NCHR Testimony at FDA’s Limited Population Pathway for Antimicrobials & Antifungals Meeting

Jack Mitchell, National Center for Health Research, July 12, 2019

I’m Jack Mitchell, director of health policy for the National Center for Health Research (NCHR).  NCHR is a non-profit think tank that conducts and analyzes research with implications for public health, and patient and consumer safety.  NCHR accepts no money for the pharmaceutical or medical device industries and has no conflicts of interest to report.

Experts agree that there is broad agreement that there is a need to develop new antimicrobials to treat serious or life-threatening infections.  Resistance to some antimicrobials has been growing and has been recognized as a serious and escalating treatment threat for decades.  The Center for Disease Control and Prevention (CDC) estimates that 23,000 people will die annually from drug-resistant infections.  Other authoritative estimates put the number higher.

Partially because of this looming health crisis, Congress created a Limited Population Pathway (LPAD) program for FDA as part of the much publicized 21st Century Cures Act, and the agency is required to implement it.

FDA should be commended for its work in attempting to resolve a longstanding and thorny medical treatment problem.  The FDA and the Centers for Medicare and Medicaid (CMS) are seeking to come to an interagency agreement on the difficult economics of antibiotic and antifungal new product research, which has lagged because of the limited number of patients affected, and the expense of getting new drugs approved.

Nevertheless, the proposed guidance raises some critical questions that must be addressed.  A key issue is that just having more drug options on the market often does not necessarily help patients.  One analysis of antibiotics approved between 1980 and 2009 found that 47%—or 26 drugs out of 61—were taken off the market due to poor sales, or safety and efficacy problems.

The best way to make certain that new drugs are safe and effective is by requiring well-designed and valid clinical trials.  Relatively few patients have an “unmet need”—a situation when none of the drugs currently available work for their infection.  That makes it difficult to study new drugs on the patients most likely to benefit.

For that reason, the guidance suggests that an experimental drug should be tested in a broader population of patients with the intent that, if approved, the drug would be indicated for a narrower “limited population” of patients who do not have good options.

However, if the drug is not tested on the specific population for which it is intended, it would be very difficult to determine the efficacy and safety for that particular population.  Drugs approved by testing in a more general population would not provide patients and their physicians with the evidence needed to determine appropriate treatment for patients in the “limited population”.  It would not be clear if the benefits outweigh the risks for the intended patients.

In fact, this drug was be “misbranded” based no FDA’s definition, because the evidence does not support “the conditions of use listed or suggested in labeling” which is the standard of law.  FDA regulations specifically state that FDA should not approve a drug if there is a lack of scientific evidence of benefit in the labeled population.

The proposed guidance describes the use of small clinical trials that are not powered to test meaningful efficacy and safety endpoints, or that use wide non-inferiority margins.

In addition, trials that use non-inferiority designs cannot answer the most important questions for doctors and patients—Is the drug at least as good if not better than other options already on the market?  Furthermore, the use of wide non-inferiority margins allows new drugs to be approved that are potentially worse than the comparator.

The designing of such trials exposes patients to the risks of an experimental drug without the upside of potential benefit for themselves or others. These trials are more likely to be scientifically invalid and thus, would be a wasteful use of research resources.

This disparity raises concerns about ethics and adequate informed consent.  Many or most patients in these trials would not need to accept the additional risks of the trial by a new or potentially less safe or less effective treatment.  They have options that would work for them.  Even if the new drug works for the limited population, trial participants who are not in that limited population are exposed to an unnecessary risk.

Ethicists will tell you that it is unethical to put patients at risk to benefit a different, unstudied group.  This violates the principles of beneficence and justice in research and is inconsistent with the Declaration of Helsinki and the Belmont Report.

If, in contrast, the new drug was expected to be safe and effective for the general population—in other words, the types of patients included in the clinical trial—then it would not need to go through the LAPD.  How can a doctor justify explaining to the clinical trial patients that, if they are randomly assigned to receive the experimental drug, the drug might be less effective or less safe than the approved drug that is already known to work for their condition?

The guidance also suggests that patients with serious disease and unmet needs are willing to accept greater uncertainty or higher risk.  Without doubt, that well may be true for many patients.  As an organization that routinely works with patients and consumers, however, we have found that is often not necessarily the case.

It is our experience that patients who are not faced with chronic fatal diseases have also expressed the need for FDA to focus on safety.  We do not think it is not accurate to assume that patients with an unmet need always have less concern for safety than for risk-to-benefit ratio.

FDA recognizes the need to warn patients about the different standards for drugs approved through the limited pathway.  For that reason, the guidance states that the labeling should include the words “Limited Population”, adjacent to the drug’s name, and include a statement about the indication for “limited population of patients”.

While appropriate, this labeling by itself is inadequate, because it does not clearly describe the limited scientific evidence used to support the drug’s approval.  Patients and doctors alike see FDA approval of a drug as the “gold standard”, and they expect FDA approved drugs to meet that high standard.

Randomized and double-blinded superiority trials can be small and provide best available treatment by comparing the standard of care and placebo to the standard of care, plus the new drug as an “add on” treatment.  This is common for cancer trials.  FDA should adapt these strategies for antimicrobials, rather than solely considering evidence from small trials of patients that are substantially different than the indication FDA approves.

The section of the 21 Century Cures Act which describes the LPAD pathway specifically states that the approval through this pathway still requires the same level of evidence as standard approvals—substantial evidence from “adequate and well-controlled studies demonstrating efficacy.

This should include sufficient numbers of participants to conduct appropriate statistical analyses.  In addition, the guidance itself states that the pathway does not allow for drugs to be approved without meeting the normal standard.  However, the use of scientifically invalid or unethical trials would not meet this necessarily high standard.

Thank you for the opportunity to speak on this important topic.