One purpose of the meeting of the Frontotemporal Degeneration Study Group (FTSG) held 4 June 2012 in Washington, D.C., was to give its scientists an opportunity to show the Food and Drug Administration how far their research has come (see Part 1, Part 2, and Part 3 of this series). The other was to get feedback on how to proceed to ensure that future trials meet success. The conversation unfolded amid the cross currents of palpable excitement about the fundamental scientific advances in FTD versus a sobering realization that the pharmaceutical industry is shrinking back from neurodegenerative indications in the aftermath of negative trials in Alzheimer’s. “The exuberance about FTD drug development is justified. Let’s keep it rational,” said James Kupiec of Pfizer’s Neuroscience Research Unit in Groton, Connecticut.

How is the FTSG to do that? Step 1 is to consult early and often with regulators on both sides of the Atlantic, said Lynne Yao of the FDA’s Center for Drug Evaluation and Research (CDER). This Alzforum story first summarizes Yao’s general remarks to the assembled group of academic, industry, and funding scientists; Part 5 excerpts agency replies to FTD-specific questions the FTSG had submitted prior to 4 June.

First off, treatments for FTD fall under the auspices of the Orphan Drug Act of 1983, because this group of diseases affects fewer than 200,000 patients in the U.S. Similar legislation is on the books in Europe as well. The law is known for its financial incentives; however, equally important is that it provides drug developers more frequent access to free advice from regulators, and Yao urged the FTSG to take full advantage of this expertise.

For context, a third of CDER’s approvals between 2006 and 2010 went to orphan products. This includes both small-molecule drugs and biologics such as antibodies. One-fifth of rare disease approvals went to first-in-disease indications. Those programs tend to be unconventional, Yao said. CDER has allowed the use of historical controls, which are frowned upon in trials for common diseases. CDER has considered evidence in related populations, non-traditional study designs, and pharmacodynamic endpoints. Those approvals went to diseases affecting 150,000 to 180,000 patients. “Studies in very rare diseases are possible and can lead to approval,” said Yao.

One example is a genetic kidney disease called NAGS deficiency. In 2009, the European Medicines Agency (EMA) approved the drug CarbaGlu to treat it. The regulators did so based on only 12 patients in the dosed group, said Christina Sampaio, formerly of the EMA. In 2010, the FDA followed suit. What clinched the case? A package of 17 years' worth of data from fewer than 100 patients altogether, a blood biomarker as a surrogate outcome, and additional data from the literature. “This program used extremely out-of-the-box thinking,” Yao said.

So, if orphan drug status is possible, then why is it still tough to obtain? The answer is that the Orphan Drug Act does not provide a separate (read "lower") standard. “You still need the same evidence for effectiveness and safety,” said Yao.

In practice, the challenge of gathering that evidence with few patients available means that an orphan drug program typically starts out without qualified endpoints, outcome measures, or biomarkers, much less a surrogate endpoint. It’s learn-as-you-go, and datasets to establish those tools and then use them in registration studies will be small. For patients, the stakes are high because their rapidly progressing, fatal disease may leave but one shot at a trial. Yao put it this way: “For a disease with a huge number of patients, let’s say hypertension, if you pick the wrong endpoint and design a fancy study, you may get a mess of data and have wasted time and money, but you can enroll thousands more patients for a better second study. You do not have that luxury here. So I recommend that you plan carefully, because these patients desperately need you to get it right the first time.”

What does planning carefully mean? The clinical development plan should rest on natural history studies that generate information on pathophysiology and the mechanism of action of a planned intervention. That forms the basis of IND-enabling data, which open the door to clinical trials. In developing a coherent plan, the FTSG should bring everyone to the table, notably toxicologists, pharmacologists, and patient community representatives, Yao said. For this work in particular, the orphan designation offers ample access to regulators.

An IND then requires animal pharmacology and toxicology data to permit an assessment of whether the drug is reasonably safe, as well as data about manufacturing, product composition, stability, appropriate production, assurance that the drug will be available, and other information.

INDs for rare diseases vary, but invariably they open the door to the next big step: dose finding. This is difficult in rare diseases, Yao acknowledged, as more doses studied mean the groups become awfully small. Even so, it's critical. “You must do some dose finding. You can’t tell the dose based on a mouse, or a different human indication. We will not insist on five doses having been fully tested. But do tell us what dose makes sense based on good pharmacokinetics from your first human data,” Yao said.

Both the FDA and EMA have two ways of approving a drug. Besides regular or full approval, there is also accelerated approval, which came into being as a result of HIV/AIDS activism. It is granted when the drug moves a surrogate endpoint in a way that is reasonably likely to produce a clinical benefit later.

Researchers in the FTSG, and also AD researchers preparing Dominantly Inherited Alzheimer Network (DIAN) and Alzheimer's Prevention Initiative (API) trials, covet this. It sets a lower bar than showing clinical or even global benefits in prodromal, asymptomatic, or very clinically heterogeneous populations. But what does “reasonably likely to produce a clinical benefit” mean, exactly? There is no blanket answer, Yao said. Basically, the drug must come with substantial evidence of safety and likelihood to predict clinical effectiveness. That means the study clearly distinguishes the effect of the drug from other influences, for example, by using adequate controls and ensuring that the outcome instruments do not have their floor or ceiling in the study population and duration. Specifically, FTD markers that were discussed on 4 June—above all, serum progranulin—at present are far from amounting to a surrogate endpoint, Yao said. “But when you think you have one, talk to us early.”

Adaptive and Bayesian trial methods drew attention at the meeting, but Yao cautioned that in many rare diseases, too little is known about pathophysiology and the drug’s mechanism of action to execute such designs. Even though the orphan drug group at the FDA is sympathetic to adaptive approaches, in reality it sees few such trials.

With accelerated approval, the sponsor must conduct post-marketing research to show that the surrogate outcome indeed generates a clinical benefit later. When that fails, the FDA withdraws approval. Earlier this year, for example, the FDA revoked the metastatic breast cancer indication for Avastin, which the agency had conditionally granted in 2008.

Regulators at the EMA approach orphan drug development in much the same way as does the FDA. In particular, EMA scientists facilitate development planning, and orphan drug evidence must be as strong as for any drug, said Sampaio, who spoke personally, not on behalf of EMA, which she left in 2011 to head drug development for the Cure Huntington’s Disease Initiative in Princeton, New Jersey.

One difference between the FDA and the EMA concerns the terminology around surrogate markers. Thomas Fleming, a noted biostatistician at the University of Washington, Seattle, wrote an influential article in Health Affairs about the pitfalls of surrogate markers and accelerated approval (Fleming, 2005). Fleming’s classical definition requires proof that the effect of the drug on the surrogate is correlated with the effect of the drug on the clinical outcome, and that the size of the effects is correlated. “There is no surrogate in existence that fulfills these conditions. They are nearly impossible to prove,” Sampaio said. For this reason, both agencies, in essence, are moving away from the classic concept of the surrogate endpoint and toward the concept of cumulative evidence that the endpoint is connected to the clinical outcome. “This cumulative endpoint is a matter of judgment. It is a matter of acceptance by the scientific community. It is a matter of building history. It may take years or even decades,” Sampaio said. The terms "surrogate endpoint" and "accelerated approval" persist because they are written into FDA regulations, but for its part, the EMA has come to use the terms "cumulative evidence" and "conditional approval" instead, Sampaio said.—Gabrielle Strobel.

This is Part 4 of a five-part series. See also Part 1, Part 2, Part 3, Part 5. Read a PDF of the entire series.


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News Citations

  1. Scientists Strategize With Regulators for Frontal Assault on FTD
  2. Toward FTD Therapeutic Trials: Diagnosis Firm, Outcomes Still Soft
  3. Case Studies Crystallize Trial Ideas at FTD Conference
  4. For FTD Drug Development, a Q&A With Regulators

Paper Citations

  1. . Surrogate endpoints and FDA's accelerated approval process. Health Aff (Millwood). 2005 Jan-Feb;24(1):67-78. PubMed.

Other Citations

  1. Read a PDF of the entire series.

External Citations

  1. Orphan Drug Act of 1983
  2. metastatic breast cancer indication for Avastin

Further Reading