A recent article in the Journal of the American Medical Association (JAMA) discusses how to “Build Comparative Efficacy and Tolerability Into the FDA Process.”
The current responsibility of FDA is to provide the public with the “science-based information” it needs to use drugs and devices to improve health. To provide such information “under the current Code of Federal Regulations (CFR), new drug approval is typically based on demonstration of efficacy in 2 or more randomized clinical trials (RCTs), often in comparison with placebo.”
The authors assert that because of the “continued progress of science, approval of a new drug or device implies to physicians and the general public that the product represents an advance over older treatments.” Such a claim leads them to argue that current FDA standards “for approval fail to assess whether newly approved drugs and devices are less efficacious or less well-tolerated than existing alternatives.” In particular, the authors are worried that patients could be harmed by newly approved treatments instead of using an alternative with established efficacy and safety.
Current FDA Approval Requirements
Current regulations state that the FDA may not reject an application on the basis of efficacy if the treatment demonstrates a statistically significant benefit over placebo (justifying label claims of efficacy), even if the new treatment appears to be less efficacious than established treatments or produces benefits of questionable clinical significance. The authors believe that such a regulation is a “potential risk” for patients to have poor outcomes.
Such a suggestion ignores the fact that many drugs within a class of drugs work differently on different patients. Imagine if the only statin approved was Mevacor, and that in comparative effectiveness trials you approved Baychol but not Zocor (Simvastatin) or Provachol (pravastatin). Both are less effective than Baychol (cerivastatin), which was withdrawn from the market due to side effects. This example highlights how we would still be dealing with a bad medicine had the good medicines not been developed, or if we had not found the side effects that were discovered post FDA approval.
Or take for instance the diabetes drug Troglitazone (Rezulin), and imagine if it was the only drug in the TZD class. Perhaps Rosiglitazone (Avandia) may have been approved, but the drug with the best safety profile in the class Pioglitazone (Actos) would probably never have been developed under such systems as the authors discuss.
Heart Failure is another example. If Beta Blockers are not approved for hypertension, which they only do minimally, then we would never get to the much longer process of heart failure, and many drugs in the class of beta blockers don’t work in heart failure. These examples, along with the fact that there are a “vast number of comparative effectiveness questions,” suggest that the high costs of RCTs may limit the potential benefits of federally funded comparative effectiveness research.
Despite the doubts and questions of comparative effectiveness in helping patients, the authors assert that the FDA needs strict “oversight of required active-comparator trials, which could be designed and powered to demonstrate superiority, equivalence, or non-inferiority.” The authors suggest that these “trials would yield highly relevant comparative efficacy and tolerability information at the time drugs and devices reach the market.”
The results would then be reviewed by “a panel of experts commissioned by the FDA who could recommend the best active comparator, its dosing scheme, and the margin of superiority, equivalence, or non-inferiority used in sample size calculations.” In other words, unelected bureaucrats would be deciding what patients get to take with the primary goal of saving money, secondary to saving patients.
Such an idea came from the European Medicines Agency (EMA), who wrote in 2004 that when possible, trials with both active-comparator and placebo-control groups should be performed to help establish new drug efficacy and risk. They give such guidance with the belief that the trials will provide information about assay sensitivity and also the clinical relevance of changes. The authors feel that this example could be used by the FDA to approve decisions based on the balance of relative efficacy and tolerability.
Patient-Centered Health Care
The idea of “Charting a Path From Comparative Effectiveness Funding to Improved Patient-Centered Health Care” was further elaborated in another JAMA article, which examined how physicians have been able to “tailor recommendations to the unique characteristics and circumstances of each patient.” While they assert that many of the decisions doctors make “today must be made without reliable comparative information,” they too easily forget that finding good medicine also entails finding the bad.
Consequently, they suggest that there is an “information gap” that frustrates patients who “too often undergo trial and error medicine.” Such a suggestion forgets the following example: if you were a dying patient, and were given the option of taking a trial drug that could save your life or taking nothing, wouldn’t you take the risk to save your life? Answering such a question demonstrates that choosing what is “comparatively effective” is not as simple as “this works, and this does not.”
The authors argue that comparative effectiveness (CE) research in health care organizations is an important accelerator for achieving the promise of personalized medicine. The problem however, is that the “scientific foundation from which to advance this enterprise are not clearly defined.” In fact, the Institute of Medicine (IOM) committee commissioned by the US Congress to identify priorities for CE research “had no clear inventory of published studies or research in progress to inform their deliberations.”
A bigger issue for CE research however, is the fact that researchers do not know whether comparative information will be useful to clinicians and patients or if it can even be used. For example, the authors of the study “identified only 11 studies (11%) that compared medications with nonpharmacologic interventions and 32 studies (31%) that compared different pharmacologic strategies (31%); both are essential to helping clinicians and patients make fundamental therapeutic decisions.”
Another problem the authors found was that “only 20 CE studies (19%) focused on safety.” Such a small number showed an “incomplete overlap between these CE and safety, which suggested fruitful opportunities for collaboration.”
Conclusions
In the end, the obstacles facing CE research seem to necessitate a closer look into its use and impact on patient centered care. While it is important that the United States continue to lead the world in biomedical science, “implementing a framework for research that advances patient-centered care” must be carefully created.
While the authors believe that the public would benefit from new protections against new treatments, they also acknowledge that “an FDA requirement for active-comparator trials could conceivably reduce new drug and device development due to the increased costs of trials.” The reduction of new drug and device development would also result because of “the increased risk of discovering late in the development process that a new treatment is inferior to existing treatments.” Another negative consequence would be the need for additional time to approve a drug, which would lead to lost lives for those who are forced to wait.
The author’s suggestion is also bad policy for pharmacy in cases where there is a need for multiple medications to treat the disease, as is the case for oncology, hypertension, asthma, and many other major diseases.
Accordingly, although “collaboratively designed active comparator clinical trials could help the FDA and industry work together to improve the health of the public,” such work should not come at the risk of reducing new drug and device development. In fact, reducing such innovation would also limit the number of trials done on drugs so that we may never find the answer to key scientific questions, which help develop newer medications.
Ultimately, it is foolish to think the FDA should only approve one drug in a class or ignore classes based on arbitrary comparators. In the field of medicine, there is never a 100 percent guarantee which therapy will work until you test the drugs and try them on patients for tolerability. Preventing such tests to save patients will probably end up hurting more.