Quality in clinical trial activities

“Achieving quality in clinical trial activities is a key target for both regulators and developers of medicines. Discuss whether this quest for quality and the approach taken to achieving it are justified”

Introduction:

Quality is often described as meeting consumer’s needs, depending on the perspective, the needs of pharmaceutical consumers can encompass budget, ethics, law & regulation, good practice, credibility, and reliability of clinical data (Kleppinger and Ball, 2010). As such, many definitions of quality exist in the pharmaceutical setting which include aspects of these perspectives (Haleem et al., 2015). In the clinical setting, quality can be thought of as the emergence of high-quality data that is free from errors that would otherwise compromise the integrity of conclusions drawn from the trial data (Bhatt, 2011).

Consumers must trust and rely on the quality of medicines they receive (Haleem et al., 2015). These individuals are unable to determine nor confirm the quality of their medicines before they use them. Poor quality drugs can impact patient health in both direct and indirect ways. The regulators act behalf of the public, to ensure these products are of an acceptable quality and in doing so, they determine what constitutes acceptable quality (Woodcock, 2004).

The efficacy, tolerability and safety of medicines is determined by their quality. The quality of a drug therefore depends as much on its manufacturing, contents (active and inactive), storage and distribution as it does on the data derived and interpreted from clinical work carried out on these products (Kaufman and Novack, 2003). The verification and assurance of quality is determined by procedures and regulatory requirements. The work required to ensure and maintain high quality represents significant time, energy and cost (Fàbregas-Fernández et al., 2009).

Failures of manufacturing quality are not new issues nor figments of history, regulatory agencies were fist established in response to the high-profile quality breach of 1937, with contaminated sulphanilamide in the USA (FDA, 1981). Meanwhile, as recently as 2012, failures in the production of methylprednisolone acetate led to the death of nearly 70 individuals (Smith et al., 2013). Likewise for clinical quality failures can have dramatic effects. The advent of novel therapies mean that while quality guidelines may be met, the principle of these guidelines may not. An example of this would be the TGN1412 disaster where initial starting dose was with hindsight, miscalculated (MHRA, 2007). The result of this ushered in changes to clinical quality guidelines and legislation with regards to calculating first time in human dosing as well as, the concept of sentinel dosing, among other changes (TSO, 2006). The legacy of such clinical practice quality failures are not simply limited to the bankruptcy of the drug sponsor but, widespread impact on the whole industry and increased reticence in volunteers and patients alike to take part in clinical research (Nada and Somberg, 2007). The unpredictable nature of human participants variable in clinical research adds further complexity, compared to other areas of research (Kleppinger and Ball, 2010).

Continual monitoring and improvements from sponsors and trial investigators can ensure regulatory compliance on quality clinical research which should go some way to safeguarding data integrity and participant life. However, the meeting of regulatory standards is not always achieved and equally does not always ensure that quality outcomes are fully met.

A Regulatory Approach to Quality

From a regulatory perspective, approaches taken to ensure quality are defined though guidelines and legislation.

GxPs or good ‘x’ practices were introduced to prevent fraud, protect consumers and maintain data integrity (Carson et al., 2007). They are now the legal requirement for drug development and are quality benchmarks based on best practise to ensure drugs are safe and fit for their designed use and that clinical activities involving them are therefore of good quality (EudraLex, n.d.). GxPs are dynamic and are updated by individual regulatory agencies, when appropriate. The main GxP guidelines cover manufacturing, clinical activities, non-clinical work and drug distribution.

Good Manufacturing Practice (GMP) outlines the minimum acceptable standards for the manufacture, processing and packaging of drugs and devices. The MHRA require GMP compliance and the passing of manufacturing site inspections before they will issue a licence (MHRA, 2019a). Good Distribution Practice (GDP) concerns the distribution of drugs and regulates how they are transported from the manufacture site to the end user (MHRA, 2019a). Good Laboratory Practice (GLP) outlines best practice relating to non-clinical studies. Compliance with GLP ensures that submitted data can be relied on when making risk and safety assessments on investigational products (MHRA, 2019b). Good Pharmacovigilance Practice (GPvP) provides the minimum acceptable standard for monitoring of drug safety. GPvP represents a legal requirement of drug safety monitoring to detect changes to a drug’s risk-benefit balance (MHRA, 2019c).

Good Clinical Practice (GCP) is a guideline that provides the ethical & scientific minimum acceptable standards for the development of drug products, the conduct of clinical activities and the recording and reporting of the data and results from these activities. GCP compliance provides assurance that research participants are safeguarded and that the data produced from this research is both reliable and credible (EuraLex, 2005). Regulatory inspections ensure compliance with legislation (MHRA, 2019d). GCP guidelines further explain that quality assurance (QA) systems and procedures must be implemented and the maintenance and control of quality must be defined in standard operating procedures (SOPs) in order to ensure these clinical activities, documentation and the data derived from them are carried out and reported as defined in the protocol. SOPs are required to meet GxPs. without them, no quality standard can be met (EuraLex, 2005).

We accept that we cannot be 100% certain of the quality of the research that precedes the development of a drug or the clinical activities where this drug is tested (Griffith, 2004). Uncertainties exist and monitoring processes are put in place to catch unknown problems ideally, before they can cause harm. The compliance to GxPs and other regulatory frameworks of quality are proxies used to infer quality in drug products, the clinical activities that use these drugs and all pharmaceutical practice.

An Industry Approach to Quality:

Several different systems exist for companies to ensure and maintain quality in their operations and clinical activities. QA is an internal audit process that is kept independent from the rest of the company functions, it aims to ensure the data and findings from clinical work are collected and reported are GCP compliant (EuraLex, 2005) and that SOPs and GxPs are being met and maintained across the business. Quality Control (GC) represents the activities carried about as part of QA, which validate the clinical trial plan and help to ensure uncertainties are minimised and characterised effectively (Pettersen, Aird and Olsen, 2008). QA is becoming more challenging and resource hungry as trial protocols become more complex (Getz et al., 2008). As clinical work is increasingly outsourced and internationalised maintenance of quality standards is more challenging as both the analysis of quality defects and the required corrective action becomes difficult to conduct and oversee (Bhatt, 2011).

Quality by Design (QbD) is a concept that frames quality as something that must be built-in to the product and not just tested for (ICH, 2009). Successful QbD concerns ensuring quality of materials and production processes to ensure that the drug performs as planned and that aspects of clinical practice that would impact on decision namely, primary endpoints and issues of patient safety (Yu, 2008).

QMS is the system that encompasses QA, QC (Kleppinger and Ball, 2010), ensuring a company complies with its quality commitments (Lakhal, Pasin and Limam, 2006) ICH Q10 describes a model for a QMS that is grounded in principles from International Organization for Standardization (ISO) 9000 (ICH, 2018) . The focus of ISO system is to ensure that consumers needs and regulatory compliance is met and introduces the principle of continuous improvement in these areas (Haleem et al., 2015). ISOs represent a model for working towards GxP, data integrity and document control compliance.

GxPs are not QA systems, but they provide guidelines for practice and control of processes that provide assurance that quality requirements have been satisfied. GxPs should be integrated with Quality Management System (QMS) in order to ensure that quality is a feature in all aspects of the business (Bhatt, 2011).

Meeting Quality Targets

Risk assessments are a key feature of both regulatory and corporate approaches to quality. Risk is the probability of quality failures occurring, that impact data integrity and regulatory or standards compliance. By identifying and focussing on these areas, risks can be well managed and minimised, preserving quality. During clinical activities, risks are continually addressed and mitigated when identified (EMA, 2013a). GxPs, the FDA and EMA all recommend the use of risk-based monitoring and management (Agrafiotis et al., 2018).

Internal Monitoring

Risk-based monitoring ensures that the resources devoted to this activity safeguards participants and protects data quality (Gupta, 2013). Study risks are assessed, such as the investigational drug, trial population and study design and the monitoring level is then determined (FDA, 2013). A 2012 study found that in the UK over half of registered trials carried out risk-based monitoring (Hurley et al., 2016).

GCP guidelines state clinical trial monitoring as a key quality standard (EMA, 2016). 100% source data verification (SDV) is a model of clinical monitoring and requires data validation for all case report form (CRF) contents. Its impact on clinical trial data quality is questionable (Tudur-Smith et al., 2012) while adverse impacts on site performance caused by the time burden to maintain it are well-established (Getz et al., 2008). Results from risk-assessment may mean 100% SDV may not be required if there is sufficient on-site monitoring in place (FDA, 2013).

Regulatory inspections

Even the best QMS and QA systems are imperfect. Regulatory inspections take place to ensure that companies adhere to the legislation and meet quality guidelines. Risk-based inspections represent a pragmatic approach to monitoring and ensure quality compliance. It is not feasible to inspect every element of every process for every clinical trial. By focusing on a small number of trials, investigators make inferences of how the company adheres to their SOPs and regulatory requirements more widely (Simović and Nikolić, 2015).

The frequency of inspections is based on a risk assessment, identifying the most likely causes of quality failures and areas where quality failures will have the greatest impact. To this end, any organisational changes, or findings from previous visits would raise the risk profile of a pharmaceutical company. Higher risk sites will result in more frequent inspection, short-notice, or unannounced inspection. Random inspections will also take place for those companies who are judged to be medium to low risk. Phase I units can undergo specific accreditation to verify the quality of clinical work and are routinely inspected every other year (MHRA, 2019d). These inspection procedure are harmonised across the EU through GCP IWG in order to ensure there is an equal standard of quality being maintained across the whole EU (EMA, 2013b).

Inspection Findings

The most recently published Annual Review of MHRA GCP Referrals from the MHRA is for 2018, where 115 total referrals were made up from 76 serious breaches of GCP and a further 15 which are still being determined. Most of these breaches were related to patient safety. Of all the serious breaches, 15 of the resulted in some kind of inspection (MHRA, 2018). The number of breaches in 2018 is not dissimilar to the number found over the previous 2 years of referrals (MHRA, 2017; MHRA, 2016) demonstrating that the pursuit of quality is ongoing and furthermore, that despite the plethora of regulatory guidance, critical and major issues are still be identified at routine inspections.

Conclusion

The underlying philosophy behind achieving quality in clinical activities is based on the social contract between the pharmaceutical companies and society, to safeguard of human life while providing efficacious medicine. The inability of most consumers of medicines to independently assess the quality of their purchased products places further responsibility on the pharmaceutical industry that must take priority over the maximisation of profits and shareholder dividends. To this end, the quest for quality is a noble one and must continue to develop and grow, despite the increasing financial burden this may place on manufacturers.

Many companies view quality standards and regulations as tasks to be achieved and areas of comprising quality may be introduced either unwittingly or, through cost minimisation strategies. Furthermore, the aims for quality from a company perspective might, cynically, be described as only to provide sufficiently robust data to support marketing authorisation and reimbursement applications and nothing more, instead of the pursuit of highest possible quality.

Regulators must stay up-to-date with technological advances. As knowledge and technology improves, the expectation of quality and the minimum acceptable standards are raised, to ensure new products are launched with less uncertainty surrounding their benefit-risk profile. This creates a never-ending quest for quality in the name of improving medicines for both individuals and society. Regulatory checks on drug companies are conducted by risk-assessment, which is only as effective as the risk determination model. The nature of these inspections mean that individual visits may not be representative of the conduct and quality of the range of clinical activities. Acceptable variability between trials and trial sites do somewhat limit the ability of regulatory inspections to infer quality standards are always being met. Furthermore, year-on-year, quality deficiencies are being detected and reported by regulatory agencies, which show the pursuit of quality is ongoing.

The high level of drug quality shows the effectiveness of these systems and the considerable resource allocation directed in this pursuit. Further work can be done to rethink models of quality and QA to improve the effectiveness of these systems while managing the resource burden required to maintain them.

Other ideas such as, the streamlining of research to prevent unnecessary wastage as well as the improvement of outcome measures and selections to gain patient involvement (Minogue et al., 2018) and the use of models and techniques from other industry areas to improve and integrate QMS and QA processes such as, Total Quality Management (Issac, Rajendran and Anantharaman, 2004) can go some way to adjust the need for resources, however regulatory acceptance of these novel models must also be provided for them to be attractive options for industry to introduce and apply.

A principle of continual improvement should be instilled in companies so quality initiatives and guidelines are not seen as targets, but that the philosophy behind the regulation is understood and acted on accordingly. Unfortunately, history shows that left to their own devices, these principles are relegated when it comes to maximising profits. The risks of product quality failures are huge and where human life is concerned, the pursuit of quality is always justified, even though to approaches used may not be.

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