Introduction
Commercially marketed drug products are often used in clinical trials in direct comparison with an investigational medicinal product. As defined in regulatory guidance, a comparator is “an investigational or marketed product (i.e. active control), or placebo, used as a reference in a clinical trial1,2." The clinical studies are designed to evaluate safety, efficacy, and therapeutic advantages for the new investigational compound in comparison to already marketed drugs.
Comparative agents can be used in clinical studies in their commercial presentation (open label) or in a blinded presentation.
Blinding
Blinding is defined in regulatory guidance as “a procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s)2.” This ensures that the effect of the drug will not be influenced by its characteristic features recognizable by the patient (e.g. color, shape, smell, or taste) or by the behavior of the investigator. Therefore, the risk of false positive or false negative bias in clinical study results is minimized. It is important to note that blinding a dosage form only refers to disguising physical properties of the product. Some drugs will produce very specific side effects (physiological, psychological, or both). Such drug reactions are impossible to match in the placebo or comparator products, and are not part of the blinding effort.
Clinical Trial Designs
Some of the common clinical trial designs include:
- Open label: All trial participants are aware what drug is being dispensed.
- Single blind: Only the patient is blinded. The doctor or investigator knows which medication each patient receives.
- Double blind: Both the patient and the investigator are blinded. Neither of them knows which participants are receiving experimental drug and which are receiving placebo (or another therapy).
- Double blind, double dummy: Both the patient and the investigator are blinded. In this case however, the patient has to take both active and placebo medication. The availability of a matching placebo is a necessity to perform double blind double dummy studies.
- Third party blind: The medication itself is not blinded. However, neither the patient nor the investigator could recognize the medication, as the medication is dispensed by a third party (e.g. a pharmacist or nurse).
- The clinical trial design impacts the blinding strategy, and vice versa. For example, in the case of a lyophile, does the placebo need to physically match the lyophile, the reconstituted solution, or the point of infusion? Will the product be reconstituted by the investigator, or can it be performed by a third party?
Blinding Techniques
A comparator can be blinded in several ways:
Mask comparator appearance and make a placebo to match the blinded product
This is the most widely used approach. Examples include overencapsulation, removal of markings (deinking), overprinting, overcoating, altering secondary packaging components (e.g. exchanging plunger rod and finger grip of a pre-filled syringe), etc.
Purchase non-commercially marked product (clinical image) and either purchase or manufacture matching placebo
This can be difficult to find an innovator or generic manufacturer that is willing to make a clinical image of their marketed product. Agreements between the requestor and manufacturer need to be in place to obtain clinical image. It can be difficult to match up the clinical demand with the agreement. Typically this approach is only used when a study requires large quantities, multiple re-supplies, or the product has unique blinding challenges.
Modify comparator appearance to match that of the Investigational Medicinal Product (IMP)
This approach has the advantage in that only one placebo can be used for both the blinded comparator and blinded IMP. However, the comparator and the IMP would need to be the same dosage form, and have drug product characteristics that would allow both comparator and IMP to be blinded the same way.
Manufacture a near match placebo
Early phase studies may not have the time, budget, or quantity needs to warrant modifying or masking the commercial comparator. The blinding should be fit-for-purpose. Using a near match placebo may be more appropriate.
Manufacture a market image placebo
A market image placebo is a placebo formulation that is designed to visually represent a commercial presentation of an active comparator product. Appearance is identical to the commercial product presentation (e.g. color, shape, and markings on the dosage form). The active comparator needs no modification.
Market image placebos can be useful for low bioavailability or early onset products where the bioavailability may be affected by traditional blinding techniques. It can also be useful if the tablet is too large to encapsulate or if large quantities are needed.
Blinding of Solid Oral Dosage Forms
Table 1 lists the various blinding options for solid oral dosage forms, with advantages and challenges for each technique.
Table 1. Blinding Options for Solid Oral Dosage Forms
Blinding of Non-Solid Oral Dosage Forms
Table 2 lists the various blinding options for non-solid oral dosage forms, with advantages and challenges for each technique. Sterile products generate an additional complication. In order to maintain sterility, all primary packaging that is in the drug path should not be breached for the marketed product. In addition, developing a placebo to match a sterile product adds significant cost and time to the manufacture, development, release and stability.
Table 2. Blinding Options for Non-Solid Oral Dosage Forms
Blinding Strategy Considerations
- When blinding a drug product, the goal is to minimize:
- Patients’ ability to identify the blinded product.
- Blinded product is no more challenging to dose the patient than marketed product
- Risk to the integrity of the commercial dosage form.
- Resources/cost required for manufacture, blinding, qualification, release and stability.
Overall, the blinding strategy should be “fit for trial purpose”. Blinding strategy is evaluated based on a variety of comparator drug product characteristics, such as those listed in Table 3.
Table 3. Blinding Strategy Evaluation
Conclusion
Clinical studies that incorporate a comparator are performed to evaluate the efficacy and safety of a new investigational drug in relation to a marketed product. The design of the clinical study, drug product characteristics of the comparator, as well as advantages and challenges for each blinding option must be weighed to determine the best blinding option. All blinding options should be vetted beforehand for any legal and/or ethical concerns.
Acknowledgments
I would like to thank the following reviewers for their constructive comments: Karen Alsante, Lester Arnold, Mike Arnold, Dave Healy, Ellie Krasney, Heather McDonald, Chris Reitmeyer, and Scott Sweney.
References
- European Commission, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use, Annex 13: Manufacture of Investigational Medicinal Products (EU-GMP Annex 13, February 2010)
- ICH Harmonised Tripartite Guideline, Guidance for Industry, E6(R1) Guideline for Good Clinical Practice
- Onset of action is the time required after administration of a drug for a response to be observed. Mosby’s Medical Dictionary, 8th edition
- Bioavailability is the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action. US Code of Federal Regulations, 21 CFR Part 320 – Bioavailability and Bioequivalence Requirements [320.1], revised as of 1 April 2014, www.fda.gov