510(k) is the simplest and quickest route to the regulatory authorization required to market and sell a medical device in the US, and is, thus, the route most startups pursue. The challenge with a 510(k) is to find a predicate device to which the new device can be compared (a requirement for the 510(k) route). The company NOMOS found a straightforward 510(k) regulatory path for its extracorporeal Peacock radiation therapy product even though Peacock was a totally novel product. Strangely enough, NOMOS was able to argue that the predicate was intracorporeal brachytherapy, allowing Peacock to receive clearance in 1996 for the delivery of radiation therapy. The clearance effectively was a tool claim, not limited by disease type or disease site, meaning it could be used for delivering radiation anywhere in the body for any reason, but the company could not make marketing claims that it was useful in the treatment of any form of cancer or other disease.
The Intuitive Surgical da Vinci robot first followed a premarket approval (PMA) path. A clinical trial of 228 patients compared the da Vinci system to conventional laparoscopic techniques for removing the gall bladder and for the surgical correction of gastroesophogeal reflux (heartburn). The FDA determined through a review of the PMA submission in 2000 that the current and future submissions for Intuitive robotic devices – including new clinical indications – could be reviewed through the 510(k) clearance process using the AESOP surgical robot authorization (cleared via 510(k) in 1993) as the predicate device.
By the time the FDA reviewed the PMA submissions by the two focused ultrasound manufacturers who were working in the prostate tissue ablation space in 2015, the philosophy of prostate cancer treatment had changed: Low-risk cancer (primary or recurrent) was no longer felt to require a therapeutic intervention. As a result, the FDA panels that convened to review the data – in one case for primary low-risk prostate cancer and in the other for recurrent prostate cancer – while identifying focused ultrasound ablation as an effective and safe treatment in the studied patient populations, recommended against approval, stating that the low-risk patients treated in both trials should not have been treated at all. As a result, the PMAs were abandoned.
Through a cooperative effort between the FDA and each of the two manufacturers independently, “tool grants” (an authorization for a specific use of a device like a scalpel or scissors used to cut) for prostate ablation, granted through the De Novo process, rather than an indication-specific PMA approval for the treatment of prostate cancer, were received by both companies in late 2015. The devices could be advertised and sold for the ablation of prostate tissue, with the clinical use for the ablation determined by the user. Both manufacturers began selling their products in the US in 2016.
FDA regulatory authorization is required to sell a device in the US, and there are three main paths for achieving authorization:
- 510(k) clearance
- De Novo grant
Approximately 4,000 510(k) applications are submitted to the FDA each year, compared to less than 100 PMA applications.
Premarket approval (PMA) is the most stringent type of device marketing application required by FDA. This FDA regulatory review process was established to evaluate the safety and effectiveness of Class III medical devices.
Class III devices support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential, unreasonable risk of illness or injury. PMA usually requires the performance of a rigorous clinical trial, with stringent performance criteria approved by the FDA prior to the start of the trial, and with oversight provided by an investigational review board (IRB). It can take 5 to 10 years or more to negotiate the basis for a clinical trial with the FDA, amass the data required by the trial, compile and present the data to the FDA, and receive approval. If approved, the technology will have one or more specific medical claims associated with it (e.g., the treatment of prostate cancer) that can be used to promote and market the technology. If denied, the resulting path forward might be a new trial incurring a similar timeframe or abandonment of the technology, leading to the potential demise of the product and even the company. The final eventual approval rate for PMA submissions is currently at around 90% (See Medtech Dive).
A 510(k) is a premarket submission made to FDA when it is possible to demonstrate that the device to be marketed is as safe and effective (i.e., substantially equivalent) as a legally marketed device, defined as a device marketed prior to May 28, 1976, a device reclassified from Class III to Class II or I, a device found substantially equivalent through the 510(k) process, or a device granted marketing authorization via the De Novo classification process. Submitters must compare their device to similar, legally marketed devices and support their claim of substantial equivalence. If the new device is found equivalent to the prior device, it is “cleared” to be marketed with the same claims as the prior device. 510(k) submissions usually take much less time than a PMA because there is little if any need for extensive clinical data; but a 510(k) usually does not include a specific disease indication for use. The final clearance rate for a 510(k) is greater than 95% (See Emergo Group).
De Novo Grant
The De Novo process provides a pathway to bring a novel medical device to market for which there is no legally marketed predicate device but for which general controls alone, or general and special controls, can provide reasonable assurance of safety and effectiveness for the intended use. Safety data is required for a De Novo “grant” (demonstrating the use of the device causes no untoward side effects) but, since it is not necessary to provide disease outcome data (e.g., demonstrating the use of the device can cure cancer), the time it takes to assemble the data and the degree of rigor of the data can be much less than for a PMA.
Therefore, the timeline for bringing a successful De Novo grant to market is much shorter than for a PMA. As with a 510(k), a De Novo grant does not carry disease treatment claims. For example, the granted use for a De Novo device could be prostate tissue ablation rather than the treatment of prostate cancer (the claim that would accompany a PMA). While this distinction may or may not be important to different stakeholders within the organization, it is important to explore upfront the specific goals held by each of the stakeholders, thereby making sure the regulatory path taken is consistent with those goals.
The FDA also has other regulatory pathways that can provide a reprieve from many of the time-incurring requirements of those described above. For instance, the Humanitarian Device Exemption (HDE) Program is for products intended for diseases or conditions that affect small (rare) populations of not more than 8,000 patients. There are also several less well-known pathways applicable to select products or markets, and there are additional pathways under consideration by the FDA, each designed to be sensitive to the needs of specific patient populations (such as pediatrics).
The Breakthrough Devices Program was created by the FDA to provide patients and health care providers with timely access to certain medical devices and device-led combination products that provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. The program speeds up the development, assessment, and review of the technology. Receiving Breakthrough Device designation may also allow a new technology to benefit from companion Centers for Medicare & Medicaid Services (CMS) reimbursement programs that are currently under development and review.
Determining the Best Path
While regulatory authorization is a universal prerequisite for the sale of technology in the US, the optimal regulatory path for a given company or technology may not always be apparent, especially given the impact the decided path may have on the commercialization timeline. A 510(k) requires the least amount of time and the least amount of clinical data – e.g., bench safety data is usually sufficient. A De Novo grant, while often requiring clinical data on short-term side effects, does not require clinical evidence of disease control and therefore can be submitted after a short period of patient follow-up. A PMA is the most costly and lengthy pathway, given its need for a clinical trial complete with disease control outcome data that may require years to acquire, but it provides two things the other paths do not – a disease-specific marketing claim and data of the type that may be of value for guideline inclusion and subsequent favorable reimbursement coverage decisions.
The corporate value of a disease specific marketing indication varies depending on the field, the market, and the goals of investors. For instance, the more generic claim of prostate tissue ablation realized as part of De Novo authorization allowed the two focused ultrasound devices to be sold and used for multiple indications in the prostate – cancer and BPH, for instance – but it does not allow the devices to be marketed with the claim of treating cancer or benign prostatic hyperplasia (BPH). A PMA claim of cancer control adds bragging rights to marketing, may make the device more competitive with existing technology that carries a cancer claim, may make investors happier, and may suggest to the medical community a higher level of approval by the regulatory authorities.
Importantly, however, PMA-level authorization does not change the payment level assigned to the technology, which is related only to the work involved in performing the procedure, not the medical indication for doing the work. The payment rate for focused ultrasound ablation of the prostate would be the same with either a PMA or 510(k) authorization (the payment might be different for cancer versus BPH ablation if the two procedures took different lengths of time or required the use of different additional equipment or personnel). That said, when it comes time to coverage decisions, as will be discussed in upcoming blogs on “Reimbursement” and “Guidelines,” the clinical data acquired as part of a PMA may be, but is not guaranteed to be, sufficient for the treatment to be included in published clinical guidelines, a prerequisite for most coverage decisions. This contrasts with the data acquired for a 510(k) or even a De Novo submission, which under almost all circumstances would not reach the bar required for guideline inclusion. Thus, while the cost of performing a PMA is significant and is borne upfront when investor capital is most expensive, it may prove ultimately less costly than the revenue loss incurred while waiting for clinical evidence from early adopters of the technology to be published and used to support guideline inclusion and favorable coverage decisions.
The importance of making the right regulatory path decision early in technology development cannot be overemphasized. On one hand, if a PMA is submitted where a 510(k) would have been sufficient to realize all market objectives, many years and multiple millions of dollars may end up being wasted, with those additional years and cost at the front end where investor dollars are the most expensive, leading to increased investor dilution. On the other hand, finding out late in the game that a PMA would have proven more fruitful than a 510(K) when it comes to realizing reimbursement coverage will add cost and time at the back end that may result in revenue loss that is greater than the cost if incurred upfront, and may cause significant dissatisfaction among the investor pool.
In many cases, where uncertainty about the correct regulatory path exists, a meeting with the FDA prior to electing any regulatory path may be worthwhile. However, once a recommendation is made by the FDA, a company is pretty much stuck following that path. On some occasions, adopting a path and then working with the FDA after the fact to make that path work may make more sense, especially if there is a gray line between the various filing options (asking for “forgiveness” rather than “permission”).
Finally, and regardless of the regulatory path chosen, it is important to understand that several aspects of the clinical and regulatory development plans carry risk for incurring delays. These timeline risks should be identified early, and cushions should be built into timelines and fundraising plans to account for them. For instance:
- The FDA may assign a device to a PMA pathway when the company was expecting to pursue a 510(k).
- The company may incur delays in obtaining investigational device exemption (IDE) approval for their clinical trial or in securing IRB approval at one or more of the institutions slated to participate in the trial.
- The FDA may require a trial sample size larger than the one the company originially anticipated and for which it budgeted.
- Recruitment of participants for the clinical trial may go slower than planned.
- The occurrence of a major adverse event may require suspension of patient recruitment until the adverse event can be shown not to be caused by the device, or the device is corrected to eliminate the risk of the event.
- The FDA may require additional bench or laboratory testing as part of a 510(k).
- The FDA may require additional reprocessing validation runs on the device or associated single use disposable items that are in turn dependent on the availability of testing laboratories to perform the required analysis.
- The clinical environment may change during the regulatory process negating or altering the value of the submission. For instance, in the case of prostate focused ultrasound, PMAs were filed based on field-wide consensus that Gleason 6 disease should be treated. By the time review panels were convened to assess the submissions, Gleason 6 disease was no longer being treated, which meant that the data was found to be lacking for not being compliant with clinical trends.
It is highly likely that at least one of these “road bumps” will be experienced with any device submitted to the FDA. Failure to build contingencies into the funding requirements and commercialization timelines to account for them can have ripple effects across the entire commercialization process, with the potential to negatively impact the likelihood of commercial success or the timeline for that success.
Mark Carol, MD, is a senior consultant at the Focused Ultrasound Foundation.
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