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Clinical Trials BudgetingClinical Trials BudgetingMethods & Best PracticesInstructor: Jennifer L. Kellen

Obj ti

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Objectives

Components of a clinical trial

Allowable expenses and indirect cost rates

Factors impacting budgets

Budget template and examples

Budget negotiation tips and tactics

Resources and questions

+Contracting at UCSFBest Practice

g

RSA RolesContracting coordinator

Industry Contracts Division (ICD) participationp pAdvise all parties on timelines, required materials, policies, etc.

Document gatekeeperVersion controlBudget responses should be in PDF

ICD & RSA ResponsibilitiesCompliance with UC policy and state lawslawsSensitivity to the Investigator’s relationship with the Sponsor

+Types of Trial Contractsyp

Drug OnlyDrug Only

Single site

M l i di i iMulticenter, coordinating site

Correlative science

+Clinical Trial AgreementC ca a g ee e tTo qualify for clinical trial facilities and administrative rates, a Clinical Trial Agreement

Involve the controlled, clinical testing of Investigational New Drugs (INDs) or Investigational Devices (IDEs) using either a sponsor or investigator developed protocol under FDA Phase I, II, III, or IV drug study or a FDA-regulated medical device

(CTA) must either:

p , , , g y gstudy; or

Involve the controlled, clinical testing of a protocol performed under the sponsorship of an approved national cooperative consortium* for clinical trial services; or

An ancillary study at UCSF that supports an FDA-approved clinical trial performed at an outside agency, or under a clinical trial sponsored under the direction of an approved national cooperative consortium* also qualifies for the CTA rate; and

May not include projects involving animal subjects. These should not be classified as y p j g jclinical trials.

*Contracts and Grants maintains a reference list of approved national cooperative groups

+Phases of Clinical Trial Research

Preclinical Studies

I it (t t t b )

Phase 0

Prior to clinical trials Clinical trials

In vitro (test tube)

In vivo (animal)

Results determine future t ti i ti ti l

Phase I

Phase IItesting as an investigational new drug Phase III

Phase IV

+Phases of Clinical Trialsases o C ca a sPhase 0

First-in-human trials

AKA as microdosing studies

Establishes very early on whether drug or agent behaves in human subjects as was expected from preclinical studies

By definition, it is the administration of subtherapeutic doses of study drug to a small number subjects (10 – 15) to gather preliminary data on the agent’s pharmacokinetics (how the body processes the drug) and pharmacodynamics (how the body processes the drug) and pharmacodynamics (how the drug works in the body).

Provides no safety or efficacy data (per definition)

+Phases of Clinical Trialsases o C ca a sPhase 1

First stage of testing in human subjects

Normally, a small group (20-50) of volunteers are selectedIn oncology & HIV patients are under palliative care; treatment to In oncology & HIV, patients are under palliative care; treatment to ease symptoms without curing the underlying disease (typically end-stage)Volunteers are paid an inconvenience fee for their time spent in the volunteer center (up to approx. $6,000, depending on length of time)( p pp p g g )

Assesses safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug

Often conducted in an inpatient clinic for full-time observation

Includes dose-ranging; also known as dose escalation so the appropriate dose for therapeutic use can be found

+Phases of Clinical Trialsases o C ca a sPhase II

Performed on larger groups of 20 to 300 participants

Assesses how well the study drug worksWhen new drug development fails, this is normally the phase when it is discovered to not work as planned or have toxic effects in humans.

Phase IIA studies are specifically designed to assess dosing requirements (how much drug should be given).

Phase IIB studies are specifically designed to study efficacy Phase IIB studies are specifically designed to study efficacy (how well the drug works at the prescribed dose(s).

Some trials combine Phase I and Phase II, and test both efficac and to icitefficacy and toxicity.

+Phases of Clinical Trialsases o C ca a sPhase III

Randomized controlled multicenter trials on large patient groups (300 –3,000+) depending upon the disease/medical condition studied

Aimed at being the definitive assessment of how effective the drug is g gwhen compared with the current standard of care

Due to their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, p g gespecially in therapies for chronic medical conditions.

Study continues while the regulatory submission is pending at the United States Food and Drug Administration (USFDA).

Allows patients to continue on therapy with access to study drug

Sponsor may attempt “label expansion” to show that the drug works for additional types of patients/diseases beyond the original use approved for marketing

+Phases of Clinical Trialsases o C ca a sPhase IV

Also known as Post Marketing Surveillance Trials

Ongoing pharmacovigilance and technical support of a drug after it receives sales permission

May be required by regulatory authorities or undertaken by the SponsorTo find new marketsStudy interactions between drugs or certain population groups that are unlikely to subject themselves to trials (e g pregnant women)subject themselves to trials (e.g. pregnant women)

Designed to detect any rare or long-term adverse effects over a very large population and long period of time

Harmful effects may result in drug removal from market or restriction to certain uses. Vioxx (Merck)

Increased heart attack & stroke associated with long-term, high-dosage useOne of the most widely used drugs to ever be withdrawn from the market.

+Clinical Research Coordination Roles & Responsibilities

Regulatory processing

Contracts management

Patient accrual and monitoring

Collection and processing of research specimens

Dispensing of study drugs

Data collection, management, and query resolution, g , q y

Auditing

Billing and payment reconciliationBilling and payment reconciliation

+Factors Impacting Budgetsp g g

Research personnel composition

The type, phase, and acuity or complexity of the protocols involvedinvolved

Industry sponsored trials tend to be more labor intensiveCooperative group trials are more labor-driven by disease site

The actual time it takes to do the workOrganization of clinical trial research services within the research centerLong-term follow-up, if the endpoint is death

Associated or indirect costsPreaward and Postaward workPreaward and Postaward work

+Trends in Academic Clinical Research

Workload of Clinical Research Coordinators (CRCs) continues to increase

Measuring actual work (task times) instead of the number of patients or protocols managed by a CRC seems to be the best approach

Each protocol is different.

The Sponsor’s payment plan drives the internal budget development

One size does not fit all. Customized approaches taking local realities into consideration are needed.

+Publicized Benchmarks

NIH/NCISociety of Clinical Research

A i t (S CRA)

1 FTE manages 25 patients on study and 50 in follow-up

1 FTE handling all responsibilities (i e

NIH/NCI Associates (SoCRA)

study and 50 in follow-up

Not clear if this is data management only or also i l d i d

responsibilities (i.e. regulatory, IRB, patient monitoring, data management, sponsor encounters/audits)

includes nursing and regulatory activities

could effectively manage ~30 new patients per year.

+Key Variables to Consider for yResource Budgeting & Allocation

Phase of trial (I, II, or III)

Type and stage of disease treated

Anticipated complicationsAnticipated complicationsSample processing and/or shipping logisticsPatient treatment logistics and scheduling challengesData management in busy studiesTime limits on patient accrual reporting and data query resolution Time limits on patient accrual reporting and data query resolution

Case Report Forms (CRF)The “deliverable” in clinical trial contracts, often triggering payments.Request a copy of the Sponsor’s draft CRF to accurately estimate labor.

Online data entry tends to consume more study team laborManually transferring data from paper sources to the electronic format the Sponsor chooses never goes as smoothly as planned and for some groups, this doubles the amount of data entry.Sponsor software may operate slowly. Request to test drive it.p y p y q

+Elements of Successful Budgetingg g

Thorough analysis of the specific protocol tasks

Appropriate knowledge of and familiarity with institutional resources

Delineation of standard of care from research events & procedures

Understanding CPT coding & billing

F ili it ith l t f d l & t t l i t i lFamiliarity with relevant federal & state laws governing trials

Estimating a reasonable, average number of cycles or days each patient will be on study

Clear understanding of the study completion timeline and requirements triggering payments as stated in the draft CTA

Access to updated research rates provided by the Medical Center

+Tips for Successful Budgetingp g g

Flow charting – break down the protocol into specific paths for each patient with sections divided by service provider

Create a master timeline that plots each participant’s usage of p p p gcritical, limited resources over time

Limited access to specialized care areas such as only one research MRI test space available per weekHow patients are accrued onto a protocol will often determine the How patients are accrued onto a protocol will often determine the overtaxing of clinical research resources

Create a worst-case scenario timeline and one according to plan.p

Create a billing grid - usually derived from the study calendar

A break-even point and bottom line should be analyzed.

+Tips for Successful Budgetingp g g

Review disease registry data to note the number of patients normally seen to accurately estimate accrual rate.

Study team labor, ballpark recommendationsy , pAllow 4-12 hours per visit or 1-2 hours per time point for CRC labor.

Allow 1-3 hours per visit for faculty labor

Allow 1-2 hours per visit for nursing, if applicable

A 20% screen failure rate is considered to be fair.

Hold firm on time required to chart screenings and logs that can consume enormous amounts of timeconsume enormous amounts of time

Perform a workload analysis by tracking all trial activities in monthly reports to document the amount of work done within a certain time frame to create benchmarks for your institution or groupframe to create benchmarks for your institution or group.

+Common Mistakes

Overestimating the ease of obtaining subjects

U d ti ti th ti Underestimating the time required for regulatory affairs

Under-budgeting for the unexpected

Overestimation of research staff efficiencystaff efficiency

+Commonly Missed Budget Itemsy g

A lengthy consent form process

Screening for accrual

10 pts. will need to be screened

Pharmacy costs

Storage costsTemporary storage of samples for

d tp

in order to accrue 1 participant

Screen failures

Supplies and expenses necessary

send-outLong term storage for trial recordsLabor needed to pack & ship (e.g. PK samples)D ice

pp p yfor the trial office

Office supplies

Photocopying charges

Phones

Dry ice

Follow-up visits not included in the original schedule of events

Phones

Computer support agreements

Furniture

Computers

PI conference callsPhase I trials can be 1 to 2 hours per week between cohorts for safety analysis & discussion with the Sponsor.Spo o

+Commonly Missed Budget Itemsy g

Equipment (e.g. freezers, centrifuges, pagers, etc.)

Labs sent to a central lab for analysis

Labor for assembling patient binders and other Sponsor supplied materials

Labor for quality-of-life surveys and h ll h ianalysis

Labor for lengthy screening/baseline eligibility reviews

Ph I t di i

phone calls they may require

Labor for enrollment log completion and submission

N t if th l d t b b itt d Phase I studies may require up to 2 days for each patient

Labor for creating a calendar, patient information packet,

d/ h kli ( ) f h

Note if the log needs to be submitted within a certain time frame

Concurrent labor such as study team meetings or procedures & events

and/or checklist(s) for each patient

Labor for obtaining a second or revised consent

g prequiring more than one staff person for execution

Labor associated with patients that need additional assistanceadditional assistance

+Commonly Missed Budget Itemsy g

Labor for lengthy adverse events and serious adverse events reporting, depending on the type of drug involved.

L b f di i i i i f

Advertising and shipping costs

Travel to meetings, conferences, and/or monitoring other study iLabor for coordinating participation of

other research collaborators or sites

Labor for scheduling lab tests, biopsies, cardiology or radiology procedures, and

sites

Unexpected market adjustments

Salariescardiology or radiology procedures, and other service unit participation (e.g. CCRC)

Labor for data entry and management

Hospital ancillary costs

Labor needed to produce invoices and reconcile payments

Labor spent with monitors and query resolution

payments

Labor necessary for financial analysis and review

+Negotiation of Clinical Trialsg

+Sponsors & Clinical Research pOrganizations (CROs)

Never agree to the Sponsor’s initial offer no matter how incredible the dollar amount

d ith t th h sounds without a thorough analysis of the specific protocol

All Sponsors and CROs have a business plan to make money

Remain a neutral mediatorRemain a neutral mediator

+Negotiation Tipsg p

Establish that you represent the University and are negotiating the budget on behalf of the study teambehalf of the study team

Keep the PI in your cornerKeep him/her informedReady to interveneReady to remind the Sponsor of the benefits of opening the study at UCSFopening the study at UCSF.Good Cop/Bad Cop

Keep momentum going if ti ti i i i klnegotiation is moving quickly

+Budget Requisition Formg q

+What is Standard of Care?Tort Law

It is the degree of prudence and caution required of an individual who is under a d t f duty of care.

A duty of care is a legal obligation imposed on an individual requiring that individual requiring that they adhere to a standard of reasonable care while performing any acts that could possibly harm others.

A breach of the standard is necessary for a successful action in negligenceaction in negligence.

+Who determines standard of care?

The Principal Investigator must document standard of care for each protocol.

Nonstandard of care events should be circled on the study calendar

This document is scanned and kept as a permanent SOC record for the life of the trialrecord for the life of the trial.

+Standard of Care Certification

+Nonstandard of Care Research Pricing

+CPT CodesCurrent Procedural Terminology

Maintained by the American Medical Association

When new technologies become il bl dd CPT d available, new add-on CPT codes are

created.

Over time, this can develop into a group of CPT codes needed for a group of CPT codes needed for a particular procedure.

CPT codes can also be revised and retired.

Refer to a current CPT code book and online resources for the latest groupings and information on new releases and changing codes.releases and changing codes.

+Trial Budget Componentsg p

Start-up• CHR fee• Pharmacy fee• Study team budget• Preaward team budget

Trial P f

g

• Study funded procedures• Program budget• Radiology budget• Pathology budgetPerformance • Pathology budget• Correlative science budget• Postaward budget

Follow-up • Follow-up as invoice item• Postaward budget

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Internal Budget SummaryShows exactly how much each Shows exactly how much each research service group should expect to receive assuming full enrollment of patients completing all cycles of budgeted therapy.

+% Effort to Billable Hours

Annual total working hours at UC is 2088.

Multiply by total project years

Multiply by % effort for project working hours

Subtract the following:Subtract the following:Vacation HoursHoliday HoursSick Leave Hours (if app.)Administrative Hours

This gives you total trial project hours

+Start-Up Budgetp g

If you don’t ask for it, you won’t get it.

Th t t i l The start-up is always nonrefundable because the University has already incurred these project related p jexpenses.

Ask for prepayment of one or two patients if patients are two patients, if patients are lined up already or the accrual rate is fast.

+Study Team Budgety g

+Postaward Budgetg

+Variable EventsVa ab e ve tsExpenses that may not apply to every patient

Remember…Keep them out of the per patient cost!

They raise the “do not exceed” fund limit in RAS.

All relevant labor should be included.

Consider including an “invoice fee” per invoice or invoice item to cover administrative costs.

+Variable Event Chargesg

Without CPT Codes With CPT Codes

+Negotiation Tipsg p

Use the team approach

Don’t let aggressive CROs push you around

Remain calm and exercise some patience

Be ready to move on a contract in a moments noticeBe ready to move on a contract in a moments notice

Confirm receipt of information or documents from Sponsors and/or CROs quickly

“Confirming receipt. I’ll get back to you.”

Reach out to resources within the UCSF community for advice

+Developing Standard Rateseve op g Sta da d atesLong Term Record Storage

+Terms to Remember

NIH definition of “X Sponsored” NIH definition of X Sponsored means X wrote the protocol. UCSF equivalent term is “X Initiated.”

A study calendar represents all treatment options for all patents.

A flow chart represents a ptreatment path for one patient.

Research rates = Medicare rates

UCSF does not profit from clinical trials. A reasonable inflation margin is allowed in budgeting expenses.

+Unallowable Costs

Government SponsoredIRB review feesAll other NIH restrictions applyReview the RFA/RFP for specific restrictions

Industry SponsoredDriven by CTA terms

Nonprofit SponsoredDriven by CTA terms

Cost sharing Review the RFA/RFP for specific restrictions

+Allowable Costs by Sponsor Typeowab e Costs by Spo so ypehttp://or.ucsf.edu/icd/home/faculty/policies.html

+F & A Rates for Clinical Trials

26%

Single site clinical trials33%

Single site clinical trials

Industry & Nonprofit* Government Agencies

Single site clinical trials

Total Direct Costs (TDC) with base code C

33%

Single site clinical trials

Multicenter clinical trial projects

Modified Total Direct Costs 33%

Multicenter clinical trial projects

UCSF is the coordinating

Modified Total Direct Costs (MTDC) with base code A

gsite

Subcontracts are involved

Modified Total Direct Costs (MTDC) with base code A

*Nonprofits may have a different indirect cost rate

(MTDC) with base code A

+Steps for Amendmentsp

Review the original contract and all subsequent amendments.

PI & CRC must identify only what is being added or changed.

Analyze current trial financial status and determine how this supplement may impact invoicinginvoicing.

Create a budget representing only the additional items or eventsevents.

+Confidentiality Agreementsy g

Protect a party’s proprietary or nonpublic information

What are they?

nonpublic information.

Typically used when parties must disclose such information i d l ibl in order to evaluate a possible relationship with the other party.

+Confidentiality AgreementsConfidentiality AgreementsCo de t a ty g ee e tsAcronyms

y g

CDA = Confidentiality Agreementg

NDA = Nondisclosure Agreement

+Confidentiality Agreementsy gTwo Types

If the UCSF PI expects to disclose any confidential

If the UCSF PI expects to merely receive but not

Two-way CDA One-way CDA

disclose any confidential information to the outside entity, then a CDA should be established between UCSF

merely receive, but not disclose, confidential information, then a CDA should be established

and the other party.

PIs are not authorized to sign on behalf of UCSF.

between the UCSF PI and other party.

g

+Confidentiality Agreementsy gBest Practice: Contact your ICD officer

Describe the type of information expected to be disclosed by each party and th f th the purpose of the disclosure(s).

Forward the industry supplied y ppCDA to your ICD officer for review.

Turnaround time is usually 48 Turnaround time is usually 48 hours.

+Partnerships with Industry…a t e s ps w t dust y…are expected to increase