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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.