Step 7: Execute your clinical plan

Healthcare product development is complex. It is critical to know the general product development lifecycle so that you can follow the correct path. Knowing which pitfalls to avoid will speed your time to market. This article outlines step 7 of the 10 steps to develop a healthcare product.

For a healthcare product that requires a clinical trial (or trials) to support product licensing or regulatory clearance,ⁱ the execution of the clinical plan is probably the most critical stage in the development process. The results gathered on safety and efficacy/effectiveness will ultimately determine whether a successful licensing/clearance application can be made. If the application is successful, this will determine the final claim that can be listed on the product label. This in turn drives the marketing and advertising activities and produces the return on investment.¹ The purpose of the clinical trial program is to collect objective evidence that the product is safe and effective/efficacious in human use under a specific condition (that is, per the claim) to the extent that the risk-benefit relationship is acceptable.²

The extent of clinical information required for a drug, biologic, or medical device may vary; however, the general principles outlined below apply to all product types.

Before initiating the clinical trial

Certain activities are required before a clinical trial can be initiated. These include:

• Collecting the results from non-clinical studies
• Finalizing the product design or formulation
• Establishing the product manufacturing process and related quality activities
• Designing the clinical trial and identifying the countries for testing
• Meeting with the regulatory agency as need be
• Submitting clinical trial applications to the ethical review board(s) and/or regulatory agenciesⁱ

Non-clinical studies

Non-clinical studies³ are used to demonstrate that the risks to human subjects from the proposed clinical trial are outweighed by the anticipated benefits and that there is reason to believe that the product as proposed for use will be effective. These studies should be conducted using Good Laboratory Practice (GLP) and may include toxicology, pharmacology and pharmacokinetics for drugs and biologics, and bench (non-clinical), animal and biocompatibility studies for medical devices.

Investigational products

Any product that is to be tested in a clinical setting should be manufactured under Good Manufacturing Practice (GMP) conditions or recognized standards (such as for sterilization).³ Extensive investigations should take place to establish product quality. For drugs and biologics, these may include collecting information on the composition, chemistry, manufacture, control and stability of the drug substance and drug product. For medical devices, these may include gathering data on the methods, facilities and controls used for the manufacturing, processing, packaging, storage and installation of the product.

It is critical to ensure that product tested in clinical trials is the version that is “finalized” (for example, the formulation and dosage form of a drug or biologic should not change, nor should the prototype of a device). Any subsequent changes in the final product may affect the conclusion that can be drawn at the licensing stage to support the quality, safety and/or efficacy and may lead to the need for an additional study (such as a bridging study).

Clinical trial design

Clinical trials should be designed⁴, conducted and analyzed according to sound scientific principles to achieve their objectives. Each part should be defined in a written protocol before study starts. This study plan, or protocol, should describe the objective(s), design, methodology, inclusion/exclusion criteria, statistical considerations, safety/efficacy end point, and organization of the trial.

Pre-submission meeting and clinical trial applications (CTAs)

The purpose of the pre-submission meeting is to discuss and resolve any issues relating to the clinical trial and to obtain feedback or agreement from the regulatory agency on the clinical plan/protocol design as well as the statistical analysis plan prior to submitting the corresponding clinical trial applications (CTAs)ⁱⁱ to the regulatory agency(ies) for approval⁵. This is to ensure that the plan developed (if successfully conducted) is able to support the proposed claim in the licensing or clearance application.

CTAs should be submitted to the relevant countriesⁱⁱⁱ where the study will be conducted as well as to the appropriate institutional review boards (IRBs)^iv for approvals.

Executing the clinical trial

Once the clinical trial application is approved, the clinical study should be initiated according to the approved protocol. The clinical trial must be conducted in accordance with applicable Good Clinical Practice (GCP) standards⁶. A clinical research organization (CRO) is normally involved in the conduct of study; however, the ultimate responsibility lies with the study sponsor.

The conduct of a clinical trial has many activities, which may be specific to your product. Some of the key principles are highlighted below:

• The investigator(s) responsible for the conduct of the clinical trial must have adequate education, training and experience appropriate to the study. They are responsible for managing the recruitment of study subjects, executing the study product(s), monitoring subjects and recording responses. They should also be involved in preparing the study protocol and report.
• A principal investigator must be identified for a multi-centre clinical trial.
• The study must be conducted in compliance with the study protocol. If an amendment is required and is deemed to be significant or substantial (for example, it affects the safety of the trial subject or the quality of the investigational product), a CTA amendment must be submitted to relevant IRBs and/or regulatory agencies for approval.
• Procedures to obtain informed consent from subjects involved in the study must be properly followed according to applicable regulatory requirements.
• Proper record keeping of essential documentation is required, such as documenting any deviations and administration related to the clinical trial and any concomitant medication, adverse events, trial results and other information as identified in the case report forms.
• Safety reporting (for example, spontaneous and/or periodic reports) must be submitted as per regulatory requirements.
• Study subjects, regulatory bodies and IRBs must be promptly notified of any premature termination or suspension of the clinical trial.
• The clinical trial should be properly monitored (for example, with regard to the overall conduct of trial, data handling and data verification).
• The final study report should be prepared according to applicable standards.

Did you know?

Many documents are associated with the conduct of a clinical trial. These may include but are not limited to:

• Protocol, amendment and case report forms
• Informed-consent form and other information given to study subjects
• Advertisement to recruit subjects
• Insurance statement (where required)
• Signed agreements (for example, between the investigator/institution and the sponsor, or between the sponsor and the contract research organization [CRO])
• Regulatory and/or ethics board approvals
• Curriculum vitae (résumés) of investigators
• Investigational product labels
• Randomization scheme
• Clinical study reports

ⁱ Some products may not require clinical studies as part of the licensing application―for example, low-risk class I medical devices and a majority of medical devices subject to 510(k) submission in the US. Make sure to check the regulations related to your product to confirm the clinical requirements.
ⁱⁱ Pre-submission meetings may cover pre-IND, pre-CTA, pre-IDE and pre-ITA.
IND = Investigational New Drug
CTA = Clinical trial application
IDE = Investigational Device Exemption
ITA = Investigational Testing Application
ⁱⁱⁱ Under some circumstances, a clinical trial application may not need to be submitted to a regulatory agency for approval (for example, a class I medical device in Canada or non-significant risk device in the US).
^iv In Canada, this ethics board is referred to as an ethics review board; in the US, as an institutional review board (IRB); and in the EU, as an ethical committee.

Read the next step in the 10 steps to develop a healthcare product: Step 8: Collect your data for regulatory submission

Read the previous step: Step 6: Execute your healthcare product development plan

Disclaimer

The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.
Published: October 17, 2012

References

1. Ansel, H.C., Popovich, N.C. & Allen, L.V. Jr. (1995). Chapter 2. New drug development and approval process. In Pharmaceutical dosage forms and drug delivery systems (6th ed.). Baltimore: A Waverly Company.
2. Tobin, J.J. & Walsh, G. (2008). Chapter 5. Clinical trial. In Medical product regulatory affairs. Pharmaceuticals, diagnostics, medical devices. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.
3. Tobin, J.J. & Walsh, G. (2008). Chapter 4. Non-clinical studies. In Medical product regulatory affairs. Pharmaceuticals, diagnostics, medical devices. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.
4. International Conference on Harmonisation. (1997, July). E8: General considerations for clinical trials. Retrieved September 18, 2012, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E8/Step4/E8_Guideline.pdf.
5. Grignolo, A. (2008). Meeting with the FDA. In Pisano, D.J. & Mantus, D.S. (Eds.), FDA regulatory affairs: A guide for prescription drugs, medical devices, and biologics (2nd ed., pp.109-23). New York: Informa Healthcare.
6. International Conference on Harmonisation. (1996, June). E6(R1): Good clinical practice. Retrieved September 18, 2012, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf.