Drug Development Stages, Departments & Careers Clinical ... · Drug Development Stages, Departments...

Drug Development Stages,

Departments & Careers

Clinical trials: The various Roles &

Obligations; SOP for a Clinical trial

Patrick Brunel, MD, MSc, Cardiologist

Fundamentals in Clinical Research – Module 4 Clinical trial

Conduct & Data Handling,

10-Jan-2015, Beirut, Lebanon

Drug Development Stages

A new path to drug discovery will be essential:traditional discovery & development takes a long time

10’000 compounds in the beginning

1 new Medicine on the market

10 compounds in the clinic

Preclinical

Phase incl.

Research

Clinical

Phase I

1’000 compounds in vitro testing

~14 years

Clinical

Phase II

Clinical

Phase IIIRegistration

ICH E8 Guidelines(Federal Register. 29540, May 30, 1997)

“ The studies may be classified according to their objectives.

The concept that clinical drug development is comprised of

four temporal phases, I through IV, is widely used. It is

important to appreciate that this is a description not a set of

requirements, and that for some drugs and development

programs the typical sequence will not be appropriate or

necessary.”

Phases in Drug Development

Discovery

• New compounds are evaluated for their potential to treat disease

• Limited preclinical safety studies are conducted

• A route of synthesis is established

Pre-clinical

• Determines the efficacy and tolerability in animal models

• Successful candidates are tested to substantiate safety

• Pharmacokinetic parameters are defined

• Preliminary formulation is developed

Clinical Phase I

• Tolerability in humans

• Successful products are tested in an initial Proof of Concept study to demonstrate activity in man

• Pharmacokinetics and metabolisms are evaluated in humans (usually healthy volunteers)

• Formulation is refined

• Animal safety studies required for longer term treatment are conducted

• A Pre-GPT is formed


Clinical Phase II

• Phase in which dosage and efficacy in patients is determined

• Some preliminary data provided on the effectiveness of the drug for a particular indication or indications in patients with a disease or condition

• This phase helps determine the common short-term side effects and risks associated with the drug

• Safety and clinical pharmacology studies also take place

Clinical Phase III

• Large-scale clinical trials for safety and efficacy in large patient populations

• Controlled and uncontrolled trials are conducted in this phase to gain additional information about effectiveness and safety needed to evaluate the overall benefit-risk relationship of the drug


Registration

• Product registration occurs

• Regulatory agencies review documents and decide about approval

• Marketing authorization is granted

• Additional studies, both post-marketing requirements and profiling studies (Phase IV,) are set in motion

Launch/Post-Launch

• Physicians prescribe the product to patients

• Phase IV studies continue to profile the product, and to comply with regulatory requirements

• Additional indications and/or formulations may be developed (life cycle management)

Flexible Designs (Definitions)

• Seamless designs join two distinct subsequent trials in a drug program into a single trial without combining the information.

The trials should not differ operationally (essentially the same CRF, centers, indication, …) and be defined in a single protocol.

• Adaptive designs allow for initial uncertainties in trial design to be confirmed/adapted during the trial.

The integrity of the trial is maintained and the evidence for the same hypothesis before and after the adaptation is combined.

• Adaptive seamless designs (ASD) take advantage of both: Information gathered in the first stage (IIb) of the trial is used to adapt the design for the next stage (III), which seamlessly follows; the information from the learning stage will contribute evidence to the overall conclusions

Examples of Adaptations in Adaptive Designs

• Re-estimation of sample size

• Dropping or adding or changing treatment arms.

• Sample size allocation to treatment arms

• Patient population (selection, exclusion or enrichment)

• Statistical testing strategy

Adaptive Seamless Design & Comparison with classical Phase II-III

11 | Presentation Title | Presenter Name | Date | Subject | Business Use Only

Advantages of Structured Development

Clear defined goals and data collection.

Operational convenience and simple.

Decision process well defined.

• In control of the sponsor with advice on development from broad external experts with evidence (safety and efficacy).

• Little or no pre-definition of decisions required prior to each phase completion.

Easier regulatory framework with meetings and advice at clearly defined milestones.

Higher probability of success.

Rationale for Flexibility

Treatment less toxic.

Therapeutic efficacy manifested due to different mechanisms than historical standard

Accumulating evidence from the current trial or other trials.

Availability of target patient population.

• Each patient is valuable resource.

May require less patients (not always!)

Allows for initial uncertainties in trial design.

Conclusions

Structured development works reasonably well in most cases.

Combining Phase I and II should be considered only where applicable and not be considered as “default”.

• Saving time and resources should be adequately justified.

Combining Phase II and III should be considered only in rare (orphan) diseases.

• Exceptions should be clearly justified.

• In all cases, prior regulatory acceptance is strongly recommended.

Innovative approaches should be considered more in exploratory phases to accelerate development.

Clinical Trial Team:

The various Roles and their Obligations

Clinical trial Team Mission

The Clinical Trial Team (CTT) has the mandate to:

• plan, implement and execute a clinical trial as outlined in the Clinical Development Plan (CDP) to ultimately deliver the clinical study report

• provide leadership, overarching and cross-functional strategic guidance and coordination

• ensure efficient and timely execution of the clinical trial

• align Line Functions (LFs) represented on the CTT with trial goals and objectives

• facilitate and encourage open, honest and objective communication and transparency within and across all LFs, “top down and bottom up”

• anticipate potential risks and issues, come up with mitigation strategies, and make prompt decisions

• provide periodic progress report to the International Clinical Team (ICT)

• ensure detailed project timelines are defined, documented, and maintained taking into account cross-functional dependencies for achievement of intermediate and major milestones

The CTT has the global responsibility to drive the clinical trial forward and to ensure that the objectives set in the CDP and yearly goals are met. The ultimate goal is to deliver the clinical study report on time, on budget with high quality.

Clinical Trial Team Working Principles

Continuity

• Assume day-to-day responsibilities for the clinical trial, encourage communication between team members, LFs and make decisions and take prompt action.

Teamwork

• Lead by the Clinical Trial Head (CTH) who has global accountability for the trial and serve as the central contact person for coordination of all aspects of the clinical trial.

• The progress of the clinical trial is reviewed on a regular basis.

• Issues should be discussed and resolved at the CTT level whenever possible. Line Functions (LF) members on the CTT will provide expertise and guidance supporting the decision making and/or issue resolution process.

• Each team member is empowered by his LF and expected to represent a consensus of his/her respective LF to the CTT.

• If activities are outsourced to a CRO, the CRO representative becomes a CTT member in addition to the LF representative.

CTT Working Principles

Communication

• Good communication between all team members is key to the success of the CTT.

• Teams may rely on a range of tools including using available electronic team tools, one-to-one discussions, and team meetings.

• All team members are expected to initiate interactions and discussions within the team

• The CTH/CTT is responsible for on the study progress. Deviations from the planned study timelines and trial issues that may impact other trials or the overall project should be brought promptly to the attention of ICT.

The CTT, under the leadership of the CTH, has to set yearly CTT goals to be endorsed by each LF member and their management. These objectives must be in line with the ICT/GPT objectives, reviewed at least yearly and when significant changes arise, and are expected to be reflected in individual team members’ personal objectives.

They are considered as a contractual agreement between the CTT and the Line Functions.

Clinical Trial Team CompositionTitle Core/Extended

Clinical Trial Head (CTH) Core

Global Clinical Leader (GCL) Core

Clinical Managers (Sr/Ex) Core

Trial Data Manager Core

Trial Statistician Core

Global Lead CRA Core

DRA Manager Extended

Project Allocation Resource Manager

(PARM)

Extended

Clinical Trial Budget Manager (CTBM) Extended

CRO representative(s) Extended

Trial DM Programmer

p CRF Developer

e-CRF/Database programmer

Report programmer

Extended

Trial Statistical Programmer Extended

Drug Supply Manager Extended

Brand Safety Leader Extended

Medical Writer Extended

Biomarker Clinical Scientist Core or Extended*

Imaging Operations Scientist Extended

Clinical Pharmacology Expert Core or Extended*

Region Medical Advisors Extended

CPO Medical Advisors Extended

Japan Extended

Roles and Responsibilities of CTT members

Clinical Trial Head (CTH)

• Chair CTT meetings

• Lead and matrix manage the global multidisciplinary CTT to ensure that all trial deliverables are met according to timelines, budget, quality standards and operational procedures

• Report study progress and issues with their resolution plan to ICT

Global Clinical Leader (GCL)

• Responsible for the achievement of indication-specific objectives and goals as defined by the CDP

• Responsible for providing medical leadership to the protocol, clinical components of regulatory documents/registration dossier and brand related medical information, clinical communication and publications relating to this trial


Clinical Manager (CM)

• Supports the CTH with deliverables for the study

• Assists with meeting organization, and drafting agenda and minutes

DRA Manager

• Responsible for providing guidance on regulatory issues/questions/strategy

Project Allocation Resource Manager

• Represents all GMO functions at the CTT serving as an interface between the CTT and field monitors

• Responsible for trial allocation and executing the monitoring plan

• Responsible for negotiating country level budget and monitoring resources

• Prepares the global recruitment plan, provides information on recruitment status/issues and implements contingency plans


Trial Data Manager (TDM)

• Leads CRF development, contributes to the review of protocol and contributes to the monitoring plan

• Responsible for chairing Validation & Planning meeting and finalizing VAP documents

• Informs CTH of key data issues from all sources including CRF data entry/query resolution status and data quality

• Appraise team on the status of the database

Trial Statistician (TS) and/or Clinical Pharmacology Statistician (CPS)

• Shares responsibility with CTH for trial design, protocol and CRF development

• Responsible for randomization scheme

• Chairs Report and Analysis Plan meeting and responsible for finalization of RAP documents

• Contributes to monitoring plan, VAP, data review and trial report shell


Clinical Trial Budget Managers

• Prepare in collaboration with CTT the TTG

• Evaluates the impact of CTT decisions on the clinical trial budget

CRO Representative(s)

• The CRO representative(s) serves in addition to the LF that is outsourced on the CTT, under the responsibility of the line function who has contracted out this activity with regards to compliance to the company quality and timelines standards.

Trial DM Programmer (Based on roles)

• Responsible for CRF development/database specification/design.

• Responsible for development of data transfer specifications for third party data


Trial DM Programmer (Con’d)

• Produces exception reports, monitoring data listings, and Patient Profiles for data cleaning and validation efforts

• Provides input to Protocol Deviation (PD) Specification and Development of PD programs.

• Contributes to protocol review and VAP documents

Trial Statistical Programmer

• Responsible for derived analysis data set specifications

• Performs dry runs

• Produces summary tables and data listings for the Clinical Study Report

• Contributes to CRFs, VAP and RAP documents


Safety Leader (SL)

• Represents Drug Safety and Epidemiology

• Responsible for assessment and interpretation of safety and pharmacovigilance activities

• Contributes to protocol preparation and the safety sections of the Clinical Study Report

Global Lead CRA (GLCRA)

• Represents field monitoring

• Responsible for preparing the monitoring plan

Drug Supply Manager (DSM)

• Contributes to protocol development

• Forecast and coordination of drug supplies


Medical Writer (MW)

• Coordinates the editing and/or writing of trial documents (i.e., CSR, SAE narratives, summary reports)

• Contributes to the AP

Biomarker Clinical Scientist (BCS)

• Provide input for all aspects of biomarker samples (consent, lab SSWs, data management, CRFs, data transfers, site/monitor training).

Imaging Operations Scientist

• Imaging Operations Scientists provide support to clinical teams on all aspects of imaging related activities including ISSW and selection imaging CRO vendor, study start up activities (input to imaging lab manuals etc), and provide input to clinical trial documents


Clinical Pharmacology Expert (CPE)

• Responsible for providing clinical pharmacology leadership to the protocol, clinical components of regulatory documents/registration dossier and brand related medical information, clinical communication and publications relating to this trial

• Shares responsibility with CTH and TS or CPS for trial design, protocol and CRF development

• Provides input to the clinical pharmacology and pharmacokinetics objectives and analyses in the protocol

• Co-ordinates activities related to exploratory and modeling and simulation analyses of the study; convenes as needed members of the “quantitative circle” (i.e. CPE, TS and/or CPS, Modeling and Simulation Expert, Biomarker Clinical Scientist)

Region, Country, Japan Medical Advisors

• Provide input from their respective countries/regions with regards to the preparation and conduct of the trial locally

| Change Advocate Onboarding | DEV OD | June 2012 | Fran/GCO Better Development | Business Use Only27 27

What is RACI?A tool used for clarifying ownership & decision making

Responsible“The Doer”

Individual who:

actually completes task or supports

task completion with other Rs or A

Responsible for action / implementation

Degree of Responsibility is determined by the

Accountable individual

Accountable

Individual who:

is accountable to ensure it happens

Signs-off on work completed: answerable for the

correct & thorough completion of the deliverable or task

Only one “A” can be assigned to a decision, task, or

deliverable

Informed

Individual who:

needs to be informed after a decision

or action

One-way communication

Kept up-to-date on progress, typically at task or

deliverable completion

Consulted

Individual who:

is consulted during decision-making

process or action

Two-way communication

A strong role, includes right to escalate

Typically Subject-Matter Experts

“The Expert”

“The Notified”“The Approver”

| Change Advocate Onboarding | DEV OD | June 2012 | Fran/GCO Better Development | Business Use Only28

Clinical trial Team charter

Clinical Development Plan


Involve :• Therapeutic Area Head

• Global Project Leader

• Clinical trial Head

• ...as appropriate

Consult :• External scientific experts

• Health Authorities: FDA (IND meeting), EMEA (Scientific advice)

Include :• Clinical studies (Phases I-III)

• Supportive studies (Specific populations, drug interaction,

population PK etc.)

Clinical Development Plan


CDP – Points to consider

Defining the unmet need and assessing the benefit-risk

• Is the unmet medical need established in the intended population and are the benefit-risk assumptions realistic?

• Is there alignment with the assumptions made in the TPP?

• Are the decision criteria for Go/No-Go adequately defined?

• Are the critical safety and other project risks adequately prioritized with mitigation steps in place?

• Has modeling and simulation been engaged and is there a plan to evaluate dose response and the minimally effective dose?


CDP – Points to consider

Optimizing Response/Facilitating Market Access• Have potential active comparators been well delineated?• Have novel or innovative clinical trial designs been considered?• Can the program be executed within the defined timeline (encountering

regulatory feedback, operational aspects, etc.)?• Does the strategy utilize profiling/biomarkers? Has development and timing of a

companion diagnostic been considered, if applicable?• Is there a plan for development and validation of other clinical outcome

assessments, if applicable?• Does the plan include clinical trials needed in “real world settings” to address

market access needs at the time of registration?• Have special populations been adequately considered and reflected?• Is the regional strategy adequately represented?• Is there a plan for payor engagement prior to approval and registration?


IPS

CDP

OpsPlan

CDP is supplemented by mandatory OpsPlan for RDPs (Resource Decision Points on each study)and other appendices as needed.

Appendices contain functional development activities with more granularity than in the high-level, one-slide-equivalent summary included in the CDP.

Key Project Information table, TPP, and Program Risk and Mitigation are generally owned by the GPT and should be identical in IPS and related CDP.

The clinical development strategy of the first CDP around DDP builds on the considerations outlined in the preceding IDP document.

IPS, CDP, OpsPlan, Appendices to CDPHow do those pieces fit together?

CDP = Clinical Development PlanOpsPlan = Operational PlanIPS = Integrated Product Strategy


CDP Template: Example of a critical path outline

Clinical Study Set-up



Study set-up Roadmap (Clinical trial Toolkit – NIH)


EU Clinical Trial Directive General

Came into force in May 2004 and has been implemented into

National Legislation in all EU countries. A Clinical Trial

Directive update is expected to be published in 2014.

Substantial differences across countries

Transposition

Country specific requirements

Scope of the Directive:

•Applicable for all interventional Clinical trials with Medicinal products

-Phase I (patient & healthy volunteers), II, III and IV studies

-Bio-availability and bio-equivalence studies

•Applicable to industry as well as academia sponsored clinical research

Directive National Legislation


EudraCT Databasehttps://eudract.ema.europa.eu/

Purpose of this database:▪ The registry of all clinical trials in EU (contains for each trial: HA&EC

authorisation, protocol, amendment, end of trial….)

▪ To facilitate communication on clinical trials between authorities (accessible

by National HA, EMA, EU Commission)

▪ To enhance protection of subjects and patients receiving Investigational

Medicinal Product (IMP)

▪ To be linked to the EudraVigilance database (containing SUSAR database)

▪ Each clinical trial protocol is identified by a unique mandatory reference

number (EudraCT Number)

European database of all Clinical Trials within the EU

EudraCT Number format: YYYY-NNNNNN-CCYYYY: Year in which the number is issued

NNNNNN: six digit sequential number

CC: check digit39 _ Clinical trials in the EU_ June 2013_ Business Use Only


CTA Dossier

Standard CT

Application Form

including

EudraCT Number

•Protocol & amendments

•Informed Consent Form

•Case report Form

Clinical Trial

Information

•Quality data

•Non-clinical pharmacology & toxicology data

•Clinical trial & previous human experience data

•Benefit/risk assessment

IMPD

(Core Dossier)

•Subject related

•Protocol related

•Facilities & staff related

•Finance related

Member State

Specific

Information

Changes to: protocol and/or key evolving data

impact on CTA documents Amendment

Not applicable in all countries


CTA

Dossier

1.4 List of Competent Authorities

1.4.1 List of countries

…1- General

2.3 Arrangements for

Recruitment of Subjects2- Subject

Related

3.1.2 Case Report Form

3.2 Summary of the Protocol

in National Language…

3- Protocol

Related

4.2.2 Non clinical

4.2.3 Clinical trial & human exposure

4.3 SmPC…

4- IMP

Related

5.3 CV of Each Investigator

Responsible for the Conduct of a

Trial in a Site in the MS Concerned

5.4 Information about Supporting Staff

5- Facilities

&Staff related

6.6 Agreement between the

Investigators and the Trial Site

…

6- Finance

Related

1.1 EudraCT Number

1.2 Cover letter

1.3 Application form

2.1 Subject Information

and Informed Consent Form

2.2 Subject Information Leaflet

3.1 Protocol

with all Current Amendments

&Post-text supplements

4.1 Investigator’s Brochure

4.2 Investigational

Medicinal Product Dossier (IMPD)

4.2.1 Quality Data

5.1 Facilities for the Trial

5.2 CV of the Coordinating

Investigator in the MS Concerned

6.3 Compensations to Investigators

6.4 Compensations to Subjects

6.5 Agreement between Sponsor

and the Trial Site

IMPD/CTA preparation Detailed content of the CTA Dossier


Preparation of

“global”

documents

Compilation

&

Publishing

QC

Dispatch

Through regulatory

Link to

Country Resp

Addition of

local

documentation

HQ CPO

IMPD/CTA preparation General process


Submit a CTA dossier to

Health Authority (HA)

Positive vote from EC

Start Clinical Trial

Initiate Trial

Submission

parallel

or

sequential:

country

specific

Approval of clinical trials is the responsibility of individual EU Member States

Maximum 60 days assessment period (incl. validation) + Question/Answer period

Review/Validation

Authorisation from HA

Voluntary Harmonization Procedure (VHP) as an optional regulatory

pathway for multinational clinical trials in EU

Review/Validation

Submit a CTA dossier to

Ethics Committee (EC)


Assessment by HA & EC HA & EC Questions

HA

Questions

Coordination

of response

document

Submit

response

document

to HA

Sent

response

document

to DRA

CPO

DRA CPO DRA CPO DRA Lead DRA Lead DRA CPO

ICRO/CROClinical

ICRO/CROICRO/CRO

EC

Questions

Coordination of response

involved all LFs affected with

the questions

Sent

translated

HA

question

to DRA

Receipt of

HA

Questions

Receipt of

EC

Questions

Coordination

of response

document

Submit

response

document

to EC

Answer document to be

recorded in trial system

Standard Operating Procedures

for a Clinical Study

What are SOPs?

International Conference on Harmonization (ICH) defines a SOP as “Detailed, written instructions to achieve uniformity of the performance of a specific function.” (ICH

GCP 1.55)

In simple terms a SOP is…

• A written process

• A way for the clinical site to perform a task the same way each time it is completed.

SOPs are used to:

Identify the responsible person for each task.

Describe actions (what is to be completed).

Train staff.

Monitor site performance.

Are SOPs Required by Law/Regulations?

SOPs are not specifically mentioned in the FDA regulations

• However there is guidance and regulations that infer responsibility and SOPs formalize investigator responsibilities.

• 21 CFR312.53 the investigator will “ensure that all associates, colleagues, and employees assisting in the conduct of the study (ies) are informed of their obligations in meeting the above commitments.”

Additionally, SOPs are mentioned repeatedly in the ICH GCP Guidelines.

ICH GCP 2.13 -“Systems with procedures that assure the quality of every aspect of the trial should be implemented

Benefits of a SOP?

Ensures that all research conducted within the clinical site follows federal regulations, ICH GCP, and institutional policies to protect the rights and welfare of human study participants.

Provides autonomy within the clinical site.

Improves the quality of the data collected, thereby improving the science of the study.

Utilized as a reference and guideline as to how research will be conducted within the clinical site

Excellent training source for new employees and/or fellows

SOP Topics

Preparing and Submitting Initial IRB Documents

Preparing and Submitting Continuing Review IRB Documents

Preparing and Submitting Amendment IRB Documents

Establishing and Training the Clinical Study Team, and Delegating Responsibilities

Establishing Study Files

Establishing Source Documents

SOP Topics

Study Subject Recruitment Plan

Contacting and Scheduling Potential Study Subjects for an Initial Visit

Obtaining Informed Consent from a Potential Study Subject

Enrolling a Subject

Recording Subject Data

Making Corrections on Study Documents

SOP Topics

Monitoring Subject Compliance During a Study

Responding to a Clinical Hold Order

Receiving and Storing Investigational Drugs

Drug and Study Supply Transfer Between Sites

Dispensing Study Drugs to Study Subjects

Identifying and Reporting Adverse Events

Packing, Labeling, and Shipping Samples

Identifying and Reporting Protocol Deviations

SOP Topics

Contact with potential sponsors

Budget review and determinations

Pre-study study site visit

Initiation Site Visit

Monitor Visits

Audits

Data management

Study closure

Long term storage

Writing SOPs

Develop a template for the SOP to be used throughout the document.

Potential elements of the SOP

• Header – title, original version date, revision date, effective date, approved by

• Purpose – why one has the policy

• Responsibilities – who the policy pertains to

• Instruction/Procedures – how to accomplish the items of the policy

• References – what the policy is based on

• Appendix – source documents/case report forms

Process Mapping for Writing SOPs

Determine which clinical site task needs mapping.

Lay out all the steps currently used to complete that task.

“Mapping” involves taking each step in the task and making it more efficient and easier to follow.

Process Mapping for Making a Cup of Coffee

Primary Step

Ensure the coffee maker is ready

Add the water

Turn on the machine

Serve the coffee

Add the coffee

Woodin, K. (2004) The CRC’s Guide to Coordinating Clinical Research p. 60-65. Centerwatch

Process Mapping for Making a Cup of Coffee

Ensure the coffee maker is ready

Add the coffee

Add the water

Turn on the machine

Serve the coffee

Secondary Step

Ensure the machine is plugged in

Ensure carafe is empty and clean

Place a filter in the basket

Measure the coffee

Use the carafe to measure the water

Place the carafe on the heating element

Wait until the coffee has stopped dripping

Process Mapping for Writing SOPs

Once you have finished mapping, convert your process map to an outline for easy use.

Once a task has been mapped, it should be tested.

Implementing and Monitoring SOPs

SOPs should be introduced gradually.

Prioritize most relevant SOPs and present them first.

Principle Investigator should approve all SOPs and designate an effective date.

SOPs should be reviewed on a regular basis (usually annually) to ensure policy based regulations are up-to-date.

Previous versions of SOPs should be retained.

SOP Training

All staff should have SOP training.

Training should be documented.

SOP should be accessible to staff.

What is the difference between a SOP and a Manual of Procedures (MOP)?

These terms have been used interchangeably.

Both provide a standardization of a process.

SOP provides general information that is to be utilized throughout any research study.

• How as a clinical site we will assess delegation of duties.

MOP is specifically written for a particular research study which will incorporate elements of the SOP.

MOP

The MOP should be written so that anyone in your clinical site can follow the procedures for that study and find all relevant materials.

The MOP should be extremely detailed.

SOP Resources Examples from National Cancer Institute

https://cabig.nci.nih.gov/workspaces/CTMS/Meetings/SIGs/Best_Practices/SOPs/SOPs

Standard Operating Procedures for Good Clinical Practice at the Investigative / Centerwatch

http://www.ccrp.com/sop.shtml

Standard Operating Procedures (SOPs) for Good Clinical Practice / University of Washington

http://www.crc.washington.edu/Resources/GCPSOPInvSites.aspx



http://www.ccrp.com/sop.shtml

http://www.crc.washington.edu/Resources/GCPSOPInvSites.aspx

Date post:	13-May-2018
Category:	Documents
Upload:	trinhlien
View:	220 times
Download:	0 times