Original Post Date: December 17, 2010
Author: John English
Recent warning letters have contained two new trends and they have been repeated this week. The first is still rare but it is the inclusion of a cease to market order in the warning letter itself. The second is an enhanced FDA comment about what the letter does and doesn’t say about “your facility.”
Several times so far this year, FDA warning letters have included a ‘cease to market’ order. These orders have usually been for “off-shore” companies, although the last one referenced in this group was for a NY-based contract manufacturing company. Another warning letter has just been made available (14 DEC2010) for a domestic company that produces diagnostic assays, a CDRH regulated product. The text is quite to the point:
FDA requests that FIRM NAME immediately cease marketing, promoting, and distributing all in vitro diagnostic products that require PMA approval or 510(k) clearance without FDA approval or clearance. The adequacy of your corrective actions will be evaluated during our next inspection…..
It may be a coincidence that the other US-based example had issues related to testing as well but that one was under CDER. (Integrity of test results is certainly a key FDA focus point – whether the results are “traditional” or electronic.) This new letter also contains another item – it is one of two this week that includes a new ‘disclaimer’ if you like.
Warning letters usually contain a summary text that is similar to the following (also posted 14 DEC 2010):
Finally, you should know that this letter is not intended to be an all-inclusive list of the violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA.
Recent letters have added the additional ‘disclaimer’ – which is not unprecedented, but it isn’t a common one. That said, it was also in two letters made available this week. The CAPITALS are my insertion:
The specific violations noted in this letter and in the lnspectional Observations, Form FDA 483, issued at the close of the inspection MAY BE SYMPTOMATIC OF SERIOUS PROBLEMS IN YOUR FIRM’S MANUFACTURING AND QUALITY ASSURANCE SYSTEMS. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance….
The new FDA focus on enforcement ties in with their attention to two key areas – the Quality and Manufacturing systems. It also points out the responsibility to take investigations seriously and make your CAPA system work:
“You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.”
Many of you may observe that all of the above is quite basic and should go without saying, to use an old phrase. While I agree, the agency keeps saying it – and saying it more pointedly. The question should be therefore – is the industry listening? More specifically, since these letters are addressed to Senior Management, will there be additional efforts by FDA to question why quality activities are not carried through? Another letter posted this week (CDER product) includes this statement – the unsaid question is why is this happening. Again, the CAPITALS are my addition.
“Our inspection found your firm’s quality unit failed to adequately review batch records. The above major batch record deficiencies underscore the importance of appropriate quality unit oversight at YOUR firm……
YOU are responsible for investigating and determining the causes of the violations identified and for preventing their recurrence and the occurrence of other violations. It is YOUR responsibility to ensure your facility operates in compliance with all requirements of federal law and FDA regulations….”
Those of you who do the field level compliance work know who you are. The question is who has the authority to enable these efforts? And what steps are being taken to ensure the field level efforts are successful?
NOTE – Since these letters represent trends, the specific companies are not identified.
John English is a consultant to the life sciences industry.
Original Post Date: April 1, 2010
Author: Mindy Allport-Settle
Some things will never change when it comes to getting a new drug or medical device to a state of commercialization that includes profits beyond simple revenue. Regulatory approvals, mountains of paper work, clinical trials, research and development efforts that sometimes lead nowhere are only a few. Some things, though, are changing.
Most of the people who develop an idea for a new drug or medical device product have more than one idea — more than one viable target. Traditionally, we sift through our ideas and choose the one that seems like it has the best chance of success. Maybe that means it will treat the largest patient population or be the most appealing to a venture capital firm. What do we do with the ideas that don’t make that cut? We frequently abandon them — especially in favor of a target that has a higher dollar value down stream. Maybe we should be taking advantage of more of those ideas.
Two new entrepreneurial strategies for financing research and development efforts and eventually bringing flagship products to market have emerged over the last few years.
1. Commercialize first in countries outside North America and the European Union
While drug and medical device sales in the United States account for an average of 80% of a company’s revenue, ignoring the rest of the planet is a mistake. Many countries are eager to approve products for commercial sale with abbreviated clinical studies. The revenue might not be much, but it will provide additional patient data and might provide enough of a revenue stream to off-set the cost of U.S. commercialization efforts.
2. Develop a non-drug product that doesn’t require regulatory approval
OTC (over the counter) products are a multi-billion dollar industry. There are even countries that will brand their product with your name to provide you with products to help establish your brand.
One product that illustrates both of these concepts is Monster Be Gone / Monster Be Good™. This product addresses a very real and sometimes difficult to manage condition in pediatric-aged patients: fear of monsters. The revenue from this product alone would not support a company, but in combination with other similar products, the revenue can pay base salaries and facility costs. Being able to keep the lights on and paying salaries takes some of the fear factor out of the normal research and development cycle leaving the company a little more freedom to grow.
Mindy Allport-Settle is the CEO of PharmaLogika, Inc and is a consultant to the life sciences industry. She has worked extensively with the manufacturing development of traditional and non-traditional vaccine platforms.
Stringent Compliance Required in Pioneering Biotechnology, says Physician & Human Gene Therapy Researcher
Original Post Date: February 1, 2010
Author: Evan Scullin, MD
A clinical trial conducted at the University of Pennsylvania went horribly awry in 1999 when one of the gene transfer trial subjects, an 18 year old man named Jesse Gelsinger, spiraled into a devastating immune reaction and died as a result. Jesse suffered from ornithine transcarbamylase (OTC) deficiency, a rare genetic disease caused by the inexpression of a functional OTC gene, preventing the normal elimination of ammonia from the body. This deficiency results in a toxic build up of ammonia, a protein metabolite. For the gene transfer trial study, the team at the University of Pennsylvania utilized an engineered strain of the adenovirus, which causes the common cold.
In an April 2009 Article in Molecular Genetics and Metabolism, Dr James M. Wilson, the director of the clinical trial said, “It is clear now that the Clinical and Quality Assurance (QA) groups did not have the resources necessary to assure complete compliance for such a dynamic and complex protocol. They were asked to cover too much territory; each clinical research nurse oversaw as many as three gene therapy protocols at any one time, while the QA group, which numbered seven staff members at its peak, was responsible for most aspects of [Good Manufacturing Practice] GMP, [Good Clinical Practice] GCP, and [Good Licensing Practice] GLP compliance for up to seven active investigational new drugs. Support for these programs was provided primarily from grants and contracts that, individually, did not provide sufficient Clinical and QA resources to fully support specific protocols.”
Wilson said that insufficient Quality Assurance played a major role in the trial’s shortcomings along with a conflict of interest with a biotechnology firm, Genovo that had invested heavily in the treatment. By not rigorously considering the QA aspects of the trial, he said, patient safety had been placed at risk.
In a later interview in September 2009 with the journal Scientific American, the director of the trial, Dr. Wilson posed the question in an interview, “If the worst-case scenario played itself out—not the potential or likely, but the worst—would [going ahead with the study] be acceptable?” His answer to this question was — absolutely not. This central question, he says, would have been an excellent gauge as to whether his team was ready to proceed with the study. It would also serve as a solid cue to the industry as a whole today for evaluating whether all supports for a trial are in place before moving ahead, particularly in regard to Quality Assurance.
This specific case demonstrates the high importance firms must place on GMP, GCP, GLP toward preventing scenarios where patient safety can be compromised amidst powerful forces that often act on those studies. When companies have invested in research, clinical trials become high stakes endeavors. Companies want to develop solid products for the least in cost, but following short-cuts in testing and bringing those products to market threaten the very innovative products themselves, by casting a cloud over the specific technologies when things go wrong.
Aggressively pursuing new therapeutic technologies is important in order to bring effective cutting-edge treatment to patients, but this is only worthwhile when patient lives and interests are fully protected first. In the competitive world of scientific discovery – especially in the life-sciences, the industry must seek safety first before seeking return on investment. Life-sciences firms must consider good compliance practice as “routine” and as part of the cost of doing business in successfully developing and manufacturing new products for patients.
The following are Dr Wilson’s enumerated lessons learned from the failed project, as listed in the April 2009 article:
Lesson #1: The clinical protocol is a contract with the research subjects and regulatory agencies that must be strictly and literally adhered to.
Lesson #2: If you think about reporting – then do so!
Lesson #3: It is very difficult to manage real or perceived financial conflicts of interest in clinical trials.
Lesson #4: Informed consent may require objective third party participation
These lessons could apply to most any clinical study and would certainly serve as part of a helpful roadmap for innovative biotech and pharmaceutical endeavor in the decade ahead.
Molecular Genetics and Metabolism:
Dr. Evan Scullin is the Director of Business and Product Development of PharmaLogika, Inc and is a consultant to the life sciences industry. His work focuses on both domestic and cross-border pharmaceutical ventures and collaboration between medical institutions, governments and private firms.