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FDA Issues Draft Guidance on Developing Drugs for Treatment of Early Stage Alzheimer’s Disease

Posted by Brook White on Mon, Mar 25, 2013 @ 09:23 AM

Herbert Harris, Rho Medical DirectorThe following article was contributed by our medical director, Herbert Harris, MD, PhD. 

On February 7, the FDA issued a proposal designed to assist companies developing new treatments for patients in the early stages of Alzheimer’s disease, before the onset of noticeable (overt) dementia.

Although we have an enormous amount of information about the underlying molecular pathophysiology of Alzheimer’s disease, translating this knowledge into effective new treatments has been exceedingly difficult. Part of this difficulty arises from the slowly progressive nature of the disorder. We have known for many decades that the accumulation in the brain of a protein known as amyloid is a central part of this process. Abnormal accumulation of amyloid triggers many other biochemical processes that lead to neuronal cell death and dysfunction that cause cognitive deterioration characteristic of the disease. This understanding has led to the development of many drugs that have the potential to prevent or oppose the abnormal accumulation of amyloid. However, these new drugs have typically been tested in patients in whom cognitive impairments are already fairly far advanced. Yet in recent years, advances in imaging technology and neuropathology have indicated that amyloid accumulation may begin years, or even decades before the appearance of measurable cognitive deficits. Such findings imply that interventions targeting amyloid accumulation are unlikely to show significant clinical benefits if they are not used until cognitive deficits have manifested. Instead, medicines that target amyloid accumulation and other fundamental molecular processes should probably be introduced well in advance of the onset of cognitive changes in order to be optimally effective. This understanding has led to a fundamental rethinking of the methods and strategies for drug development in Alzheimer's disease. Recognizing these new challenges that face the field, the FDA has developed a draft guidance document for the development of drugs to treat early stages of Alzheimer's disease. The guidance identifies a number of critical drug development issues and has indicated potential solutions that could move the field forward. In an accompanying press release, Russell Katz, M.D., Director of the Division of Neurology Products at the FDA’s Center for Drug Evaluation and Research noted: “The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain. It is in this population that most researchers believe that new drugs have the best chance of providing meaningful benefit to patients.”

developing drugs for Alzheimer's patientsPerhaps the most problematic issue is that of identifying appropriate patient populations to study. Conventional clinical trials involving Alzheimer therapeutics typically enroll patients who meet criteria for a mild to moderate level of dementia as measured by various cognitive tests. Currently, there are a number of diagnostic entities that have been defined so as to capture patient populations at an early stage. These include Mild Cognitive Impermanent (MCI) and prodromal Alzheimer's disease. However, these diagnoses still depend on identification of some level of cognitive dysfunction. To identify patients at even earlier stages may require the use of genetic and other biomarkers. In developing their industry guidance, the FDA has acknowledged the potential importance of conducting trials in enriched populations defined by combinations of clinical findings and biomarkers. Unfortunately, to date, no biomarkers have been identified with sufficient predictive power. However, a great deal of progress is being made in this area.

The development of treatments for early stage Alzheimer's disease may also require the development of innovative outcome measures. Conventional studies of mild to moderate Alzheimer's disease typically employ cognitive testing used in combination with either a functional or global outcome measure as a co-primary endpoint. In the FDA guidance, it is acknowledged that in early stage Alzheimer's subjects, there may be little or no functional impairment. Therefore, it is recognized that in some cases the use of a co-primary outcome measure may be impractical. However, it is noted that as patients progress to later stages in which both functional and cognitive impairment begin to manifest, it may be appropriate to use composite scales that capture elements of function and cognition. The Clinical Dementia Rating Scale–Sum of Boxes score, which is been validated in patients whose level of impairment does not meet the threshold of frank dementia, is given in the guidance as an example of such a scale,. In the draft guidance, the possibility was also raised that a treatment might obtain approval under the accelerated approval mechanism based on effects demonstrated on an isolated cognitive measure. It was noted that in this scenario a sponsor might be required to demonstrate sustained global effects as a post-marketing condition.

The draft guidance contains an extensive discussion of the topic of biomarkers as primary and secondary outcome measures. It is noted that the use of a biomarker as a primary efficacy endpoint is a theoretical possibility under the accelerated approval mechanism, but there is currently no biomarker for which there is sufficient evidence to justify its use as a proxy for clinical preventive Alzheimer's disease. The draft guidance states “until there is widespread evidence-based argument in the research community that in effect on the particular biomarker is reasonably likely to predict clinical benefit, we will not be in a position to consider approval based on the use of a biomarker as a surrogate outcome measure in Alzheimer's disease (at any stage of illness).”

While many issues such as the potential role of biomarkers will have to await scientific development within the field, the development of an industry guidance document represents an important step that will focus the energies of the research community and enable much-needed progress in Alzheimer research. The agency is currently seeking public comments on the draft guidance. It is likely that they will begin finalization of the document next month. The FDA proposal is part of U.S. Department of Health and Human Services initiative known as the National Plan to Address Alzheimer’s Disease. This calls for both the government and the private sector to intensify efforts to treat or prevent Alzheimer’s and related dementias and to improve care and services.

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4 Types of Dose Finding Studies Used in Phase II Clinical Trials

Posted by Brook White on Mon, Mar 11, 2013 @ 12:07 PM

phase II clinical trials dose finding studiesOne of the key goals of phase II is to determine the optimal dose that you will use going into your phase III trials and that ultimately will be used on your product label submitted for approval as part of the new drug application (NDA).  The optimal dose is the dose that is high enough to demonstrate efficacy in the target population, yet low enough to minimize safety concerns and adverse events.  There are a number of strategies to determine the optimal dose, but here we will look at the four most common dose finding study designs.

Parallel Dose Comparison

Parallel dose comparison studies are the classical dose finding studies and are still one of the most common study designs. In a parallel dose escalation study, several potential doses are selected and subjects are randomized to receive one of the doses or placebo for the entire study. At the end of the study, you can compare each treatment group to the control group and examine both safety and efficacy. Because all treatment groups, including the higher dose cohorts, are dosed at the same time, this study design is best suited for situations where you have a good idea about the safety profile before the study starts. The design is also the basis for some adaptive studies (such as adaptive randomizations or pruning designs) that can reduce the number of subjects exposed to unsafe or ineffective doses.


In a cross-over design, subjects are randomized to a sequence of investigational product (IP) and placebo. Specifically, they are given a dose of the IP and then switched to dosing with a placebo or they start dosing with a placebo and then are switched to doses of IP. The difference between the subjects' response to placebo and IP is the result of interest and by having different groups of subjects exposed to different doses, you can pick the optimal dose. The value of cross over studies is they can determine efficacy of a dose within a subject because subjects act as their own control.  This reduces the variability and can therefore reduce the number of subjects you need to study. However, cross-over designs only work when the drug is quickly eliminated from the body. You need to be able to give a subject the treatment, wait for it to clear, and then give the second treatment in the sequence. It also requires a product that is designed to be used multiple times. For example a product that is intended to be given once, such as a drug to lower blood pressure during heart surgery, can’t be tested in a cross-over study because you won’t do the surgery again just to give the second treatment in the sequence.

Dose Titration

In a dose titration study, you titrate to the maximum tolerated dose within a subject. This means that each subject will start at a low dose and receive an incrementally higher dose until the maximum dose is reached.  In some studies, like chemotherapy for cancer studies, this dose is determined by the onset of side effects--this dose is called the Maximum Tolerated Dose (MTD).  In other studies where the product is less toxic, it may depend on the blood levels of the IP, a metabolite, or a maximum dose determined from preclinical studies.  Dose titration studies work well for treatments of chronic conditions where a drug will be used for a long period of time, and where the dose is likely to be tailored to the subject's weight or reaction.  This design is also good for situations where it is likely that you will see significant differences in the way each subject reacts.  Chronic hypertension medications are a good example of products where dose titration is useful. There is a lot of variability in how individual patients respond to hypertension products and with titrating the dose, you can give a lower dose to those who respond to it.

Dose Escalation

If you are unsure of your safety profile and want to start exposing subjects to lower doses first, consider a dose escalation study. In this type of study, you start with one group of subjects (often referred to as a cohort) and give them a low dose. You observe this group for a period of time, and, if no safety issues are noted, you enroll a new group of subjects and give them a higher dose. This process is repeated until either you reach the maximum tolerated dose or you reach the highest dose you plan to consider. This design increases patient safety because you can start by exposing a small number of subjects to the lowest dose possible. You are mitigating risk both by limiting the initial number of subjects and limiting the exposure of each subject to study drug. You can also add control subjects to each cohort if you want to look at efficacy measures with an appropriate comparison group.

There are other types of study designs and many variations on each of these study designs that may be useful in determining the optimal dose before heading into your phase III clinical trials. Interested in learning more? Check out this video where Dr. Karen Kesler talks about whether an adaptive design is right for your study.

View "Is Adaptive Design Right for You?" Video

Dr. Karen Kesler, Senior Statistical Scientist and Dr. Andrea Mospan, Program Manager contributed to this article.  Check out the video below where Dr. Kesler discusses the basics of adaptive design.

4 Types of Efficacy Outcomes to Consider in Phase II Clinical Trials

Posted by Brook White on Mon, Mar 04, 2013 @ 01:50 PM

measuring efficacy outcomes in phase II clinical trialsYou will often hear the phrase “learn and confirm” related to clinical trials. Phase II clinical trials are where you “learn” about your treatment and phase III clinical trials are where you “confirm” what you know for regulatory agencies.  One important part of the learning that takes place in phase II is looking at various efficacy outcomes to determine which primary end point you will use for phase III and what specific label claims you will be able to make following an approved NDA.  

Biological Mechanism

These outcomes measure some component of the biological mechanism the treatment is targeting.  An example an endpoint of a biological mechanism would be measuring hemoglobin levels for a treatment of anemia.  An advantage of this type of outcome is that they are clear and objective.  This type of endpoint may not be an option in the case where the mechanism of action is not well understood or easily measured, such as in many psychiatric drugs. 

Physical Manifestation

Measuring some aspect of the physical manifestation of the disease can serve as an outcome.  For example, cystic fibrosis impacts lung function.  To demonstrate efficacy of a treatment for cystic fibrosis you can use spirometry to assess lung function.  This is especially useful when your therapy doesn’t attack the disease state itself, but ameliorates the symptoms of the disease.  It’s also good in the situation where the disease progresses slowly, but the symptoms have a much earlier onset.  

Qualitative Improvement

You can also look at qualitative aspects of subject improvement.  Sometimes these are qualitative assessments by the physician or patient, like rating their pain on a scale of 1 to 10.  It can also be a more objective measurement like looking for a decrease in the number of hospitalizations during a period of time.  These can be important endpoints because there is an opportunity to clearly demonstrate the impact on a patient.  Since these types of outcomes are more subjective, it is important to provide as much structure as possible to the assessment to limit the potential for bias in the results.

Disease Progression

Often, the outcome of most interest is a direct measure of disease progression, as when you measure death or cancer progression in an oncology study. This sometimes overlaps with the physical manifestation or symptom endpoints, but is more focused on the direct consequences of the disease instead of the early symptoms of progression or opportunistic events.

A few other considerations when considering the types of outcomes you will measure in your phase II trials:

  • Collect any measurement you might consider using as an endpoint in your phase III trials.  You don’t want any surprises in phase III when mistakes are much more expensive because of the scale of the trial.
  • If there is a “typical” endpoint for the indication you are studying, you should collect it, even if you don’t plan to use it as your primary endpoint.  This makes comparing your results to prior results in other studies easier to do.
  • The types of outcomes described above are all about demonstrating efficacy.  Safety is important in all stages of development, including phase II, so consider if there are specific safety endpoints that you should also be measuring.

Each investigational product and indication is unique, and it would be impossible to provide one set of rules or guidelines for picking endpoints, but hopefully you find the information provided here useful.  

Dr. Karen Kesler, Senior Statistical Scientist and Dr. Andrea Mospan, Program Manager contributed to this article.  Check out the video below where Dr. Kesler discusses the basics of adaptive design.

View Adaptive Design 101 Video

5 Ways Smart Animal and Manufacturing Work Can Mitigate Risks to Your Clinical Development Plan

Posted by Brook White on Mon, Feb 18, 2013 @ 10:33 AM

preclinical work will impact your clinical developmentFor those of us focused on clinical trials management, it is easy to forget all of the work that happens before a potential treatment reaches the clinical trial stage of development.  In this article, we will explore five key ways pre-IND animal and manufacturing work can impact your overall clinical development plan. 

  1. Pharmacodynamics and an Early View into Efficacy
    The primary goal of a phase I clinical trial is to demonstrate safety that allows progression to phase II. Of course, no one wants to move into costly human trials with a treatment that has a low probability of being effective. Pharmacodynamic studies look at the effect of the drug on the body (or in the case of an antibiotic on the effect of the drug on the target organism) and pharmacodynamic studies in animals provide an early indication of an efficacy target. By carefully selecting animal models that have the pharmacodynamic effect being pursued in humans you have a higher likelihood of getting meaningful safety information.

  2. ADME and Safety
    Understanding the ADME (Absorption, Distribution, Metabolism, and Excretion) profile of your product as determined by preclinical pharmacokinetic studies is an important component for predicting safety issues as you move into human trials. The bioavailability of the product, where the product ends up, where and how the product is broken down, and how the product is excreted give you key insights into which physiological systems are likely to be impacted by your investigational product. If your product is broken down in the liver and excreted through the kidneys, you know these are two systems that should be monitored closely first in toxicology studies and then in human trials. Moreover, if you know that your drug is metabolized in your toxicology species similar to how it is metabolized in cultured human cells; for example, you will have more confidence that the toxicology of metabolites is adequately modeled in your toxicology program.

  3. Therapeutic Index and Your Dosing Strategy
    Pharmacodynamic effects and toxicity are compared relative to dosing for something known as the therapeutic index. The therapeutic index is the range of doses between ED50 (the dose at which the pharmacodynamic effect elicited in animals is 50% of the maximal effect) and the MTD (the maximum tolerated dose). The therapeutic index as determined in preclinical studies is the starting point for your dose finding strategy as you move into human studies. It provides valuable information about a dose range with the highest probability of being both safe and effective in humans. Once a minimum effective dose is determined in animals the starting dose in humans should generally be one tenth of this dose, correcting for allometric scaling (i.e., quantifying the differing body sizes and shapes between two species and then using that mathematical relationship to adjust the dose from one species to the other).

  4. Development Stage Chemistry, Manufacturing, and Controls (CMC)
    From short stability windows to manufacturing problems, issues on the CMC side of drug development can cause huge headaches and costly delays once clinical studies are underway. Here are a few things to be on the lookout for:

    • Product stability: Although you can extend expiration dates as you go based on stability studies that are being conducted concurrently with clinical work, you want to make sure that initial stability data supports your early phase trials. You also want to ensure that plans for on-going stability work are coordinated to eventually support the entire duration of anticipated exposure to your product with clinical trial timelines.

    • Storage and packaging: Find out early if special storage conditions are required. This is something you will have to consider when qualifying sites. Also, take a look at the packaging for concerns that investigators might have or problems that subjects might run into during the trial. If you are using unusual container closure systems or blister packs with complicated labeling, you may need to address these during investigator meetings and/or site training. Monitors should be aware of any of these concerns, so they are prepared to address questions and problems during site visits.

    • Drug substance and drug product availability: Manufacturing delays come from numerous sources, and cannot always be avoided. By understanding the likelihood of these problems and through close communication between CMC experts and clinical operations staff, you can mitigate the impact of investigational product shortages and delays on clinical trial timelines.


  5. Meeting IND Requirements
    Assuming you are planning trials in the US, you will need an IND to start any testing in humans and preclinical work is necessary to support an IND. While INDs do not require approval (no news is good news in this case), FDA may place you on a clinical hold if your preclinical work is substandard or incomplete. A clinical hold will stop you from starting any clinical trial activities and any activities you have started will have to be stopped. You will have to have sufficient pharmacology and toxicology data to convince FDA that the potential benefits outweigh the potential risks of moving studies into humans.

In the best of situations, the people working on the clinical development plan, the people responsible for the preclinical work, and the people who will execute the clinical work are able to work in a closely coordinated manner. By doing so, you can reduce time and costs associated with clinical development, eliminate poor product candidates early, and bring successful products to market quickly without sacrificing quality.

5 Things You Should Know about Phase 1 Clinical Trials

Posted by Brook White on Mon, Jan 07, 2013 @ 09:09 AM

1. In Vitro and animal studies  are rarely sufficient to anticipate safety problems that may result in the development of pharmaceuticals.

preclinical studiesPreclinical studies, including both in vitro and animal studies provide valuable information and are the foundation for designing for “First in Man” phase 1 studies, but the results are rarely directly transferrable for humans.  Subject safety is paramount in carefully controlled phase 1 clinical trials, which typically use healthy volunteers.  Subjects are dosed and observed in clinical trial units where medical personnel are available immediately to avert any untoward events unanticipated from the previous work done in animals.   

2. The purposes of phase 1 clinical trials are initial estimation of safety and tolerability, assessment of pharmacokinetics (PK) and pharmacodynamics(PD), and potential indications of a product’s clinically relevant activity.

The goals for safety in phase 1 include determining the tolerability of the dose range expected to be needed for later studies and determining the nature of the adverse events related to the product by attempting to find a maximum tolerated dose.  Pharmacokinetics provides data on how the body affects the drug in terms of absorption, distribution, metabolism and excretion (ADME).  Pharmacokinetics also examines food effects and special physiologically-compromised populations.  Pharmacodynamics provides data on what the drug does to the body.  For example, pharmacodynamics provides data to evaluate the therapeutic window (minimum effective dose versus minimum toxic dose) and the duration of action.  Phase 1 clinical trials often include some measures of clinically relevant activity to give sponsors an indication of the potential efficacy of a compound.

3. An Investigational New Drug application (IND) is required for phase 1 clinical trials conducted on investigational drugs and biologics in the US.

This requirement comes from 21CFR312.20.  The sponsor company must present FDA with data that show the new product is safe in animals and is stable and manufactured reproducibly within pre-defined specifications.  They must also demonstrate that the clinical trial will be 1) conducted by qualified personnel; 2) will be conducted under a protocol providing safety for subjects, and 3) will generate scientifically useful results.  The IND must include:

  • Chemistry, Manufacturing and Controls (CMC) information- assures proper identification, quality, purity, strength, and stability of the investigational drug
  • Pharmacology information-effects and mechanism of action in animals that potentially will prove therapeutic in humans
  • Toxicology information-integrated summary of the sponsor’s data on completed toxicology studies
  • Investigator Brochure (IB)-a synopsis of the IND that informs the investigators on what is known from preclinical studies about the pharmacodynamics, pharmacokinetics, and safety of the investigational product, the manufacturing process, and the clinical rationale for development
  • Protocol-outlines the investigation that will be performed including the number of subjects, subject characteristics, study design, safety monitoring, and toxicity based rules for stopping or adjusting the dose

4. FDA does not provide an explicit approval of an IND.

An IND goes into effect 30 days after it is received by FDA, unless FDA notifies the sponsor that the investigation described in the IND is subject to a clinical hold under 21CFR312.42. A clinical hold is an order issued by FDA to delay a proposed clinical investigation or to suspend an on-going investigation.  So, while the FDA does not approve trials, they can stop them.

5. First in Man is only one of several kinds of phase 1 clinical trials.

phase 1 clinical trials food effect studiesOther common phase 1 studies include food effect studies, age/gender/race effect studies, dose finding studies, liver or renal impairment studies and drug-drug interaction studies.  Food effect studies are recommended for all orally administered new drugs and evaluate the effect of food on the bioavailability of the product.  Food can change bioavailability by delaying gastric emptying, changing gastrointestinal pH, increasing blood flow, or physically or chemically interacting with a drug product’s dosage form.  Age/gender/race effect studies are designed to assess differences among subgroups that can occur because of age-related metabolic changes, hormonal differences, and genetic polymorphisms.  Dose finding studies generate safety and PK information to choose a dose range for clinical efficacy trials.  Hepatic impairment studies explore the impact of liver disease on pharmacokinetics and are required if the liver contributes more than 20% to drug metabolism and excretion or if there is a narrow therapeutic window.  Renal impairment studies explore the impact of renal disease on pharmacokinetics and are required if alteration to PK is expected in patients with renal disease or dose adjustment is likely needed for patients with renal disease (for example, when elimination occurs primarily through the kidneys).  Drug-drug interaction (DDI) studies evaluate potential PK interactions between the investigational product and marketed compounds likely to be coadministered.  These studies are important because they may impact dosing or warnings on the label.