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Members from an ASQ working group provide analytical methods to enable PAT.
GxP regulations are in place to ensure the purity, quality, and safety of pharmaceuticals. Manufacturing and quality control testing of approved drugs falls under good manufacturing practice (GMP) regulations. Safety studies for drugs are regulated by good laboratory practice (GLP) regulations. There currently are no guidelines for drug discovery and biomedical research activities. This phase of drug development is relevant to stage 1 product design in the pharmaceutical product lifecycle. Because researchers have no standard to follow, there is often wasted time and effort when unreliable studies need to be repeated.
A working group from the American Society for Quality (ASQ) Food, Drug, and Cosmetics Division (FD&C) published its first technical report, Best Quality Practices for Biomedical Research in Drug Development, in June 2012. This report addresses the need for biomedical research standards and provides the first step leading to the eventual creation of an ISO standard. Drugs and therapeutic products touch our daily lives in myriad ways. From the vitamins and aspirin we take for common ailments to the cardiac and cancer treatment medicines for serious illness to the hormones in animal feeds, these drug products find their way into everyday use. The public's interest is captured by the expectations provided by biomedical research and drug development. Besides the commercial value, the governmental and private funding support in the developed countries, primarily the US, provides the overarching hope of curing human illness and suffering, while providing the additional benefit of greater economic development. One aspect all drug developments have in common is specific government regulations known as GMPs. These regulations ensure that drug products are safe, pure, and efficacious. The GMP regulations ensure that all aspects of the manufacturing processes use "good practices" and science to produce drugs with the integrity and validity the process was intended to produce. These regulations can all be found under their respective sections of the Code of Federal Regulations (CFR) Title 21, Parts 210 and 211 in the US. Similar documents exist in Canada, Europe, and globally through the World Health Organization's guidance.
Routine medical laboratories involved in patient care are covered by well-defined international quality standards (ISO 15189) and national laws (42 CFR 493). In pharmaceutical R&D, only the nonclinical laboratory safety studies are governed by the GLP regulations 21 CFR Part 58. There are no other well-defined quality standards existing for other non-GLP laboratory research, including biomedical research that may lead to new drug discovery. This potentially causes an incongruous situation in a biomedical research laboratory, where for example, a blood sample from a rabbit is subjected to stricter quality standards than a human sample. FDA expects that "sound quality principles" are applied to the processing of human samples, but these principles are not well defined or delineated.
Much of the aforementioned investment, both financial and research, comes from the US. For example, the proportion of the global drug-development pipeline belonging to organizations headquartered in the United States has increased to 80% in the past decade (1). In the US alone, about $68 billion per year is spent on biomedical research. Due to poorly designed studies or the irreproducibility of biomedical research data and studies, the consequences of pursuing a drug development dead end have become an increasingly serious issue. The credibility of this biomedical research data has lead to costly and often futile attempts at repetition of these studies. These efforts are a unnecessary waste of scarce valuable funding resources. Is it not better that the spending on these drug-development programs find new therapeutics for the many unmet medical needs and not be squandered on irreproducible or worse, fraudulently reported research?
The National Center for Dissemination of Disability Research published a whitepaper that supports this concept... "the widespread belief that the quality of scientific research is often uneven and lacking in credibility, making it difficult to make a confident, concrete assertion or prediction regarding evidence for improving practice or consumer outcomes (Levin & O'Donnell, 1999; Mosteller & Boruch, 2002; Shavelson & Towne, 2002). ...is also due, in part, to the lack of consensus on the specific standards for assessing quality research and standards of quality for assessing evidence (Gersten et al., 2000; Mosteller & Boruch, 2002). For example, several researchers have contended that some of the current peer review processes and standards for assessing quality are not well suited for research in the disability arena (Gersten et al., 2000; NCDDR, 2003; Spooner & Browder, 2003)" (2).
There has been an overall significant decline of productivity in pharmaceutical biomedical research over the past 15 years when comparing the number of new medicines to the equivalent funding spent in R&D (see Figure 1).
Figure 1: New Molecular Entities (NME) and R&D spending 2001-2009.
Obstructions to new drug entity breakthroughs have received much scrutiny since the recent decade-long decline in new drug approvals. Thus, notwithstanding the doubling of biomedical research funding and the shift toward clinical research by pharmaceutical companies, "the number of new molecular entities approved by FDA has fallen...as a consequence, pharmaceutical productivity decreased over the last 10 years, and it is lagging behind that of the biotechnology and device sectors... Financial return to investors has paralleled those changes in productivity" (3).
One of the root causes for the reproducibility problem is the lack of a common quality standard for nonregulated biomedical research. Traditionally, non-regulated biomedical research has been considered off-limits for formal quality standards. Scientists in general regard their work as a highly intellectual activity where quality is knowledge and experience is an integral part of the scientific rigor that they apply. A longstanding tradition of quality control in science has been peer review of the results, but modern pharmaceutical research has become so complex that peer review has a limited value today. Also, "some scholars suggest that while standards such as peer review and standardized reporting are important benchmarks, research should not be judged solely by whether or not it is published in the leading journals (Boaz & Ashby, 2003). While journal publication and citation analysis provide quantitative data, it is a faulty assumption that all 'research' that is published in journals or cited by others is accurate, reliable, valid, free of bias, non-fraudulent, or of sufficient quality (Boaz & Ashby, 2003). Further, citation analysis is primarily a measure of quantity and can be artificially influenced by journals with high acceptance rates (COSEPUP, 1999)" (4).
The scope and dimension of modern research is moving science out of the realm of individual scientists and into a globalized team where standards, transparency, and reproducibility have become key requirements. Scientific work that cannot be reproduced or independently verified by others is a waste of valuable limited resources. Also, biomedical research generates intellectual property, which has become increasingly subject to internal and external scrutiny and is often challenged in litigations. The authenticity and integrity of scientific data underlying an intellectual property claim are therefore of utmost importance. To prove the authenticity and integrity of scientific data, studies and experiments must be conducted under controlled and verifiable conditions.
A common quality guideline when utilized in biomedical research and drug development will ensure the validity and credibility of scientific data from different research institutions and facilitate the mutual acceptance of research results. Such a document will help to eliminate unnecessary duplication of existing research work, make published research data more reliable, and increase the overall lagging productivity of biomedical research. These attributes will benefit patients worldwide by speeding drugs to market, meet global regulatory compliance requirements, and enhancing investor interest in developing new innovative drug product that produce a solid return on investment (5).
The FD&C Division of ASQ has published a technical report addressing the need for biomedical research standards (6). The ASQ guideline specifies the general quality requirements for non-regulated biomedical research in drug development to ensure credibility of biomedical research results. This includes both large- and small-molecule discovery and non-clinical development that is not covered by GXP (6-11).
The target audience for this report is the scientific staff at institutions and companies involved in drug development. Compliance with applicable regulatory and safety requirements is not covered by this report. The following summarizes the major sections covered in detail in the technical report.
Management of the research institution shall establish and document policies and procedures for its activities. Management shall ensure appropriate organizational structures, resources, and processes to implement, maintain, and continuously improve the quality system.
The research institution shall have necessary authority and resources to perform duties and responsibilities; policies restraining external influences; protection of intellectual property; accountability of data and reports; effective, independent quality management systems; and proper facilities and equipment to perform study.
The research program should follow good management practices and have a well-defined work structure, track and communicate reporting progress and performance, and have change control for study objectives and outcomes.
Quality management system. Management shall establish, implement, and maintain a quality management system (QMS) appropriate to the scope of its activities. The QMS established must be capable of ensuring reproducibility of biomedical research results to support effective drug development (e.g., deviation management, self-inspections [audits], research review, internal review, external reviews) (see Figure 2).
Figure 2: Quality management system interrelationships.
Study plans, procedures, and activities shall be documented in writing to assure data quality, integrity, authenticity, and reproducibility. Research institutions shall, therefore, establish and maintain procedures to control all documents that prescribe how studies and experiments are to be conducted and describe how studies and experiments were conducted. Documents can be divided into two broad classes:
Document control and approval. Research institutions must establish procedures for the control of prescriptive and descriptive documents. Procedures must include a formal review, approval, and distribution policy such that only the most recent approved documents are available for staff use. In addition, such procedures must include the following:
Training. Training of personnel is critical to develop and maintain competence. All personnel should be made aware of the importance of training and its impact on the quality objectives. Research institution management shall ensure that staff assigned to perform research activities have the appropriate combination of education, experience, and training to be competent with their assignments.
Facility and infrastructure. The research institution shall have facilities and equipment sufficient for the conduct of the study and to maintain the infrastructure. Infrastructure includes buildings and workspace, utilities, storage areas, computer and communications networking, and safety equipment.
Test equipment. Test equipment shall be designed, located, and maintained to suit its intended purpose and meet good practices, cleaning, calibration, and validation.
Test methods and method validation. Validation is the confirmation by examination and the provision of objective evidence that the particular requirements for a specific intended use are fulfilled. Validation of methods used in a research institution is critical for the integrity and authenticity of study results.
Sampling and chain of custody. Adequate and correct sampling is critical for ensuring that the sample taken is a true representative of the whole. The research institution shall, therefore, have a sampling plan and procedures for collecting samples of substances, materials, or products for subsequent testing.
Receiving, handling, and storage. The handling, storage, and types and quality of materials used in the conduct of biomedical research can affect the outcome of the research.
Test articles, control articles, and test systems. The purity, concentration, and stability of test articles and control articles (where used) can greatly affect the outcome and repeatability of a study or an experiment. Therefore, the purity, concentration, and stability and storage of test articles and control articles shall be specified and evaluated and documented periodically following standard operating procedures.
Legal and ethical considerations. All personnel involved in biomedical research activities are to act in an ethical manner. Examples of non-ethical behavior include, but are not limited to, plagiarism, fabrication, selective or biased data reporting, and financial or external influencing of study results.
Protection of IP. An understanding should exist between the parties regarding ownership of IP. In addition, a non-disclosure agreement may be established to ensure that the confidential nature of the study and study results are maintained.
Research institutions may outsource a portion of their research activities to a third party. The subcontracted work may be subject to the research institution's quality system. As such, care must be taken to place such work with a competent subcontractor. The research institution shall have a policy and procedure(s) for the selection and purchasing of services and supplies it uses that affect the quality of its research work.
A. Mark Trotter is president of Trotter Biotech Solutions, Inc. and is a section board member of the American Society for Quality's Food, Drug, and Cosmetics division, firstname.lastname@example.org. Rick Calabrese is global corporate director of Quality Systems at Sartorius Stedim Biotech and is a senior member of ASQ's FD&C division. Ulo Palm, MD, PhD, is senior vice-president of Clinical Operations and Biometrics at Forest Research Institute and is a senior member of ASQ's FD&C division. Alice Krumenaker is manager R&D QA at CorePharma and is a senior member of ASQ's FD&C division.
1. PhRMA, Pharmaceutical Industry Profile 2011, Washington, DC: PhRMA (April 2011).
2. National Center for Dissemination of Disability Research, "What Are the Standards for Quality Research?" Quality Matters 4 (2011).
3. H. Moses III et al., JAMA, 9 (2005).
4. National Center for Dissemination of Disability Research, Quality Matters, 4 (2011).
5. R. Calabrese and U. Palm, Quality Digest (2008).
6. ASQ, Technical Report, ASQ TR1-2012, Best Quality Practices for Biomedical Research in Drug Development, FD&C Division (June 2012)
7. WHO, World Health Organization, Handbook: Quality Practices for Biomedical Research (2006).
8. ISO 17025, ISO 900X.
9. BARQA, Guidelines for Quality in Non-Regulated Scientific Research, BARQA (2008).
10. ICH, Q2 Validation of Analytical Procedures: Text and Methodology, 1994/1996.
11. 21 CFR Part 58.
12. ICH, Q9 Quality Risk Management.