Electronic Submissions: Time = Money
A more computerized, modernized and automated FDA could result in significant reduction of time lost, as well as cost containment opportunities
A United States patent provides protection (in exchange for disclosure) for a period currently set at 20 years. Unlike some countries in which that 20-year period begins with approval of a product, the U.S. Freedom of Information Act makes the submission of a new drug application (NDA), biologics license application (BLA), or medical device application a public disclosure, requiring the filing of the patent prior to regulatory submission.
As the U.S. Food and Drug Administration (FDA) reviews, questions, awaits answers, ponders and eventually (hopefully) approves the application, the patent clock is running, losing the time for exclusive marketing of the product and hastening the day when a generic equivalent can drive down price and capture market share. In the medical device area, the effect may not be significant: most devices are accepted (or rejected) within six months. But it is not unusual for an NDA or BLA to drag on for years, costing the company an estimated $25 million per day in lost revenue.1
Any tool or technique that can shorten the review time represents significant cost containment. And, to date, the most effective way of speeding the preparation, review, modification and eventual approval of a new drug or biologic product is the use of electronic submissions.
The time gained by use of electronic submissions falls into two categories: increased speed and efficiency on the part of the submitting company, and increased speed and efficiency on the part of the FDA. Unfortunately the savings at the FDA end have not been as dramatic as the potential, although this is improving. Increased speed of submission and response by submitting companies has represented significant cost containment, and is likely to generate even greater savings in the future.
An investigatory new drug application (IND) can easily run 10 or more volumes, largely consisting of reviews and copies of published studies of the drug in questions. An NDA or BLA may consist of thousands of pages of clinical data in addition to the documents detailing the design of those studies, and directions for researchers conducting the studies (the investigators’ brochure). Assembling, transmitting and managing that volume of materials is a major task in itself, particularly if paper copies are used.2
And again, each day used to check to make certain that all copies have complete versions with every page included and numbered represent significant lost revenue as the patent continues to run.
Most applications result in some follow up questions from the FDA. These questions may necessitate insertion of additional materials in the NDA or BLA, corrections or other changes. Re-adjusting the page numbers for the table of contents can be a formidable task; if the changes cannot be handled with an addendum, a new paper copy may need to be reprinted, re-proofed and resubmitted. Again, without an electronic submission, valuable days may be lost.
An electronic submission also can significantly ease — and speed — the burden on FDA reviewers. With hyper-linking, the cross-checking of a cited reference with the actual article is a simple click process. Electronic indexing and searching can all but instantly find whether and where a specific issue is addressed. And the management of the multiple volumes of a complex application is simplified when that entire text is contained on one or two disks. In discussion of questions with submitting companies, the ability to get everyone literally on the same page and to move efficiently from the section in question to a specified response document can avoid delaying misunderstandings and confusion. And the mundane act of checking logistics, including complete page numbering, document inclusion, form completion and other administrative matters, can be reduced from days to minutes.
With all of these advantages it may be surprising that the FDA was so slow off the mark in accepting electronic submissions, and perhaps even more surprising that the agency often seems to prefer paper over electronic copies even today. In the early 1980s, the author was a member of an industry–FDA panel attempting (obviously without success) to establish standards for electronic data management. Even by FDA standards 20+ years is an unusually glacial pace. The reasons for the slow transition are complex but, finally, standards of formatting and transmission are emerging. As test projects are completed, support organizations fine-tune their tools, and FDA personnel become familiar with common products, a series of de facto or de jure electronic submissions standards are likely to supplement the guidelines currently in place, and the use of electronic submissions will become the norm in the drug, biologics and device industries — a major cost containment development.
The electronic submission of clinical and pre-clinical data provides a potential secondary benefit for both the industry as a whole and for individual submitting companies. This secondary benefit can provide substantial cost savings for the entire clinical testing process. In addition to providing electronic text that is easily indexed and electronic citations that can be effectively hyperlinked, the submission includes what are, in effect, two electronic databases of clinical findings. The first database can be mined to find the significant and subtle effects of the drug, biologic or device under investigation. Sophisticated statistical analyses can determine interactive effects, secondary side effects, counter-indications with linked diseases and other results of the protocol. The second database, consisting of control cases to whom the drug, device or biologic was not administered, is used to isolate and identify placebo effects.
As the second “control” database grows over time, it can serve two important cost containing functions. First, by matching subjects in the control database with subjects in a given experimental database, it may be possible to avoid the need for as many control patients in future clinical studies. In effect, the same patient might serve as a control in multiple experiments. Not only would this redundancy save some of the costs in clinical studies, but it also would eliminate a major ethical hurdle in clinical research: the withholding of treatment from a randomly selected control group to measure the true effects of a new therapy.
Second, as the control group database grows, it will be increasingly likely to provide information about the interactive effects of linked and of independent diseases. For example, it may be possible to study the effects of progressive heart disease on patients who are being actively treated for type II diabetes; or the effect on dementia with Lewy body disease on patients undergoing treatment for Parkinson’s disease. These finding not only would have potentially valuable research results, but could significantly contain the costs associated for clinical research in these areas.
These secondary benefits from electronic submissions (and from the commonly and cooperatively available databases the submissions produce) will not only help contain the costs of regulatory compliance, but ought to have a significant impact on the costs — and time — involved in clinical trials. With the potential for overlapping control groups, the time required for recruiting clinical subjects, in administering placebo therapies to the randomly selected (and blinded) control subjects, and in following those individuals should be reduced or eliminated. And, again, time is money as patent protection is finite and fleeting.
Initially the widespread use of electronic submission of clinical trial-based NDA, BLA and PMAs will reduce the review bottleneck and speed the review process, resulting in significant reduction of time lost while patent exclusivity is running. Over time, increased regulatory familiarity with the databases constituting those submissions will lead to cost savings in study designs as control groups are combined and interactive effects are modeled.
A more computerized, modernized and automated FDA will likely lead to other cost containment opportunities for the drug, device and biologics industries, as increased agency efficiency and improved industry-agency interaction permit more rapid, exact and efficient regulatory compliance.
1. Alex O’Mera, Chasing Medical Miracles, Walker Publishing, 2009
2. See S. Weinberg, Guidebook to Drug Regulatory Submissions, Wiley, 2009.
Sandy Weinberg is an associate professor of health care management and Ron Fuqua is an assistant professor of health care management at Clayton State University. They may be reached at editor@ScientificComputing.com.