REGULATIONS & STANDARDS
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Jeffrey N. Gibbs, JD, is a director at Hyman, Phelps & McNamara, a Washington, DC-based law firm, and is a member of IVD Technology’s editorial advisory board. He can be reached at jng@hpm.com. |
IVD companies face many challenges as they seek to commercialize new tests in the United States, such as issues relating to intellectual property, reimbursement, competition, manufacturing, and pricing. There is also another major hurdle: FDA. Sometimes manufacturers need to make multiple efforts to clear this hurdle, which delays market launch. Some IVDs fail to clear it at all.
This hurdle is not going to get any lower. If anything, FDA’s data requirements and the rigors of its reviews of IVDs are increasing. The political environment is also pressuring FDA to tighten, not loosen, regulatory standards.
Given the regulatory environment, many IVD companies have been reporting that obtaining clearance or approval for their products has been getting harder, especially for new technologies, intended uses, and markers. Some difficulties are unavoidable and are inherent in the regulatory system Congress established. Other difficulties are outside of a manufacturer’s control, stemming from how FDA reviews applications. While the IVD review process can and should be improved in many ways, companies can avoid or at least minimize certain regulatory challenges. This article identifies factors within a company’s control, which can lead to better, faster regulatory outcomes.
Keeping Current
FDA’s regulatory requirements are not static, and IVD companies must keep themselves updated on the current regulations. The laws themselves occasionally get changed, but more frequently, FDA revises the regulatory requirements. For IVDs, a new regulation is most commonly due to the issuance of a new device classification. However, because FDA dislikes promulgating regulations, OIVD is more apt to change policies through guidance documents, which companies should monitor and evaluate. While the guidance documents have no legal effect, they often represent OIVD’s most current thinking. A company that disregards even a recent draft guidance is overlooking a valuable source of insights into OIVD’s expectations. Special control guidance documents that follow de novo classifications can also be an important resource.
IVD manufacturers should track even less-formal sources of information. Although advisory panels give only nonbinding recommendations, a company that ignores them (along with the key panel and FDA comments) does so at its peril. One good example is the recent advisory panel on CLIA waivers for hematology devices. Decision summaries of newly cleared 510(k)s and summaries of the safety and effectiveness for premarket approvals (PMA) can also provide useful intelligence on what data OIVD found acceptable.
Policy changes may be communicated by other informal means, such as presentations by OIVD officials at scientific or professional meetings, which are often posted on FDA’s Web site. IVD companies can also learn from their colleagues. For example, OIVD has recently held up the clearance of test kits because they referenced research-use-only instruments or reagents. Whether this new policy is fair, consistent with the law, or conforms to Good Guidance Practices is debatable. Nonetheless, the policy exists, and IVD companies cannot discount information shedding light on this policy or other new policies.
To improve the odds of getting product clearance or approval, IVD manufacturers must review and address all sources of information regarding OIVD’s requirements. For example, the performance data that were sufficient three years ago may no longer be considered adequate today. Whether the data requirements should change without being communicated more broadly is a separate question. Science brings new knowledge and questions, and regulatory expectations are not constant. The reality is that data requirements evolve, and it is critical for companies to learn about such changes by researching all available sources of information (e.g., attending conferences, networking with colleagues, reading news articles).
Defining Intended Use
An IVD’s intended use is the linchpin of the regulatory process. The intended use can determine the study design, the quantity of data, and whether a product will be reviewed through the 510(k) process, de novo classification, or PMA. The intended use also drives regulatory and clinical strategies. For example, OIVD scrutinizes the clinical intended use to determine whether it conforms to the clinical trial design.
However, the intended use is often developed late in the regulatory process. Sometimes the intended use is revised just before the pre-investigational device exemption (IDE) meeting. At other times, the intended use is changed after the meeting to better match FDA’s feedback. At that point, the intended use may no longer conform to the proposed clinical study, or the company’s corporate objectives or reimbursement strategies.
The intended use plays a key role in an IVD’s marketing and reimbursement. A manufacturer must promote its product in accordance with the intended use/indications for use. But marketing input is difficult to obtain when a company is making last-minute modifications to the intended use. Ideally, an IVD company will develop a coordinated strategy, examining from multiple perspectives the marketing impact triggered by regulatory changes. Changing the intended use the day before an FDA meeting makes it more difficult to achieve that goal and reduces the value of the meeting since the agency will have reviewed a different set of claims. It can also result in a product with crimped claims.
IVDs are not just analytical technologies. Rather, they are analytical technologies whose function is defined, at least for regulatory purposes, by the intended use in the intended population. At an early stage, an IVD company needs to consider not only what its product is technologically capable of doing and for whom but also what is the intended use of that capability, and then integrate such decisions into a coordinated regulatory and marketing strategy.
Listening Carefully
During the course of the review process, IVD companies will sometimes hear a negative or skeptical comment from an OIVD official. The comment may be an off hand remark at a pre-IDE meeting, a sentence in the meeting minutes, or a seemingly casual e-mail.
Such comments may not mean much and may not reflect OIVD’s view. They may be based on a misunderstanding or may be passing remarks that signify nothing. However, the comments can also be a portent of problems.
Some IVD manufacturers tend to shrug off such comments. Disregarding or minimizing criticism is natural, particularly if it seems wrong or ill founded. However, doing so can be a mistake. Expressions of concern by a reviewer, whether conveyed as statements, opinions, or questions, can reveal issues that companies need to resolve to obtain product clearance or approval. Manufacturers need to consider and assess such signals, and not ignore them. The reviewer may be conveying unofficial feedback that will affect the application process. Thus, at pre-IDE or presubmission meetings, companies should pay close attention to any skepticism expressed by FDA officials. The questions raised at the meetings may next appear in a letter requesting additional information in the 510(k). Companies need to focus on not only giving their presentations but also listening for the challenging questions.
Getting Third-Party Perspectives
Many new IVD products are supported by robust data and address important medical needs. The company personnel working on the product may therefore reasonably conclude that it should not encounter any major regulatory impediments. Since the IVD is beneficial and the data are compelling, FDA clearance and approval should be a slam dunk.
While such assessments may be right, particularly with products offering novel technologies, markers, or intended uses, that view is likely to be too rosy. In any event, FDA reviewers will scrutinize the application far more skeptically.
IVD companies should prepare for such dispassionate FDA reviews by asking neutral third-party experts to look at their products, clinical plans, and regulatory strategies. Manufacturers will benefit from having objective advisers critique their plans and provide a broader, more disinterested perspective that can help companies craft better FDA submissions. Advocates for a product sometimes have a hard time stepping back and anticipating FDA’s questions. They can also have difficulty playing the role of devil’s advocate when preparing for an FDA meeting. Third parties can help play that essential role of the dubious skeptic.
Challenging When Necessary
Not all opinions or conclusions by FDA reviewers will be correct. They may misunderstand the data, or misapply the regulations or policies. The data requests may also be unreasonable or based on a mistake.
IVD companies need to decide when to acquiesce and when to challenge. FDA’s regulations permit formal appeals of decisions. The agency has mechanisms by which manufacturers can seek formal or informal reviews by supervisors of decisions. Such mechanisms permit appeals to be raised at various points, including after a PMA has been denied or a not substantially equivalent letter has been issued. However, these are not the only triggering events. Companies can also seek higher-level reviews if a pre-IDE meeting reveals a fundamental disagreement over a key issue.
IVD companies should not appeal decisions lightly or without having strong grounds. They also should not make the issues personal, and there is no room for ad hominem attacks. At the same time, manufacturers should not forgo a meritorious appeal on an important point out of fear of retribution or creating an adversarial climate. In addition, companies should consider which route will be more expeditious. For example, generating additional data may take less time than appealing the decision asking for the data.
Not Overselling
There can be a tendency for an IVD company to oversell the clinical significance of its diagnostic, which is understandable. A manufacturer and its employees often have reason to believe that its product offers a meaningful advance, perhaps even a lifesaving one. In talking to potential investors or medical thought leaders, a company tends to position its novel product as a revolutionary breakthrough.
However, such an approach can bring its own regulatory pitfalls. For example, touting a new product to FDA as a breakthrough that can save lives can make it more difficult to establish substantial equivalence or qualify for de novo treatment. Describing the device’s lifesaving attributes may not be compatible with Class II status.
Furthermore, a stronger claim of an IVD’s clinical significance can result in a higher data bar. An IVD company that tells FDA of its vital clinical utility may have to provide corroborating data, which can be very challenging.
An IVD manufacturer cannot and should not ignore the potential clinical value of its assay in its discussions with FDA. Rather, communications with FDA should avoid hype or unduly aggressive claims. A company’s enthusiasm for its product should be tempered in its FDA submissions.
Getting Help at the Right Time
Many IVD companies do not seek outside regulatory assistance during the review process, which often works well. Many companies have sophisticated regulatory experts in-house, so external assistance is unnecessary.
However, if an IVD manufacturer is going to seek clinical, statistical, legal, or regulatory help, it should obtain such assistance earlier in the review process. For example, if a company does not have the necessary statistical capabilities, getting a statistician’s input before a pre-IDE meeting is critical. If a manufacturer wants to determine whether a sample size is adequate, the statistical basis for the number of specimens should be provided, which requires statistical expertise. Similarly, guidance on regulatory strategies is also more useful early in the process. The ability of an external regulatory resource to assist is greatest at the beginning of the review process and limited as it wears on. Identifying potential problems with a claimed intended use can be much more beneficial before a pre-IDE is submitted and FDA forms its first impressions of a product.
Using Meetings Wisely
OIVD is amenable to scheduling meetings to discuss products and provide feedback. Presumably, OIVD does so partly because it recognizes that offering timely insights helps IVD companies during the review process, facilitates clearances and approvals, and results in a more efficient use of FDA’s resources. While FDA’s comments, including concurrence with a study plan, are not legally binding, they are often helpful. This is particularly true of questions or expressions of concern. While such statements will not always be welcome, they have significant positive predictive value since concerns tend not to dissipate unless adequately addressed.
However, productive meetings do not just happen. An IVD company must provide written materials in advance so that FDA has ample time to review them. The materials must be meaningful and focused. If a manufacturer wants comments on a protocol, it should provide detailed information about the study design. For statistical guidance, a company should give the key elements of its statistical plan and the underlying assumptions. A manufacturer should also include specific questions since open-ended questions can lead to open-ended answers. If any significant changes emerge between the time when a company sends its materials and the meeting, it should inform FDA. Agency officials will probably not appreciate spending time reviewing an obsolete version of the materials.
Answering the Questions
During the review process, FDA is likely to have many questions. Such questions may arise during preliminary discussions, at pre-IDE or presubmission meetings, or in response to an IVD submission.
While many questions can be answered directly, there can be a tendency not to respond to questions. This may be due to ambiguities in the questions, uncertainty about how to respond, or occasionally recognition that FDA may view a direct response negatively. IVD companies should respond to questions from FDA about product submissions. Sometimes the answer to a question is already in the submission, in which case the reply should reference the materials the manufacturer previously supplied.
FDA plays the role of gatekeeper, and the answers to its questions are part of the toll IVD companies pay to get the gate lifted. Failing to answer questions is unlikely to satisfy the gatekeeper. Indeed, OIVD reviewers sometimes express frustrations when they perceive that a manufacturer has repeatedly failed to answer the questions. Companies should read FDA’s questions carefully to ensure that their answers do address the questions asked. If a key question is ambiguous, seeking clarification from FDA before responding may be worthwhile.
Doing Good Science
Ultimately, the quality of the science will determine an IVD’s regulatory success or failure. A great technology will not overcome a poorly designed or executed study, and regulatory creativity cannot overcome flawed data. Conversely, compelling data may overcome some regulatory mishaps.
OIVD often refers to the need for good science, giving the phrase almost a talismanic quality. There can be significant disagreement over what constitutes good science. Nevertheless, when strategizing about their product development and positioning, IVD companies cannot lose focus of the need to develop scientifically sound approaches to preclinical, clinical, and statistical requirements, and other data-driven elements.
In this vein, IVD companies should maintain their credibility. Companies will sometimes submit data in a pre-IDE and then present conflicting data in the product application. OIVD will often identify such data inconsistencies and request an explanation. Granted, data sets will not always be consistent between submissions, and new information or revised formats or analyses may result in readily explainable differences. However, if such discrepancies are significant or numerous, they can raise uncomfortable questions regarding the data’s reliability.
The audience of the submission is OIVD, not the personnel within the IVD company. In addition, the goal is not to get the product submission into FDA in time to meet an internal deadline, but to get it out of FDA successfully.
Conclusion
This article hardly presents an exhaustive list of regulatory suggestions. IVD companies can take many other steps to improve the likelihood of obtaining FDA clearance or approval in a timely manner.
The article’s fundamental message is that navigating the regulatory process is complex and demanding, and it will not get easier in the foreseeable future. Just as IVD companies should strive for continuous improvement in manufacturing by examining all aspects of the process, they should also continuously consider how to educate themselves and upgrade their regulatory capabilities to make the FDA review process more productive and successful.
