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Spotlight on the FDA : Oct 15, 2009 ( )
Update on Evolving Regulatory Guidance
Companies Need to Be Cognizant of and Continually Adjust to Changing Guidelines
The FDA’s position on a myriad of issues is constantly evolving. Companies need to be aware of these pending and implemented changes and adjust their practices accordingly. This month’s column will focus on ghost writing of medical journal articles, personnel training, access to investigational drugs, foreign inspections, and cancer vaccines.
Exposing industry ghost writing of articles for clinical investigators has been high on the agenda of Senator Charles Grassley, who has been asking major medical journals what their policies regarding such articles are. In fact, many sponsors of clinical studies, faced with the slowness of their clinical investigators to write up the data, have tried to expedite the process by organizing the clinical data tables and even writing the first draft.
Obviously, some larger pharmaceutical companies have taken this one step further and employed medical writers to completely ghost write clinical articles. Companies are now faced with a dilemma—how much assistance can they give clinical investigators to facilitate article preparation?
One solution currently being implemented is to put a separable, deliverable payment clause in the clinical site/investigator agreement that facilitates the timely preparation of a final manuscript ready for submission. Another option that several companies are pursuing is providing an acknowledgement in an article footnote stating what the company provided, for example, statistical and data charts and/or methods and materials section drafting.
Senator Grassley appears to be receptive to the idea of footnoted disclosure in the published article. It remains unclear how journal editors and reviewers feel about such practices, however.
GCP: Personnel Training
In a recent warning letter, FDA made clear to both clinical investigators and sponsors that the level of good clinical practice experience in clinical coordinators needs to be explicitly demonstrated. The warning letter in question cited an inexperienced clinical investigator for his reliance on equally inexperienced clinical coordinators, all of whom lacked sufficient training.
This warning letter, and several others like it that were also recently sent, bring to the forefront the fundamental problem of sponsors not adequately conducting site-initiation visits and site-personnel training before allowing clinical protocols to be initiated. Inadequate corporate monitoring and quality-assurance auditing are likely responsible for these failures.
Needless to say, FDA inspected the sponsor after inspecting the clinical investigator.
New Access to Investigational Drugs
In mid-August, FDA published two guidance documents that allow expanded patient access to investigational drugs/biologics outside of a clinical trial. The documents also defined the circumstances under which individual patients, as well as intermediate and larger size patient populations, can obtain unapproved investigational drugs.
Additionally, the FDA clarified the circumstances under which companies can charge for access to an unapproved investigational drug/biologic and what type of costs can be recovered. (Additional information can be found at www.fda.gov)
As a result, companies developing promising new therapies are now likely to have more inquiries from patients who have failed approved therapies. Companies should anticipate such requests with policies regarding access. They should also consider how to best use the opportunity that these two new guidances present; specifically, companies with orphan drugs should look at the utility of the guidance to facilitate clinical exposure beyond their clinical study.
Foreign vs. Domestic Inspections
Earlier this year, the FDA was criticized for the lack of technical strength in its foreign inspection program. As a consequence, FDA recently announced that it is doubling the number of overseas facility GMP inspections that it conducts. The FDA also reported that these could be unannounced inspections.
I am aware of one non-U.S. manufacturer of OTC drugs that did have a surprise inspection, but it was merely to validate that the non-U.S. company is an active OTC drug manufacturer. Nonetheless, unannounced FDA inspections present a new challenge to non-U.S. product manufacturing facilities.
A shift in CBER’s stance on therapeutic cancer vaccines was evident in the organization’s recent “Draft Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines” (September 2009).
FDA has recognized that testing cancer vaccines using the conventional model in metastatic cancer patients may not allow time for development of an antitumor immune response needed for demonstration of potency/effectiveness.
The agency concluded that the administration of an investigational vaccine in patients with metastatic cancer, who are receiving multiple treatments that are detrimental to the immune system, likely minimizes the potential responsiveness to the cancer vaccine being tested.
However, testing cancer vaccines in patients with no evidence of residual disease or who have minimal burden of disease, as discussed in this guidance, may provide adequate time for the immune response elicited by the cancer vaccines to develop and manifest.
This new position focuses the initial clinical effort on safety and demonstration of an immune response, as well as on determining the optimal-vaccine dose, dosing regimen, and maximum-tolerated dose. FDA previously stated that the demonstration of an immune response is not considered an indicator of potential efficacy.
The interesting question is whether investors will accept an immune response as a sufficient proof of principle and support the continued development of the experimental vaccine.
Bruce F. Mackler, Ph.D., J.D., a senior advisor in FDA matters, is lead contributor to GEN’s “Spotlight on the FDA” column. Web: www.brucemackler.net.
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