By Daniel R. Matlis
On September 15 2008, FDA’s final rule on “Current Good Manufacturing Practice and Investigational New Drugs Intended for Use in Clinical Trials” will become effective.
The Rule makes “early phase 1 clinical drug development safe and efficient by enabling a phased approach to complying with current good manufacturing practice (cGMP) statutes and FDA investigational requirements.” Additional detail is available in the FDA’s Companion Guidance Document.
Phase 1 trials are used as the initial introduction of an investigational new drug into humans. These studies are closely monitored and may be conducted in patients, but are usually conducted in healthy volunteer subjects. These studies are designed to determine the metabolic and pharmacologic actions of the drug in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness. Phase 1 clinical trials, are often carried out in small-scale, academic environments, typically involving fewer than 80 subjects (many of them college students).
The rational for exempting most phase 1 investigational drugs from the requirements in 21 CFR § 211 (cGMP) is based on the premise that since most products do not proceed beyond the clinical trial phase of development, the burden of full compliance with cGMP at the phase 1 stage outweighs the benefits.
According to Rachel Behrman, M.D., associate commissioner for clinical programs and director of FDA’s Office of Critical Path Programs, “The new rule and guidance are intended to assure that manufacturers meet high standards for the safety of phase 1 drugs and biologics while removing unnecessary barriers that can slow the development of these potentially life-saving products.”
The FDA will continue to exercise oversight of the manufacture of these drugs under FDA’s general statutory CGMP authority and through review of investigational new drug (IND) applications.
I asked a friend, who is Director of R&D and product development at a large Pharma company in Central New Jersey, to review this article before publication. She commented that: “There may be a balance or even some good that this will do to expedite the process and invest the cost savings elsewhere, which may add value in the long run. The entire drug development process is very costly and very unpredictable, but to your point, patient safety needs to be at the forefront.”
The fact is that bringing a new drug to market is a time consuming and expensive process. According to latest estimates it on average 12 to 15 years to bring a drug to market (See Figure)
The cost for bringing a new drug to market, that is from discovery to FDA approval, hovers around 1 Billion (yes with a B) dollars.
As we globalize and outsource development and manufacturing, it is critical to bear in mind that while mature sponsor organizations will often “do the right thing” even they are not obliged, these expectation are not always met by operating practices at “less than mature companies or those in economies” (do Heparin and Rambaxy ring a bell)
In the current drive to outsource, clinical manufacturing is a reasonable and viable development avenue. According to Jeffrey Meltzer, Director of Quality Management at Pharmaceutical Manufacturing Research Services Inc., “a key challenge of this approach is that some people and organizations think manufacturing outsourcing means that they are also outsourcing responsibility.” Meltzer added, “The implementation of this final rule makes it even more critical to partner with a mature, well established contract organization that has in place systems to confirm mutual expectations including contractor and sponsor responsibility.”
Failure to establish appropriate procedures and controls over Phase 1 manufacturing may in fact delay drug development and make it more costly. “Sure, you may get your Phase 1 done a bit faster and cheaper, but if the work is not well documented and well controlled, it increases the risk of incorrect development decisions” commented Meltzer.
My R&D Director friend at the Big Pharma Company (who shall remain nameless) pointed out that I seem pessimistic. She is right I am a bit concerned about this rule, especially as we outsource to less mature markets.
This concern stems from the experience that individual and organizational responses to regulatory compliance fall into four categories. (See Regulatory Compliance – Nature or Nurture?)
In my experience, many regulatory Zealots and Rationalist are in mature companies, for whom “Thou Shalt Do The Right Thing Even If Not Obliged” has been ingrained into the fabric of the organization. On the other hand, I have a sense that you would find many more Contrarians and Illusionned at less mature organizations.
Although the vast majority of Life-Science companies will do the right thing even if there is no regulatory requirement to oblige them. I am afraid that for some, aggressive development timelines and short term financial pressures may trump patient safety, especially where “doing the right thing” is not a core value.
This is one time when I hope I’m wrong. Because as the adage goes, there is never enough time to do it right, but there is always time to do it over.
In our industry, the consequences of a do-over can be life-threatening.
So please, do the right thing even when no one is looking.