An MD&DI November 1999 Column
- Harmonization power grab?
- FDA to appeal free-speech defeat
- Y2K won't bother many devices
- FDA's "least burdensome" guidance
Your device is approved, and locked in fierce competition with a rival. A scholarly professional journal, peer-reviewed, publishes an article comparing your device favorably with its competitorbut there's a catch. The use described in the article has not been approved by FDA for your competitor's devicealthough it has been for yours.
The marketplace is volatile, the article's credentials are impeccable, and if you don't strike while the iron is hot you could come under stockholder criticism. So, at the next available professional meeting, you flood the place with reprints and promotional materials, including a video presentation of your product in use. The result: you receive a warning letter from FDA calling your device both "misbranded" and "adulterated." This is official correspondence your competitor can use against you in retaliation. In fact, your competitor is probably the means by which FDA found out about your promotion.
This is what happened in August to Thoratec Laboratories Corp. (Pleasanton, CA). According to an agency warning letter, Thoratec's promotions took parts of two articles in the Annals of Thoracic Surgery out of context in claiming that its ventricular-assist device (VAD) had an 88.5% patient survival rate compared with 50% for the BVS-5000 VAD from Abiomed Inc. (Danvers, MA) when both were used as a bridge to heart transplantation.
Notwithstanding the fact that the articles were circulated in a respected journal for the medical profession to assess as it saw fit, it has been FDA's long-held policy that such publications cannot be used in device manufacturers' commercial promotions, even when presented as "educational" communications. Although this policy has been dealt a serious legal blow in recent litigation (Washington Legal Foundation (WLF) v. FDA, see related item on page 36), FDA is not yielding easilyas its eight-page letter to Thoratec on August 12 illustrates.
There were several problems with Thoratec's use of the articles, the letter said. Beyond the fact that the comparator device had not been approved by FDA for "bridging" use, the articles in question were not based on "a controlled clinical trial conducted by either Thoratec or Abiomed," but instead reflected European clinical experience with circulatory support devices.
"The portions of the articles are taken out of context and provide only the briefest statements of comparison between devices," the letter continued. "Although such presentations may encapsulate the appearances of superiority for the Thoratec device that Thoratec apparently wishes to create, they are misleading presentations of clinical experience and conclusions."
Even the clinical experience of survival rates of the two devices, although correctly reported by Thoratec from the articles, was faulted as "misleading"because the Abiomed device was not approved by FDA for bridging and because the study in question had not been conducted by either company. Moreover, the letter said, it was "not clear" that the comparisons of the survival rates were based on "statistically significant differences, and it is misleading for the company to imply that the differences are meaningful if they are not and if the devices have not been directly compared with each other for a specific outcome."
It thus becomes apparent that, despite the recently changed legal landscapewhich includes explicit permission under both the WLF legal decision and the FDA Modernization Act (FDAMA) for manufacturers to disseminate unapproved-use information in published studiesFDA intends to continue to control the content of what manufacturers provide to health professionals. In other words, in FDA's view, the mere publication of an unapproved use in a peer-reviewed journal does not confer on the manufacturers of the studied devices the right to extract from the publication favorable mentions or recommendations that FDA might feel need contextual balancing, much less the right to amplify selective findings.
Though highly unlikely, it is conceivable that a truly objective manufacturer might extract such mentions so carefullywith relevant balancing information both intact and given all due emphasisthat FDA would not object to the finished promotional piece. The safer course is either to present the proposed promotion with all its scientific backup for voluntary FDA preclearance before use (and FDA does not afford such offerings its highest priority) or to file a supplemental application with the agency seeking to have the unapproved use approved and added to the product labeling.
Is FDA helping other government representatives seize control of the multilateral Global Harmonization Task Force (GHTF) that has been set up to bring consistency and equivalence to all the various regulations that govern the medical device industry?
Robert Britain, of the National Electrical Manufacturers Association, represents U.S. industry on an ad hoc group established recently to develop a consensus procedural document to be considered next year by GHTF. In August, Britain commented that an FDA-drafted version of the document looked to some like an attempt to tilt power to government and away from the concept of government and industry as equal partners. "For example," he said, "industry was excluded in a procedure written for final signoffs. We've always had consensus in the past because all sides had done so much homework. And there was acknowledgment of industry as an equal partner. But a document prepared by FDA would have excluded manufacturers from having any approval say-so."
Britain explained that "there are pros and cons to such a position. Those who favor it say that if guidances are approved only by the governments, there can't be any suspicion of industry contamination. Some U.S. companies think the decisions may carry more weight if they come only from government, so they were not as upset as the Europeans were. But some manufacturers, especially in Europe, don't like being left out of the process now after having been so fully involved for so long." Britain said that he shared the Europeans' concern, which led to his involvement in the ad hoc group being established with representatives from government and industry to "come up with a procedural document we all can live with."
CDRH deputy director for science Elizabeth Jacobson, who chaired the task force until September, admits that the draft she introduced to the ad hoc group "caused quite a stir." But she said that the task force has matured to the point where it needs a formal structure for resolving membership and other issues that are being raised. "I think it's normal for an organization to have this kind of operational struggle," said Jacobson. "I don't think this needs to be half as controversial as some people say."
FDA has decided to appeal its July 28 defeat in the Washington Legal Foundation (WLF) First Amendment case. Although an appeal risks being reviewed by the same hostile panel of judges that sweepingly ruled against FDA in the Durk, Pearson et al. dietary-supplement-labeling case earlier this year, the agency is gambling that this time it could draw different judgesespecially someone other than Reagan appointee Laurence Silberman, who wrote the Pearson decision.
In its appeal, which the court has agreed to expedite, FDA plans to argue that "quirky" District Judge Royce G. Lamberth (another Reagan appointee) overstepped Supreme Court policy when he ruled that portions of FDAMA were unconstitutional. Not only did Lamberth fail to defer to FDA's judgment, but he also failed to defer to Congress. The agency plans to cite Supreme Court precedents establishing that both the administrative and legislative branches of government are entitled to more deference than Lamberth gave them in this case.
FDA also plans to cite the investigational history of the drugs encainide and flecainide, in which many patients received incorrect doses and had fatal reactions. FDA will argue that this was a vivid example of a case in which even more deaths could have occurred had the sponsor been able to promote unapproved uses. The agency is also considering introducing studies showing that even highly educated physicians are not immune to subtle promotional influences that can induce dangerous prescribing patterns, and that commercial incentives can increase this phenomenon.
FDA believes it can present a much stronger case to the appellate judges on WLF than it did in Durk, Pearson. According to one source, even Silberman has acknowledged that dietary-supplement issues are not as serious as drug issues.
In a statement updating its activities involving the Y2K computer problem, FDA says that the "vast majority of computer-controlled medical devices used and marketed in the United States will not be significantly affected by the Y2K date problem." However, according to the agency, "there are a few products, primarily in hospitals and laboratories, in which correct processing of date information is critical to the device's functioning."
Devices that could potentially be affected by the Y2K problem include those that use dates in a calculation or algorithm or for critical recordkeeping, such as radiation-therapy planning systems, hemo-dialysis machines, some clinical-laboratory systems, some blood-product devices, and some ultrasound systems.
FDA says most manufacturers of such machines have already identified solutions, provided upgrades for them, and notified their customers of the availability of those upgrades. FDA's statement describes steps the agency has taken and notes that inspectors are checking during regular inspections of manufacturing facilities to see what firms have done to ensure that their products, manufacturing processes, and distribution systems are Y2K compliant. The agency says it does not believe that Y2K date problems will lead to device failures of a type that would warrant mandatory recalls.
At the end of August, CDRH released its much-awaited draft entitled Guidance for Industry and FDA Reviewers on Evidence Models for the Least Burdensome Means to Market. The document addresses the first of several issues in determining the "least burdensome" means to allow appropriate premarket development and review of a product without unnecessary delays and expense to manufacturers. The "least burdensome" standard was imposed on the agency by FDAMA, with strong industry backing.
Tools that could be used by sponsors and reviewers to facilitate the process of determining the least burdensome means to market, the document says, include:
- A decision algorithm to determine the need for clinical data.
- A checklist for the contents of a submission.
- Submission templates for some common situations.
- Rapid access to data in the public domain via a Web page.
- Rapid access via the Web page to current guidances for clinical data and study-design options.
The agency said it decided to address the clinical data issue first because it emerged in discussions with stakeholders as their greatest concern. The remaining tools will be evaluated, prioritized, and developed as appropriate.
FDA proposes a consistent process approachrather than a table or hierarchythat focuses on two key questions. First, does available valid scientific evidence provide reasonable assurance that the subject device is safe and effective, or establish substantial equivalence to a predicate device, when used as indicated in the target population? And second, what is the most appropriate and reasonable way to obtain such evidence?
The guidance lists points that should be considered in answering each question. For example, factors to be considered in determining whether available data meet the need would include the device and the use environment, the indication and the claim, current knowledge of the interaction of the disease or condition and the product, the relevance and applicability of the clinical data, and specific questions about the data.
If the existing dataincluding available clinical dataare not sufficient to answer "yes" to the first question, then implications raised by answering the second must be considered. FDA says stakeholders tend to focus their concerns on the least burdensome approach related to the need for a randomized, controlled trialassuming that this would be the most costly approach in terms of time and money. The guidance says that FDA's experience is that such a trial is not always the most costly approach. Although the agency does not say what its real-world experience of trial costs is (probably little or none), this document shows that FDA is trying to be realistic about "least burdensome" requirements.