Innovation in US: Regulatory hurdles may lead to dominance of overseas markets

The United States has long taken an active role in shaping the current state of health care as it exists in this country and all over the world.

Recently, this point was highlighted in a PricewaterhouseCoopers (PwC) analysis, which found that the United States is the world leader in medical technology innovation, a rank it has historically held. This, according to the analysis that was published in January, is due to decades of innovation dominance and demonstration of the strongest capacity for innovation in the medical technology market.

José R. Romero, MD, noted that while some improvements to the regulatory process could be made, the need for a thorough process is vital to ensuring product safety and validity. Photo coutesy of: José R. Romero, MD

As the director of clinical trials research at Arkansas Children’s Hospital Research Institute, and a member of the FDA’s Vaccine and Related Biological Products Advisory Committee, José R. Romero, MD, has experience from both the research and regulatory angles and told Cardiology Today that the FDA’s approval process for medical technology, overall, has helped innovation.

“The regulatory measures put in place see that the product that is brought to market is the safest product we have and that it’s a valid product for what it’s being licensed for,” Romero said. “There is constantly an introspective look by the FDA committee I’m on to determine whether we are doing the right thing, whether we are licensing using the proper metrics to assess their validity, and then we move forward. But is there room for improvement with the regulatory processes? Of course, there is always room for improvement.”

The need for improvement, in fact, was also highlighted in the PwC analysis, which stated that the innovation foundation in this country is weakening and that medical technology companies are increasingly going outside the United States to seek clinical data, new product registration and first revenue. According to the analysis, “US consumers are not always the first to benefit from advances in medical technology and could eventually be the last in line.” Specifically, the analysis predicted that by 2020, innovators will likely move into markets in emerging countries before entering the United States.

And the consequences of losing the top spot in innovation, said Renu Virmani, MD, president and medical director of CVPath Institute, in Gaithersburg, Md., and an Editorial Board member of Cardiology Today, would be devastating for the economy.

“Economically speaking, the United States needs to be first in innovation,” Virmani said. “We used to do all the clinical trials first, but now that is no longer the case. They are being done first in Europe, and drugs are being approved there before the US. The hurdles here [for manufacturers] are just too much. Therefore, our patients are not getting the best of what is available.”

Many phases to drug approval

A number of the hurdles faced by manufacturers are revealed on close inspection of the approval processes in the United States. For drug manufacturers, the process by which their product goes from discovery to becoming an FDA-approved therapy is a particularly long and costly one. On average, for every one compound that is approved, 5,000 to 10,000 compounds fail to meet approval. And the cost for this one success, which takes into account the thousands of failures, is estimated at $800 million to $1 billion.

From start to finish, drugs, which are regulated in the United States by the Center for Drug Evaluation and Research (CDER), have an average developmental process of 8 to 10 years. This process begins with preclinical studies to establish safety and biological activity of the drug in animal models. After the submission of the investigational new drug application with results of the preclinical research, three trial phases must occur before FDA approval:

• Phase 1: Trial establishes safety, pharmacokinetics, pharmacology and safe dose range of the drug in a typically small population of humans.
• Phase 2: Trial features patients with the targeted disease state and is intended to determine optimal dosing for phase 3 trial.
• Phase 3: Trial is a large, pivotal trial with resulting data often used by FDA to determine approval status.

In some instances, the FDA may grant approval after a phase 3 trial on the condition that a phase 4 trial be conducted, which generally examines quality-of-life and cost/benefit issues of the drug.

Under certain circumstances, a drug product will receive a priority review, provided the product, if approved, would be a significant improvement compared with marketed products. As of 2009, this applied to 13% of submitted new drug applications (NDAs), which was the lowest rate since 2002. For those that apply, this can have a substantial difference in clearance time, as one analysis reported that priority new molecular entities (NMEs) were cleared 8.2 months faster than standard-rated NMEs in 2009. In terms of dollars and cents, the report estimated that this was worth $159 million in incremental sales for NMEs cleared that year.

Renu Virmani

Despite the attempts made by the FDA to speed the approval process along for innovative drugs, for Virmani, the rigidity of this process has and continues to be a major hindrance for new technologies. “Partly [the FDA] is asking too many things to be done, especially when clinical studies have already been conducted in other parts of the world,” she said. “To then say, ‘fulfill the requirements of preclinical,’ to me is absurd. If there are 60 people who have gone into a trial and they look good, I don’t think doing a study on 200 animals is going to help us.”

AstraZeneca, manufacturers of ticagrelor (Brilinta), which was approved in July for the reduction of MI and CV death in patients with acute coronary syndrome, experienced the cautiousness of the FDA in the approval process of its drug. After a nearly unanimous vote of confidence by the Cardiovascular and Renal Drugs Advisory Committee 1 year earlier, the manufacturer was told by the FDA in December that the agency would not approve the drug until further analysis of the pivotal PLATO trial was conducted and reported, coming at a surprise to many in the industry.

But according to Barry Sickels, vice president of US regulatory affairs for AstraZeneca, the manufacturer replied to the FDA’s complete response letter in January by providing the requested additional analyses of the PLATO data regarding the interaction between ticagrelor and high-dose aspirin. Sickels said the caution the agency exhibited was beneficial.

“AstraZeneca supports an FDA that can conduct independent, thorough, consistent and data-based reviews of potential new therapies. We appreciate the diligent approach the FDA took in reviewing the extensive data package we submitted for the Brilinta NDA,” he said.

Pathway for devices

In what is often a less painstaking approval process compared with drugs, devices, which are regulated in the United States by the Center for Devices and Radiological Health (CDRH), fall into one of three classes, depending on risk level:

• Class I: Devices having the lowest risk level, which are subject to minimal regulation. Most are exempt from premarket review.
• Class II: devices posing more of a risk and usually undergo 510(k) premarket notification process, which requires demonstration of substantial equivalence to a predicate device.
• Class III: Devices that pose the highest risk of injury, which can include life-supporting and life-sustaining technologies. Most class III devices require premarket approval (PMA), the most rigorous device application, which requires manufacturers to prove safety and effectiveness.

Because innovative devices often require more time and information for approval, the Center for Devices and Radiological Health (CDRH) of the FDA established an expedited review process in 1994 for certain Class III devices subject to a PMA that are intended to either treat or diagnose a life-threatening or irreversibly debilitating condition, or address an unmet medical need.

However, according to the Innovation Initiative, published by the CDRH in February, expedited review times for the 7% of devices that qualified between 2005 to 2010 were typically “longer than standard review times and have not reliably met the targets FDA agreed to as part of Medical Device User Fee Act (MDUFA) negotiations.” This, the document added, was primarily due to the unique regulatory and scientific challenges presented by devices that are granted expedited review status.

As an attempt to help bolster the development of innovative devices, the CDRH has recently made updates to the 510(k) process intended to clear up the uncertainty many manufacturers experience navigating through the clearance procedures. Among the 25 specific items involved in the updates include changes intended to clarify when companies may need to submit clinical data, photographs and schematics should be submitted, as well as streamline the “de novo” review process used for lower-risk devices in which there is no predicate.

The agency has also proposed a new regulatory pathway in their Innovation Initiative called the Innovation Pathway, which is intended to benefit device manufacturers with pioneering technologies.

Jeffrey E. Shuren

“There are several components to this, as the Innovation Initiative is intended to facilitate the development and regulatory evaluation of innovative medical devices, strengthen the US research infrastructure, promote high-quality regulatory science and to prepare for and respond to transformative innovative technologies and scientific breakthroughs,” Jeffrey E. Shuren, MD, director of CDRH, told Cardiology Today. “In the case of the Innovation Pathway, we would get involved far earlier in the development of the device, not to tell the manufacturer how to develop the device but to start to identify whether there are any unanswered scientific questions and to start laying out what the pathway may be for addressing and reviewing that technology.”

Yet, even with measures such as these in place to encourage innovation in the United States, it still may not be enough to stop the paradigm shift in global leaders of medical technology innovation some experts are predicting is well on its way. Part of the reason for this, Virmani said, is that the initiatives do not do enough to address the ultimate challenge faced by manufacturers — cost.

“For example, if you want to make a minor change to a drug-eluting stent, like changing a stent from 150 micron thickness to 100 micron thickness, you need to start the approval process over and the resulting financial burden on manufacturers is too great. It is just impossible,” she said. “These are the things that are making this country no longer competitive.”

As the manufacturer of a first-of-its-kind technology, the Arctic Front cryoballoon, Medtronic recently went through the approval process for its innovative device. Although it required a more involved approval process in terms of proving the technology and clinical requirements, Mike Hess, vice president of innovation excellence for Medtronic, said the additional hurdles they went through would not be a surprise to most manufacturers.

Nevertheless, Hess said: “The ongoing discussion right now is about how we start some of the early-stage research, the early investigational device exemptions (IDEs). That’s an area where we are seeing more work shift to Europe because it is getting more difficult to get those early-stage IDEs approved. As a result, it is pushing some early, preapproval out of the United States and then it is returning here as pilot data to justify its larger trials.”

In response to this concern, Shuren said the FDA is currently in the process of putting together a document intended to encourage early clinical studies in the United States.

“We will be putting out a policy by the end of October in a guidance document for public comment about circumstances where first in-human studies can be conducted earlier in the device development pathway than they could in the past to hopefully encourage those studies to begin here in the US,” he said.

Lessons learned from the PARTNER trial

The randomized controlled PARTNER trial has taught the world of cardiology several important lessons on the value of the innovative device for transcatheter aortic valve implantation (TAVI; Sapien, Edwards Lifesciences) in the treatment of aortic stenosis, including its cost-competitiveness and superiority to medical therapy in patients ineligible for surgery, as well as its similarity to surgery in terms of mortality in surgical candidates. However, according to Peter Block, MD, one of the trial investigators, the PARTNER trial has also elucidated certain points on how the approval process in the United States can hinder and possibly harm the well-being of patients. “The FDA mandated a medical arm for the PARTNER trial in patients that were not operative candidates. From the very beginning I thought this was an unethical trial because the data had been out showing superiority of TAVI vs. standard therapy in a number of European registries,” Block said. “Sure enough, the data from the randomized trial showed the exact same thing: mortality of 50% to 60% in 1 year for standard therapy. A lot of people died for the PARTNER trial that didn’t have to.” Although randomized controlled trials are the only way to evaluate a device objectively on a scientific basis, Block said the PARTNER trial has shown that, from a humanitarian viewpoint, this belief is flawed. He took mortality statistics at 30 days, 6 months and 1 year regarding TAVI for all of the European registries and created a line graph starting at 100% survival at the day of admission. Although the FDA said registries are flawed and not science, Block said: “All of those [registries] are absolutely superimposable with the PARTNER data. The slide demonstrates that if there are enough registry data and that they are from disparate sources rather than just one and all of those data are superimposable-supported, than truth has to lie within repetition of data. And the FDA simply refuses to acknowledge that.” Jeffrey E. Shuren, MD, director of the CDRH, said the agency has lingering safety concerns with TAVI, in particular the higher stroke risk associated with the procedure. And, regarding the European data: “These data are very different from what you have in the US, due to smaller study size, a lot of loss to follow-up and no answers to the questions on benefit,” he said. “In fact, there has been a lot of discussion in the cardiology community around TAVI in regards to who should use this device if it comes out on the market and whether it should only be at certain centers with certain people, and that’s all based on the data being generated from the clinical studies being performed for the US.”

FDA in the crosshairs

A recent survey of 204 medical technology companies could help further explain why many companies have begun to take their business overseas. In the survey, 44% of participants from the United States reported that partway through the premarket process they experienced untimely changes in key personnel, including those responsible for product evaluation, and 34% also stated that appropriate FDA staff and/or physician advisers were not present at key meetings between the FDA and the company.

Compared with the EU authorities, for example, the survey also found much less favorable assessments of the performance of the FDA, including lower ratings of being highly or mostly reasonable (25% vs. 91%) and transparent (27% vs. 85%), as well as providing an excellent or very good overall experience (16% vs. 75%).

But, for Shuren, there are a number of important limitations with these statistics.

“The survey was sent out to a little over 1,000 of the 5,000 manufacturers we have in the US, and only 204 responded, which is a very low response rate. And most of the responding companies were small, single-product manufacturers, so not a lot of experience with the FDA,” he said. “The people who tend to respond to a survey also tend to be the ones who are most dissatisfied and, as a result, have the most incentive to respond, which is why normally with surveys, when there’s a low response rate, you question the responses you get.”

There are also some who argue that the speed and convenience of getting a device or drug approved in the EU comes at a price.

“The CE mark is not as rigorous an approval process as it is here in the United States. They don’t have the same number of requirements. In some ways, they are more lax than I would want them to be,” Virmani said. “The reason for this has to do with reimbursement. In Europe, the reimbursement is different. Here, physicians are reimbursed by the procedure, which is a wrong incentive.”

Peter Block

Still, according to Peter Block, MD, professor of medicine and cardiology at Emory University in Atlanta, the role of the CE mark for marketing in Europe has become the crux upon which companies are leaning to gather funding for further evaluation in the United States. “Without a CE mark, I don’t think there is anyone coming to the United States for a trial,” Block said.

As a result, the United States continues to lose ground in the area of medical technology innovation. Although currently ranked on top in the PwC analysis, the United States fell from its historical ranking of 7.4 (out of 9) to 7.1 in the Innovation Scorecard assessment of the analysis. The analysis also included rankings of eight other countries and indicated that the next three closest were all located in the EU — Germany, 5.4; United Kingdom, 5.4; and France, 5.0. However, only the bottom three countries — China, 3.4; Brazil, 2.7; and India, 2.7 — were reported as having improvements over their historical score.

Staying on top in the years ahead

According to the PwC analysis, the decline in medical technology in the United States is far from foreordained: “Countries that overcome their current weaknesses and develop a supportive ecosystem to help medical technology companies seize the new value-driven innovation dynamic will lead in 2020,” the analysis stated.

As part of the measures needed to stay competitive against other countries, Block said it may be necessary for the United States to develop an approval process that is more akin to the CE mark.

“The need for randomized trials within all panels of the FDA has become such a mantra that it becomes burdensome and difficult to do those trials for certain kinds of devices where the benefit is not huge,” Block said. “The number of patients that need to be enrolled in a trial where the delta between the device vs. standard therapy is not huge is enormous, whereas if there’s a large delta in benefit, you don’t need as many patients.”

Shuren also sees room for improvement in the approval process. “We need and have been in the process of working to assure that our current programs are well-designed to provide sufficient predictability, consistency and transparency for manufactures to know what they need to do to get their product to market,” he said. “Then there are needs for additional efforts for the truly innovative and breakthrough technologies that come along because we are usually dealing with scientific issues for which few people have an understanding. We also need a robust program here at FDA, and we have the people to do the work. This is critical because a strong FDA means a strong industry.”

In the future, as more focus is placed on health care reform and the cost of health care, Hess said although technological innovations will continue to have a positive effect on health care costs by replacing existing therapy in a more cost-effective way, whether they experience adoption in the United States will depend largely on the regulatory pathway in place at the time.

“The difference between getting innovative technology to market or not might be the size of clinical trial, which is required in current guidelines to get approved,” he said. “So that will require more dialogue with industry and FDA about how those kinds of technologies are evaluated and approved.” – by Brian Ellis

For more information:

• FDA. CDRH innovation initiative. February 2011. Available at: www.fda.gov/downloads/AboutFDA/CentersOffices/CDRH/CDRHInnovation/UCM242528.pdf.
• Makower J. FDA impact on U.S. medical technology innovation: a survey of over 200 medical technology companies. November 2010. Available at: www.inhealth.org/doc/Page.asp?PageID=DOC000188.
• Parexel International. Drug innovation, approval, market access and the “new normal.” 2010. Available at: www.parexel.com/services-and-capabilities/consulting/our-thinking/whitepapers/drug-innovation-approval-market-access-and-the-new-normal/whitepaper-request-form/.
• Pharmaceutical Research and Manufacturers of America. Drug discovery and development: understanding the R&D process. 2007. Available at: www.phrma.org/sites/default/files/159/rd_brochure_022307.pdf.
• PricewaterhouseCoopers. Medical technology innovation scorecard: the race for global leadership. January 2011. Available at: www.pwc.com/us/en/health-industries/health-research-institute/innovation-scorecard.
• Redberg RF. Arch Intern Med. 2011;171:1011-1012.
• Sweet BV. J Manag Care Pharm. 2011;17:40-50.
• Zuckerman DM. Arch Intern Med. 2011;171:1006-1011.

Disclosures: Dr. Block is a member of the Circulatory System Devices Panel; Dr. Romero serves on several additional FDA-related committees, including the Pediatric Advisory Committee; Dr. Shuren reports no relevant financial disclosures; Dr. Virmani is a consultant for numerous companies, including Medtronic, Abbott and W.L. Gore.