Thursday, June 19, 2014

Clinical Trials and Rare Diseases

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases, including cancer, will come after we have developed cures for rare diseases.

Here is a book excerpt, from Chapter 14, Section 2:

It can be difficult or impossible to enroll all the patients required for a clinical trial. In an analysis of 500 planned cancer trials, 40% of trials failed to accrue the minimum necessary number of patients. Of cancer trials that have passed through preclinical, phase I clinical, and phase II clinical trials, three out of five failed to achieve the necessary patient enrollment to move into the final phase III clinical trial [12]. Most clinical trials for cardiovascular disease, diabetes, or depression are designed to be even larger than cancer trials [12].

Overall, about 95% of drugs that move through the clinical trial gauntlet will fail [13]. Of the 5% of drugs that pass, their value may be minimal. To pass a clinical trial, a drug must have proven efficacy. It need not be curative; only effective. Of the drugs that pass clinical trials, some will have negligible or incremental benefits. After a drug has reached market, its value to the general population might be less than anyone had anticipated. Clinical trials, like any human endeavor, are subject to error [14–16]. Like any human endeavor, clinical trials need to be validated in clinical practice [10]. It may take years or decades to determine whether a treatment that demonstrated a small but statistically significant effect in a clinical trial will have equivalent value in everyday practice.

Funders of medical research are slowly learning that there simply is not enough money or time to conduct all of the clinical trials that are needed toadvance medical science at a pace that is remotely comparable to the pace of medical progress in the first half of the twentieth century.

14.2.2 Rule—Clinical trials for common diseases have limited value if the test population is heterogeneous; as is often the case.

Brief Rationale—Abundant evidence suggests that most common diseases are heterogeneous, composed of genotypically and phenotypically distinct disease populations, with each population responding differently with the clinical trial.

The population affected by a common disease often consists of many distinct genetic and phenotypic subtypes of the disease; essentially many different diseases. A successful clinical trial for a common disease would require a drug that is effective against different diseases that happen to have a somewhat similar phenotype. One-size-fits-all therapies seldom work as well as anticipated, and more than 95% of the clinical trials for common diseases fail [13].

14.2.3 Rule—Clinical trials for the rare diseases are less expensive, can be performed with less money, and provide more definitive results than clinical trials on common diseases.

Brief Rationale—Common diseases are heterogeneous and produce a mixed set of results on subpopulations. This in turn dilutes the effect of a treatment and enlarges the required number of trial participants. Rare diseases are much more homogeneous than the common diseases, thus producing a uniform effect in the trial population, and thus lowering the number of trial participants required to produce a statistically convincing result.

Rare diseases often have a single genetic aberration, driving a single metabolic pathway that results in the expression of a rather uniform clinical phenotype. This means that a drug that succeeds in one patient will likely succeed in every patient who has the same disease. Likewise, a drug that fails in one patient will fail in all the other patients. This phenomenon has enormous consequences for the design of clinical trials. When the effects of drugs are consistent, the number of patients enrolled in clinical trials can be reduced, compared with the size of clinical trials wherein the effects of drugs are highly variable among the treated population. In general, clinical trials targeted on rare diseases or on genotypically distinct subsets of common diseases require fewer enrolled participants than trials conducted on heterogeneous populations that have a common disease [13].

It is wrong to assume that because rare diseases affect fewer individuals than do the common diseases, it would be difficult to recruit a sufficient number of patients into an orphan drug trial. Due to the energetic and successful activities of rare disease organizations, registries of patients have been collected for hundreds of different conditions. For the most part, patients with rare diseases are eager to enroll in clinical trials. The rare disease registries, made available to clinical trialists, eliminate the hit-or-miss accrual activities that characterize clinical trials for common diseases.

- Jules J. Berman, Ph.D., M.D.

tags: clinical trials, orphan drugs, drug trials, rare diseases, zebra diseases, rare disease organizations, rare disease advocates, cancer trials, diabetes trials, clinical trials for common diseases, clinical trials for rare diseases, rare diseases and orphan drugs