On 7 January 2011, the leaders of the Alzheimer’s Prevention Initiative convened scientists at the U.S. and European medicines regulatory agencies, in industry, and academia, with statisticians and public and private funders in Washington, D.C. Their goal was to push an ongoing conversation with industry toward specifics of what sorts of trials to run, and for industry scientists and funders to hear some regulatory feedback right on the spot. Eric Reiman, Pierre Tariot, and Jessica Langbaum of the Banner Alzheimer’s Institute are leading the API team. Together with related proposals coming from the Dominantly Inherited Alzheimer Network (DIAN) and the Alzheimer’s Disease Cooperative Study (ADCS), the collective push is for therapeutic trials to start within the next two years in three different types of patients.

First, both API and DIAN are proposing studies in carriers of autosomal-dominant Alzheimer’s disease mutations, using their non-carrying relatives as controls. API researchers would like to set up a system where a given carrier gets a candidate drug for a set period of time, then undergoes evaluation of whether the drug had a benefit, and either stays on the drug if it did or moves on to a different candidate drug if it did not. Led by Randy Bateman of Washington University, St. Louis, Missouri, DIAN’s trialists are envisioning small, short studies of drug pharmacokinetics and dynamics preceding a larger efficacy trial. Second, API is proposing drug studies in people who carry two copies of the ApoE4 risk gene and have aged to within a few years of being highly likely to develop AD symptoms. Third, Paul Aisen of the ADCS is proposing a secondary prevention trial in cognitively normal people in their seventies, who are selected not genetically but by dint of having brain amyloid. In toto, these three sets of preclinical patient groups span the spectrum from rare deterministic forms to late-onset sporadic forms of AD in the general population. If results from these three groups hang together, the totality of evidence could potentially help sway regulators, even if a given trial alone is insufficient for approval, the scientists hope.

Overall, both regulators at the meeting, Rusty Katz of the U.S. Food and Drug Administration and Cristina Sampaio of the European Medicines Agency, expressed clear support for such trials. This was a big shift in the perception of many at the meeting. “You should get an award for your talks,” William Potter, formerly of Merck and now an independent consultant, told the regulators afterwards. “Industry should take notice that regulatory is not the holdup here.”

It is difficult—and quite theoretical—to design a trial without a specific drug in mind (see upcoming Part 6 of this series). A particular conundrum is that “because of the inherent lag between biomarker and clinical outcome, we do not know what outcome to pick for the trials,” Tariot said. On this problem, the regulators took a “bring ’em on” approach. They recommended that, rather than pre-specify an outcome based on thin data and then hinging the trial’s success on that guesstimate, researchers should have the trials measure a range of biomarkers and determine which is the most informative about the drug, and which, if any, is most clinically relevant to the patient.

Both Katz and Sampaio said about the proposals that the agencies are likely to take a different approach to each of the three patient populations, even though evidence from one type of trial (e.g., an ApoE4 trial) is highly welcome as additional information in the consideration of another (i.e., an autosomal-dominant Alzheimer’s disease [ADAD] trial). Regarding the DIAN and Colombia trials, Katz said that ADAD may be a valid indication by itself. Sampaio recommended that sponsors seriously consider orphan drug designation for this indication as a means of obtaining repeated and free protocol assistance along the way. “You have nothing to lose by doing that,” Sampaio said. Moreover, because of the scarcity of patients with this form of ADAD, a single pivotal trial may be enough to support approval if it comes with confirmatory evidence from outside that particular study, Katz said, repeating advice he gave at a prior DIAN meeting in London (see ARF related news story). Usually, the FDA and EMA require at least two trials. In addition, an ADAD drug need not be perfectly safe. “There is a view that a drug to treat asymptomatic patients must be extremely safe. If we had a drug that delayed the onset of inherited AD for a significant time, then that would be a huge advance. For such a drug, we could tolerate significant toxicities. We would expect the usual toxicity studies, not much more,” Katz said.

AD caused by ApoE4 is different in the regulator’s eye. Unlike presenilin or APP mutation carriers, not all ApoE4 carriers develop AD. For this reason regulators in the U.S. and Europe would set the safety bar higher for a secondary prevention drug in this group. Moreover, they do not view ApoE4 homozygote AD as a valid indication. They would not automatically extrapolate results from ApoE4 homozygote trials to all AD and approve a drug for sporadic preclinical AD based solely on ApoE4 homozygote trials. The API scientists might be asked to assess the same drug in other ApoE genotypes as well; as before, corroborating data on the same drug from any of the other populations would be welcome, Katz said.

With regard to the proposed ADCS trial of amyloid-positive elders, Sampaio encouraged Aisen. “You must do it. It is extremely important, and you should consider adaptive designs,” she said (see Part 5). At the same time, she called this trial an “academic adventure,” indicating that the current uncertainties about which outcome to use at the very early stage of sporadic AD would preclude approval for a secondary prevention drug in this population in the next five years. “I foresee getting approval in Europe in that timeframe only for ADAD. However, the trials you propose in all three populations will really give us the biomarker data we need for subsequent registration trials,” Sampaio summed up. This did not sit well with pharma scientists, who said their companies need registration trials in order to bite. This prompted discussion of public-private funding models for such trials.

Both regulators agreed that trials in a prodromal population—be it genetic or sporadic—who have even a subtle cognitive deficit that could be measured will be easier to evaluate than trials in the stage prior, where people have a genetic or biomarker risk but are truly asymptomatic. In the former, a change in a cognitive test may be sufficient clinical evidence for approval, Katz said, qualifying “‘MAY’ stands in upper case here. We’d want some ancillary data from another setting, some other cohort.” This is a big change from the previous regulatory stance, which required a cognitive plus a global clinical change. A global change may be impossible to measure at the prodromal stage; hence, a cognitive effect plus a biomarker change might be an adequate basis for approval with a disease-modifying claim, Katz said. What about the truly asymptomatic? “At this time we would not approve a treatment on the basis of an effect of a surrogate marker alone, though eventually this is likely to be the approach in patients without any pathology present,” Katz said.

One final note on a question that nags pharma companies: What if a drug causes a serious side effect in an autosomal-dominant Alzheimer’s disease patient? Would that endanger trials with the drug in late-onset AD, i.e., put the company’s investment at risk? As when often faced with a simple question, the regulators replied with an “it depends.” If the side effect seems to be due to the drug, i.e., liver failure, then it would cloud future development of that drug for LOAD and indeed any other disease, Katz said. If the side effect appears linked to ADAD, then it would not.

What does all this amount to? The regulators want these trials to happen. They offer advice on the designs. They are holding out the prospect of approval based on a single adequate trial with a biomarker and a cognitive effect, though only for ADAD at this point. That is a much more encouraging note than the agencies sounded a few years ago. “Even if the proposed studies do not, in themselves, lead to an approved indication, we hope that they will provide the evidence needed to allow for an accelerated approval pathway using biomarker endpoints,” Reiman said. And a researcher from a pharma company with late-stage AD drugs added, “I thought the regulatory pathway was the problem, but we heard a lot today to clarify that. That’s progress.”—Gabrielle Strobel.

This is Part 4 of a six-part series. See also Part 1, Part 2, Part 3, Part 5, Part 6. View a PDF of the entire series.


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News Citations

  1. London: Europe-U.S. Regulators Mull Prevention Trial in Familial AD
  2. Can Adaptive Trials Ride to the Rescue?
  3. Colombians Come to Fore in Alzheimer’s Research, Mass Media
  4. A Neurologist’s Devotion Puts Familial AD Research Onto New Plane
  5. Detecting Familial AD Ever Earlier: Subtle Memory Signs 15 Years Before
  6. Time to Open the Kimono—Which Drugs in Preclinical Trials?

Webinar Citations

  1. Treating Before Symptoms—ADCS Invites Ideas for Clinical Trials in Very Early AD

Other Citations

  1. View a PDF of the entire series

Further Reading


  1. Colombians Come to Fore in Alzheimer’s Research, Mass Media
  2. A Neurologist’s Devotion Puts Familial AD Research Onto New Plane
  3. Detecting Familial AD Ever Earlier: Subtle Memory Signs 15 Years Before