Lina Genovesi, PhD, JD www.linagenovesi.com

Lina Genovesi, PhD, JD

A blog version of this article can be found 

As the pharmaceutical industry continues to face increasing cost of drug development, sample banking for future clinical research provides the pharmaceutical industry with new opportunities to obtain biological sample collections that will allow it to investigate safety and efficacy in future clinical research and answer regulatory authority questions related to safety and efficacy at the time of registration.

Patients respond differently to drugs and often are not identified, until after clinical trials are closed, either because these patients are rare or because new data emerges to further classify patients who participate. As one of the goals of future use sampling is to obtain sample collections, which are highly representative of the clinical study population, the value of future use samples increases as the size of the sample collection increases.

Below are some of the considerations, issues and challenges around sample banking for future clinical research.

Going global in a clinical trial context has its own sets of issues and challenges when it comes to sample collection for future clinical research. These challenges include managing the logistics of sample procurement, storage and sample lifecycle in a conflicting regulatory framework while taking into consideration ethical issues relating to the protection of patient confidentiality within the framework of the institutional approval process.   

Country-related and global regulatory efforts are currently ongoing to harmonize the regulations governing sample banking for future clinical research. 

The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) published guidance documents addressing efficacy, joint safety/efficacy (multidisciplinary), quality and safety.  These guidance documents are the ICH’s attempt to harmonize standards between Europe, Japan and the USA. (

http://www.fda.gov/RegulatoryInformation/Guidances/UCM122049

In addition to these guidance documents, each country involved in sample collection for future clinical research has its own set of regulations. These regulations may create challenges in terms of conflicting interpretation and applicability.

There is a single European Union Clinical Trial Directive (EUCTD 2001/20/EC) issued in 2001 and revised in 2012 and is pending approval by the Council and the European Parliament in the ordinary legislative procedure before it can be implemented.

In addition to the EUCTD, there are several directives related to biobanks and privacy and data protection. The current EU Data Protection Directive 95/46/EC does not sufficiently consider important aspects like globalization and technological developments like social networks and cloud computing. A proposal for new guidelines for data protection and privacy released in early 2012, will take effect in 2016. The new guidelines are likely to have an impact on sample collection for future clinical research.  

In addition, on a local level, there are 27 National Competent Authorities and over 2000 ECs. Each country has individual laws/regulations that affect sample collection. There are no uniform regulations and several inconsistencies exists relating to informed consent language,  duration of sample storage, sample usage and return of patient level research data, 

In 2008, the Pharmaceuticals and Medical Devices Agency (PMDA) issued a guidance outlining the general principles of pharmacogenomics in clinical trials and supporting the collection of future use samples. 

In January 2013, the US FDA issued a draft guidance with one of its goals, the assistance of parties engaged in new drug development in evaluating the effect of variations in the human genome on the clinical responses of drugs. (

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM337169.pdf

A new rule “Modifications of the HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act” became effective on March 26, 2013 .The rule establishes national standards to protect medical records and personal health information. (

http://www.gpo.gov/fdsys/pkg/FR-2013-01-25/pdf/2013-01073.pdf

In addition to HIPAA, the Federal Policy for the Protection of Human Subjects, frequently referred to as the Common Rule governs the protection of human subjects participating in research. In July 2011, the US Department of Health and Human Services issued an Advanced Notice of a Proposed Rulemaking aimed at the Common Rule. (A comparison of the existing rule and some of the changes under consideration is at 

http://www.hhs.gov/ohrp/humansubjects/anprmchangetable.pdf.pdf

Samples of blood, tumor biopsies, and serum/plasma are collected during medical procedures and provide a source of valuable data to support pharmacogenomics studies and multicenter clinical trials. Blood samples are a source of DNA for genetic testing and RNA to recover an RNA population that mirror the biology of the sample at the time of collection. Tumor biopsies and serum/plasma samples are also a source of DNA, RNA and proteins.  

Prior to collecting biological samples, patients must provide their informed consent and a protocol approved by the Institutional Review Boards (IRBs) or Ethics Committees (ECs) of the institution is generally in place. The protocol .addresses specific issues including the intended use of the collected samples, the length of time the samples will be stored, sample coding procedures, management and limits of access of the data collected, maintenance of subject privacy and confidentiality, sample storage locations and storage conditions, sample destruction, publication and dissemination of results.

To address specific issues of patient confidentiality, processes and standards must be in place that minimize the possibility of linking genetic data back to a patient’s identity. Processes involve de-identification of samples such that a coded sample is relabeled with a unique second code, while maintaining a link between the two codes (i.e., double- coded); or anonymization of samples such that the link between the two codes of a double-coded sample is permanently deleted. While the process of anonymization provides for maximum security while allowing for genotype to phenotype analyses, it does not allow for returning results, sample withdrawal, clinical monitoring, or patient follow-up which cannot be undertaken on anonymized samples.

To assure sample integrity, the appropriate storage of biological samples is one of the key challenges in sample collections. Biological sample must be stored in fully validated storage units at different temperatures and conditions depending on the biological samples and ranging from controlled room temperature storage, cold storage, ultra low-temperature storage, and vapor phase liquid nitrogen storage. Sample temperatures must monitored and the sample storage facility supported by multiple backup systems and an inventory tracking system.

One of the key issues with facilities involved in sample storage for future clinical research is accreditation. Accreditation is provided by the College of American Pathologists (CAP) Biorepository Accreditation Program. The CAP Biorepository Accreditation Program is a three-year, peer-based accreditation developed to drive the adoption of standards through consistent application of best practices and evidence-based standards. Launched in 2012, the intended goal of CAP is to strengthen the quality of patient care and ensure consistent and verifiable quality of biological samples and their biorepositories.

Other regulations applicable to accreditation and compliance include US FDA 21 CFR Part 11 for compliant technology systems.

Because biospecimen collections exist to enhance the translation of basic research to the clinical setting, collaborations have formed to make the most of the opportunities presented.

Several institutions have provided their investigators access to an extensive repository of biological samples.   

Indiana University, Purdue University and the University Of Notre Dame are such institutions, and have formed a statewide collaboration, the Indiana Clinical and Translational Institute (CTSI). CTSI maintains and operates the Specimen Storage Facility. The Facility provides the infrastructure for the storage of biological samples in dedicated freezers and liquid nitrogen facilities. The Facility operates under formal standard operating procedures for controlled access, facility and equipment monitoring, alarming, and quality and administrative oversight in compliance with International Society of Biologic and Environmental Repository (ISBER) and the NCI Best Practices. 

The CTSI offers investigators a “one-stop” platform to request samples from the biobanks across Indiana University. “Through CTSI’s “one stop shop, we assist investigators who need access to specialized biospecimen collections and biobanking services relating to sample collection, sample processing and DNA isolation,” states Colleen Mitchell, Joint Biorepository Operations Manager for Indiana University Melvin and Bren Simon Cancer Center Tissue Procurement and Distribution Core and the Indiana University Genetics Biobank.

These biobanks collect, process, track, store, and distribute their own biological samples. 

The Indiana Biobank (IB), which is a repository of blood and saliva samples from Hoosier volunteers.

The Susan G. Komen® Tissue Bank (KTB) at the IU Simon Cancer Center, which is a repository for normal breast tissue and matched serum, plasma and DNA.

The IU Simon Cancer Center (IUSCC) Tissue Procurement and Distribution Core. The IUSCC Tissue Procurement and Distribution Core includes the IUSCC Tissue Bank and the Hematological Malignancies Biobank.

“The IUSCC Tissue Procurement and Distribution Core provides shared facilities and infrastructure support for tissue procurement and distribution,” states Mitchell. “Within this Distribution core, the IUSCC Tissue Bank is a tissue procurement resource for solid cancer tissue. Solid specimens with confirmed histology and diagnosis are available from surgical patients following excision from a large variety of cancers.”

“The Hematologic Malignancies Tissue Bank is a tissue procurement resource for hematological samples including blood and bone marrow specimens. Hematologic samples with confirmed histology and diagnosis are collected from patients at the point of care, under broad informed consent and IRB-approved protocols,” states Mitchell. 

“All malignant samples are accompanied by clinical and pathological data. Patient confidentiality is maintained by using a database system, which utilizes unique patient identifiers and limits access by investigators to the encryption code,” concludes Mitchell.

“Biobanking is a science and a business,” states Andrew Brooks, PhD, COO, of RUCDR Infinite Biologics.

RUCDR Infinite Biologics and BioStorage Technologies, Inc. have developed the Bioprocessing Solutions Alliance to provide the pharmaceutical industry with an integrated scientific approach and technology infrastructure for the delivery of advanced sample bioprocessing and biobanking solutions. 

The Alliance pools a host of services such as tissue collection, clinical trial sample bioprocessing, nucleic acid extraction, cell-line establishment, sample management consulting and sample storage.

One of the challenges of the Alliance is the need for integration and tailoring of services to meet the requirements of both the pharmaceutical industry and academia. The Alliance leverages BioStorage Technologies’ sample management system, the Intelligent Specimen Inventory Storage System (ISISS®). 

 “ISISS® provides a number of critical features, states Gregory Swanberg, CEO, Biostorage Technologies, Inc. “ISISS® maintains a historical electronic audit trail of samples allowing complete data tracking and regulatory compliance for future audits. The system is linked to a single database that gives users complete access to samples.”

“We have incorporated the ISISS system into our workflow to deliver a streamlined view of sample lifecycle,” states Brooks.

Sample banking for future clinical research will continue to be of utmost importance to develop safe and effective medications. There is a need for local and global regulatory guidance and for the standardization of collection procedures for sample procurement. 

In order to build trust on how industry is using future research specimens, there is a need for on-going education to help inform patients, investigators and IRBs/ECs regarding the importance of the role that future use samples play in the characterization of the safety and efficacy of drugs.

There is also a need for international guidance. Several national and international groups have emerged to address issues of global sample collection for future clinical research. 

 The Pharmacogenomics Working group (PWG) (

). One of its goals is to work with the FDA, EMEA, regulators and various policy groups to provide information on noncompetitive issues related to pharmacogenetic research. 

http://www.nigms.nih.gov/Research/FeaturedPrograms/PGRN/

). One of its goals is to identify safe and effective drug therapies for individual patients and interact with scientists in academia, industry, and government regulatory agencies. 

The Council for International Organizations of Medical Sciences (CIOMS) (

). It includes senior scientists from drug regulatory authorities and pharmaceutical companies, plus experts from WHO and academia. One of its goals is to consider drug development and the regulatory, ethical, educational, and economic issues related to pharmacogenetics. 

The AAPS Pharmacogenetics and Pharmacogenomics Focus Group (

http://www.aapspharmaceutica.com/inside/focus_groups/PGX/index.asp

). One of its goals is to facilitate communication between academia, biotechnology, genomics firms, pharmaceutical companies, and regulatory agencies.

The Pharmacogenetics for Every Nation Initiative (PGENI) (

). One of its goals are to enhance the understanding of pharmacogenetics in the developing world, build local infrastructure for future pharmacogenetic research studies.

Articles

Sample Banking for Future Clinical Research

You can find the full article version of this blog 

Sample banking for future clinical research provides the pharmaceutical industry with new opportunities to obtain biological sample collections.  

However, several considerations, issues and challenges come into play.  

ICH published guidance documents to harmonize standards between Europe, Japan and the USA. 

Europe issued a proposal for new guidelines for data protection and privacy released in early 2012, which will take effect in 2016. 

Japan issued a guidance outlining the general principles of pharmacogenomics in clinical trials and supporting the collection of future use samples. In 2008.

In the US, the FDA issued a draft guidance on January 2013. The “Modifications of the HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act” became effective on March 26, 2013. On July 2011, HHS issued an Advanced Notice of Proposed Rulemaking relating to the Common Rule.

Operational considerations relate to accreditation and managing the process of sample procurement, storage, and de-identification.  

To make the most of sample banking, collaborations have formed.

Indiana University, Purdue University and the University Of Notre Dame CTSI have formed the Indiana Clinical and Translational Institute (CTSI). CTSI offers investigators a “one-stop” platform to request samples.  

RUCDR Infinite Biologics and BioStorage Technologies, Inc. have formed the Bioprocessing Solutions Alliance for the delivery of sample bioprocessing and biobanking solutions. 

Several national and international groups have emerged to address issues of global sample collection for future clinical research. 

Sample banking for future clinical research provides the pharmaceutical industry with new opportunities to obtain biological sample collections.

The Omnibus Final Rule (Final Rule) entitled “Modifications of the HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act” became effective on March 26, 2013.
  Here are some of the modifications requiring compliance by the various stakeholders by September 23, 2013: 

The Privacy and Security Rules impact transactions involving PHI for a broader definition of Business Associate which now includes a subcontractor of a Business Associate. 

The Privacy and Security Rules impact a Business Associate and its subcontractors which now have increased accountability to a Covered Entity under its business associate agreements (BAAs) with the Covered Entity.

The Privacy Rule providing for compound authorizations, authorization for the use of PHI in future research and the use of deceased person’s PHI in clinical research impact a Covered Entity, its researchers and institutional review boards.

The Breach Notification Rule now requires notification of affected individuals for an impermissible acquisition, access, use of disclosure of PHI with the ultimate responsibility falling on the Covered Entity. 

These modified HIPAA Rules are subject to enforcement by the Office of Civil Rights (OCR):

The Enforcement Rule provides that OCR will now investigate all complaints relating to the HIPAA Rules.

The Enforcement Rule provides that OCR can now proceed directly to impose civil monetary penalties (CMPs).

The impact of compliance with the modified HIPAA Rules and enforcement by OCR remain to be tested and future regulatory developments may come into play. 

The Omnibus Final Rule (Final Rule) entitled "Modifications of the HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act" became effective on March 26, 2013.

Blog: The HIPAA/HITECH Omnibus Final Rule: Compliance and Enforcement

On January 23, 2013, the Department of Health and Humans Services (HHS) published the Omnibus Final Rule (Final Rule) which modifies the “HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act and the Genetic Information Nondiscrimination Act of 2008.” 

  The Final Rule became effective on March 26, 2013. Research entities have until September 23, 2013 to come into full compliance.  

The Final Rule modifies the use of an individual’s protected health information (PHI) outlined in the Privacy Rule.  

Here are the modifications which are likely to have implications on the conduct of research:

The Final Rule provides      for compound authorizations for combining conditioned and un-conditioned      authorizations. A compound authorization must differentiate between the      conditioned and unconditioned research components.  The individual retains the option to      opt-in to the unconditioned research activities. 

The Final Rule allows an      authorization for the use of PHI in future research. The authorization      must describe the future research in such a manner that an individual      expects that his or her PHI will be used or disclosed for such future      research.  

The Final Rule provides      that any information that would otherwise constitute PHI of a deceased      person ceases to be PHI 50 years after the death of the deceased      person.  

There are likely benefits of the Omnibus Final Rule for research such as the alleviation of administrative burdens, the removal of barriers for future research, and the ability to use a deceased person’s PHI. 
  
These benefits remain to be tested. 

On January 23, 2013, the Department of Health and Humans Services (HHS) published the Omnibus Final Rule (Final Rule) which modifies the "HIPAA Privacy, Security, Enforcement, and Breach Notification Rules under the HITECH Act and the Genetic Information Nondiscrimination Act of 2008."

Lina Genovesi, PhD, JD

Articles

Sample Banking for Future Clinical Research

Sample Banking for Future Clinical Research

Blog: The HIPAA/HITECH Omnibus Final Rule: Compliance and Enforcement

The HIPAA/HITECH Omnibus Final Rule: Implications for Clinical Research Blog