Therapeutic drug products touch our lives daily in innumerable ways. Starting with the nutraceuticals we take to supplement our diets and the analgesics we take for common ailments to the cardiac and cancer treatment medicines for serious illness, these drug products enter into our everyday lives. The public's hopes have been nurtured by the expectations provided by biomedical research and drug development. Governmental and private funding provides the support for drug discovery to help cure human illness and suffering. One aspect all drug manufacturing processes have in common is the government regulations known as Good Manufacturing Practices or GMPs. These regulations can all be found under their respective sections of the US Code of Federal Regulations Title 21 CFR Parts § 210, and § 211. Similar documents exist globally; WHO and in European and Asian Pharmacopoeia. In pharmaceutical research and development, only laboratories performing clinical safety studies are governed by the Good Laboratory Practices (GLP) CFR Part 58. There are no other well-defined quality practices or standards existing for non-GLP laboratory research, including biomedical research that may lead to new drug discovery.
The proportion of the global drug development pipeline belonging to research organizations based in the United States has increased to 80% in the past decade. In the U.S. about $68 billion per year is spent on biomedical research.1 Hastily designed experiments coupled with the irreproducibility of biomedical research data and studies have the consequence of drug companies pursuing a therapeutic development dead-ends. This outcome has become an increasingly serious issue. The credibility of this biomedical research has lead to costly and often futile attempts to replicate these studies. The efforts to confirm and duplicate these defective studies often result in an inexcusable misuse of scarce, valuable funding and time resources.
A White Paper published by The National Center for Dissemination of Disability Research 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
Notwithstanding the doubling of biomedical research funding and the shift toward clinical research by pharmaceutical companies,...' the number of new molecular entities approved by the 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...' 3. Obstructions to new drug entity breakthroughs have received much scrutiny since the recent decade-long decline in new drug approvals. 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, Figure 1.
A venerable tradition in scientific publications is the peer review of the study results. However, as the latest biopharmaceutical research has grown in complexity, often requiring in-depth specific knowledge, that general peer review has a diminished role 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
Modern biomedical research is moving scientific research out of the realm of individuals to globalized teams wherein quality practices / standards and reproducibility become key requirements. Scientific work that cannot be reproduced or independently verified is a squandering of valuable capital and time resources. Additionally, to prove the authenticity, integrity, and reproducibility of the data and experiments, they should be conducted under controlled and verifiable conditions. One of the root causes for the reproducibility problem is this lack of common quality practices for non-regulated biomedical research.
The ASQ FD&C 'Best Quality Practices for Biomedical Research in Drug Development' technical report can provide the guidance for creditable and reproducible work without hindering the essential creative environment in basic research. This quality guidance can lessen or eliminate the duplication of research work, make published study data more reliable and enhance the productivity of biomedical research. These quality practices can benefit patients by speeding novel drugs to market, meet regulatory drug requirements, augment investor interest in developing innovative drug product that produce the necessary return on investment.5
Summary of Technical Report Content & Scope 7-12
The FD&C Division of ASQ has published a technical report, Best Quality Practices for Biomedical Research in Drug Development, ASQ TR1-2012, which addresses the need for biomedical research standards (6). This Technical Report specifies the quality requirements for non-regulated biomedical research in drug development, Figure 2. The scope and intent is to ensure credibility and reproducibility of these biomedical research studies. This includes both large and small molecule discovery and non-clinical development that is not covered by GxP.
The target audience for this report is the scientific staff at institutions and companies involved in drug development and biomedical research. The following summarizes the major sections covered in detail in the aforementioned 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 /reports, effective, independent Quality Management Systems, and proper facilities and equipment to perform study.
The research program should follow good management practices: well defined work structure, tracking and communications reporting progress /performance, 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.
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 therefore be divided into two broad classes:
Prescriptive documents, which give specific instructions on how a study or experiment is to be conducted, e.g., Standard Operating Procedures, (SOP).
Descriptive records, which describe what was actually done and what happened during the course of a study or an experiment, e.g., Data / Reports / Lab Books /Publications.
Document control / Document approval and issue:
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:
The research institution shall establish and maintain a change control process for impact, repeatability, approval, traceability, and implementation. Training must be documented.
Documents shall be stored in a secure and suitable environment that provides confidentiality and prevention from loss, deterioration and destruction. Retention times shall be established and, if applicable, be in compliance with appropriate laws and regulations.
Personnel: Training 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 those staff assigned to perform research activities has 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, safety equipment.
Equipment Design - Equipment shall be designed, located and maintained to suit its intended purpose and meet good practices, cleaning calibration, validation etc.
Test methods / 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 / biased data reporting, financial / external influencing of study results. Protection of intellectual property - an understanding between the parties regarding ownership of intellectual property. In addition, a non-disclosure agreement may be established to ensure that the confidential nature of the study and study results are maintained.
Vendor Selection and Qualification:
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, MS, MBA, President, Trotter Biotech Solutions, Inc.
- Rick Calabrese, Global Corporate Director Quality Systems, Sartorius Stedim Biotech
- Li-Chung Huang, Chair ASQ-Philadelphia Section, Process design/improvement expert
- Alice Krumenaker, Manager R&D QA, CorePharma.
- Ulo Palm, MD, PhD, MBA, Sr.VP Clinical Operations & Biometrics, Forest Research Inst.