Clinical Trials Budgeting

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Clinical Trials Budgeting Methods & Best Practices Instructor: Jennifer L. Kellen

Obj ti 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

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Contracting g at UCSF Best Practice „

RSA Roles „

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Contracting coordinator „ Industry Contracts Division (ICD) p participation p „ Advise all parties on timelines, required materials, policies, etc. Document gatekeeper „ Version control „ Budget responses should be in PDF

ICD & RSA Responsibilities „ „

Compliance with UC policy and state laws Sensitivity to the Investigator’s relationship with the Sponsor

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Types yp of Trial Contracts

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Drug Only

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Single site

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M li Multicenter, coordinating di i site i

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Correlative science

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Clinical C ca Trial a Agreement g ee e t To qualify for clinical trial facilities and administrative rates, a Clinical Trial Agreement (CTA) must either: „

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 p g study y or a FDA-regulated g medical device study; or

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

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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

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

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

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Phases of Clinical Trial Research Prior to clinical trials „

Preclinical Studies „

I vitro In it (test (t t tube) t b )

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In vivo (animal)

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Results determine future t ti as an investigational testing i ti ti l new drug

Clinical trials „

Phase 0

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Phase I

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Phase II

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Phase III

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Phase IV

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Phases ases of o Clinical C ca Trials as Phase 0 „

First-in-human trials

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AKA as microdosing studies

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

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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 drug works in the body).

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Provides no safety or efficacy data (per definition)

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Phases ases of o Clinical C ca Trials as Phase 1 „

First stage of testing in human subjects

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Normally, a small group (20-50) of volunteers are selected „

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

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

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Often conducted in an inpatient clinic for full-time observation

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

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Phases ases of o Clinical C ca Trials as Phase II „

Performed on larger groups of 20 to 300 participants

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Assesses how well the study drug works „

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

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

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

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

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Phases ases of o Clinical C ca Trials as Phase III „

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

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

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

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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

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Phases ases of o Clinical C ca Trials as Phase IV „

Also known as Post Marketing Surveillance Trials

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

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May be required by regulatory authorities or undertaken by the Sponsor „ „

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To find new markets Study interactions between drugs or certain population groups that are unlikely to subject themselves to trials (e.g. (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 use „ One of the most widely used drugs to ever be withdrawn from the market.

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Clinical Research Coordination Roles & Responsibilities „

Regulatory processing

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Contracts management

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Patient accrual and monitoring

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Collection and processing of research specimens

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Dispensing of study drugs

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

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Auditing

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Billing and payment reconciliation

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Factors Impacting p g Budgets g „

Research personnel composition

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The type, phase, and acuity or complexity of the protocols involved „ „

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The actual time it takes to do the work „ „

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

Organization of clinical trial research services within the research center Long-term follow-up, if the endpoint is death

Associated or indirect costs „

Preaward and Postaward work

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Trends in Academic Clinical Research „

Workload of Clinical Research Coordinators (CRCs) continues to increase

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

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Each protocol is different.

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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.

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Publicized Benchmarks Society of Clinical Research A Associates i t (SoCRA) (S CRA)

NIH/NCI „

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

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Not clear if this is data management only or also i l d nursing includes i and d regulatory activities

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1 FTE handling all responsibilities (i.e. (i e regulatory, IRB, patient monitoring, data management, sponsor encounters/audits) could effectively manage ~30 new patients per year.

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Key y Variables to Consider for Resource Budgeting & Allocation „

Phase of trial (I, II, or III)

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Type and stage of disease treated

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Anticipated complications „ „ „ „

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Sample processing and/or shipping logistics Patient treatment logistics and scheduling challenges Data management in busy studies 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 labor „ Manually 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 p software may y operate p slowly. y Request q to test drive it.

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Elements of Successful Budgeting g g „

Thorough analysis of the specific protocol tasks

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Appropriate knowledge of and familiarity with institutional resources

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Delineation of standard of care from research events & procedures

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Understanding CPT coding & billing

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

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

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

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Access to updated research rates provided by the Medical Center

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Tips p for Successful Budgeting g g „

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

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

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

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

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Create a billing grid - usually derived from the study calendar

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

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Tips p for Successful Budgeting g g „

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

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Study y team labor,, ballpark p recommendations „ „ „

Allow 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

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

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

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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 group. group

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Common Mistakes „

Overestimating the ease of obtaining subjects

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

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Under-budgeting for the unexpected

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Overestimation of research staff efficiency

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Commonly y Missed Budget g Items „

A lengthy consent form process

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Pharmacy costs

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Screening for accrual „ 10 p pts. will need to be screened in order to accrue 1 participant „ Screen failures

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Supplies pp and expenses p necessary y for the trial office „ Office supplies „ Photocopying charges „ Phones „ Computer support agreements „ Furniture „ Computers

Storage costs „ Temporary storage of samples for d t send-out „ Long term storage for trial records „ Labor needed to pack & ship (e.g. PK samples) „ Dry D ice

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

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

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Commonly y Missed Budget g Items „

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

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Labor for assembling patient binders and other Sponsor supplied materials

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Labs sent to a central lab for analysis

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Labor for quality-of-life surveys and phone h calls ll they h may require i

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Labor for lengthy screening/baseline eligibility reviews „ Phase Ph I studies t di may require i up to 2 days for each patient

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Labor for enrollment log completion and submission „ Note N t if the th llog needs d tto b be submitted b itt d within a certain time frame

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Labor for creating a calendar, patient information packet, and/or d/ checklist(s) h kli ( ) ffor each h patient

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Concurrent labor such as study team meetings g or p procedures & events requiring more than one staff person for execution

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Labor for obtaining a second or revised consent

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Labor associated with patients that need additional assistance

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Commonly y Missed Budget g Items „

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

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Advertising and shipping costs

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Travel to meetings, conferences, and/or monitoring other study sites i

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Unexpected market adjustments „ Salaries „ Hospital ancillary costs

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Labor needed to produce invoices and reconcile payments

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Labor necessary for financial analysis and review

Labor L b for f coordinating di i participation i i i off other research collaborators or sites Labor for scheduling lab tests, biopsies, cardiology or radiology procedures, and other service unit participation (e.g. CCRC)

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Labor for data entry and management

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Labor spent with monitors and query resolution

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Negotiation g of Clinical Trials

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Sponsors p & Clinical Research Organizations (CROs) „

Never agree to the Sponsor’s initial offer no matter how incredible the dollar amount sounds d without ith t a thorough th h analysis of the specific protocol

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All Sponsors and CROs have a business plan to make money

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Remain a neutral mediator

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Negotiation g Tips p „

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

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Keep the PI in your corner „ Keep him/her informed „ Ready to intervene „ Ready to remind the Sponsor of the benefits of opening the study at UCSF. UCSF „ Good Cop/Bad Cop

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Keep momentum going if negotiation ti ti iis moving i quickly i kl

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Budget g Requisition q Form

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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 off care. duty

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

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

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Who determines standard of care? „

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

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Nonstandard of care events should be circled on the study calendar

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

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Standard of Care Certification

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Nonstandard of Care Research Pricing

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CPT Codes Current Procedural Terminology „

Maintained by the American Medical Association

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

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

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CPT codes can also be revised and retired.

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

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Trial Budget g Components p

Start-up

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CHR fee Pharmacy fee Study team budget Preaward team budget g

Trial P f Performance

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

Follow-up

• Follow-up as invoice item • Postaward budget

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

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% Effort to Billable Hours „

Annual total working hours at UC is 2088.

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Multiply by total project years

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Multiply by % effort for project working hours

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Subtract the following: „ Vacation Hours „ Holiday Hours „ Sick Leave Hours (if app.) „ Administrative Hours

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This gives you total trial project hours

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Start-Up p Budget g „

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

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

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

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Study y Team Budget g

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Postaward Budget g

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Variable Va ab e Events ve ts Expenses 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.

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Variable Event Charges g Without CPT Codes

With CPT Codes

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Negotiation g Tips p „

Use the team approach

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Don’t let aggressive CROs push you around

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Remain calm and exercise some patience

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Be ready to move on a contract in a moments notice

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

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

Reach out to resources within the UCSF community for advice

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Developing eve op g Sta Standard da d Rates ates Long Term Record Storage

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Terms to Remember „

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

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A study calendar represents all treatment options for all patents.

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A flow chart represents p a treatment path for one patient.

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Research rates = Medicare rates

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

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Unallowable Costs „

Government Sponsored „ „ „

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Industry Sponsored

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IRB review fees All other NIH restrictions apply Review the RFA/RFP for specific restrictions

Nonprofit Sponsored

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Driven by CTA terms

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Driven by CTA terms

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Cost sharing

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Review the RFA/RFP for specific restrictions

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Allowable owab e Costs by Spo Sponsor so Type ype http://or.ucsf.edu/icd/home/faculty/policies.html

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F & A Rates for Clinical Trials Industry & Nonprofit* „

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26% „ Single site clinical trials „ Total Direct Costs (TDC) with base code C 33% „ Multicenter clinical trial projects „ UCSF is the coordinating g site „ Subcontracts are involved „ Modified Total Direct Costs (MTDC) with base code A

Government Agencies „

33% „

Single site clinical trials

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Multicenter clinical trial projects

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Modified Total Direct Costs (MTDC) with base code A

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*Nonprofits may have a different indirect cost rate

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Steps p for Amendments „

Review the original contract and all subsequent amendments.

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

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

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Create a budget representing only the additional items or events. events

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Confidentiality y Agreements g What are they? „

Protect a party’s proprietary or nonpublic information. information

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

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y Agreements g ee e ts Co de t a ty Confidentiality Acronyms

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CDA = Confidentiality Agreement g

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NDA = Nondisclosure Agreement

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Confidentiality y Agreements g Two Types Two-way CDA „

If the UCSF PI expects to disclose any confidential information to the outside entity, then a CDA should be established between UCSF and the other party.

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PIs are not authorized to g on behalf of UCSF. sign

One-way CDA „

If the UCSF PI expects to merely receive, receive but not disclose, confidential information, then a CDA should be established between the UCSF PI and other party.

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Confidentiality y Agreements g Best Practice: Contact your ICD officer „

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

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

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Turnaround time is usually 48 hours.

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