New Clinical Trials Regulation EU No. 536/2014 on Clinical Trials with Medicinal Products for Human Use

Regulation (EU) No 536/2014 published on 16 April 2014 by the European Parliament and the Council of the European Union on clinical trials on medicinal products for human use.  This regulation will repeal Directive 2001/20/EC. 

Dirty Medicine

Original article, "Dirty Medicine: The epic inside story of long-term criminal fraud at Ranbaxy, the Indian drug company that makes Lipitor" by Katherine Eban:

http://features.blogs.fortune.cnn.com/tag/ranbaxy/

First successful MHRA prosecution under Good Laboratory Practice Regulations

The Medicines and Healthcare Products Regulatory Agency (MHRA) announced yesterday that a man was sentenced to three months in prison for altering pre-clinical trial data designed to support applications to perform clinical trials.

Steven Eaton was found guilty at Edinburgh Sheriff’s Court in March following a prosecution under the Good Laboratory Practice Regulations 1999.  This is the first time the MHRA has successfully used these regulations to bring a prosecution.

The case came about when Aptuit informed the MHRA that they had identified serious irregularities in pre-clinical data generated to support human clinical trials and the registration of new medicines.

The irregularities involved changing or providing false analytical data that would be used to determine the concentration of medicine that could be given to clinical trial subjects used to assess the safety and efficacy of a new medicine.

The MHRA launched an investigation to identify the number of studies affected and the impact the data irregularities would have on the interpretation of important safety data. The investigation concluded that Mr. Eaton had selectively reported analytical data over a number of years, dating back to 2003. During this period he selectively reported data which was used to assess whether analytical methods were working properly or to assess the concentration of the drug in blood. The data manipulation ensured an experiment was deemed successful when in fact it had failed.

The actions led to the review of many hundreds of safety studies assessing the impact of the data manipulation and to ensure that the compromised data was not used in future submissions to relevant authorities without their knowledge.

As a result of Mr. Eaton’s actions the development of a number of new medicines were significantly delayed and considerable cost to the study sponsors was incurred as a result of the delay.

Following a full assessment by the MHRA’s inspection team and assessors it was concluded that the data integrity issues did not invalidate the results of the clinical trials that were affected.

Gerald Heddell, MHRA Director of Inspection, Enforcement and Standards said, “Mr. Eaton’s actions directly impacted on the validity of clinical trials and delayed a number of medicines coming to market, including one to treat depression. The sentence sends a message that we will not hesitate to prosecute those whose actions have the potential to harm public health."

[Medicines and Healthcare Products Regulatory Agency. (2013). Man jailed in pre-clinical trial data scam case (Press release]. Retrieved from http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON263951.]

Join our mailing list to receive periodic updates and information

The 7th System: Integrating Clinical Systems into a Comprehensive Quality Audit Program

Clinical quality systems are often managed independently of manufacturing and laboratory operations.  This can result in a fractured view of each compliance area (GCP, GMP and GLP) and a failure to provide adequate oversight of an organization’s overall compliance.  Using FDA’s six-system inspection model as a starting point, this article will discuss how to integrate the requirements of clinical quality systems with a GMP compliant quality program to provide a system for comprehensive quality oversight. (View the original article)

The goals of a quality audit program are: 

• to provide an accurate view of compliance across the organization, including suppliers and vendors; 
• to identify and prevent or correct compliance issues; and 
• to inform management of the compliance status of the organization.  

However, differences in the implementation of GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice) compliance programs may occur due to the different focus of each program.  The GMP audit program is concerned with ensuring the identity, strength, safety, purity and effectiveness of the product or device, whereas the GCP audit program is focused on subject rights and safety, protocol conduct and data integrity.

Communication between the manufacturing and clinical disciplines may be obstructed in part by the use of different terminology, or by not using terms in the same manner to appropriately compare audit observations.  For example, use of the audit observation type “Validation” may describe an issue related to methods, equipment, packaging, or computer systems.  Without an appropriate description, this audit observation type is too ambiguous to be useful in assessing, preventing or correcting compliance issues.  “Investigational Product” is a common audit observation type used by clinical auditors, but this term is not sufficiently descriptive when relayed to manufacturing personnel as it does not describe whether the issue is related to the use, storage, labeling, or quality of an investigational product.

The use of different audit observation terminology and separate reporting systems may also obstruct an accurate assessment of the impact of systemic compliance issues and weaker compliance signals may be lost because they are maintained and reported separately. 

The accurate assessment of compliance with Standard Operating Procedures (SOPs), personnel training, vendor management, and complaints requires the ability to view issues across the organization, and the use of separate terms and reporting procedures may make it difficult to accurately quantify the total compliance risk of these activities or identify cross-functional issues that could impact investigational product integrity and/or subject safety.  Information from inspections of raw materials, production activities, packaging, labeling, warehouse and distribution, and clinical use may not be communicated effectively if issues are reported and communicated separately.

A shared quality system, using integrated audit observation categories, terminology and reporting can help to improve communication across functions and better meet the objectives of the quality audit program.  It should be noted that integrating the GMP and GCP quality audit programs does not necessitate a particular organization of the Quality Unit, although it is recommended to use the same system for assessing, reporting and resolving audit observations across the organization.

The Six-System Inspection Model defined by the U.S. Food and Drug Administration (FDA) provides an excellent foundation upon which to define the categories of a quality audit program. The model defines the following six systems:
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labeling System
• Laboratory Control System

Most of the systems defined in the six-system model are readily transferable to audit observation categories useful for the inspection of both manufacturing and clinical activities.  Many clinical requirements can be integrated into the six-system model.  Within the Quality System, observation types such as audit program, complaints, deviations, personnel training and qualification, Standard Operating Procedures, and vendor qualification may be appropriate to both GMP and GCP activities.  Audit observation types related to the Facilities 
and Equipment System, such as calibration/preventive maintenance, equipment management, facility security, cleaning, and sanitation may be appropriate to both GMP and GCP functions.  However, audit observation types related to contamination controls, environmental monitoring, HVAC systems and water systems may be used primarily 

for manufacturing rather than clinical activities.  Although the six-system model provides an excellent starting point, not all clinical audit observations fit well into the six-system model.  

The addition of a seventh Clinical System can accommodate the addition of clinical audit observation types within an integrated inspection model.  Examples of audit observation types within the Clinical System may include: adverse events, case report forms/source documents, ethics committee, informed consent, monitoring, protocol compliance, regulatory approval, serious adverse events, trial management and oversight, and trial master file. Although it may be appropriate to create additional systems or categories (e.g., to distinguish safety from other trial management activities) for the purpose of this discussion we will 

create only one additional category for Clinical Systems (Figure 1).  With the integration of clinical requirements into FDA’s inspection model, and the addition of a Clinical System to accommodate additional GCP observation types, the seven-system inspection model provides an integrated structure of audit observation categories to help achieve the goals of the quality audit program.  The use of audit observation terms in the same manner to define, report and compare audit observations promotes improved transparency and communication between GMP and GCP functions, and a more accurate view of compliance across the  organization to effectively assess, communicate and resolve compliance issues identified by the quality audit program.

If you like this article, please recommend it using the social sharing links below:

FDA Proposes New Rule for Acceptance of Data from Clinical Studies for Medical Devices

The Food and Drug Administration (FDA) is proposing to amend its regulations on acceptance of data from clinical studies for medical devices. The proposed regulation would require that clinical studies conducted outside the United States in support of an investigational device exemption (IDE) application, a premarket notification (510(k)) submission, a premarket approval (PMA) application, a product development protocol (PDP) application, or a humanitarian device exemption (HDE) application be conducted in accordance with good clinical practice (GCP), which includes obtaining and documenting the review and approval of the study by an independent ethics committee (IEC) and obtaining and documenting freely given informed  consent of study subjects.  The proposed rule is intended to update the standards for FDA acceptance of data from clinical studies conducted outside of the United States and to help ensure the protection of human subjects and the quality and integrity of data obtained from these studies.  As part of this proposed rule, FDA is also proposing to amend the IDE and 510(k) regulations to address the requirements for acceptance of data from clinical studies conducted inside the United States.  The proposed amendments are intended to provide consistency in FDA requirements for acceptance of clinical data, whatever the application or submission type.

The proposed rule is available using the following web link:  http://www.gpo.gov/fdsys/pkg/FR-2013-02-25/pdf/2013-04201.pdf

Sharpen Your Skills with Online Courses

ComplianceLogix referenced in article at HealthCallings.com.  Read the full article here: http://career-news.healthcallings.com/2013/02/08/sharpen-your-skills-with-online-courses/

Online Six Sigma Training Course Preview (playlist)