**4.4 Governance**

770 Biomedical Science, Engineering and Technology

The IDB is uniquely located for purpose as the local population in Lambeth and Southwark is large (~4 million) and extremely diverse. Indeed, after English the second most common spoken language is Yaruba (African) and then Portuguese (Lambeth census, 2001). This community also suffers from some of the highest rates for HIV infections, the viral hepatitides and sexually-transmitted infections in Europe. The prevalence of UK HIV infections is highest within this area and over 10% of all UK HIV cases are treated by local clinics. This is exemplified by the facts that amongst pregnant women attending St Thomas' Hospital to deliver their babies around 1% are infected with HIV and 2% with hepatitis B (Health Protection Agency, 2008). The IDB is embedded within the KCL Department of Infectious Diseases which is affiliated to King's Health Partners and Guy's And St Thomas' NHS Foundation Trust. The latter hosts an Academic Health Science Centre (AHSC) and also an NHS National Institute of Health Research (NIHR) comprehensive BioMedical Research Centre (cBRC). The latter offer considerable advantages since it has established two clinical research facilities (CRFs) that effectively comprise of two wards and resources

The prerequisites for the IDB's ethics included the concept of the dignity and autonomy of the volunteers yet also acknowledged the uncertain future research uses of biobank samples. Thus, the patient's information sheets and consent forms were designed to make it absolutely clear about the uncertainty of future usage. They also make it transparent that their samples would probably be used for genetic research and, the possibility that they would be used both for academic or commercial research purposes anywhere in the world. It is also made clear to participants that their healthcare would be unaffected by their decision to donate a sample, that they could withdraw from the biobank project at any time (and also demand that previously donated samples be destroyed) in line with most recommendations (Gertz, 2008) and that all samples would be annonymised. An additional safeguard was that should a downstream third-party researcher make a finding that was pertinent to the health care of the volunteer, this information would be passed back up through the management chain *via* the biobank to the clinicians at the tissue collection centre (TCC) who could then break the code and advise patients accordingly (since codes linking the patient's NHS number and the biobank code are only held at TCCs). These core principles were consequently remarkably similar to those proposed by the German Research

The timing of the establishment of the IDB was far from ideal since the HTA act was just being implemented. Like any such legislation it is the interpretation which sets the precedents, a process which can take some time. Currently the IDB has ethical permission from the Southampton and South West Hampshire Research Ethics Committee (B) which extends until 2014 (reference # 09/H0504/39) to collect research samples (blood, urine and faeces) and (any) residual diagnostic samples from patients (adults, children and infants) with any infectious or

The IDB cannot recruit from patients who are prisoners or those who are incapable of providing informed consent (other than children where the parent/guardian can consent for them). There are also restrictions for researchers and IDB samples cannot be used for 'trivial' or 'controversial' research projects such as those involving: fertility, reproduction, stem cells, cosmetics or animals. The IDB can establish TCCs at any NHS location in England, Wales or Northern Ireland with the co-operation with a local medical Consultant. Local NHS R&D

**4.2 Location and setting** 

in which to conduct clinical trials.

**4.3 Ethical permissions for the IDB** 

Ethics Council some four years later (Deutscher Ethikrat, 2010).

inflammatory disease who are attending a routine clinical appointment.

The IDB has a Governance Committee comprising of scientists, doctors, representatives of funding bodies and of the patients. This Committee is responsible for managing the IDB, strategy decisions, insuring that it conforms to current legislative requirements and also to local Medical school regulations. The IDB is regularly audited by the internal KCL Medical School representatives and by the HTA (~four times in 2010) and the results of these checks are passed back to the Governance Committee. Researchers wishing to access the IDB's samples submit a simple two-page application detailing what they propose to do and, the type and numbers of samples required. These details are scrutinized by the IDB's Governance Committee for scientific validity and also for any ethical dimensions. If successful, researchers sign a materials transfer agreement (MTA) and the samples are released.

Staff involved in recruiting volunteers must all have completed 'in house' courses on 'consent taking', 'good clinical practice' and phlebotomy. Copies of these certificates are held by the IDB. Members of the IDB staff are also encouraged to undertake an academic module in ethics, philosophy and religion (a three year 'Associate of KCL' course). The Governance Committee has also established a clear policy on charging researchers to access the IDB's material; they may either agree to pay a fixed rate for the individual samples or contribute funds towards the salaries of IDB staff, to offset the processing and storage costs incurred by the IDB. Researchers are encouraged to approach the IDB early on during the preparation of grants so that projected costs can be included in their applications.

### **4.5 Quality control**

The IDB utilizes standardized operating procedures (SOPs) based upon EEC standards (ISO guideline 34,# 17025:2005) and works within the UNE-EN-ISO 9001:2000 guidelines to facilitate future inter-biobank networking capabilities. Samples are continuously tracked from the time of venepuncture, the time of courier collection from the TCCs, through to freezing at the IDB, with a target of processing >75% of samples within four hours of the bleed. All materials from patients with infections are processed in negative-pressure category III laboratory and stored in locked -80 ºC freezers. All of the freezers are: on a protected hospital electricity supply; alarmed to the IDB's staff mobile telephones; and, checked daily for temperature fluctuations. None of the released samples from the collections have undergone a freeze-thaw cycle. Purified DNA samples are tested for the concentration of DNA and, by polymerase chain reaction (PCR) amplification of the housekeeping gene β-globin, for the absence of PCR inhibitors prior to release. In-house assessment of viral RNA viability has also revealed that viral RNA and sequences can be recovered from all plasmas of HIV patients so far tested (for those with viral loads of >350 copies *per* ml). Similarly, an independent analysis of human genomic RNA integrity has demonstrated that all of 104 samples were of highquality (mean RNA integrity values of 9.3, on a scale where 1=degraded and 10=completely intact RNA) and were successfully used to generate DNA for transcriptome analysis (Kozlakidis *et al*., 2011). Ultimately, the IDB aims to have all of its procedures, SOPs and operations validated by the International Standards Organisation.

In addition to merely maintaining the samples under the IDB's custiodianship we have also sought to enhance their research value. For example, for the core cohort of HIV infected patients approximately 33.3% of samples have been genotyped for their HLA class I and II alleles and their plasma viruses have had their Gag genes sequenced. The Gag region is important as protein products of this reading frame are believed to be important determinants in viral escape from the innate and adaptive arms of the immune system (Deml *et al*., 2005). To date, several hundreds of full-length Gag genes have been cloned and sequenced (and the latter data deposited in Genebank: accession numbers FN597659- FN600533). These cloned Gag genes are available to researchers by arrangement. The intention is to obtain equivalent data for the complete HIV cohort. The other type of quality control that the IDB is actively involved in is monitoring that the samples being collected are those which are of (a) most clinical significance and (b) representative of the local community. Initial analyses of the first 200 HIV patient volunteers indicated that it was collecting a population greatly enriched for those with unusual rates of disease progression and that the ethnicity of the volunteers matches well with that of the local community (Kozlakidis *et al*., In Press).

### **4.6 Transparancy**

772 Biomedical Science, Engineering and Technology

Staff involved in recruiting volunteers must all have completed 'in house' courses on 'consent taking', 'good clinical practice' and phlebotomy. Copies of these certificates are held by the IDB. Members of the IDB staff are also encouraged to undertake an academic module in ethics, philosophy and religion (a three year 'Associate of KCL' course). The Governance Committee has also established a clear policy on charging researchers to access the IDB's material; they may either agree to pay a fixed rate for the individual samples or contribute funds towards the salaries of IDB staff, to offset the processing and storage costs incurred by the IDB. Researchers are encouraged to approach the IDB early on during the

The IDB utilizes standardized operating procedures (SOPs) based upon EEC standards (ISO guideline 34,# 17025:2005) and works within the UNE-EN-ISO 9001:2000 guidelines to facilitate future inter-biobank networking capabilities. Samples are continuously tracked from the time of venepuncture, the time of courier collection from the TCCs, through to freezing at the IDB, with a target of processing >75% of samples within four hours of the bleed. All materials from patients with infections are processed in negative-pressure category III laboratory and stored in locked -80 ºC freezers. All of the freezers are: on a protected hospital electricity supply; alarmed to the IDB's staff mobile telephones; and, checked daily for temperature fluctuations. None of the released samples from the collections have undergone a freeze-thaw cycle. Purified DNA samples are tested for the concentration of DNA and, by polymerase chain reaction (PCR) amplification of the housekeeping gene β-globin, for the absence of PCR inhibitors prior to release. In-house assessment of viral RNA viability has also revealed that viral RNA and sequences can be recovered from all plasmas of HIV patients so far tested (for those with viral loads of >350 copies *per* ml). Similarly, an independent analysis of human genomic RNA integrity has demonstrated that all of 104 samples were of highquality (mean RNA integrity values of 9.3, on a scale where 1=degraded and 10=completely intact RNA) and were successfully used to generate DNA for transcriptome analysis (Kozlakidis *et al*., 2011). Ultimately, the IDB aims to have all of its procedures, SOPs and

In addition to merely maintaining the samples under the IDB's custiodianship we have also sought to enhance their research value. For example, for the core cohort of HIV infected patients approximately 33.3% of samples have been genotyped for their HLA class I and II alleles and their plasma viruses have had their Gag genes sequenced. The Gag region is important as protein products of this reading frame are believed to be important determinants in viral escape from the innate and adaptive arms of the immune system (Deml *et al*., 2005). To date, several hundreds of full-length Gag genes have been cloned and sequenced (and the latter data deposited in Genebank: accession numbers FN597659- FN600533). These cloned Gag genes are available to researchers by arrangement. The intention is to obtain equivalent data for the complete HIV cohort. The other type of quality control that the IDB is actively involved in is monitoring that the samples being collected are those which are of (a) most clinical significance and (b) representative of the local community. Initial analyses of the first 200 HIV patient volunteers indicated that it was collecting a population greatly enriched for those with unusual rates of disease progression and that the ethnicity of the volunteers matches well with that of the local community

preparation of grants so that projected costs can be included in their applications.

operations validated by the International Standards Organisation.

**4.5 Quality control** 

(Kozlakidis *et al*., In Press).

Given the multiplicity of studies that any individual sample may be used in, the Governance committee decided that logistically it would be impossible to provide individual volunteers with research feedback on their individual samples, despite reports that this is the preference of potential volunteers (Meulkamp *et al*., 2010). However, the IDB does attempt to provide feedback in the types of studies performed and these data are displayed on the IDB's website (http://www.kcl.ac.uk/schools/medicine/research/diiid/centres /pii/ biobank/index.html). The IDB has also publicised its mission and was reviewed in *Nature Medicine* (Towie, 2006), has published in *Retrovirology* (Williams *et al*., 2009), *Biopreservation and Biobanking* (Kozlakidis *et al*., 2011) and has made presentations to national and international meetings (*e.g.* the 2010 Biobanking Conference; the European Virology Congress in 2008 & 2010, Nuremberg and Como). The IDB director has served on the feasibility study of Biobanking in Northern Ireland (NI) for the NI NHS R&D committee (2008), the KCL College Research ethics committee and associated sub-committees (2010-) and, is chair of the IDB Governance and ethics committees. The IDB has also consulted with patient representatives and has, as a consequence, increased its electronic footprint by establishing KCL IDB sites on the social networking sites 'Facebook' and 'Linkedin'.

### **4.7 Growth of the IDB**

Since sample collection was initiated in January 2007 there has been a logarithmic growth in the number of patient visits to TCCs as well as the numbers of studies approved to access IDB samples (Figure 2). Indeed, currently the IDB is processing over three litres of peripheral venous blood *per* week. These examples of growth have also been matched by the expansion of the IDB into new categories of diseases. These now include those with hepatitis C virus or papillomavirus virus infections and patients with inflammatory diseases (including: as diabetes, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, and, pre-multiple sclerosis syndrome). Some of the currently approved studies are listed (Table 2), and a steady stream of research publications is starting to ensue (Nath *et al*., 2006, 2007; Alvarez *et al*., 2008; Thorborn *et al*., 2010). In addition, publications arising from the contract research work of the IDB are expected to increase significantly (4.8 below).

Fig. 2. Year-on-year growth of the IDB's HIV sample collection. Gray bars indicate the recruitment of new patients in total, whereas black bars indicate the number of donations per year.

T-Regulatory cells in HIV infection

Ps20 studies in HIV infections

The roles of vpu and tetherinin HIV/AIDS pathogenesis

The control of inflammation in immunity and autoimmunity

Naive B cell responses in older people

Gene expression signatures of HIV-1 infection *in vivo* and *in vitro*

ccess and study residual clinical samples made available during routine joint surgery.

Genetic variations in IL28B on the natural history of hepatitis B and C and their treatment response.

Non-infectious co-morbidities in HIV infection

Renal function and bone homeostasis in patients starting HAART

Defining the function of CD161+ CD8+ T cell subsets in HIV infection and their response to therapy

Investigating the effect of Maraviroc on Microbial Translocation in HIV infected individuals who are receiving antiretroviral therapy

The metabolic impact of Darunavir/ritonavir maintenance monotherapy after successful viral suppression with standard Atripla in HIV-1-infected patients

Table 2. Some of the types of studies currently accessing the IDB.

### **4.8 The IDB as a contract service**

The IDB's skill and expertise is also being currently utilized to provide research support for clinical studies performed locally, these are often intervention studies and hence require independent ethical permissions from LRECs other than that of the IDB. The largest of these is currently the KCL Human Immune Response Dynamics (HIRD) study. This ground-breaking longitudinal study is investigating the response in humans to vaccination with the H1N1 ('swine flu') influenza vaccine using a protocol was approved by the Brent LREC (09/H0717/88). Briefly, the study involves the IDB collecting and archiving of peripheral venous blood samples from overnight fasted volunteers at the CRFs. Two pre-vaccination samples are harvested and, after vaccination (with PandremixTM H1N1 vaccine: GlaxoSmithKline Biologicals Ltd), a further four samples are collected until six weeks post vaccination. To date over 170 volunteers have completed the course of bleeds and vaccination.
