Biosamples collected for future research provide a valuable source of material for the pharmaceutical industry to investigate new hypotheses related to drug efficacy and safety in a timely and efficient manner. However, collection of samples for future research remains a challenge for the pharmaceutical industry. As clinical trials increasingly become global, current regulation and law surrounding informed consent, collection of biosamples, and usage of samples beyond the close of the clinical trial must be navigated. Many countries and regulatory bodies are changing thought processes around the allowance of biosample collection and storage, and this changing regulatory landscape makes it difficult to implement an effective single global strategy for collection of biosamples. This paper will attempt to discuss elements of informed consent that are most often contested during global collection of biosamples and the implications of changes in each section of informed consent to the future utility of the sample.
Informed Consent Strategies for Biosample Collection
Whether to use a separate or combined informed consent for biosample collection is an internal decision for pharmaceutical companies. The strategy selected is typically chosen to balance optimal sample collection while maintaining study timelines.
In general, pharmaceutical companies have found that having separate informed consent for collection of biosamples decreases the initial operational burden for health authority (HA)/Institutional Review Board (IRB)/Ethics Committee (EC) approval and site initiation.
This decreased upfront operational burden has resulted in many companies using separate consent forms for biosample collection. However, this strategy may result in higher overall operational burden for internal sample management groups within companies because of the ongoing requirement for oversight of biosample consent submissions to HAs/ IRBs/ECs in a timely manner and all subsequent negotiations associated with this late submission. Also, sampling rates may ultimately be lower for companies using separate consent because it is easier for countries and sites to opt out of biosample collection altogether. Companies have found that by combining the biosample consent with the main consent, there is an increased sampling rate overall. However, this strategy increases upfront logistics efforts for protocol submission and approval, and therefore, site initiation. Any nonessential protocol elements that affect study timelines are often rejected by clinical teams in charge of development programs, and therefore this strategy has not been universally implemented.
Elements of Informed Consent for Biosamples
Many of the required elements of informed consent for biosamples overlap with required elements of general clinical trial informed consent. However, there are some unique aspects of informed consent that apply to biosamples (see Table 1 for a summary of required sections) [1]. Whether this informed consent is presented as a separate informed consent for biosample collection or as part of the main clinical trial informed consent, all elements of informed consent should be addressed with respect to biosample collection.
Several of these required sections for biosample consent, however, are the subject of detailed scrutiny by regulatory authorities, IRBs, and ethics committees. Table 1 highlights those sections that are most often points of concern.
Common Areas of Discussion with Regulatory Bodies
Purpose and Intent of PGx/BM Studies (including future unspecified analysis)
The scope of research that will be allowed for biosamples collected for future study is the most commonly debated section of informed consent. Samples with the most utility have broad informed consent for future study, allowing new research findings that are discovered during the clinical trial or even after the trial has closed to be quickly investigated. However, many regulatory bodies (i.e., health authorities, institutional review boards/ethics committees, and principal investigators) often have concerns about broad consent for future research. These concerns usually focus around the ability of the regulatory body to adequately review research plans of the company for approval in order to ensure patient protections are in place. To address this concern, a distinction has been made between “blanket consent” which would allow any type of future analysis to be conducted and “broad consent” which would allow future analysis to be conducted within a pre-specified scope of research.
Prohibitions on broad future scope of research have been implemented by some regulatory bodies. This policy may be in direct conflict with the position of other regulatory bodies who want the industry to have tools in place to quickly research new clinical findings without the time delay that a prospective clinical trial would impose. Meeting the requirements of both positions represents a challenge for the industry.
From a practical perspective during the conduct of global clinical trials, multiple changes to scope of study at individual study sites presents a problem for tracking patient informed consent. Appropriate sample permissions must be applied to all samples collected at each clinical site, linked to the sample in an automated tracking system, and followed throughout the “lifecycle” of the sample to ensure that the scope of research agreed to by the study participant is followed. Companies have developed individual strategies to address this problem.
Storage of Samples and Length of Storage
Some regulatory bodies contest the location and length of sample storage. In particular are some health authorities who do not allow export of biosamples from their country or debate the length of time following the close of a clinical trial that samples can be stored.
For some companies, setting up storage facilities in multiple countries is cost prohibitive. Also, the appropriate infrastructure for quality long-term sample storage is often not in place (i.e., power grid infrastructure, back up generators, etc.). Therefore, most companies attempt to unify sample conditions/logistics by establishing central biosample storage/analysis locations. In some cases, this means that in a global clinical trial, subjects from entire countries will not be represented in biomarker studies since samples could not be exported to this central storage/analysis location. This will impact the generalizability of any genetic association study to subjects in that country if no other country has a similar ethnic makeup.
Some countries do not allow storage of biosamples beyond the close of the clinical trial or require that they be analyzed within 2-5 years of trial close. This policy prohibits prompt pharmacovigilance activities of the industry for marketed compounds. Without the resources to investigate new unexpected findings of altered drug response discovered in a general medical population, companies must then commence prospective studies to investigate, which can take years to complete.
Coding Schema for Samples
Although the International Conference on Harmonization published terminology standards for coding of genetic samples [2], there is still misuse and confusion of sample coding terminology (see brief summary Table 2). Most regulatory bodies view the “level” of coding of the sample to be related to the ability of the company to ensure privacy for subjects contributing samples for future use. However, due to different interpretations of coding schemas and implementation of privacy protections, often the level of coding is unrelated to that guarantee. Therefore, an explanation of both coding and privacy protections should be included in the informed consent and protocol to describe how each company interprets and implements privacy protections for subjects. Options for Communication and Sharing of Results with Patients (or statement that no results will be shared) Many regulatory bodies have requirements that all data generated from samples be available to be shared with subjects. However, for samples collected to be analyzed in the future, this presents a logistics problem. Additionally, this requires that patients be re-contacted long after studies have closed, introducing patient privacy protection issues. Finally, samples analyzed for exploratory research are often not conducted under the laboratory conditions that are normally required for diagnostic testing and pertain to markers of response that may not have any known clinical meaning at this time.
Standardization of Informed Consents
There is no current common template for biosample informed consent for the pharmaceutical industry. Most companies have developed internal templates that are used across studies for the company. Companies have adopted different strategies for determining whether a separate informed consent should be required for biosample collection or whether this informed consent should be part of consent for primary clinical trials. However, there have been recent efforts to discuss elements/strategies for biosample informed consent that may result in more unified standards for the industry by groups such as the Industry Pharmacogenomics Working Group (I-PWG) (www.i-pwg.org).
Conclusions
Biosample collection is an important part of ongoing pharmaceutical research. There is a need for better sample collection strategies to ensure adequate sampling to support response to regulatory questions and pharmacovigilance activities. Education of ethics committees and regulatory agencies on the utility of the samples, procedures for safeguarding subject privacy, and need for long-term storage are key components of industry success in collection of samples.
References
1. Anderson C, Gomez-Mancilla B, Spear BB, Barnes DM, Cheeseman K, Shaw P, Friedman J, McCarthy A, Brazell C, Ray SC, McHale D, Hashimoto L, Sandbrink R, Watson ML, Salerno RA, on behalf of The Pharmacogenetics Working Group. Elements of Informed Consent for Pharmacogenetic Research; Perspective of the Pharmacogenetics Working Group. Pharmacogenomics Journal 2002;2:284-92.
2. ICH E15: Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding Categories. November 2007.
Amelia Wall Warner, PharmD is Head of Clinical Pharmacogenomics for Merck Research Laboratories. Dr. Warner oversees all clinical pharmacogenomics projects, oversees policies and procedures for biosample collection and storage for clinical trial samples, and is co-chair of the pharmacogenomics Strategic Scientific Oversight Committee. She is the current co-lead of the Pharmacogenomics Integration Workstream for Merck and will be setting up the new department of Clinical Pharmacogenomics.
She is the immediate past chair of the Industry Pharmacogenomics Working Group (I-PWG) and is a PhRMA representative to ICH E16.
Before her current role she was Associate Director in the department of Early Clinical Research and Experimental Medicine at Schering-Plough. Dr. Warner headed the Global Clinical Pharmacogenomics group, managed the clinical pharmacogenomic strategy for clinical programs, oversaw the SP Biorepository, oversaw all biosample collection on SP clinical trials, established and oversaw all protocol and informed consent language and database tracking for biosamples, oversaw company involvement and responses to new global regulations for biosample collection and analysis, was responsible for incorporation
of biomarker collection and analysis into SP clinical protocols, in addition to participating and leading other various committees and strategic planning groups regarding clinical biomarkers. She was a member of the Global Leadership team for Molecular Profiling and Biomarker Review and chaired the Biosample Usage Committee.
Prior to Schering-Plough, she was at Wyeth Pharmaceuticals in the Global Medical Affairs Anti-infectives division. Previous to that she was heading the Pharmacogenomics laboratory group in the Division of Clinical Pharmacology and Therapeutics at the Children’s Hospital of Philadelphia.
Amelia completed a residency in Pediatric Pharmacotherapy at St. Jude Children’s Research Hospital with John Rodman, PharmD and a fellowship in Clinical Pharmacology/ Pharmacogenomics at St. Jude Children’s Research Hospital with William Evans, PharmD. Amelia holds a PharmD from the University of North Carolina at Chapel Hill and a Bachelor of Science in Biology from Wake Forest University.
This article was printed in the May/June 2010 issue of Pharmaceutical Outsourcing, Volume 11, Issue 3. Copyright rests with the publisher. For more information about Pharmaceutical Outsourcing and to read similar articles, visit www.pharmoutsourcing.com and subscribe for free.