Members of the Patient, Consumer, and Public Health Coalition appreciate the opportunity to comment on the Innovation for Healthier Americans white paper and we look forward to working with the HELP Committee on these public health issues.
Goals
We share the overarching goal of a healthier America, and to scrutinize the FDA and NIH to determine what works and what doesn’t. However, the specific goal of the effort outlined in the white paper is “to support accelerating medical innovation and patient access to important medicines and medical technologies” (p. vii). We are deeply disappointed that safety and effectiveness is not included in the key goal. Patients want the safest and most effective medical products to be available in a timely manner. Accelerating medical innovation and patient access to new treatments will not necessarily improve the health of Americans. An innovative medical product is new and different, but not necessarily safer or more effective. Although patients and consumers like to try new and innovative medical products, and some patients desperately need new treatment options, most patients and consumers assume that the FDA will only approve new products that are better than the old ones. Unfortunately, that is not accurate.
If the goal of this HELP Committee effort is to candidly assess the status quo, the place to start is with these facts: The United States spends more per capita on medical care than any other countries,[1] and yet American men and women live shorter lives, on average, than men and women in 41 countries, including Canada, the EU, South Korea, Singapore and Malta.[2]
If the goal is healthier Americans, it is essential to improve the safety and effectiveness and cost-effectiveness of medical treatments, as well as access to affordable health care. An essential part of that goal is to have the research data that shows which treatments are best for which patients. And yet the focus of this paper is primarily on speeding the process of getting new (not necessarily better) drugs and devices to market. For example, the question, “What tools are needed for the FDA to build a regulatory system that is efficient, predictable, streamlined, and aligned to the needs of a globalized medical product industry”? (p. 35) fails to mention the needs of patients and consumers. Throughout the paper, too little attention is paid to determining the quality of new (or older) treatments, and too many of the suggestions for speeding the approval process are likely to have a negative impact on quality of care, by rushing unproven products to market.
The FDA’s primary mission is to protect the public’s health. We agree that should be done through an efficient, predictable, and streamlined regulatory system, but the patients’ needs should come first, not the needs of the medical product industry.
There is increasing emphasis on evidence-based medicine – providing medical care on the basis of scientific evidence that it is safe and effective, rather than based on advice from industry sales reps and promotional materials. A major need is for objective comparative effectiveness research, research conducted by independent researchers to compare the safety and effectiveness of different treatments for different kinds of patients, such as men, women, racial/ethnic groups, children, and adults above and below 60 years of age. Unfortunately, the FDA rarely requires comparative effectiveness research, and always relies on studies bought and paid for by the sponsors. We strongly urge the HELP Committee to consider how comparative effectiveness research could be used to greatly improve the health of all Americans.
Instead, a central thesis of the paper is that companies pay too much to bring medical products to market. It implies that the costs are too burdensome. And yet, pharmaceutical company stocks are among the strongest performers, rising an average of 54% in the last two years, for example.[3] Device companies are doing even better; if one looks at the medical device industry’s stock market performance, sales, and profit margin over the last decade, it is clear that the cost of developing new medical devices and getting them approved is not burdensome compared to other industries. A 2015 study found that stock prices for the largest US-based device companies increased an average of 66 percent over just the last two years, and even more for the smallest device companies; these increases were higher than for pharmaceutical companies, as well as higher than NASDAQ or the New York Stock Exchange.3 In addition, the study found that profit margins remained very strong and steady for device companies over the last decade – even during the recession of 2008-2009.
The white paper does not adequately reflect the goals of the millions of patients, consumers, scientists, and public health advocates that we represent. They want to live healthier, longer lives and they want healthcare that is affordable and treatments that are proven to be the best options for them. Our specific concerns follow:
FDA Reviews: Speed vs. Safety?
The Executive Summary states that “A lengthy approval process not only slows down the product under review; it keeps resources, researchers, doctors, providers—from moving onto the next treatment or investigational therapy” (p. 1). We agree. But data show that the average review time for a new drug application has decreased from more than 30 months in the 1980s to 9.9 months for applications submitted in 2011.[4] Between 2001 and 2010, the FDA approved 64% of new applications earlier than the European Medicines Agency (EMA).[5]
These statistics show that FDA is not the reason for long medical product development times. As the Executive summary noted, “FDA has reviewed drugs in as little as three months, and meets the timelines set for medical device reviews the majority of the time.” Approximately 99% of all regulated medical devices are cleared by the FDA through the 510(k) process, and the FDA reviews 90% of 510(k) applications within 90 days.[6] Only 1% of devices are approved by the FDA’s more rigorous Premarket Approval (PMA) process, which is comparable in work load to a drug review but provides only about 10% the user fees as a new drug application. Most PMAs are supplemental PMAs, rarely require clinical trials, and like the 510(k) applications, are reviewed very quickly
The white paper states that high risk medical devices—which as we noted above are only 1% of medical devices—approved in the U.S. were available four years earlier in Europe (p. 1). However, Europe has very different policies than those in the U.S. EU countries require clinical trials even less often than the FDA, rarely require evidence of effectiveness, and reviews are conducted by private third parties rather than government regulatory agencies.[7] However, the EU has strong safeguards that the U.S. lacks, which protect patients from unsafe medical devices. For example, many medical devices that are sold in Europe are not reimbursed by national health plans, so that most patients do not have access to them. It is only when medical devices are proven safe and cost-effective that national health plans are likely to reimburse for them.[8], [9] In addition, numerous European countries have registries that provide excellent post-market data on implants and other medical devices. For example, it was a British registry (National Joint Registry for England and Wales) that was the first to reveal and metal-on-metal hip joint replacements were failing much sooner than other types of hip implants.[10] In addition, the lower standard for breast implants in Europe resulted in a scandal that revealed that a French company, Poly Implant Prothèse (PIP) had lied about their products, using industrial grade silicone rather than medical grade silicone. This resulted in a panic among breast cancer patients and augmentation patients throughout Europe as they rushed to have their implants removed. In contrast, PIP implants had been taken off the US market years earlier by the FDA because of safety concerns.7
The white paper gives an example of European patients having access to a heart valves before it was available in the U.S. (p. 34), but fails to acknowledge the advantage of having safety and effectiveness data for heart valves so that physicians and patients can make informed decisions about their treatment options.
NIH vs. Medicare?
The white paper notes that “the purchasing power for NIH has declined” (p. 6) and then suggests that this is due to “entitlement spending critically impeding our ability to appropriately prioritize funding for critical research that saves and improves lives” (p. 7). This is a false and dangerous dichotomy, given that entitlement programs such as Medicare, Medicaid, Social Security, and SNAP provide essential, life-saving safety nets to millions of Americans. Moreover, spending on programs such as Medicaid and Medicare increase the revenues for pharmaceutical companies and device companies; the development of cost-effective medical treatments (rather than merely new treatments) would in turn save the costs of those entitlement programs. Moreover, there are numerous ways to increase revenues for NIH’s budget that would not require cuts to essential programs that America’s most vulnerable citizens rely on.
The white paper notes that “the federal government remains the largest supporter” of basic research and that for years, private sector investments in basic research has declined and only recently increased. While the lack of private sector investment threatens America’s global leadership in medical innovation, it is important to question the reason for those cuts in light of huge profits and increase in stock values of those companies, previously noted in this document.
Improving Clinical Trials
The white paper states that “personalized medicine demands responsive and flexible clinical trial designs” (p. 15). However, the devil is in the details. There is currently no conclusive evidence that flexible clinical trial designs reduce time and ensure that medical products are as safe and effective as the results suggest
Increased flexibility can actually require more time and resources from FDA, and result in less consistency and more uncertainty for companies. The white paper notes, “There is regulatory uncertainty in how to shape clinical trials, leaving device developers having to negotiate with regulators about issues like efficacy and safety endpoints, statistical techniques, and trial size” (pp. 16-17). Industry wants flexibility but it also wants certainty from the FDA. If the FDA is flexible enough to vary requirements for clinical trials for different drugs, guidance documents and rulemaking would not be able to provide sufficient information to make the process as predictable as companies want it to be.
Although addressed later in the white paper, the role of surrogate endpoints and biomarkers is an important part of the discussion of clinical trials. At the encouragement of Congress, the FDA increasingly relies on surrogate endpoints, including biomarkers, to speed up drug approvals. However, surrogate endpoints are subject to confounding effects, introduce statistical difficulty, and require detailed understanding of both disease progression and drug mechanism of action.
Biomarkers are a type of surrogate marker that are laboratory measurements that reflect disease process activity.[11] Biomarkers are chosen because they seem likely to predict a health outcome, such as glucose levels correlating with days in the hospital for a patient with diabetes.[12] However, whether a surrogate marker will accurately predict a patient’s health is uncertain.11 Moreover, the mechanism of the treatment may not be fully understood, leading to unanticipated consequences.[13] Unfortunately, surrogate markers can often provide misleading information, which may suggest clinical benefit when there is none or when a new product may be especially harmful for some patients. In other situations, surrogate markers may find no significant impact, and yet the patient’s health improves. That is why it is risky to rely on surrogate markers as primary measures of effectiveness of a medical product or procedure, instead of relying on health outcomes that are known to be “clinically meaningful,” such as survival.11, [14] Surrogate endpoints must be rigorously studied to establish their validity before use, but increasingly the FDA is relying on post-market studies to validate these surrogate endpoints.
Adaptive/flexible trial design is not a “cure-all” to streamlining clinical trials. Some diseases do not have any surrogate endpoints that have been clearly established to indicate clinical benefit, and therefore cannot be significantly shortened by an adaptive design which requires interim data.[15] Trials which require fast recruitment may not benefit from adaptive designs, as recruitment must be delayed during data analysis phases. Appropriate use of adaptive trial design is still an area of ongoing development with significant operational and statistical challenges, which sponsors and contract research organizations are still trying to address themselves.15
Orphan Drugs
We recognize the need to stimulate the development of treatments for rare diseases. However, in a global society with global pharmaceutical companies, defining orphan drugs by the number of patients in the U.S. makes no sense and reduces incentives to develop treatments for truly rare diseases. For example, one third of the world’s population is infected with tuberculosis (TB),[16] but TB is treated as an orphan disease by the FDA because TB affects less than 200,000 persons in the U.S. Of course, once a TB drug is approved in the U.S., it will be used worldwide if it is safe and effective. If it is not safe and effective, its priority development under favorable orphan drug statutes is not beneficial to anyone, and could be very harmful in the U.S. where Medicare and Medicaid cover the majority of FDA-approved drugs.[17]
Ethical considerations require that the risk/benefit profile match the clinical need and intended population for all drugs. The white paper points out that the average Phase III clinical trial for orphan drugs has approximately one quarter as many patients “and cost about half as much” (p. 16). An altered risk/benefit profile may be appropriate when no safe and effective treatments are available and few patients would be exposed to potential risks. However, the standards should be higher when other safe and effective treatments are already available.
The white paper states that since “sponsors cannot anticipate with certainty the information that an FDA reviewer will request, they design clinical trials that are unnecessarily expansive” (p. 15). However, there are numerous opportunities for sponsors to communicate with FDA staff about the agency’s expectations; Subpart E (21CFR312.80) allows early consultation and discussion of clinical trials between FDA and the sponsor. Moreover, more than half of the novel new drugs approved in 2014 have been approved through expedited pathways and early engagement mechanisms including Breakthrough Therapy Designation, Fast-track designation, Accelerated Approval Pathway, and Priority Review Designation.[18]
The white paper points out that “in establishing regulatory pathways to reduce the time it takes to develop and review promising drugs, Congress built in requirements for increased engagement between FDA reviewers and sponsors to accelerate access to critical treatments. However, the impact of these provisions remains unclear as it has not been long enough to have the data necessary to make an informed analysis” (p. 16). We strongly agree. In the interest of informed policy decisions, Congress should delay requiring new FDA pathways until there is sufficient time to judge the effect of laws that have passed in recent years.
Public-Private Partnerships and the Role of Industry at Federal Agencies
The white paper states that CDER has 22 public-private partnerships and it is not clear “who is accountable for ensuring that these partnerships are folded into systemic change” (p. 26). We urge Congress to also closely monitor the impact of these public/private partnerships on the integrity of FDA’s scientific and public health mission. What efforts have been made to ensure that public health is enhanced rather than harmed by these public-private partnerships?
Three examples of public private partnerships in the white paper focus on their contributions, but neglect to mention how the clout of regulated industries can undermine their roles:
- Other than FDA appropriations, the Reagan-Udall Foundation is currently funded primarily by pharmaceutical companies, particularly for IMEDS post-market surveillance research. There is no mechanism in place to determine the impact of that funding.
- The Medical Device Innovation Consortium’s (MDIC) 43 members are primarily industry groups, such as Boston Scientific, Johnson & Johnson, and AdvaMed.
- The Accelerating Medicines Partnership (AMP), which began in 2014, is a joint venture between NIH, 10 biopharmaceutical companies and 12 non-profit groups (p. 10). The nonprofit groups include PhRMA as well as patient advocacy groups that receive millions of dollars from pharmaceutical companies every year.
The purpose of federal public health agencies is to support scientifically sound research and protect the integrity of the scientific enterprise. Federal scientists do not depend on industry funding or stockholders for their salaries and job security, and can therefore be unbiased. However, public/private partnerships provide regulated industry with access to FDA and NIH decision-makers, and this can influence their work. For this reason, Congress should monitor whether public-private partnerships reduce the objectivity of federal officials and unduly influence the agencies’ research agenda or scientific research safeguards. The American taxpayer is the primary customer for U.S. public health agencies, not private industry.
We agree with the statement in the white paper states that U.S public sector investments continued to lead the world. We share the concerns that “private sector investment shrank by almost $13 billion and largely reallocated to Asia” in the biomedical industry (p. 31). However, industries go overseas for a variety of reasons – most notably lower wages, lower taxes, and lower environmental standards. However, we believe that the claim that FDA regulations are driving companies overseas is over-stated; drug and device companies want to sell products in the U.S. because we have a large population and we pay top dollar for those products compared to other countries. If a company wants to sell medical products in the U.S., they need to meet FDA standards. Moreover, FDA standards are seen in other countries as a gold standard that is an important selling point for companies when they market their products in other countries.
Qualifications for New Development Tools
We are concerned with qualifications for new development tools because they focus on biomarkers, clinical outcome assessment (COA) and animal models (p. 29). We have described our concerns about biomarkers earlier in this document. With COAs, we are concerned that patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes could shift evidence for safety and effectiveness to postmarket studies instead of premarket studies. Medical products should be shown to be safe and effective before they are marketed; if we rely on post-market studies, millions of patients can spend billions of dollars on medical care that is inferior to other available treatments.
We are very concerned that these proposed tools will lower the safety and effectiveness standards for medical devices. The Institute of Medicine, the Government Accountability Office, and studies published in JAMA Internal Medicine have all found that the current medical device review process lacks adequate safety and effectiveness data.[19], [20], [21], [22] The approval process for medical devices has much lower standards than for drugs, and current device user fees are inadequate to provide the resources needed to substantially improve those standards. However, the proposed solution, to move data requirements into the post-market time frame, is dangerous to patients and would continue to disparity between costs of US medical care and the longevity of its citizens.
Harmonization
Harmonization is an ideal, but only if it results in better medical products for patients and consumers. Since FDA standards tend to be higher, harmonization with other countries is likely to lower standards. For example, harmonization between FDA and the EU on the regulation of medical devices would provide few advantages and numerous risks for U.S. patients. Since FDA is clearing or approving most devices more/as quickly than foreign countries, there would be very few devices that would come on the US market earlier. Moreover, patients around the world currently have access to devices that were subject to FDA standards and then sold worldwide. If the FDA lowered its device approval standards to those of other countries, the world markets would be flooded with unproven medical devices. In Europe, restrictions on insurance coverage for devices would be used to help keep European patients safe, and European registries would provide post-market data, but the U.S. would have no such safeguards unless the standards for insurance coverage and registry requirements were also harmonized. The statement that “In some cases, it has been said that manufacturers must redo entire clinical programs to market in the U.S., regardless of the safety and efficacy data seen [in] pre and post-market overseas” (p. 33) is not footnoted. Clear and convincing evidence is needed to justify changing FDA standards.
Conclusions
The aim of the white paper is “to examine the current process of drug and device development and identify inefficiencies” and examine what is and is not working at NIH and FDA (p vi). We strongly support that. However, we do not support the goal of “accelerating medical innovation and patient access to important medicines and medical technologies” (p. vii) because safety and effectiveness is not included in that goal.
A truly innovative approach in drug development would be to harmonize the research standards between the NIH and the FDA. The FDA currently relies entirely on research paid for by companies whose products are under review. In contrast, the NIH provides funding to encourage the conduct of unbiased research. When submitting research to FDA for approval, however, drug companies usually pay university researchers to study their products. This creates a conflict of interest for researchers who want research funding, which they need to keep their jobs. Why not change the paradigm so that the research funding is provided to the FDA by the companies, and the agency uses those same funds to select and pay university researchers to conduct the studies? With that arrangement, the university researchers would be beholden to the FDA and therefore motivated to do the most objective and accurate studies, rather than motivated to please the company whose product is being evaluated.
We strongly urge the HELP Committee to re-conceptualize the goals of improving drug and device development by focusing on the need to develop products that will help patients live longer and healthier lives through access to affordable and cost-effective treatments. We agree that there is a great need for innovative thinking, but the ideas should also come from public health researchers and advocates, as well as consumer advocates; their voices are missing from this white paper.
The Patient, Consumer, and Public Health Coalition can reached through Paul Brown at (202) 223-4000 or pb@center4research.org
[1] The Henry J. Kaiser Family Foundation (April 12, 2011). Snapshots: Health Care Spending in the United States & Selected OECD Countries. http://kff.org/health-costs/issue-brief/snapshots-health-care-spending-in-the-united-states-selected-oecd-countries/
[2] Central Intelligence Agency. The World Factbook; Life Expectancy at Birth. https://www.cia.gov/library/publications/the-world-factbook/rankorder/2102rank.html
[3] Silcox, C (2015). National Center for Health Research. Analysis of Impact of Device Excise Tax on
U.S.-Based Medical Device Companies; Sales, Profits, R&D, Stock Prices and other Economic Indicators.
[4] Darrow J, Avorn J, Kesselheim A, (2014) “New FDA Breakthrough-Drug Category–Implications for Patients,” New England Journal of Medicine, 370(13):1252-8.
[5] Downing NS, Aminawung JA, Shah ND, Braunstein JB, Krumholz HM, Ross JS (2012). Regulatory review of novel therapeutics— comparison of three regulatory agencies. N Engl J Med 366:2284-93.
[6] Food and Drug Administration (2011). Analysis of Premarket Review Times Under the 510(k) Program.
[7] Zuckerman, D, Booker, N, and Nagda, S (2012). Public Health Implications of Difference in US and European Union Regulatory Policies for Breast Implants, Reproductive Health Matters, 20 (40), 102-111.
[8] Fox, D and Zuckerman D (2014). Regulatory Reticence and Medical Devices (Commentary), The Milbank Quarterly, Vo. 92, No 1, (pp. 151-159).
[9] International Society for Pharmacoeconomics and Outcome Research (2010). ISPOR Global Health Care Systems Road Map. http://www.ispor.org/HTARoadMaps/UKDiagnostics.asp
[10] Meier, B (September 15, 2011). Metal Hips Failing Fast, Report Says. The New York Times. http://www.nytimes.com/2011/09/16/health/16hip.html
[11] Katz, R (April 2004) “Biomarkers and Surrogate Markers: An FDA Perspective,” 1 NeuroRx).
[12] Rothman, M (April 2012) “Surrogate Endpoints,” FDA. http://www.fda.gov/downloads/Drugs/NewsEvents/UCM300741.pdf
[13] Lesko, LJ, Atkinson Jr, AJ (2001). “Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies,” 41 Annu Rev Pharmacol Toxicol.
[14] Fleming, TR (Jan. 2005).“Surrogate endpoints and FDA’s accelerated approval process,” 24 Health Affairs.
[15] Chow, S and Chang, M (2008). Orphanet Journal of Rare Diseases, 3:11.
[16] Centers for Disease Control and Prevention (2013). Data and Statistics; Tuberculosis (TB). http://www.cdc.gov/tb/statistics/
[17] Chambers J, May K, Neumann P (June 2013). Medicare covers the majority of FDA-approved devices and Part B drugs, but restrictions and discrepancies remain. Health Aff (Millwood). 32(6):1109-15. doi: 10.1377/hlthaff.2012.1073. http://www.ncbi.nlm.nih.gov/pubmed/23733986
[18] Food and Drug Administration (January 14, 2015). FDA Voice: CDER Approved Many Innovative Drugs in 2014. http://blogs.fda.gov/fdavoice/index.php/tag/fast-track/
[19] Institute of Medicine (2011). Report brief: medical devices and the public’s health: the FDA 510(k) clearance process at 35 years. http://www.iom.edu/Reports/2011/Medical-Devices-and-the-Publics-Health-The-FDA-510k-Clearance-Process-at-35-Years/Report-Brief.aspx
[20] US Government Accountability Office (2009). Medical devices: FDA should take steps to ensure that high-risk device types are approved through the most stringent premarket review process. GAO-09-190. http://www.gao.gov/products/GAO-09-190, 2014.
[21] Zuckerman et al. (2014). Lack of Publicly Available Scientific Evidence on the Safety and Effectiveness of Implanted Medical Devices. http://archinte.jamanetwork.com/article.aspx?articleid=1910556
[22] Zuckerman et al. (2011). Medical Device Recalls and the FDA Approval Process. Archives of Internal Medicine. doi:10.1001/archinternmed.2011.30. http://center4research.org/nrc-in-the-news/medical-journal-articles/medical-device-recalls-and-the-fda-approval-process/