). Donor consent isn’t even considered necessary for research use of anonymized samples. The issue gets even more complicated especially as it pertains to data privacy when archival material is newly mined for research purposes.
Depending on the situation and country, consent can be explicit, implied, presumed, not required at all or waived under different circumstances. Consider the situation in Denmark for example where one author noted that the opt-out system for routine tissue storage (23),
‘has created a strange system of double standards: no consent is needed for using a tissue sample for research if it is taken for diagnostic purposes and used for research only at a later stage; while samples taken specifically for research must be collected with consent.’
Given the prevalent imperative for big data and inexorable globalization of biomedical research, how secure is the anonymization process for human biospecimens? However, even that question cannot be fully answered since there isn’t even a consensus definition for anonymization (see below from 24).
Would be a mistake to relegate this discussion as an issue of dry, stultifying bureaucratese since it concerns nothing less than public trust in biomedical research. People’s willingness to share data and specimens turns on whether or not the process can guarantee their privacy and confidentiality. Confidentiality is defined as (25),
‘the respectful handling of information disclosed within relationships of trust, such as healthcare relationships, especially as regards further disclosure. Confidentiality serves privacy. Researchers invariably promise to respect data-subjects’ privacy, either by de-identifying the data to make them impersonal or by handling them securely.’
Consider then the shocking conclusion from a 2013 study (, emphasis mine) that,
‘a combination of a surname with other types of metadata, such as age and state, can be used to triangulate the identity of the target. A key feature of this technique is that it entirely relies on free, publicly accessible Internet resources. We quantitatively analyze the probability of identification for U.S. males. We further demonstrate the feasibility of this technique by tracing back with high probability the identities of multiple participants in public sequencing projects.’
Informed consent about human biospecimens remains a fractious issue and if history is any guide, clarity will emerge one bestseller, one lawsuit at a time.
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