N of 1 Clinical Trial Design and its Use in Rare Disease Studies

In the beginning (February) of this year, I attended a workshop titled “Clinical Trial Design for Alpha-1 Deficiency: A Model for Rare Diseases”. During the meeting, the N of 1 design was mentioned as one of the study methods to address the challenges in clinical trials in rare disease areas.

This was echoed in FDA’s “Public Workshop – Complex Issues in Developing Drug and Biological Products for Rare Diseases”. Session 2: “Complex Issues for Trial Design: Study Design, Conduct and Analysis” had some extensive discussions about the N of 1 trial design and its potential use in rare disease clinical trials.

In a presentation by Dr. Temple in FDA titled “The Regulatory Pathway for Rare Diseases Lessons Learned from Examples of Clinical Study Designs for Small Populations”, N of 1 study design was mentioned along with other methods such as randomized withdrawal, enrichment, crossover designs.  

According to Wikipedia, “an N of 1 trial is a clinical trial in which a single patient is the entire trial, a single case study. A trial in which random allocation can be used to determine the order in which an experimental and a control intervention are given to a patient is an N of 1 randomized controlled trial. The order of experimental and control interventions can also be fixed by the researcher. “

While N of 1 is not commonly used in clinical trials, the concept of the N of 1 method with focusing on the single patient is actually pretty common in the clinical trial setting. There is some similarities between Aggregated N of 1 and the typically crossover design, especially the high order cross over design. For safety assessment in clinical trials, challenge – dechallenge – rechallenge (or CDR) is often used to assess if an event is indeed caused by the drug. CDR can be considered as an simple N of 1 design.

“Challenge–dechallenge–rechallenge (CDR) is a medical testing protocol in which a medicine or drug is administered, withdrawn, then re-administered, while being monitored for adverse events at each stage. The protocol is used when statistical testing is inappropriate due to an idiosyncratic reaction by a specific individual, or a lack of sufficient test subjects and unit of analysis is the individual. During the withdraw phase, the medication is allowed to wash out of the system in order to determine what effect the medication is having on an individual.
 CDR is one means of establishing the validity and benefits of medication in treating specific conditions as well as any adverse drug reactions. The Food and Drug Administration of the United States lists positive dechallenge reactions (an adverse event which disappears on withdrawal of the medication) as well as negative (an adverse event which continues after withdrawal), as well as positive rechallenge (symptoms re-occurring on re-administration) and negative rechallenge (failure of a symptom to re-occur after re-administration). It is one of the standard means of assessing adverse drug reactions in France.”

While N of 1 is the experiment on a single patient, using aggregated single patient  (N-of-1) trials will involve multiple patients – quantitative analyses become more feasible. See examples below for using aggregated N of 1 trials.  

• Using aggregated single patient (N-of-1) trials to determine the effectiveness of psychostimulants to reduce fatigue in advanced cancer patients: a rationale and protocol
• Aggregated n-of-1 trials of central nervous system stimulants versus placebo for paediatric traumatic brain injury – a pilot study

N of 1 clinical trials could involve some complicated statistical analyses. See the discussions below:

• the presentation of “N-of-1 Randomized Clinical Trials” on Henry Steward Talks  
• A Comparison of Four Methods for the Analysis of N-of-1 Trials
• Aggregating single patient (n-of-1) trials in populations where recruitment and retention was difficult: The case of palliative care
• N-of-1 Trials by Christopher H Schmid

N of 1 clinical trial design is rarely discussed in statistical conferences, perhaps because of the perception that not too much statistics is involved in the analysis of N of 1 study data. However, we do see that N of 1 study can be a very effective method in demonstrating the efficacy if the characteristics of the indication/drug fit.

• Feasibility Study of N-of-1 Trials With Blood Pressure Self-Monitoring in Hypertension
• N of 1 Tests in Primary Care: A New and Better Way to Prospectively Monitor Chronic Care Drugs for Safety
• Don't Overlook "n-of-1" Trials, Urges UK Expert
• Clinical Trials for Cancer, One Patient at a Time

One of the key questions is that the N of 1 study design is only applicable in certain situations – it  depends on the disease characteristics, treatment (short washout period), endpoint (quick measurements). We can see some of the discussions about the situations where the N of 1 study design may be used from the transcripts of the FDA Public Workshop on Complex Issues in Rare Disease Drug Development Complex Issues for Trial Design: Study Design, Conduct  and Analysis:

“Ellis Unger: We have no ... No comments right now, so let me put a question to the group. I  presented us a slide on the N of 1 study, which we almost never see. Just to remind you, the N of 1 study is a scenario where a patient doesn't contribute and end, but of course the treatment contributes an end, and of course the treatment can be capped in a certain number above ... weeks.
 Unless someone has the amount of interest, in which case, you give up on that course, that aborts that course to treatment and then they re-randomize. Are there therapies, disease states people around the table can think off that would be ... where this design could be applicable, because we don't see these studies. Dr. Walton?
 Marc Walton: I'll just mention that by firing away in all the clinical trials I've reviewed, the most powerful piece of evidence about the effectiveness of a drug came from a N of 1 type of study where it was a study with Pulmozyme cystic fibrosis where patients were treated Pulmozyme that are pulmonary function tested, then the Pulmozyme was discontinued and then tested again, and then several cycles, and I think it was maybe five cycles and you saw such remarkably reproducible effects that it was utterly convincing that the drug was effective for that.
The utility comes about though when you have, as you have said, a disorder that has enough stability and drugs that have a short enough washout period, that you are able to have that repeatedly look as if it was a new exposure to the patient. In disorders where we have that and treatments that are expected to have that sort of reversible effect, this N of 1 becomes a truly powerful piece of information, as well worth considering when those circumstances present themselves.
 Ellis Unger: Typically, a company will come in and say, "You randomize to our treatment or placebo. We're going to count the number of exacerbations or pain episodes or whatever over the course of the study." This is basically saying once you have one of these events, we're going to re-randomize you. Just again, so anybody around the room ... Okay, Dr. Summar.
 Marshall Summar: Yeah, it seems like from the intermediary metabolism, the effects where you have frequent attacks of hyperammonemia, acidosis, things like that, that actually might be a fairly ideal group washout for most of the treatment is pretty fast. That seems like a group where that might actually play out pretty well. I have to think about that but it seems to make some sense.
 Ellis Unger: Dr. Kakkis?
Nicole Hamblett: Thanks. I think the N of 1s, studies are incredibly intriguing and I think one thing I need to wrap my head around is the consigning by commons in medications, for instance, if you're measuring exacerbations during on and off periods in their treatment for that event could alter what's going to happen during the next events. I think that's a little bit difficult to the chronic study, but I guess I also wonder what are the parameters for being able to use an N of 1 study or N of 1 studies for your pivotal trial, as well as difficult enough to conduct confirmatory study. How would we define that for these types of newer or more customized study designs?
 Ellis Unger: Well, I think the N of 1 study, again, you have to have a treatment where there's an offset that's reasonably rapid and you're not expecting the effect on the disease to be ... the effect is not lasting. It's not like Dr. Hyde was mentioning in a gene therapy, as that would be the extreme opposite where you couldn't do this, but if you have something where there's an offset in a reasonable amount of time and patients are subjected to repeated events, I think that's the key.
 If it's progression and it happens slowly with time, you're not going to be able to do an N of 1 study, but if you have some episodic issue and you have a drug with a reasonable offset, I think it will lends itself to this and we're talking about a dozen patients to do a study, the whole deal, and that could be your phase 3 study. I mean that the example I showed was just about a dozen patients. You don't need a lot of patients. “

It is clearly that the N of 1 study design is not appropriate for a study with the efficacy endpoint measured for very long period of time. N of 1 study design may be applicable for short–term endpoints (bio-markers, metabolites, …). However, over the last 10-20 years, the direction of regulatory agencies is moving toward to the long-term endpoints. For an enzyme replacement therapy, a drug showing the increase in enzyme level would be considered sufficient for approval 20 years ago. Nowadays, an endpoint measuring the long term clinical benefit may be required. Similarly, for a thrombolytic agent, it is not sufficient to show the thrombolysis in short term, the long-term benefit of the thrombolytic agent will be required. This trend of requiring the long-term measures in efficacy endpoints make the N of 1 study design unlikely to be used in the licensure studies.