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Exploring the region that conducts most clinical trials in the world and is the flag bearer for most clinical research studies, requires considering many factors and areas. In first part of this series of article for Clinical Trials in United States, regulatory situation, site and investigators were discussed. In this part, we will be knowing about regulatory aspects for medical devices and other aspects of clinical trials in USA.

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Starting with some salient points on Clinical trials in United States

  • Language for clinical trial: English
  • Process of regulatory & EC approval: Parallel
  • Required: Registration of trial
  • Studies on minors: Age is determined at state level.
  • Export of specimens: Allowed

Regulatory for Medical Devices Clinical Trials in USA

What are regulatory bodies for Medical Devices in USA ?

FDA’s Center for Devices and Radiological Health (CDRH) is responsible for regulating firms that manufacture, repackage, relabel, and/or import medical devices sold in the United States.

CDRH regulates radiation-emitting electronic products (medical and non-medical) such as lasers, x-ray systems, ultrasound equipment, microwave ovens and color televisions.

  • Medical devices are classified into Class I, II, and III and the regulatory control increases from Class I to Class III.
  • The device classification regulation defines the regulatory requirements for a general device type.[1]
    • Class I devices are exempt from Premarket Notification
    • Class II devices require Premarket Notification
    • Class III devices require Premarket Approval.

Which regulations apply to the clinical investigation of medical device ?

The regulations in clinical studies of medical devices must comply with

  • FDA’s human subject protection requirements,
  • Institutional Review Board (IRB) requirements
  • Investigational Device Exemptions (IDE) requirements
  • Financial Disclosure for Clinical Investigators requirements, as well as
  • Any other applicable regulations, including pertinent regulations

Regulatory changes in IRB Requirements for medical device clinical trials in the USA

The organisation conducting certain type of clinical trials may now rely on central rather than for reviews required by the US Food and Drug Administration.

  • The FDA’s Center for Devices and Radiological Health (CDRH) has issued a technical amendment allowing sponsors conducting clinical studies for Humanitarian Device
  • Exemption (HDE) devices to utilize central IRBs to review their activities; previously, clinical trial sponsors and sites were required to undergo such reviews by local IRBs.
  • The allowance for central IRB review applies to Investigational Device Exemption (IDE) studies, and for multi-site clinical studies, as well.
  • This IRB oversight change is intended bring drug and device regulations more closely in line with one another, according to the FDA. [4]

When the regulations doesn’t apply ?

  • An FDA approved device to test a physiologic principle where no data is collected about the device;
  • An FDA approved device to address a research question and no data is collected about the device; or
  • Using an FDA approved device for clinical purposes (e.g., monitor a side effect, measure treatment progress);
  • As long as there is no intent to collect safety or effectiveness data or develop the device for marketing. (use of an MRI to measure a clinical outcome in a study that has nothing to do with the MRI itself.)

Approval Process

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What are the type of drug applications submitted?

Investigational New Drug (IND)

Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines.

  • New Drug Application (NDA)
  • Abbreviated New Drug Application (ANDA)
  • Biologic License Application (BLA). [6]

What is the Submission Process ?

  • In United States the sponsor should submit an investigational new drug application (IND) for the FDA review and authorization
  • Whether an IND is required to conduct an investigation of a drug to be marketed primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation.
  • Institutional ethics committee (EC) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. [7]

Clinical Trial Registry

  • Either the sponsor or the principal investigator (PI) designated by the sponsor should register electronically with the ClinicalTrials.gov databank.
  • The sponsor/PI must register 21 calendar days after the first human participant is enrolled in a trial. [8]

Electronic Regulatory Submission and Review

The Electronic Common Technical Document (eCTD) is the standard, accepted electronic format for the following submission types:

  • New Drug Application (NDA)
  • Abbreviated New Drug Application (ANDA)
  • Investigational New Drug Application (IND)
  • Biologics License Application (BLA)
  • Master files: Drug Master File (DMF) and Biologics Master File (BMF)
  • Emergency Use Authorization (EUA)

When data are submitted electronically, it is easier for FDA to review data, approve new drugs, and monitor drugs after they go on the market. [9]

When a Trial can get FDA Assistance

Drug developers can seek help from FDA at any point during drug development process, including:

  • Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research
  • After Phase 2, to obtain guidance on the design of large Phase 3 studies
  • Any time during the process, to obtain an assessment of the IND application. [10]

Regulations for import and export of medicinal products

Import and export of medicinal products are regulated primarily by the Centre for Drug Evaluation and Research(CDER).

  • Foreign drug manufacturers who wish to import drugs into the United States must register with the FDA.
  • The Federal Food, Drug and Cosmetic Act prohibits import or export of unapproved new drugs, meaning any drug that has not been manufactured with FDA approval.
  • Imported drug products are subject to inspection by the US Bureau of Customs and Border Protection and the FDA may refuse admission of any drug that appears to be unapproved, misbranded or adulterated. [3]

When can the trial be initiated ?

Clinical Trial can be initiated immediately after the 30 day approval, after receiving IND approval and approval from Ethics committee. The sponsor or the Principal investigator designated by the sponsor, should register the Clinical Trials with the clinicaltrial.gov [11]

What are the Reporting and disclosure requirements ?

Food and Drug Administration requires all applicable clinical trials to register and report results on a government-administered website (www.clinicaltrials.gov). If a clinical trial involves Phase I studies of a drug, the results are not required to be submitted.

For a clinical trial of a device, that has not previously approved by the FDA, the law allows for a delay in reporting the results until one year after the approval or clearance of the device by the FDA.

FDA obligations with respect to clinical trial subjects

The FDA requires that clinical trial subjects be given adequate information and time to make an informed decision on whether to participate in a clinical trial and ask questions and have those questions answered.

Insurance requirements for clinical trials

  • In the United States, there are no regulations mandating human clinical trial liability insurance. Multi-country trials are likely to require multiple insurance policies.
  • Hence it is recommended that companies considering clinical trials work closely with brokers and lawyers familiar with jurisdictional requirements before entering into sponsorship agreements.

What are the Data protection concerns ?

Data protection issues considered while conducting clinical trials

Most clinical trials today are designed according to International Conference on Harmonisation(ICH) guidelines with multiple jurisdictions in mind.

The data protection issues are considered into two basic categories:

  • Data integrity and retention; and
  • Patient privacy.

With regard to data integrity and retention, the FDA periodically issues guidance for industry documents on its website, which should be constantly monitored for updates.[12]

and finally

Why USA is preferred destination for clinical trials, in numbers?

The country Contributing the most clinical trial participants in the world is united states (7.4 billion), the USA (0.35) makes up a little more than 4% of the world population.

  • Trial participants of US 31% vs Non-US trial participants(69%)
  • In the year 2016 total participants in United States were 11,060 (42.64%) and rest of the world participants were 14,881 (57.36%).
  • In 2016, the most clinical trials were on Infectious disease (3,057), Dermatology (2,860), Ophthalmology (2,249) and Pulmonary disease (724)
  • In 2017 the most clinical trials were on Immune system disease (7,351) Psychotic Disorders (6,448), Infectious disease (6,059) and Oncology (6,001).
  • The total Male Participants are (53,143) and female participants are (56,181).[13][14]

Click here for more information to Conduct Clinical Trials in U.S.? Here’s what you need to know – Part 1

References:

  1. https://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/default.htm
  2. https://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127067.pdf
  3. https://www.lexology.com/library/detail.aspx?g=70f72ede-043d-4196-85d9-0a2a6679d723
  4. https://www.emergogroup.com/blog/2017/06/us-regulators-change-irb-requirements-some-medical-device-clinical-trials
  5. http://www.research.uky.edu/ori/ORIForms/D110-IRB-Review-of-Medical-Device-Research.pdf
  6. https://www.fda.gov/Drugs/ResourcesForYou/SpecialFeatures/ucm279676.htm
  7. https://clinregs.niaid.nih.gov/single_country.php?c_id=227#submission_process
  8. https://clinregs.niaid.nih.gov/single_country.php?c_id=227#trial_initiation
  9. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm
  10. https://www.fda.gov/ForPatients/Approvals/Drugs/ucm405622.htm#Asking_for_FDA_Assistance
  11. https://clinregs.niaid.nih.gov/single_country.php?c_id=227#timeline_of_review
  12. https://www.lexology.com/library/detail.aspx?g=70f72ede-043d-4196-85d9-0a2a6679d723
  13. https://clinicaltrials.gov/
  14. https://www.fda.gov/downloads/Drugs/InformationOnDrugs/UCM570195.pdf