Responsilbilities in Outsourcing Clinical Testing

Sep 1, 2008 | Contact Author | By: Theresa Callaghan, PhD
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Title: Responsilbilities in Outsourcing Clinical Testing
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Editor’s note: C&T magazine’s regular Bench & Beyond columnist Bud Brewster welcomes guest contributor and consultant Theresa Callaghan, PhD, to this month’s space.

In the major markets of Japan, the United States and the European Union, cosmetic manufacturers always retain full responsibility for the safety of their products. In Canada, that responsibility also extends to efficacy. Manufacturers are required to conduct testing to provide proof of a product’s safety—and efficacy, in the Canadian market—and they must produce that proof when called upon to do so by the authorities.

In the United States, for example, while the Food, Drug and Cosmetic Act does not subject cosmetics to premarket approval by the Food and Drug Administration, the agency has consistently advised cosmetic manufacturers to employ whatever testing is appropriate and effective for substantiating the safety of their products. It remains the responsibility of the manufacturer to substantiate the safety of both ingredients and finished cosmetic products prior to their being marketed.

Companies developing cosmetic products have three options available to meet this testing requirement: in-house facilities, universities and commercial testing laboratories such as clinical research organizations (CROs). Regardless of the testing option selected, the testers will need to develop new methods and expertise for delivering scientifically sound studies. Some examples of innovative test methods developed by CROs are described in Innovating at CROs.

Testing Routes

Prior to deciding on a particular test or trial, it is crucial to consider how the data will be used—i.e., marketing claims substantiation, peer review or internal corporate approval. Because regulation of the marketplace stems from the industry itself, it is not uncommon for companies to litigate against one another regarding commercial claims—mainly patents. 

The larger branded goods manufacturers generally try to provide the highest level of data possible, such as from a clinical trial, to support a particular marketing claim, especially if some superior benefit is claimed. Smaller manufacturers, however, may consider that demonstrating equivalence to existing, clinically proven products is an acceptable level of proof, especially if the manufacturer is not making novel or superior claims. In this case, claims can be substantiated with smaller, less costly in vitro comparison studies. However, especially in Europe, this route is becoming far less acceptable for safety and efficacy studies and European authorities are now separating marketing claims from efficacy data.3 In 2008, Colipa issued revised guidelines4 (see Colipa Guidelines on Efficacy Testing) clarifying the difference between claims, which are for communicating, and science, which is for generating data.

Understanding Responsibility

Cosmetic product trials are a complex undertaking that require significant planning and logistic project management, from volunteer identification through study completion. As the 

sponsor of a project or study, the product manufacturer—be it a raw material supplier or a finished goods producer—has a number of key responsibilities under the guidelines for Good Clinical Practice (GCP),5 an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. These guidelines must be followed regardless of whether the clinical testing is conducted in house, in a university or by a CRO. 

According to the GCP, the sponsor—i.e., the product manufacturer—is responsible not only to the university or CRO and any regulatory or advertising authorities of the EU, Japan and the United States, but most importantly to the volunteers who agree to evaluate the product before it reaches the end consumer. Cosmetic studies should always be conducted in accordance with the principles of GCP to assure the protection of human volunteers and the integrity and reliability of any data generated. Cutting corners will only result in questioning the conclusions of the research, arguments with advertising and regulatory bodies, bad press and ultimately consumer cynicism and confusion.

Manufacturers should really consider the test subjects and consider: Is the product in fact safe? Even after all the micro-adjustments are made to the formulation at its final stages? Was the testing group (i.e., internal resources, academia and/or CRO) given all the information necessary about the product before testing began? Was the individual who signed off on the provided product safety statement qualified to do so? If not, has an independent safety assessment from an experienced toxicologist been provided? Is the study being conducted at the end of the development process, or was this type of work included as part of the up-front R&D process?

There are at least 23 sponsor responsibilities within the GCP framework when it comes to running a study,5 of which the following are most important to the cosmetics industry. For simplicity, these responsibilities will be discussed in terms of the CRO, but they apply equally well in the settings of in-house and university-based testing.

Quality: The sponsor (i.e., the manufacturer) is required to implement and maintain quality assurance (QA) and quality control (QC) systems, with written standard operating procedures (SOPs) to ensure that trials are conducted and data is generated, recorded, documented and reported in compliance with the protocol, GCP and the applicable regulatory requirements.

A sponsor may transfer any or all of its trial-related duties and functions to a CRO but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, irrespective of responsibility transfers. The CRO has to be a credible legal organization and must itself also implement QA and QC systems together with quality SOPs. 

Not many sponsors understand that the responsibility for QA and the conduct of the trial is ultimately their responsibility. How can sponsors control QA? One way would be to perform a rigorous pre-study audit of systems, processes and procedures as with any customer/supplier interaction. Failing to do this can easily result in a product that is out of specification. 

An additional way to ensure QA is to make regular monitoring visits during the course of the study. If a study is not monitored, one cannot be sure that the study was conducted at all. The report/data generated could have been falsified. Even in pharmaceutical research with all the safeguards and systems in place, examples are continually being uncovered of fraudulent data collection and analysis, often as a result of financial considerations. Only by rigorously inspecting a study with trained resources can one be reasonably sure the study follows/followed the agreed upon signed protocol. 

If the study was conducted, the sponsor should also have verified qualifications and/or licenses of the responsible parties. For example, does the individual really hold a doctoral or medical degree? If so, is the degree current, from a reputable source, and valid during the time of the study?

Depending on the nature of the study, for example, those involving nutraceuticals or skin interventions, did the protocol actually go to an Independent Ethics Committee (IEC) for review? This committee exists to safeguard the rights, safety and well-being of all trial subjects. It acts as a buffer between the sponsor and volunteer to ensure that the objectives of the study are ethical and that the safety, dignity and well-being of the volunteer are upheld. 

Remember that any trial-related duty and function that is transferred to, and assumed by, the CRO should be specified in writing prior to its commencement. Anything that is transferred to the CRO must be specified and agreed in writing and any duties not specifically transferred and assumed by the CRO are implicitly retained by the sponsor.

Volunteers: Sponsors must understand and remember that the safety and welfare of individuals enrolled in their study is paramount. The origins of this standard lie in the Declaration of Helsinki:

Research involving human subjects cannot legitimately be carried out unless the importance of the objective is in proportion to the inherent risk to the subject. Concerns for the interests of the subject (volunteer) must always prevail over the interests of science and society.6 

Participation of volunteers in any study is voluntary. It should also be remembered that volunteers are freely able to withdraw from a study voluntarily without providing any reason for doing so and without penalty or loss of benefits to which they are otherwise entitled. 

Authorized persons: The designated signatory of the sponsor must be qualified to do so and must understand the weight of impact of this responsibility. If an unqualified person signs off on a test, this can be serious indeed. The authorized person must be experienced and fully understand the undertaking that person is making on behalf of the company that he or she represents. If there is, for example, a legal issue resulting in claims made against the sponsor, the authorized person is held accountable. An inexperienced recruit cannot be given that level of responsibility; experience is required.

Test products: When planning trials, the sponsor should ensure that sufficient safety data from nonclinical studies and clinical trials are available, plus relevant nonclinical efficacy data to support human exposure by the desired route at the dosages for the duration and in the trial population to be studied. 

The sponsor should determine the acceptable storage temperatures and conditions and storage times for all products, and should convey these determinations to all involved parties in the study. All products should be packaged to prevent contamination and unacceptable deterioration during transportation and storage.

For cosmetic products, a statement of safety must be included from an experienced, authorized individual within the sponsor’s company—not the clinical associate in charge of the project. If not, then an independent safety assessment must be made available. Lack of safety data contravenes the Declaration of Helsinki and the very basic standards of GCP, and can also be considered unethical and immoral. Changes in formulation must be reassessed by a qualified person and a protocol amendment produced.

Study reports: Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical trial reports are prepared and provided to the regulatory agencies as required by the applicable regulatory requirement(s).

Investigators selection: The sponsor is responsible for selecting the investigator and/or institution. Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which he or she is selected. If organization of a coordinating committee and/or selection of coordinating investigator(s) are to be utilized in multi-center trials, their organization and/or selection are the sponsor’s responsibility. 

Concluding Remarks

Attempting to predict future trends in a category that has experienced tremendous innovation over the last two decades-i.e., personal care-is both difficult and potentially misleading. Clearly, the trend to provide added value and therapeutic benefits for the consumer requires clinical research, which will continue to drive all major players in the cosmetics industry. With the final publication of the Seventh Amendment to the European Cosmetic Directive, more responsibility is being pushed back to the raw material manufacturers, notably those developing active ingredients. In addition, in recent years, the downsizing and reorganization of a number of global companies and a refocusing of their strategic development has led to the closure of technology pipelines and thus a reduction in innovation groups within R&D departments. 

Consequently, outsourcing of clinical testing will likely continue to grow and offer ever-widening services to cover all aspects of the product development process. It is anticipated that even more sophisticated clinical design and analytical techniques will continue to drive the evidence-based marketing claims of the industry. Those organizations best positioned to support the industry will be those that can best combine the requirements of the fast moving consumer goods industry with the strengths of a pharmaceutical development approach. 

 

References

1. Comparative Study on Cosmetics Legislation in the EU and Other Principal Markets with Special Attention to So-called Borderline Products, available at: ec.europa.eu/enterprise/cosmetics/doc/j457_-_final_report_-_cosmetics.pdf (Accessed Jul 10, 2008)

2. www.cfsan.fda.gov/~dms/qa-cos4.html (Accessed Jul 10, 2008)

3. K Bird, Colipa revises guidelines on product efficacy and claims, Cosmetics Design Europe (May 22, 2008) 

4. Guidelines for the Evaluation of the Efficacy of Cosmetic Products, rev. version published by Colipa in May 2008. Available at www.colipa.com/site/index.cfm?SID=15588&OBJ=28455&back=1 (Accessed Jul 7, 2008)

5. Guideline for Good Clinical Practice and ICH Harmonised Tripartite Guideline, available at: www.emea.europa.eu/pdfs/human/ich/013595en.pdf (Accessed Jul 10, 2008)

6. Declaration of Helsinki—Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, available at: www.wma.net/e/policy/b3.htm, World Medical Assembly(Oct 1996; accessed Jul 10, 2008) 

7. PJ Caspers, GW Lucassen and GJ Puppels, Combined in vivo confocal Raman spectroscopy and confocal microscopy of human skin, Biophys J 85(1) 572–580 (2003)

8. Colipa Guideline: International sun protection factor method, 2006, available at: www.colipa.com/site/index.fm?SID=15588&OBJ=28452&back=1 (Accessed Jul 10, 2008)

9. Colipa Guideline: Method for the in vitro determination of UVA protection provided by sunscreen products, 2007, PDF available at: www.colipa.com/site/index.cfm?SID=15588&OBJ=28546&back=1 (Accessed Jul 10, 2008)                

 

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Innovating at CROs

 Innovating at CROs

Guidelines to evaluate Efficacy

 Guidelines to evaluate Efficacy

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