Module 22: Regulatory Science PiVOT

Speaker: Darlene Dagos PHA6144

August 1, 2021 Industry

Regulatory Science • Regulatory intelligence

• Regulatory affairs is vast. • Drugs and medical device
Outline • As an RA department, the documentation for regulatory
• What is Regulatory Affairs & Intelligence perspective should be consistent and complete. We don’t want
• Briefly discuss Regulatory Intelligence any rejections on submissions.
− Project Tarius • The strategy fort he interaction with RA, we should maintain
communication with them.
• Regulatory Submissions
Regulatory Intelligence Flow Chart and Benefits
− A.O 2020-0010 - Regulations on the Conduct of Clinical Trials
for Investigational Products
o process flow (FDA and SJREB)
− FDA Circular 2020-029-1 Guidelines on Applications for the
Conduct of COViD-19 Clinical Trials (Therapeutic and e ulator ew rend in updated
Vaccines) ntelli ence ources or new
and other e ulator
nchor chan e in
or anisation
enc uideline
o Process flow (VEP, SJREB and FDA, IRB) e ulator
a encies in
authorit website e ulator rend r anisation detects trend
PIVOT Regulatory Affairs & Intelligence ocal and
and updated new uideline

nternational ew or updated

• Preparation and submission of regulatory dossier to the

ndustr events
ssociates con erences
irculars mpact assessment
etwor s and ocial uideline sent or review
edia b industr
Regulatory authorities ew or updated nvolve relevant
ta eholder internal or

− Dossier is a complete package of documents required by the

hird parties e.
e ternal
vendors or other uideline ublished
sta eholders

regulatory authorities. mplement han e

• Support external regulatory agency audits, providing regulatory

input to minimize potential for findings of non-compliance
• Risk management Plans with applicable guidance document to
the Regulatory Authorities (FDA) • Networks (eg. PCRP)
• key players in pulling together that evidence to shape the policies, ▪ Example of how regulatory intelligence works (project tarius)
legislation, regulations and guidelines regulators use in
strategizing for drug development, approval and product
maintenance
− keep updated with the new legislation to see its impact with the
company and the industry.
− Collect and collate any scientific data
− Help company avoid any problems. We keep up with any
updates on guidelines so we can see the good and bad
legislations that can affect the company.
− We also serve as an interface regulatory team and channel with • Project tarius is a regulatory intelligence database
every regulatory team. We make sure that we anticipate all the • We divide it into biologics and medical device
regulatory requirements before they approve the clinical trial. • We update and track everything.
▪ Summary of description of RA • Every week or twice a week, we update the tracker.
• Each column has a header.
• Updated: is there any change in the guidelines
• Justification: legislation updated or based on experience
trate ic
(explanation on the update)
• Sobrang detailed ng database na ginagamit
lannin

• We have to really know each circular for cross-checking

ru s e ulator
edical enc
evices nteractions

• Regulatory intelligence is a database used to be updated on any

e ulator changes in the legislation or policies implemented by the FDA.
airs e ulator
e ulator ubmission
ntelli ence preparation
ubmission

e ulator echnical
ompliance and cienti ic
Writin
ore unctions

• Strategic planning
− This is important
− Having a tracker is a life of an RA
− You have a keen to any details since you are looking at various
documents
• Regulatory agency interactions
− You can see at the latter portions of the presentation on who
are the RA we mostly talked to.
• Regulatory submission
− Majority of the notion about RA
− We have to be keen to details about the documentation
− It is an advantage to have a skills about technical writing.
• Regulatory compliance

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PiVOT: Module 22: Regulatory Science PHA6144 - Industry
instructions and investigational product, until they complete
that, FDA will to accept those data and regulatory documents.
− In other countries, when you say rolling submissions, there is
an open date, I will receive application on May 1, the review
would be on August 1, and will be reviewed next on October 1.
− Sa atin, walang ganitong legislation. Ang regulatory systems
natin are not as robust as other countries.
− Walang IND and NDA sa PH. (US FDA and EMA ay meron)
− Although we need to follow ASEAN and ICH, there are still
nuisance in our regulatory system.
− Malaysia also does not accept rolling submission.
− A good thing about not having it, we can maximize the time of
reviewers. They don’t need to review a certain protocol over
and over.
• All submission documents must be complete at the time of
submission.
• The timelines published assumes that submission documents are
edical evices ar etin learance a et
complete and no query is raised on the appropriateness and
sufficiency of the submission documents of the protocol.
Regulatory Intelligence • The timeline clock will stop for any query generated by reviewer
and resumes once a response is provided by the applicant.
• From experience, the FDA does not reject any document in
writing, rather, will request for more information related to the
or tables please enter
an chan ed in ormation
in a new column and
rom now on all chan es
document.
to the ables need to
come with a simple
usti ication o wh it is
chan ed
Regulatory Pathway for Clinical Trials of Investigational
ou can put in the
usti ication in another
column some e amples
in below table . his is or
Products
purpose.

• Sample as to how regulatory intelligence is used.

Regulatory Pathway for Clinical Trials for Investigational
Products (Therapeutic & Covid Vaccines) and Non- Covid
Vaccines/Therapeutic
▪ Guidelines
• All entities intending to take part in Clinical trials for COVID-19
should follow the rules, regulation and standards in AO No. 2020- • From the Administrative Order 2020-0010 Regulations on the
0010 “ e ulations on the Conduct of Clinical Trials for Conduct of Clinical trials for Investigational Products
nvesti ational roducts” • Before we have a submission, they have tracker from the start of
− Recent circular being implemented by the FDA for clinical trials. submission of documents until the end of the trial.
− You cannot conduct clinical trials if you do not have LTO. • Screening process: will check if all documents are complete.
• Should first secure License-to-Operate (LTO) as a sponsor/CRO − The FDA will send an acknowledgement or receipt, that is the
from FDA through the unified licensing procedure as stated in AO time you need to pay for the assessment for clinical trial
No. 2020-0017 before any application to conduct clinical trials. application and import license (approx. P3335)
• 6 regulatory reviewers that FDA assigns.
• Basically the requirements are the same for regulatory reviewers
• Kapag may query ang reviewer mag stop ang clock (titigil ang
process) hanggang sa masagot yung questions nila.
• Day 54 will check the other parts of the technical document
• Day 60 is the approval and the import license.

▪ Important Considerations
• No rolling submissions in the Philippines.
− Rolling submission are usually done by some regulatory
authorities of practice wherein we allow initial submissions, and
if you have additional data that is collected all throughout the • The different forms that FDA supplies to clinical trial applications
trial, it is allowed. • You can follow the template given by the FDA.
− Ex. May phase 1 and 2 sila na data while applying for phase 3 • They are not questioning the content as long as the template is
at nagsubmit sila, pinasa nila ito plus pre-clinical data during followed.
the phase 3 application, FDA will allow them interim report
based on phase 3 protocol. They will also submit other signal
documents, labels, storage conditions, update on their

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• This comes from the sponsor. (sponsor letter head)
• Minsan di kasi lahat binibigay sa CRO ang trabaho.
▪ FDA Clinical Trial Applcation

• You need to rely on the clinical trial protocol by the sponsor to

answer the following forms.
• Sponsor information: you need to put the LTO number for local
but N/A for foreign countries

• Continuation for all the documents required by the FDA for the
clinical trials.
• There is a template that you have to follow
• Some other countries do not release a GMP certificate
− Other countries do not supply GMP certificate such as China,
there is a mandate that they will not be supplying these
certificates kasi they have an expiry and usually lasts for 3
• You can see the info in the protocol but ask confirmation from the years. The China FDA noticed that they abuse these GMP
sponsor for the contents. If you have the pharmaceutical certificate. They are ready or passed the GMP inspection
document and investigational brochure, you can find also some before receiving certs. After 3 years, some of the facilities do
information here. not uphold GMP anymore. China FDA abolished the GMP
• We usually double-check with the sponsor and global CRO if all certification.
the information inputted are correct. − We can prove GMP through inspection reports. Drug
• This is the basis of the FDA for releasing import license. manufacturing license is only given to by China FDA when
passed the GMP. The PH FDA ask the most recent inspection
reports that contain Corrective Action Preventive Action
(CAPA).
− The PH FDA also asked GMP compliance statement that
visited the manufacturing plant.
− Our PH FDA is quite struct, the inspection should be done by a
third party, either China NPA or FDA or provincial China FDA.
. mport icense orm
If it is internal GMP inspection, PH FDA does not accept that.
• This is where the FDA will assign a regulatory reviewer
• We put as well the name of the sponsor, LTO, investigational • They limit it to 7 documents.
products, placebo, ancillary supplies, lab kits, we have to list all of • Usually they will ask it in a CD or flash drive
them, we have to write a justification letter for the list of ancillary Institutional Review Board (IRB) & Single Joint Research
supplies and overage of 30%. Ethics Board (SJREB)
▪ Import For Investigational Products ▪ Institutional Review Board (IRB)
• Letter of Application • Accreditation of IRBs and ECs in the Philippines is made by the
− Same format with the first template. Philippine Health Research Ethics Board (PHREB) under the
− Shorter version and introduce the investigational product Department of Science and Technology.
− We have to have the proof of payment • There are 3 levels of accreditation.
− They are very particular GMP − Only IRBs with level 3 accreditation can review clinical trials.
• Import License Application Form • Each IRB will have each own submission requirements and fees,
• Copy of the Approval of the Clinical Trial Protocol and some requires another layer of approval (such as Technical
• Copy of the Approval of the Pharmaceutical Data; Approval within the Institution or an approval by a head of an LGU
− GMP statement from manufacturing / Certificate from for community based trials).
Regulatory Body − They have their own SOPs and own submission requirements.
− Certificate of Analysis − You have to check the requirements or have another layer
− Stability Data approval.
− Manufacturing Data • Scheduled review meeting of once a month and a cut off for
− Formulation and Product Labeling submissions.
• Proof of Payment − It is important to plan submission
• Waiver Statement • Overall the Sponsor or CRO should set a timeline of 60 to 90
• Proforma Invoices days from cut-off, release of first notification, response, review of
response, and until release of second notification letter which in
most cases contains the approval.
− They wait for the recommendation for the SJREB
▪ Single Joint Research Ethics Board
• Was instituted by the Department of Health to review research
submitted by hospitals under DOH.
• If a study is conducted by 3 or more hospitals and that one of
them is at least a hospital under DOH, the study is qualified for
review by the SJREB.
• Another requirement to submit to the FD. • Not all IRBs participate in the SJREB review

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− It is a practice of CROs and Sponsors to submit the o Minsan sinasama naming ang pre-clinical trial data and
applications in parallel with all the participating IRBs and the GMP.
SJREB.
− Such practice, however, is not a requirement.

• There is a list of hospitals that subscribes to SJREB.

• Example for form 1 and 2.
▪ SJREB Process Flow • Dapat maayos ang grammar composition kasi kapag sa ibang
bansa direct translation ang ginagawa kaya nawawala yung
meaning.
• Minsan may protocol synopsis din.
Overall Start-Up Process for Therapeutic Clinical Trial in the
Philippines

• Dapat iinform ni SJREB yung REC na magkakaroon ng review

kasi na-receive na nila yung requirements needed to conduct
review.
• Magdedecide sila kung ano yung agenda, kung full or expedite
review • Site monitoring will be detailed during the site monitoring module.
• The decision letter will be transmitted by SJREB to participating • You can see here that there would be site identification and
IRBs. prepare the materials needed to conduct the trials.
• Usually, nagcontract si sponsor ng 8 sites, they assign • Within 30 days, kailangan ma-register ang clinical trials sa
coordinating principal investigator, para sa mga meeting for Philippine registry.
review ng SJREB. Mas maganda kasi may representative during • Kapag may itatrasport need ng essential document for this.
review para may sasagot sa questions nila if meron.
• Protocols must be submitted on or before the 4th Wednesday of
▪ Estimated timeline for clinical trials
• For regular clinical trials, approximately 60 days.
the month or it to be included in the succeedin month’s meetin
agenda. The board meets every 2nd Wednesday of the month. − Complete documentation is required to gain approval.
• Please e-mail sjreb@doh.gov.ph for templates of SJREB Forms − Based on their experience, less than 60 days. It depends on
1 and 1.2. The investigator/sponsor shall submit the protocol the regulatory reviewer.
documents to the SJREB and to the participating site RECs − Kapag complete, mas less ang queries at mas mabilis ang
simultaneously. SJREB only accepts soft copies of protocols approval.
SJREB Documentary Requirements Regulatory Pathway for COVID-19 Therapeutic Clinical Trials
• Basic Requirements
− Application Form (SJREB Form 1)
− Protocol Summary Sheet (SJREB Form 2)
− Informed Consent Forms (in English and Local Language)
o Very technical sila dito.
− Recruitment and Advertising Materials
− Data Collections Forms (Diary Card, Participant, CRF)
− CVs of all PIs
− Study Budget
− Study Protocol
• Study-Specific Document (Submit as needed)
− Technical Clearance/FDA approval
o Kapag nagsubmit ka sa FDA, pwedeng mag-align sa pinasa
sa SJREB
− Patient information Sheet (for CT) • Clinical Trial for therapeutics of COVID-19 shall gain authorization
from FDA for its conduct in the PH through the process of
− Investigator Brochure
approval as shown in the illustration
− GCP certificates of PIs
− Other protocol-related documents

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• Application is considered filed once all documentary requirements be sent to the applicant; processing time or clock stops in this
have been submitted (including the payment of fees) step. The applicant is expected to respond to the query/ies within
• Upon receiving application, FDA will review completeness and 7 calendar days from sending of e-mail correspondence. If the
accuracy of documents in not more than 8 days and will assign a response is not received from the applicant within the required
regulatory reviewer for the clinical trial application period, the application shall be disapproved.
• The application will be processed by the FDA regulatory • The FDA shall issue a decision in not more than 8 calendar days
reviewers in not more than 14 days upon receipt of application. A upon receipt of the recommendation from the Regulatory
fee of 60,000 pesos will be charged to the applicant Reviewers.
• If there are any need for clarification, an electronic notification will • Also, COVID-19 vaccine trial should follow the existing zoning
be sent to the applicant - the processing time/clock stops in this guidelines issued by the Sub-TWG for Vaccine Development.
step. The Applicant is expected to respond to the queries within 7 ▪ FDA Approval Process
days from sending of the e-mail. If no response in received within
the required period, the application shall be disapproved.
• The FDA will issue a decision in not more than 8 days upon
receipt of the recommendation from the regulatory reviewers.
• Same din sa normal clinical trials pero mas maikli lang an
processes.
▪ Sub-Technical Working Group - Vaccine Expert Panel
(SubTWG-VEP) process

• Typical approval process.

• Day 14 sila talaga nagrerelease ng approval unless there are
recommendations.
• Clinical trial approval is released talaga at day 40 pero kapag
may queries baka tumagal ng konti.
▪ Estimated Timeline for Clinical Trials
• For COVID-19 trials, approximately 40-60 days.
− complete documentation is required to gain approval
• All evaluations of vaccine COVID-19 Clinical Trial must initially be Submission Documents
submitted to Vaccine Expert Panel (VEP) of Department of
Science and Technology (DOST).1 Simultaneously, the ▪ SubTWG – Vaccine Expert Panel (VEP)
application shall be reviewed by the designated Ethics Board. Recent update ng VEP for vaccine submission
Lastly, if the application was found to have merit to conduct such • Letter of Intent to addressed to the Chair of the Task Group on
clinical trials, it shall be submitted to FDA for evaluation. *(for FDA Vaccine Evaluation and Selection (Usec. Rowena Guevara)
evaluation kindly check next slide)* • Investigational Product (IP) and Ancillary Supplies Information
− Kapag complete na, magkakaroon ng letter of recommendation • Phase III Clinical Trial Protocol and Protocol Amendments where
si VEP. applicable
− Electronic naman na tayo for submission dito (pati na rin kay • Informed Consent Form / Assessment Form (if applicable, in
SJREB). English and Filipino version)
• 1- Resolution No. 65 s. 2020 Section C of Inter-Agency Task • nvesti ator’s rochure
Force (IATF) for the Management of Emerging Infectious − Pre-Clinical Data ( Data should include histopaths, data chart
Disease) & tables)
• Sponsor and/or CRO shall submit the following documents to the − Phase I Data
Sub-TWG for Vaccine Development through DOST-PCHRD via − Phase II Data
VEPsubmissions@pchrd.dost.gov.ph: • Requirements for the SJREB
− Letter of Intent to conduct clinical trial addressed to Sub-TWG − eCRF
Char and DOST Undersecretary for Research and − V’s and erti icate o all s
Development, Dr. Rowena Cristina Guevara. − Study Budget
− Investigational Product (IP) and Ancillary Supplies Information. − Philippine-Specific Annex with the proposed sites and
− Clinical Trial Protocol and Protocol Amendments where discussion of site recruitments and other specific protocol for
applicable. the Philippines
− Informed Consent Form/ Assent Form if applicable, in English • FDA Circular 2020-029 Section B-b
and Filipino Version − https://www.fda.gov.ph/wp-content/uploads/2020/10/FDA-
− nvesti ator’s rochure Circular-No.-2020-029-1.pdf
• Upon receipt of endorsement from VEP and Ethics Board through • Sites are still subject to approval after the application for the
the Sub-TWG for Vaccine Development, the applicant shall vaccine clinical Trial (VCT) has been approved by the PFDA. This
provide the complete documentary requirements and its proof of is in accordance with the IATF Resolution No. 68 for the Zoning
payment (Php 2, 525.00) to the FDA to facilitate review of the Guidelines of the COVID-19 VCTs
completeness and veracity of the documents. The application is
deemed filed only upon acceptance of such documents by the
▪ FDA Clinical Trial Application & Import Application
• A. Table of Contents for the Clinical Trial Application (CTA)
FDA. The Application shall then be assigned to the Regulatory
Reviewers. • B. Cover Letter for Application
• The FDA Regulatory Reviewers shall process the application in • C. Accomplished CTA form
not more than 14 calendar days upon its receipt and a fee of Php • D. Investigational Products (IP) and Ancillary Supplies
60, 000.00 shall be charged to the applicant. If there is a need for Information
any clarification on the application, an electronic notification shall

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• E. Accomplished Import License Application form, if the IP and
the Ancillary Supplies are to be imported into the Philippines
• F. Letter of Authorization, if the applicant is not the Sponsor
• G. Clinical Trial Protocol Amendments where applicable
• H. GCP Certificate and Protocol Amendments
• I. Informed Consent Form, Assent form (if applicable), in English
and FIlipino version
• J. Investigator Brochure (IB)
• K. Pharmaceutical Data (ASEAN Common Technical Dossier • Some of the forms are patterned in the SJREB.
should be followed)
• L. GMP Certificate
▪ Bureau of Quarantine
• M. Shipping Condition for IP
• N. Labeling Materials (Primary/Secondary Packaging) for IP
• O. Proof of Payment (Php 2,525.00)
• Upon receipt of endorsement from VEP & Ethics Board through
SubTWG Vaccine Development
• FDA AO 2020-029 - Guidance on Applications for the Conduct of
COVID-19 Clinical Trials
• https://www.fda.gov.ph/wp-content/uploads/2020/10/FDA-
Circular-No.-2020-029-1.pdf
▪ Institutional Review Board (IRB)
Depend and vary per institution.
• Basic Documents for All Studies
− Study Protocol
− Informed Consent Forms • We have to apply so that we could receive the IP to the site. It can
− Case Report Form or Data Collection Forms be an importer to do this but sometimes the CRO depending on
− CV of PI and study team members the contract.
− Good Clinical Practice (GCP) Training • Usually, iba silang document pero pareho silang binibigay ng FDA
Certificates of: (letter for approval ng FDA ar request to the bureau director)
o Principal Investigator (PI)
o Co-Investigator (Co-I)
▪ National Telecommunications Commission
o research coordinators of the study team (for clinical trials)
− Study Protocol Assessment Form
− nvesti ator’s rochure
− Site Budget
− Printed Registration and Application Form

• Identify the equipment and payment of lease

Site Budget Considerations

• Sample for Makati Med IRB requirements.

• You have to also fill-up these application forms given by the thrics
review board.
• There is a review fee so they can release approval.
▪ Visual representations of forms

• In site monitoring module

Question and Answer
• Who is the regulatory agency or agencies for COVID-19 Clinical
Trial Regulatory Approval?
− Answer: FDA, DOST, DOH
− There are all responsible for it.
− The process flow will lodge on DOST vaccine expert panel, in
paralled with DOH SJREB, after both have provided their
clearances, in practice they don’t really wait for SJREB, it is
being recommended for review by FDA, FDA will wait for
SJREB bago magrelease si FDA approval letter and import
terminal.
• What are the usual queries from FDA during the review that you
have encountered po?

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− Usually, related din sila sa document ns sinasubmit, minsan
kukang yung document na napasa.
− It is more on protocol pa rin ang tanong nila.
− They read it, but usually nirerefer siya sa sponsor kasi sila ang
nagsulat ng protocol.
− Pwede tayong mag-seek ng information sa sponsor para
makasagot sa query ng FDA.
− For technical questions for pre-clinical studies, sometimes FDA
will have questions regarding rules and forwarded it to
sponsors and forward it to their pre-clinical team. It is very
technical, they ask pictures for animal models. It is a
collaboration. FDA has technical and documental questions
and questions regarding the clinical trial protocol themselves.

End of Regulatory Science

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