Interesting WSJ article
Some Potential Blockbusters Suffered Delays Amid FDA's Tougher Safety Stance
WASHINGTON—The Food and Drug Administration approved about 21 drugs in 2010, a relatively modest figure that shows the pharmaceutical industry hasn't yet escaped its drought in recent years.
A few potential blockbusters won approval during the year, but some of the most highly anticipated new products got delayed into next year or beyond. That partly reflects a tougher environment at the FDA, with regulators stepping up their scrutiny of safety issues in drugs for obesity, diabetes and other conditions.
The final approval figures, as well as the number of applications received by the agency in 2010, won't be available until next month. The approval figures don't include dozens of approvals granted for new formulations or new uses of existing drugs.
Although the 2010 figures are a bit lower than previous years, FDA spokeswoman Sandy Walsh said there's "no systemic change in how the FDA is approaching drug approvals."
The figures include several major biologic drugs, which are created from living cells and represent a growing portion of the pharmaceutical market. Amgen Inc. won approval for Prolia, a drug that is injected twice yearly to treat osteoporosis in postmenopausal women. Roche Holding AG's biotechnology unit, Genentech, won approval for Actemra, a drug that's administered intravenously to treat rheumatoid arthritis.
Boehringer Ingelheim GmbH received approval for Pradaxa, a new type of blood-thinning drug to prevent strokes in patients with irregular heart rhythms. The company got a head start in a race among big drug makers to replace warfarin, an anticoagulent approved in 1954 that is still widely used.
AstraZeneca PLC suffered a setback in that race when the FDA earlier this month asked for more information about a study backing its application for the blood-thinning drug Brilinta. The delay drove down AstraZeneca shares more than 5%.
Patients with multiple sclerosis saw advances in treatment with the October approval of Novartis AG's Gilenya, an oral product. Multiple sclerosis has traditionally been treated by injections or infusions. Earlier in the year, the FDA also approved Acorda Therapeutics Inc.'s drug Ampyra to improve walking in MS patients.
In August, the FDA approved ella, a longer-lasting emergency contraceptive that's designed to block pregnancy up to five days after sex. The product was developed by HRA Pharma, a closely held company in Paris, and was introduced in the U.S. earlier this month by Watson Pharmaceuticals Inc.
In April, Dendreon Corp. won approval for its prostate cancer therapy Provenge, which had previously been rejected by the agency. Provenge is designed to use a patient's own cells to stimulate the body's immune system to fight the cancer and may be the first in a new class of cancer-fighting drugs.
However, 2010 may be more notable for drugs that weren't approved, as well as for drugs the agency restricted or pulled off the market.
In addition to putting off a decision on Brilinta, the FDA also rejected a long-acting version of diabetes drug Byetta, sold by Amylin Pharmaceuticals Inc. and Eli Lilly & Co., saying more clinical data are needed to address cardiovascular safety concerns.
In October, the FDA declined to approve two proposed weight-loss drugs from Arena Pharmaceuticals Inc. and Vivus Inc.
The FDA closed the books on one of the highest profile drug-safety matters in recent years by sharply curtailing the use of GlaxoSmithKline PLC's diabetes drug Avandia in September after it was linked to increased risks of heart attacks.
In October, the agency removed Abbott Laboratories' weight-loss drug Meridia from the market, saying the drug didn't work well enough to justify potential heart problems. A month later, the makers of painkillers Darvon and Darvocet agreed to take those drugs off the market, after many years of concerns about an increased risk of serious abnormal heart rhythms.
In December, the FDA said it would move to revoke the approval of Roche's cancer drug Avastin for use in breast cancer, saying the product didn't appear to help patients live longer. Roche is appealing the move, which won't affect the use of Avastin in other types of cancer.
The agency said this week it needed more time to review MannKind Corp.'s inhaled-insulin product to treat diabetes. It also said it needed until next March to review Benlysta, a highly anticipated lupus drug from Human Genome Sciences Inc. and GlaxoSmithKline
The on Guidance on the topic was first issued in 2001 but since then clinical research and outsourcing have evolved. Revisions to the document cover industry shifts and technological advances, such as the rise of electronic records, but the focus and goals of the document remain unchanged.
“These regulations establish specific responsibilities of sponsors for ensuring the proper conduct of clinical studies for submission to FDA (US Food and Drug Administration) and the protection of the rights and welfare of subjects involved in clinical studies”, says the guidance.
While retaining this focus the FDA compliance program guidance manual (CPGM) for sponsors, contract research organisations (CRO), and monitors has been revised with the addition of new sections and deletion of others.
For instance, electronic records and signatures are now covered by the guidance. Although this is new the goal is unchanged, with regulatory requirements staying the same “whether clinical data are captured on paper, electronically, or using a hybrid approach”.
Submission of information to ClinicalTrials.gov is another change. Inspectors must now determine if studies were registered on ClinicalTrials.gov, who entered the information, and whether primary and secondary outcome measures are listed.
Clinical trials are increasingly conducted outside the US and the FDA guidance accounts for this change. Overseas trials must be compliant with good clinical practice (GCP), says the guidance, and the FDA must be able to validate data through an on-site inspection if deemed necessary.
Globalization has advanced alongside multisite trials and both are addressed by the guidance. “With the prevalence of multisite clinical trials, traditional monitoring techniques – early and frequent on-site visits at all clinical sites – have become resource intensive”, says the guidance.
Other areas addressed by the guidance include: what to do when fraud is suspected; financial disclosure from investigators; and how to investigate whether emergency research followed guidelines.
In the sprit of realizing the vision of a set of end-to-end harmonized standards for the collection and submission of data from clinical studies, this standard describes the basic recommended (minimal) data collection fields for 18 domains, including common header fields, and demographic, adverse events, and other safety domains that are common to all therapeutic areas and phases of clinical research.
The Clinical Data Acquisition Standards Harmonization CDASH Version 1.1 was developed via CDISC’s consensus-based standards development process that included comments from organizations in all three ICH regions (US, Europe and Japan).
CDASH V 1.1 also includes implementation recommendations and best practice guidelines, regulatory references and other information on the CDASH project.
In addition to working towards the publication of CDASH Version 1.1, the CDASH Team has been working on a number of related and supportive projects that include the development of a CDASH User Guide, CDASH-ODM metadata, and, in collaboration with the CDISC SDS and Terminology teams, the development of new domains and associated documents for medical devices and therapeutic area CRFs. Following are short summaries about these important CDISC projects:
The CDASH Team and domain teams are currently reviewing comments from the public review of the CDASH User Guide (CDASH UG), which takes into account feedback received from early implementers and incorporates other additions and improvements that will make using the CDASH standard easier. The CDASH UG is targeted for publication in 2011 and will be available in the Members area of the CDISC website when published.
The CDASH-ODM team has developed the machine-readable metadata to accompany the CDASH standard and example CRFs created from their work are included in the CDASH UG and the updated CDASH training course. Both the ODM files (metadata) and the CDASH UG with conformant CRF examples will be available in the Members area of the CDISC website when published in 2011.
The CDISC-AdvaMed Device team is working to develop both the basic collection fields (CDASH) and the submission (SDTM) variables and mappings to support the majority of device studies. The Device team is working towards producing an initial consensus version in late early 2011.
- CDISC Therapeutic Area CRFs
The CDASH Team is working with other CDISC teams to develop therapeutic area (TA) specific CRFs to be used with the safety CRFs described in the CDASH standard. Draft TA specific CRFs will be released for public review according to the CDISC consensus process.
Go here to download the PDF http://www.cdisc.org/cdash
An FDA plan to audit the growing use of electronic records by the pharmaceutical industry has been delayed by at least several months due to bureaucratic snags, although an agency official says the widely anticipated effort is still expected to get under way soon.
At issue is industry compliance with a regulation known as 21 CFR Part 11, which was designed to catapult the agency and industry into the 21st century (see the guidance from 2001 Here). The move to conduct so-called inspectional findings comes as the FDA hopes to firm up those rules for using electronic technology for such activities as gathering info from clinical trials and manufacturing.
Last spring, an agency official confirmed the FDA’s Center for Drug Evaluation and Research, or CDER, would undertake the audits, although exact timing had not yet been determined (back story). Six months later, though, the effort has been sidetracked over scheduling issues, according to sources. In some cases, field investigators had already made scheduled visits to various facilities and making additional stops this calendar year to review 21 CFR Part 11 compliance was apparently not going to happen.
“The delay was due to administrative issues and as soon as these issues have been addressed the Part 11 assignments are planned to be put back on track and issued to the field,” Robert Tollefseon, a consumer safety officer and national expert on computers at the FDA’s division of field investigations, writes us in an email. “Unfortunately, I do not have the exact date the Part 11 assignments will be issued but I do anticipate they will be coming out soon.”