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On June 14, 2010, the Supreme Court of the United States granted an appeal in Matrixx Initiatives, Inc. v. Siracusano (No. 09-1156) case to resolve whether a publicly traded life sciences company can be held liable for securities fraud for failing to disclose a statistically insignificant number of “adverse event reports” regarding one of its products.

The First, Second, and Third Circuits had previously recognized that the undisclosed adverse event reports should rise to the level of statistical significance before disclosure to investors is required, the Ninth Circuit recently had the contrary opinion on appeal to the Supreme Court.

The Advanced Medical Technology Association (“AdvaMed”), the largest medical technology association in the world filed an amicus brief that urges the Supreme Court to overturn the Ninth Circuit’s decision and find that life sciences companies cannot be held liable for securities fraud due to lack of reporting of adverse events when they don’t meet normal statistical criteria for significance

The problem with the position of the Ninth Circuit’s is that adverse event reports are inherently unreliable and subject to biases, because in the absence of statistical significance, they are not evidence of a causal relationship and are subject to distortion by the mass media. If this is transposed to the all of the pharmaceutical industry in principle any information received could be seen as material which in turn would require that anything received should be immediately disclosed.

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We have all got used to audits and inspections  in Drug Safety, but as we get comfortable with the concept the world is rapidly changing again.

The traditional safety audit focus inspecting the deliverable/products, like expedited reporting or PSURs, coming from the safety function.

This concept has worked to some extent, but the costs for the industry – and in the end patients – is monumental.

In order to stay profitable the industry has to be flexible enough to manage significant changes in revenue when products have safety issues or go off patent. To adapt the industry is outsourcing which make it easier to upscale or downscale when the need changes, but it increases the complexities in the process – and it create new compliance risks.

Other industries like aviation, automotive or retail have seen these problems decades ago and invented the Quality Management System concept, where there is a focus on the organizations ability to ensure stable processes which are continuously monitored and improved. Read the rest of this entry →

Implementing a quality management system can seem very complicated and theoretical at first sight, but a deeper review will reveal a number of very practical activities. In this article the main components to consider is referenced. This list is developed based on ISO 9001, but will cover all general quality system components.

4 Systemic Requirements

4.1 Establish your quality management system (QMS)

Develop your quality management system

• Identify the processes that make up your quality system.
• Describe your quality management processes.

Implement your quality management system

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The  FDA Title 21 CFR Part 11:Electronic Records; Electronic Signatures; Final Rule (August 1997) will now be enforced by FDA.

The rule imposes significant requirements on development, implementation and use of electronic systems in FDA regulated industries. FDA have announced (8JULY2010) that they now will start enforcing the rule through focused inspections based on the 21CFR11 requirements and the 2003 guidance document. Below is a quote from the announcement:

“The Agency (FDA) will be conducting a series of inspections in an effort to evaluate industry’s compliance and understanding of Part 11 in light of the enforcement discretion described in the August 2003 ‘Part 11, Electronic Records; Electronic Signatures — Scope and Application’ guidance (Guidance). The Agency intends to take appropriate action to enforce Part 11 requirements for issues raised during the inspections that do not fall under the enforcement discretion discussed in the Guidance.”

This is a very interesting development after more than 10 turbulent years for the regulation.

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The US Food and Drug Administration (FDA) has launched a new Post marketing Drug Safety Evaluation website during June 2010.

The FDA posted post-market safety evaluations for some drugs approved between September 2007 and January 2008 and is continuing ot review additional products.

In accordance with the Food and Drug Administration Amendments Act of 2007 (FDAAA), the FDA summarizes information about ongoing and completed post marketing safety evaluations of serious adverse events (SAE) submitted to the FDA since September 2007.

These evaluations are completed to determine if there are any new SAE not previously identified during product development, known side effects reported in unusual number, or potential new safety concerns identified post approval.

These post marketing evaluations has to be performed no later than 18 months following approval or after its use by 10,000 individuals, whichever is later.

FDA analyzes an number of data sources for the safety evaluations:

• Adverse event reports in the AERS or VAERS databases
• Review serious adverse event reports
• Medication error analysis
• Product utilization analysis
• Risk management review
• Analysis of post-approval safety data from clinical trials and other studies, when applicable

Summaries of FDA safety analyzes on recently approved products will now be prepared quarterly and posted on FDA’s website along with a brief discussion of the steps FDA is taking to address any identified safety issues.

The drug safety function and associated safety systems has to be continuously ready for inspections by regulators and partners.

The requirements are tightening quickly and pharmaceutical companies have to demonstrate that they are in full control internally as well as externally for collaborating partners  and suppliers. It is no longer sufficient just to send expedited reports on time – a full implemented quality management system will be necessary both for the pharmaceutical company internally as well as for the suppliers and partners they work with.

Below is a list of the questions you can ask in your organization to ensure that you are better prepared to survive an inspection in drug safety without a warning letter or critical findings. The list is not all inclusive, but it will be updated when new requirements become available or if there are proposals from the readers

Pharmacovigilance Organization

1. Detailed Description of Pharmacovigilance Systems (Section 2.2 in EU Volume 9A)
2. Contact details of staff to be interviewed
3. Organizational charts
4. List of employees (names and functions)
5. Job/role descriptions
6. CVs
7. Training curriculum pr staff group and training records

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The Food and Drug Administration (FDA) has undertaken revisions to 21 CFR 312.32, 312.64, and 320.31 to better protect public health and improve safety reporting by increasing the quality of safety reports, expediting FDA’s review of critical safety information, advancing worldwide consistency in the collection and submission of safety information, and strengthening the agency’s ability to monitor the safety of certain human drugs and biological products. The final rule amends the premarketing safety reporting requirements for human drugs and biological products to codify the Agency’s expectations for timely acquisition, evaluation, and submission of relevant and useful safety information, to improve the overall quality of safety reporting, to implement internationally consistent definitions, to subject bioavailability and bioequivalence studies to safety reporting requirements, and to make other minor revisions. These revisions were proposed as part of a single rulemaking (68 FR 12406) to clarify and revise both premarketing and postmarketing safety reporting requirements for human drug and biological products. FDA plans to finalize the premarket and postmarket safety reporting requirements in separate final rules.FDA proposed rule changes for drug safety

As a general rule (ICH E2A and E2D) serious and related reports have to be submitted within 15 calendar days for both post marketing and clinical trial cases and for clinical trial cases resulting in death or permanent disability have to be reported within 7 calendar days.

As partnerships and outsourcing becomes more frequent in the industry it is often discussed when the clock starts for such expedited reporting. Is it when the first partner receives the first information or is it when the sponsor or marketing authorization holder receive the case information or is it different in different situations?

The European regulations as represented in Volume 9A section 4.2 specifies that the reporting time line for post-marketing ICSRs is 15 days counting the day the marketing authorization holder becomes aware of the case:

Post Marketing reporting timeframe Vol 9A

Often the reporting time line if a case report is received by a partner company. Here the new volume 9a has added a lot of clarity as any contractual partner is regarded the same as the marketing authorization holder:

Vol9a-Clock-Start

Some countries outside the European union have more unclear wording in their regulations like for instance Canada which says that reporting is counted from the time that the Canadian marketing authorization holder becomes aware. However they also say that the communication time to the Canadian marketing authorization holder should be minimized as much as possible – therefore ending up in pretty much the same situation as existed before the recent volume 9a update where the interpretation can be different. In effect you pretty much have to adhere to the 15 days globally no matter if your own company or a partner company receives the case first.

Investigator Sponsored Studies (ISS)

These studies are often initiated in new indications or for special sub-populations like children or elderly. Some are conducted through cooperative groups and some are individual Investigators. As a result these studies will follow the regulations related to clinical trials for unapproved products and indications at least when we are talking about reports related to the investigational products.

In the US this is covered by CFR 21 Part 312 which include requirements for investigational new drugs and CFR 21 Part 314 which covers approved drugs in the post marketing setting. In Europe these regulations and guidelines are specified in Volume 10 for clinical trials and in Volume 9A for post marketing drugs

In a warning letter from FDA to President Heather L Mason, Abbott June 2, 2010, the agency cites Abbott for lack of compliance with the devices legislation 21CFR820.
This is in line with the agency’s continuously more detailed review of both drug safety and medical devices.
The findings are grouped in 4 main categories:

1) Manufacturing quality control and testing failure
2) Follow-up on implementation of CAPA commitments failing
3) Product design control failing
4) Staff training, job descriptions and staff qualifications

1) The first finding is related to the fact that the quality control testing was not performed as described in the procedural documentation

2) The second finding relates to follow-up on some remedial actions that were not closed with an effectiveness check. In other words some problems was identified, but there were no actions defined or there were no follow-up on the effectiveness of these actions

3) The third finding relates to the rigor regarding product development specifications and version control so some design versions was not used and some where not tested appropriately within the defined time lines.

4) The fourth finding is especially interesting as agency cites 21CFR820.25 where they find that Abbott did not ensure that staff had qualifications required in the job descriptions. They refer to 4  jobs in specific, Director of Quality Systems, Regulatory Affairs Manager, Quality Control Supervisor and Calibration Coordinator. The FDA does not directly say that the staff does not have the qualifications to do the job, but simply quotes the requirements in Abbott’s own job descriptions. Abbott had initiated a review of the job descriptions, but the agency wanted a completion and effectiveness check.

These findings clearly show that the FDA now requires actions to be more specific and that they have clear completion dates and associated effectiveness check

On April 15, 1971, the New England Journal of Medicine published a report by three physicians at Massachusetts General Hospital on the association of DES therapy started during the first trimester of pregnancy by mothers of 7 of 8 girls and young women ages 14 to 22 diagnosed with adenocarcinoma of the vagina ^[1]
In November 1971, the FDA sent a FDA Drug Bulletin to all U.S. physicians advising them to stop prescribing DES to pregnant women because it was linked to a rare vaginal cancer in female offspring, and on November 10, 1971 ordered that prevention of miscarriage be removed from Indications and pregancy be added to Contraindications in the physician prescribing information for DES.[21] On February 5, 1975, the FDA ordered 25 mg and 100 mg tablets of DES withdrawn, effective February 18, 1975. DES was, however, never banned and continued to be prescribed in the U.S. and other countries well beyond 1971 (until 1978 in most European countries and as late as 1994 in some third world countries).

More than 30 years of research have confirmed that DES is a teratogen, an agent that can cause malformations of an embryo or fetus. However, not all exposed persons will experience the following DES-related health problems.

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1. ^[1] Herbst, A L; Ulfelder, H; Poskanzer, D C; New England Journal of Medicine; Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women;v:284 i:15 p:878-81; 4/15/71 ↩