Electronic Clinical Outcome Assessments in Clinical Trials

One of the advantages of being a consultant is the opportunity to be exposed to many innovative startups in the Bay Area rather than being locked down in one company. In the short months since I decided to focus 100% on my business, I noticed many creative products and innovative ideas stemming from these young startups. One of my observation is that there appears to be an uptake in companies developing consumer products such as wearables and cameras with the intention of expanding their indications to be used as electronic clinical outcome assessment (eCOA) tools for clinical trials. Now, I haven't been living under a rock and I know that traditional large tech companies like Apple and Google have entered the digital health space, but I'm amazed at how many smaller companies are focused in this area too. Some companies mistakingly believe that they need to obtain FDA 510k clearance in order to commercialize their device. I would give them the traditional Regulatory Affairs response "it depends." It really depends on the indications and medical claims they wish to seek, otherwise their device can be classified as a monitoring device which has a lower regulatory burden.

One company that I came across at an expo had developed a cam monitor that can monitor an infant's breathing rate and movement using powerful sensors from their camera and capturing the data in your smartphone in real time. Initially I dismissed this as simply a novel consumer product, but a simple device like that can do wonders in clinical trials as a tool to monitor patient's responses to drug trials. Using real time video capture, it's a bit more reliable than manually entering the information in a diary. In a recent issue of FDLI's Update magazine, the author (Ball, F. et. al) noted many advantages of eCOAs that included:

• no need for manual secondary data entry

• direct transmission into an electronic database

• alarm or reminder capabilities

• time and stamp capabilities

• real-time data recording and transmissions; and

• remit data capture.

FDA understands the value of utilizing eCOAs and requires that there be guidelines for record keeping, maintenance and access as well as compliance with 21 CDR Part 11 with respect to electronic records and electronic signatures. There's also cybersecurity risks to be considered and HIPPA requirements as the data will likely contain patient's sensitive data.

With wearables such as the Apple Watch and Fitbit that can track and monitor body temperature, heart rate, etc., these ubiquitous devices can be adopted into clinical trials as an option to monitor clinical outcomes. There are concerns regarding the accuracy of the wearables in yielding data equivalency so the sponsor will need to validate the wearables prior to including them in their trials. For example, as a former Fitbit owner, I recall driving from the Bay Area to LA and it recorded over 1000 steps on my watch when I spent 7 hours planting my butt in car during the road trip. I'm sure that the newer devices are more accurate, but I sometime question the accuracy of the data being collected. Thus the need for the sponsors to validate the device for their use.

Clinical isn't my area of expertise, but I thought that this topic is interesting to share since I'm starting to notice many articles on BYOD (Bring Your Own Device) and eCOAs being creeped up and several small startups entering this niche arena.

Notes about the author:

Alex Chang is a Regulatory Affairs consultant and founder of BioDesign Regulatory Services, LLC. Alex held several roles in the medical device, diagnostics, pharmaceuticals and biologics industries since 2000. Alex began his career in Regulatory Affairs in 2003 and has been very involved with the regulatory community ever since 2012 with RAPS. His consulting company, BioDesign Regulatory Services, LLC was established in 2018.

MDCG 2019-7 - Person Responsible for Regulatory Compliance per MDR and IVDR

On July 1, 2019, the Medical Device Coordination Group (MDCG) published their guidance on Article 15 of the MDR and IVDR regarding the Person Responsible for Regulatory Compliance (PRRC). Article 15 lists the requirements in six paragraphs. To assist the reader, I'll summarize what the requirements are and provide suggestions on how a manufacturer can comply to them.

Paragraph (1)

The manufacturer shall appoint one or more person(s) to be the PRRC. The PRRC must meet the one following qualifications:

- Evidence of completing a degree in law, medicine, pharmacy, engineering or another relevant scientific discipline. At least one year of professional experience in RA or QMS relating to medical devices, or

- 4 years of professional experience in RA or QMS relating to medical device.

Note: for custom-made devices, the PRRC must have at least two years of professional experience in manufacturing.

MDCG 2019-7 clarified that the any qualification such as university diplomas or certificates must be equivalent to EU's. The guidance also provide clarification that for organizations with more than one legal manufacturer, each legal manufacturer would have its own PRRC.

My comments/suggestions regarding Paragraph (1):

When appointed someone to be the PRRC of the organization, I would recommend that:

(a) the appointment of the PRRC is assigned by someone in the executive level and that the the individual accepting the role duly noted his/her responsibilities as the PRRC. I recommend documenting this.

(b) the individual's job description be updated to include the roles and responsibilities as outlined in paragraph 3 of Article 15.

(c) the organization chart be updated to include some reference that the individual is the PRRC, and of course,

(d) the individual assigned as the PRRC meets the qualifications as outlined in paragraph 1.

Paragraph (2)

Micro and small enterprise companies (50 or fewer employees with annual balance sheet not exceeding EUR 10 million) can assign a third party to be the PRRC but that person must be permanently and continuously at their disposal.

MDCG 2019-7 recommended that if the external party is the PRRC, the manufacturer should establish a contract laying down the provisions to ensure that the individual is "permanently and continuously" available. The guidance recommends that the individual's qualification be mentioned in the contract. II believe that it's entirely up to the manufacturer on how they wish to document the PRRC's qualification and that it doesn't have to be in the contract.

Paragraph (3)

The PRRC shall at least be responsible for ensuring that:

(a) the conformity of the device is appropriately checked, in accordance with the QMS before a device is released.

(b) the Technical Documentation and EU DoC are drawn-up and kept up-to-date.

(c) the PMS obligations comply with Article 10(10) and Article 10(9) of the MDR and IVDR, respectively.

(d) Reporting obligations such as recording and reporting of incidents and FSCA comply with the MDR and IVDR.

(e) in case of investigational devices for performance evaluation, there is a signed statement in accordance to Annex XV (MDR) or Annex XIV (IVDR).

Paragraph (4)

If there are more than one PRRC, their respective areas of responsibility shall be stipulated in writing.

My comment/suggestion on Paragraphs 3 and 4.

For procedures regarding PMS, incident reporting, investigational devices for performance evaluation, and ensuring that the Technical Documentation and DoC are up-to-date should make some references as to the role of the PRRC.

Paragraph (5)

The PRRC shall suffer no disadvantage to the proper fulfillment of his or her duties.

Paragraph (6)

The Authorized Representative shall have its own PRRC.

My comment/suggestion on Paragraph 6

Make sure that this requirement is on your Quality Agreement with your Authorized Representative and that they do have someone qualified to be the PRRC.

Hope this summary in some way is helpful to you.

Notes about the author:

Alex Chang is a Regulatory Affairs consultant and founder of BioDesign Regulatory Services, LLC. Alex held several roles in the medical device, diagnostics, pharmaceuticals and biologics industries since 2000. Alex began his career in Regulatory Affairs in 2003 and has been very involved with the regulatory community ever since 2012 with RAPS. His consulting company, BioDesign Regulatory Services, LLC was established in 2018.

For IVD manufacturers, FDA issues new draft guidance document on Biotin interference.

Author: Alex Chang

Biotin (or vitamin B7) is a water-soluble B-complex that helps metabolize proteins, fats and carbohydrates and to process glucose. The human body cannot synthesize biotin and as such it needs to be supplied in your diet. Since it aids in processing glucose, researchers believe that it plays a part in controlling diabetes. Biotin also contributes to healthy nails, skin and hair and as such, biotin supplements have been used frequently aesthetically. As I am a "man of certain age" or approaching that age, biotin supplements sounds like a great idea to stay looking rejuvenated.

Back in November 2017, the FDA warned that high doses of biotin can interfere with hundreds of common lab tests, such as TSH and troponin. Many of these tests use biotin technology due to its ability to bond with specific proteins which can be measured to detect certain health conditions, therefore having the potential to interfere with the results. Too much biotin in lab tests for thyroid hormones can lead doctors to misdiagnose Grave’s disease in children and adults. There was one incidence where one patient died from a heart attack after a blood test showed falsely low levels of troponin. The Institute of Medicine recommends that people get 0.03 mg of biotin daily, however some supplement contain 30 mg which is 650 times more than the recommended intake.

Patients and physicians may be unaware of biotin interference in lab tests and patients may not be disclosing the use of biotin products when ordering tests. The onus is on the IVD manufacturers need to make sure that biotin interference is considered when developing their diagnostic tests.

FDA has issued a draft guidance document for commenting entitled “Testing for Biotin Interference in In Vitro Diagnostic Devices”. It simply recommended the following to IVD Manufacturers:

• Consistent with the recommendations in the CLSI standard, concentrations of biotin that reflect current trends in biotin consumption should be evaluated, up to 3500 ng/mL.

• The test samples should include analyte levels near the medical decision point(s) of the device.

• For assays that are susceptible to biotin interference at concentrations less than 3500 ng/mL, the concentration of biotin at which no interference is detected should be determined.

• The results of the testing should be communicated to end-users, including clinical laboratories and clinicians. Therefore, information on biotin interference should be included in the labeling1 of the device, including the percent difference or bias at each concentration tested for both qualitative and quantitative assays and the consequence of biotin interference (e.g., falsely elevated, falsely depressed), if observed.

What’s not stated in the guidance document is that the potential for false positives and false negatives resulting from high levels of biotin should also be captured in your risk management documents.

References:

1. Nordqvist, C. (last updated 07 Feb 2017) ‘Why do we need biotin, or Vitamin B7?” retrieved from: https://www.medicalnewstoday.com/articles/219718.php

2. “The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety Communication” retrieved from: https://www.fda.gov/medical-devices/safety-communications/fda-warns-biotin-may-interfere-lab-tests-fda-safety-communication; last accessed: 18 June 2019.