Healthcare costs continue to escalate. The USA spends close to US$2.5 trillion every year on healthcare. Of each dollar spent on healthcare in the USA 31 cents goes to hospital care, 21 cents goes to physician services, 10 cents to pharmaceuticals, 8 cents to nursing homes, 7 cents to administrative costs and 23 cents to other categories, such as diagnostc laboratory services, pharmacies and medical device manufacturers Citation[101]. Medical debt is the principal cause of personal bankruptcy in the USA Citation[102]. This situation constitutes a true debacle.
Previous editorials dealt with some of the root causes of this healthcare debacle: a vicious cycle of malpractice litigation that leads to the practice of defensive (litigation pre-emptive) medicine, and the measures taken and adjustments made by insurance companies in order to continue to be profitable Citation[1,2]. In this editorial I will relate the US FDA’s role in perpetuating the escalation of drug costs. A future editorial will address the pharmaceutical industry’s role.
FDA’s raison d’être
The FDA was created in 1938 by an act of congress (FDAC Act) and charged with protecting the consumer by evaluating the safety of new products. The act was revised in 1962 (Kefauver–Harris Drug Amendments of 1962) and thereafter the FDA required that, in addition to safety, efficacy be established in two adequate and well-controlled clinical trials. In 1992, the FDA submitted a notice to the Federal Register proposing the accelerated approval (AA) program. The final rule was issued in December 1992. In 1997, the FDA’s Modernization Act (FDAMA) was approved and it allowed the FDA to accept one clinical trial and other supportive studies as evidence of efficacy. In 1996, President Clinton announced that the Administration was implementing ‘Reinventing the Regulation of Cancer Drugs’, designed to expedite development and review times for cancer products (including applying AA to cancer drugs) and to facilitate their distribution within the USA. The unifying theme and intent of all this legislation is to protect the patient, provide early access to promising new drugs and accelerate time to broad availability.
FDA’s interpretation of the law
The laws that created and modified the agency’s mandate are somewhat general and leave ample room for interpretation. The FDA interprets these laws internally and then issues ‘guidance’ documents that the regulated industry must follow. Through this and other mechanisms the agency has established an extensive list of requirements and procedures, beyond the intent of the law, that must be followed during the discovery and development of new agents. Many of these are important in assuring patient safety and the purity of the agents being investigated. However, a significant number are overly stringent and some are simply not warranted. The end result is a slowing of the R&D process and a steep escalation of costs. More importantly, treatment of patients who may benefit from a new agent may be delayed or the agent may never be approved.
Clinical development process as an example
New anticancer agents undergo clinical testing (as single agents) to determine their safety and efficacy. Initial trials (Phase I) define the dose and schedule, pharmacokinetics, pharmacodynamics and safety profile. Subsequently, (Phase II) clinical activity is evaluated. Combination studies are usually conducted simultaneously with Phase II single-agent studies. Phase III trials are conducted to establish the safety and efficacy of the new agent (usually in combination) versus another combination that is recognized as the standard for the indication being addressed. Should the studies be successful and demonstrate a benefit for the new agent, the FDA will review the data and eventually approve the new agent. The entire clinical development process from investigational new drug submission to new drug application (or biologics license application) approval averages over 7 years and from discovery to approval over 12 years. The cost has been estimated at over US$1 billion.
Nevertheless, this is just a beginning since only rarely has the optimal combination been established at that time. Post-approval, numerous trials are conducted by the oncology community evaluating multiple combinations until the most effective is found. This post-approval work is critical to the patient as the opportunity for the development of a curative regimen is maximal at that time. One historical example, the development of MOPP chemotherapy for Hodgkin’s lymphoma, occurred approximately 20 years after nitrogen mustard became available. One of the few exceptions was the development of the rituximab plus CHOP combination for non-Hodgkin’s lymphoma that occurred during development (preapproval) of rituximab Citation[5].
The development process could be significantly shorter if the FDA allowed more frequent use of the AA pathway. However, the FDA continues to favor the lengthier and more expensive route of the “two adequate and well-controlled clinical trials”. A recent review of AA statistics concluded that “…the promise of AA, i.e., shortening the time to approval and decreasing the resource burden of novel cancer drugs, is not being met as evidenced by the similar development times, emphasis on Phase III trial designs for both regular and AA, and the decreased number and percentage of oncology new molecular entities that receive AA since 2003” Citation[6].
Conclusions
The US Congress, in its legislative proposals, has not considered the role of the FDA in cost escalation (and delaying the availability of new anticancer drugs). True, pharmaceuticals account for only 10% of healthcare costs, but that amounts to US$0.25 trillion! The FDA is one more root cause of the healthcare debacle not being addressed by Congress. It seems that Congress is concerned with extending healthcare coverage, further regulation of insurance companies and providers, and finding the means to finance the even higher costs that will ensue. A future editorial will address the pharmaceutical industry’s role.
Financial & competing interests disclosure
Antonio J Grillo-López is a member of the Board of Directors of ONYX Pharmaceuticals and of the Board of Trustees of the Hope Funds for Cancer Research. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
References
- Grillo-López AJ. The USA’s healthcare reform: why it will not work. Expert Rev. Anticancer Ther.10(2), 121–122 (2010).
- Grillo-López AJ. The USA’s healthcare reform: challenges and opportunities. Expert Rev. Anticancer Ther.10(3), 295–296 (2010).
- Grillo-López AJ. The ODAC chronicles – part I: my first ODAC experience. Expert Rev. Anticancer Ther.4(5), 579–582 (2004).
- Grillo-López AJ. The ODAC chronicles: part III. The FDA’s philosophy and process for cancer drug evaluation and approval. Expert Rev. Anticancer Ther.5(1), 1–5 (2005).
- Grillo-López AJ. Regulatory process for approval of biologicals for cancer therapy. Book Chapter. In: Principles of Cancer Biotherapy. Fifth Edition. Oldham RK, Dillman RO (Eds). Springer 20, 613–629 (2009).
- Richey EA, Lyons EA, Nebeker JR. Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs? J. Clin. Oncol.27(26), 4398–4405 (2009).
Websites
- 2008 Annual Report, PHRMA www.phrma.org/index.php?query=annual+report&option=com_swishesearch&intMaxHits=20&intPageOffset=0
- Healthcare in the USA http://en.wikipedia.org/wiki/Health_care_in_the_United_States
- Reference and background material on the FDA can be found at their website www.fda.gov