The United States’ drug approval process is recognized as a “gold standard” worldwide. This standard is upheld by the Food and Drug Administration (FDA). Since the 1962 Amendments to the Federal Food, Drug, and Cosmetic Act (FD&C Act), FDA’s standard for drug approval requires “substantial evidence…consisting of adequate and well-controlled investigations, including clinical investigations,” such that the Agency can conclude that the drug will have the effects that it is purported or claimed to have in its proposed labeling (FD&C Act § 505(d)).
FDA has generally interpreted this standard to mean successful completion of at least two adequate and well-controlled clinical studies. This means each controlled trial must use statistically sound methods when testing a therapy. Prior to beginning a trial, the result that will constitute a successful trial must be defined. One measurement, or endpoint, must be designated as the key determinant on whether the therapy is effective. This one measurement is referred to as the “primary endpoint.” For a trial to be “successful,” it first needs to show that there was a difference between the investigational drug and placebo, or some other control, on the primary endpoint. Then, for the trial to be "successful," the statistical methods that were selected before knowing the results must show there is 95% confidence in that finding, referred to as “statistical significance.”
The 1962 amendments were passed to prevent a public health crisis like the one in Western Europe, where thousands of children were born with birth defects as a result of their mothers taking thalidomide for morning sickness during pregnancy. Twenty years later, the United States faced a very different public health issue: drug companies were not developing drugs to treat rare diseases (now defined as diseases affecting fewer than 200,000 persons in the U.S.).
As a result, Congress passed the Orphan Drug Act of 1983 to create financial incentives for the development of therapies for rare diseases, also known as orphan drugs. While this law does not amend or revise the FD&C Act’s statutory standard for establishing that a drug is effective for it proposed use, it has successfully incentivized drug companies and has led to the approval of nearly 500 orphan drugs. Despite this relatively recent track record of success, a huge unmet medical need still remains. The vast majority of the estimated 7,000 rare diseases that, combined, affect about 30 million Americans are still without approved therapies.
In a recent study published in Therapeutic Innovation & Regulatory Science, a group of legal and regulatory professionals reviewed the quantum of effectiveness evidence required to secure FDA approval of orphan drugs. This study updates a March 2012 analysis and is designed to determine how frequently FDA has required marketing applications of drugs for rare diseases to provide the conventional level of proof of effectiveness that is ordinarily expected (i.e., two adequate and well-controlled clinical trials) in the four years since the original study.
The updated study relied on FDA’s publicly available documents for drugs approved by FDA from July 1, 2010, to June 30, 2014 to identify the non-cancer orphan drugs approved as new chemical entities. These materials were then used to identify, analyze, and classify the basis for each drug’s approval.
The results of this study show that for just over two-thirds of all non-cancer orphan drugs approved between July 1, 2010, and June 30, 2014, FDA did not require that the applications for orphan drugs provide the conventional level of proof of effectiveness that is ordinarily expected for drugs for prevalent diseases. These findings coupled with the results of the March 2012 analysis, demonstrate consistency in FDA’s orphan drug application requirements throughout the nearly 3.5 decades since the Orphan Drug Act was enacted (see table below).
These findings highlight FDA’s “extraordinarily reasonable flexibility” in its review of certain applications for orphan drugs. With the vast majority of rare diseases still facing an unmet medical need, these findings open the door for FDA and drug companies to better understand and discuss potential areas for flexibility throughout the entire development process, from the pre-Investigational New Drug (IND) meeting through the review of, and action on, the marketing application.
This guest post was prepared by James E. Valentine, J.D., M.H.S., Associate at Hyman, Phelps & McNamara, P.C., a food and drug law firm in Washington, D.C. Mr. Valentine is admitted only in Maryland, and his work is supervised by the Firm while his D.C. application is pending.
The Network for Public Health Law provides information and technical assistance on issues related to public health. The legal information and assistance provided in this document does not constitute legal advice or legal representation. For legal advice, readers should consult a lawyer in their state.