Statement of Dr. Jennifer Yttri at the public hearing on Creating an Alternative Approval Pathway for Certain Drugs Intended to Address Unmet Medical Need

Statement of Dr. Jennifer Yttri, Senior Fellow
February 4, 2013

My name is Dr. Jennifer Yttri and I speak today on behalf of the National Research Center for Women & Families.

Our nonprofit research center includes scientists and medical and public health experts who analyze and review research to provide objective and understandable health information to patients, health care providers, and policy makers.  My PhD is in immunology from Washington University.

My statement today also reflects the written remarks of 14 members of the Patient, Consumer, and Public Health Coalition. The Coalition is comprised of nonprofit organizations united to ensure that medical treatments are safe and effective, and to enhance the scientific and public health focus of the FDA.

Thank you for the chance to speak today.  Like everyone here, we recognize the need for new drugs to reach patients with serious or life-threatening diseases but we have grave concerns about how this vaguely defined pathway will improve development of safe and effective drugs.

The FDA already has 6 pathways to quickly get drugs to patients with unmet needs. Where is the evidence that this new pathway is needed? How will it promote development of drugs that help patients live longer or have a better quality of life? Almost 50% of the drugs approved in 2009 and 2011 were through a priority pathway1  so there are many ways to get these drugs to patients.

In the President’s Council of Advisors on Science and Technology recommendations, from which the FDA’s proposal was derived, the council said such a pathway would be ineffective without changes in the FDA’s approval and regulatory processes to protect patients.  PCAST said that the FDA would need to establish clear guidelines for clinical trials of drugs to prove benefit given serious and unknown risks. They emphasized the harm that this pathway would cause to ALL patients without a change in the FDA’s authority to regulate distribution after drug approval for one indication. Without first addressing these major changes, designing this new approval pathway is premature.

FDA currently requires adequate and well-controlled trials for drug approval.  As you know, there are inherent dangers when drugs are approved based on smaller and shorter clinical trials. The quality of the research is even more important when the study is done on a narrow population.  Small, short-term studies provide limited information about drug toxicity and safety. Small studies can also overestimate the benefits to patients.

Surrogate endpoints have become common in clinical trials, but they still need to be APPROPRIATE. A surrogate endpoint is valid only if it correlates with the outcomes patients care about which are their health, quality of life, and how long they live. The therapeutic must affect the surrogate endpoint in the same way it affects mortality and morbidity. Clarithromycin was great at killing mycobacterium, with a higher mortality in patients with AIDS. Benlysta helps some patients with lupus get rid of their rash but in exchange will leave them susceptible to severe infection or death.  Avastin slowed breast cancer progression but did not extend or improve patientss’ quality of life – in fact, it did the opposite. These are all cases where surrogate endpoints showed promise but later studies proved the opposite.

The proposed pathway can’t promise improved health, quality of life, or lifespan.  It can try to make a drug available sooner, but shorter trials will have LESS information about whether the drug accomplishes ANY of those 3 patient-centered outcomes.

Waiting for data from post-market studies to identify the safety risks means that patients will meanwhile pay for unproven treatments while serve as unwitting guinea pigs.  Patients may die or be harmed for years before post-market studies are completed.

There is an added complication for approving drugs for very small groups of patients. For many of these serious and life-threatening conditions, specific target populations cannot be readily identified prior to clinical trials. A limited population pathway provides an incentive to create smaller trials but NOT ones that use APPROPRIATE studies with the right PATIENTS.

This brings up the problem of off-label use.  If these drugs are to be used in a limited population, physicians need to prescribe these drugs only in patients who clearly fit the limited population AND have no better options.

This is unlikely to happen.  Currently, 21% of all prescriptions, and 62% of pediatric prescriptions are for unapproved use.  Once a product is approved, it is likely to be taken by many patients who are not in the targeted patient group, without evidence of its efficacy or risks in a broader population. In the case of antibiotics, a class of drugs likely to seek approval through this pathway, inappropriate use, even one dose, will add to the problem of antibiotic resistance, the very condition we’re trying to fight.

Since 2004, there have been 28 settlements with companies that promoted drugs for unapproved use, often targeting patient populations in whom these drugs have never been tested.   Just last year, major lawsuits were settled against GlaxoSmithKlein, Johnson & Johnson, and Amgen.  This could change, but not for the better. The FDA has so far done nothing to overturn the recent case of United States versus Caronia, which decided that pharmaceutical representatives can promote off-label use under the First Amendment.

The FDA has not developed effective strategies to stop off-label promotion, and therefore will not be able to restrict the use of drugs to the approved limited populations. A study by Chen et al found that physicians were barely above chance in knowing if their prescription was off-label or for an FDA approved use – even though many of these doctors had prescribed the very same drugs for years. With widespread promotion of off-label use, thousands of patients will be exposed to unnecessary harm before we understand under what conditions these drugs work and what the safety risks are.

Worse yet, in another study, only 15% of medical providers stated that they provided safety information to patients if it was indicated on a drug label.  A formal designation and logo will not help much at all. Even with some extended educational plan for clinicians and patients, or medical guide inserts, most patients will not fully understand to what extent the drug is proven safe or effective for their needs.

In conclusion, this poorly defined pathway would promote unproven drugs to high-risk patients. We know that there are desperate patients who are willing to take risks, but with smaller, shorter trials, you won’t be able to tell either the patients or the doctors what the risks are.  If approved based on such limited information, there is no doubt that some of these drugs would harm more patients than they help.  Patients, some of whom would never benefit from these drugs, will die or be irreparably harmed.

There are already 6 expedited pathways used in the approval of almost half of all new drugs.  I share the FDA’s desire to help patients with unmet needs to get access to drugs that could possibly help them.  I wish there were a way to do so without jeopardizing patients who have other treatment alternatives or whom we know are unlikely to benefit.  But, wishing isn’t science.  The FDA is a scientific agency, and it has not provided the science to support this proposal.

  1. FROM: Clinical Pharmacology & Therapeutics, 2011 Pharmaceutical Innovation in the 21st Century: New Drug Approvals in the First Decade, 2000–2009 K I Kaitin and J A DiMasi