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An Overview for Sponsors and Sites
    A summary of the key steps in starting a study





                                  1
10 steps to Clinical Study Startup
10 steps to Clinical Study Startup
Dear Reader:
In early 2010, goBalto started its highly acclaimed “10 Steps to Clinical Study Start Up”
series on our blog - the Chromosome. We believe that the existing approach to starting
clinical studies is way too cumbersome.

Our “10 Steps” blog series has gotten the attention of readers worldwide and has helped
grow goBalto’s online readership to over 13,000 visits per month. Due to the unexpected
popularity of this series and in response to numerous requests, we have combined the 10
Steps series into this PDF file which will take you, step-wise through study start up. Though
our 10 steps are fairly comprehensive and typical of the start up process as it is conducted in
the US, it is not necessarily all-inclusive. Also, the order of the steps may vary from
company to company and/or study to study.

We sincerely appreciate and welcome the comments from our readers - these keep us going!

- The goBalto Team
Introduction

We all know that managing studies are challenging. However, how much thought do you
give to improving the startup phase, where much of the critical groundwork is being laid? If
you’re like most folks we’ve spoken to, you’ve accepted that study startup is done through
numerous tools including, phone, fax, email and Excel spreadsheets.

The study startup phase, which includes investigator initiation and submission of new
investigator packages, is a time-consuming component of the clinical study process.  It is
burdened by a manual, heavy paper-based process that involves a legacy IT infrastructure,
which is ripe for optimization.

The Clinical Study Startup Series

This series will focus on this key area of the clinical trial process – study startup – and show
ways on how to optimize each of the steps to gain a significant competitive advantage in
new drug product development. We’ve spent the past 9 months, interviewing sponsors,
contract research organizations (“CROs”) and investigative sites (“sites”) to determine
what goes on in the study startup phase and ways the process can be improved.

                                                     Here, we’ve summarized the 10 key
                                                     steps that sponsors take to select sites
                                                     and activate them for a clinical study.  
                                                     We will break down each of these steps
                                                     and provide you with our key learnings.
                                                     The goal is to initiate a dialogue with
                                                     the broader clinical research community
                                                     on how to improve how things are done.

                                                   In a perfect world the protocol for a
                                                   given clinical trial is complete before
                                                   site identification begins and study
                                                   start up gets underway. The reality is
                                                   that oftentimes the protocol is still
being finalized as study start up kicks o . Our 10 Steps assumes a completed protocol and
starts with Site Identification.
One of the most cumbersome and time consuming activities for anyone starting up a
clinical trial is identifying high performing investigative sites.

Recruiting high performing investigators and e ective research sites is critical for research
outcomes for a sponsor because this activity directly correlates to quick subject enrollment,
attainment of overall enrollment goals, high-quality data, fewer queries, and subject
retention for any clinical study.

The start-up phase of clinical trials has been targeted by the clinical research industry as
labor intensive, costly in terms of lost time and dollars, and rich in room for improvement.
Here, we have outlined some common methods that are used to identify research sites
and commented upon their e ectiveness along with some of their drawbacks.

Internal Databases of Investigators:
It comes as no surprise that sponsors and CROs already have internal databases of sites
that they’ve worked with in the past. The advantages of utilizing an internal database are
that it is readily accessible and is pre-populated with sites with which the sponsor has
experience. An internal database helps sponsors and CROs maintain relationships with
sites that have performed well in the past. Since quality sites are di cult to find,
maintaining an internal database helps sponsors cultivate long-term relationships with
sites they would like to use for future studies.

One major drawback is that the sponsor or CRO needs to actively maintain the database.
Data must continually be updated, manually entered and tracked, which gets even more
labor intensive as the database becomes larger. By virtue of it being a static database, it
simply cannot be comprehensive enough to accommodate any research study. Therefore,
sponsors and CROs find themselves looking outside their own databases when starting
new trials. Regardless of the type of trial, sponsors and CROs are in constant search of new
sites that will work well for them.

CRO/SMO
It is commonplace for drug and device sponsors to utilize a CRO’s service in the site
identification and initiation processes. Even when the sponsor provides its own initial list
of sites, the CRO augments the list utilizing their own site database; and still, the CRO will
look to outside resources for further site identification assistance. Sponsors and CROs go
beyond their own site databases for a variety of reasons. In part, they realize that their
own lists have limitations. Oftentimes they are in search of new sites and/or investigators
in a specific geographic area or within a specific therapeutic area of research. The reasons
vary from trial to trial and no matter the size of the CRO – the CRO manager will search
outside their own database and sponsor recommendations for new investigators and sites
using a hodge-podge of resources available. Resources available to the clinical trial
manager include SMOs, investigator or site networks, directories, databases, internet
searches, word-of-mouth, and referrals. Some of these resources cost the CRO and/or
Sponsor a significant investment of time and money. The common variable among the
tools available to the CRO manager is that they must be
managed individually through the identification and start-up
phases, and possibly throughout the entire trial.

Referrals (KOLs + other investigative sites)
Another e ective means of finding sites is identifying a key
opinion leader (“KOL”) in a particular indication. Generally, KOLs
are professionals with firsthand knowledge and experience
working in a particular indication. They may be found by
scouring scientific publications. While these KOLs themselves
may not conduct research, they and other research sites may
                    provide relevant referrals to yet other sites that may have interest and
                     ability in a particular trial.

                       Directories
                       Sponsors utilize both online and o ine directories to identify sites to
                       cast a wide net for site feasibility. Some online directories allow
                      sponsors to search for sites free of charge, while others require a fee.
Directories can be large and help sponsors broaden their list of sites, however the drawback
is that it’s still di cult to judge the quality of the sites in the directory1 .
Plus, website administrators maintain static directories, therefore the information on
individual sites or investigators is only updated yearly if at all. While online and o ine
directories can help quickly generate a short list of potential research sites, clinical trial
managers will need to contact and track each site individually throughout the identification
and start up processes, spending a significant amount of time and money in the process.

Conclusion
The methods for finding sites are many and we have covered but a few here. When using
any lists or databases of sites it is important to know how often the content is updated.
PIs and sites can come and go, and their respective areas of research expertise may also
fluctuate. Some of the best sources of intel on research sites are the CRAs that monitor
your trials. They deal with the sites first-hand and often have valuable information that
can be used during the identification process. No matter the tool or method you use in
finding potential sites, a focused approach that ties directly to your protocol will yield the
best results.

Extra time spent in site ID to speak with the PIs and really gauge their interest and ability
will pay dividends throughout the rest of the trial. Once you have a list of possible sites,
you must contact them.


1If you’d like to learn more, check out one of our past blog postings on the Chromosome:
We Review 5 Clinical Search Tools on the Web - April 2nd, 2010.
Introduction

Once sponsors have finished generating a short list of investigative sites, the next key
activity is to contact the sites to assess whether the site has the required facilities and
knowledgeable sta to successfully enroll patients and produce high-quality data for the
clinical trial. Communication is typically initiated via email, telephone, or fax and are
tracked using spreadsheets.  Sounds simple right?

How requests are sent and tracked today

Imagine if a sponsor needs to engage 50 investigative sites to enroll patients for a Phase III
trial.  The sponsor would need to find the site’s contact information, send an email, fax or
call, and then document/record each response received. As it turns out,
most sponsors use spreadsheets and email folders to track all replies
from the sites.  Though some sponsors have developed in-house
systems to tackle this activity in study startup, most companies don’t
have the resources to build and implement an internal solution to
facilitate this process. The major drawback of using spreadsheets to
manage and track responses from sites is the amount of manual work
needed to keep them updated.  A clinical research assistant/associate
or clinical project manager needs to manually update the spreadsheet
when responses from sites are received. This is tedious and also leaves
room for human error and mistakes.

The follow-up procedure when dealing with sites can be cumbersome and lengthy.
Spreadsheets might get the job done, however they require a great deal of customization
and are not the ideal solution for such an important activity of managing and documenting
responses from multiple investigative sites. This is a time-consuming activity and every
day saved represents a significant amount of money and helps pharmaceutical companies
ultimately deliver medicines to those in need faster. Sponsors need to activate sites as
quickly as possible so that they can reach the first-patient-in milestone much more
quickly.

Sending requests to investigative sites can happen throughout the entire clinical trial.  
Should enrollment fall behind and the sponsor needs to recruit sites quickly, the sponsor
needs to perform the same steps, which adds even more complexity to the tracking
procedures.

Caveat: These tasks and activities are performed in a variety of ways depending on the size
of the Sponsor, phase, and CRO involvement. However we covered the activities sponsors
perform that are general enough to cut across most organizations regardless of the
specifics and details. These activities are not necessarily performed in a step-wise fashion,
but can happen in parallel with other tasks and at multiple points during study startup.

Assuming that you’ve heard back from all of your sites with an interest in participating in
the study, the next step is to execute a confidentiality agreement with each of the sites...
Introduction

Sponsors and CROs must collect and fully execute Confidentiality Disclosure Agreements
(“CDAs”) with all sites and investigators intended for inclusion in their particular clinical
trial.  As is the case with any aspect of a clinical trial, the e ciency by which this step is
accomplished can have a significant impact on the timelines and milestones set for the
study.

The process varies dependent upon sponsor and CRO standard operating procedures
(“SOPs”).  By virtue of the inconsistencies around CDAs, the trial is already at risk for
unnecessary delays.  Add to that the cumbersome nature of managing the dissemination,
completion, and collection of CDAs for all sites/Investigators, that this simple and crucial
document can be held accountable for noteworthy study startup delays.

There are a wide variety of reasons that could lead to delays in this step.  One reason for a
delay could be that the site wants to negotiate terms of the CDA, which involves the legal
department of the sponsor &/or CRO, and several days, if not weeks, can go by before an
agreement is reached. Other possible delays could be due to shipping mishaps or multiple
parties requiring multiple CDAs (Sub-I’s, site, and PI).

How CDAs are currently sent and tracked

                            Currently, the Sponsor/CRO needs to send the CDA to each site
                            through email, fax, or mail.  After circulating the document back
                            and forth with the sites and obtaining the appropriate
                            signatures, moving to the next step may involve the sponsor/
                            CRO “batching” the signed CDAs.  This means that the partially
                            executed CDAs will be taken for full execution at a set time (e.g.
                            every Friday).  This is followed by the next step (e.g. sending the
                            protocol) in a similar ‘batch’ fashion.  Alternatively, the CDAs
                            may be handled in a piece-meal fashion, where each site moves
                            on to the next step as soon as their returned CDA is received.

This all has to be done on a set time-line, otherwise investigator recruitment can begin
falling behind schedule, thus delaying site initiations, first patient enrolled, and database
lock.  In many companies, this is an extremely manual and labor intensive process,
requiring much followup on the part of the sponsor/CRO to assure timeliness and accuracy.

Some key tips for the sponsor/CRO as well as the site are:
To ensure e ciency with the CDA process, the sponsor/CRO should communicate their
needs early and clearly with the sites.

  1.   Does the CDA need to be executed prior to the receipt of the study questionnaire
       synopsis?
  2.   Does the execution of the CDA only precede the sharing of the protocol, following
       the first wave of feasibility questionnaires?
  3.   How will the site/PI specific information be incorporated into the
       CDA?
  4.   Who are the party(s) with whom CDAs will be required?  (Some
       require the site to sign, others the PI, and still others will require
       both, including any sub-Is.)
  5.   Will the sponsor or CRO send an editable version in Word, or do they
       want just the pertinent information from the site, so that they may
       customize the document?
  6.   Will the sponsor/CRO accept a scanned version of the signed CDA to expedite the
       process of moving on to the next step?


A system should be in place for the sponsor/CRO to:

  1.   Create and disseminate CDAs en masse to sites and investigators
  2.   Track receipt of signed CDAs
  3.   Generate internal and external alerts when time lines are not met
  4.   Internally manage site requests for custom CDA’s with e ciency
  5.   Incorporate in the SOPs the acceptance of an electronic version to move on to the
       next step in the process, reducing the impact of this process by several days to a
       week.

Sites should have processes in place for the management of CDAs, including the receipt,
review, execution, return, and internal filing of the document. Communication by the site
should also be transparent.  For example, if the PI is required to sign and is currently on a
vacation, is it acceptable to wait, or will it be required to track the PI down and obtain a
signature ASAP?

The timeline in this process for a site should not exceed 48 hours.

Conclusion

This is an expected and standard process within all clinical trials.  Open and clear
communication by all parties as well as sound, professional processes in place will assure
the e cient completion of this step, usually within 48 hours. Next, you’ll need to conduct
feasibility through a site questionnaire.
Introduction

It is standard practice for the sponsor or CRO to utilize the Site Feasibility Questionnaire
(“SFQ”) to gain an initial assessment of the investigative site’s interest in and ability to
work on their trial.  This document will be circulated with far more sites than are required
by the protocol.  Note: this document may go by many names, and multiple questionnaires
may be used. Commentary herein is pertinent to all site evaluation questionnaires.

The only constant in this document is that it is almost always used to make an initial
contact with potential sites for new clinical trials.  Its content length varies from a half
page to more than 10 pages.  It is common for this questionnaire to be sent in conjunction
with a brief study synopsis.  If a CDA has not been executed at this point, the synopsis and
questionnaire must be brief and vague.  This will take its toll in the form of time-hungry
follow up required later on when the Study Manager is sorting through responses and
contacting various potential sites regarding the next step in their selection process.

The next step, as you may have surmised, is often another
questionnaire.  An intermediary step may exist where the CDA is
distributed, signed, and collected.  This will achieve the privacy
requirements necessary for the sponsor to share more of, or a
complete protocol.  The next questionnaire will be detailed and
specific with regard to the protocol.  Following the mayhem of
the questionnaire flurry, usually a pre-study visit, or pre-
selection visit (or phone call) is scheduled.

Common Roadblocks:

Assuming the initial short list of investigative sites targeted enough sites to fill the criteria
for the individual protocol in question, one of the first challenges the study team will face
is in the above-mentioned tracking process.

To add to the time-line and aggravation in this process it is common that study teams:

  •    Receive incomplete questionnaires, requiring additional follow up
  •    Receive no response by the deadline (It is common for sites to be asked to respond
       within 48 hours of receipt of the SFQ), requiring additional follow up

A couple common reasons why the SFQ is late include:
    • Immediate lack of proper personnel to answer SFQ
•   Backlog of SFQs at sites.  Often, because of poor early identification techniques,
          sites receive an inordinate number of SFQs, many of which pertain to studies
          inappropriate for their site.
  •       Receive inaccurate data*

*This problem merits further explanation.  Sites are not intentionally trying to deceive the
initiators of the SFQ; oftentimes they simply do not have enough information to
adequately address the questions.  A common ramification is that questions on the SFQ
may go unanswered, which of course requires additional follow up.  Also, it is common for
the SFQ to ask for estimations in which case the site is plagued with the question – do I
estimate high or low?

Summary & Tips

Almost 3 years ago, it was common for the SFQ to be distributed through fax blasts.  Now,
of course, e-mailing Word documents or PDFs are popular options.  Still other companies
are utilizing online tools - such as SurveyMonkey - or their own internal distribution and
tracking tools.  Factors to keep in mind for this process are:

1)    Establish e ective tactics to pre-identify sites for receipt of the SFQ.

2)    Employ e cient methods for the SFQ distribution.

3)    Utilize simple, easy-to-use, tracking tools to help monitor SFQ activity.

4)    Ideally, data from SFQs received would also be organized and sort-able, to help the
study team in the qualification process.

5)    This system would also help manage the responses to sites, helping to close the loop
on this process.

Most often though, these high-e ciency, automated tools are not in place.  The person
responsible for this task will need to be adept at shifting between hard copies, electronic
copies, their e-mail software, and some lengthy and cumbersome spreadsheet(s) to track
the receipt of SFQs and manually input data obtained from SFQs received.

As is the case with many steps in the clinical trial process – greater transparency and
technological advancements can help bring much-needed e ciencies in the process of
managing the SFQ.

At this point, you may need to complete the last step of feasibility, which may include a
pre-study visit...
Introduction

There has been a lot of discussion around the topic of the pre-study visit (“PSV”) over the
years.  Much of this discussion has come about due to a possible disconnect between
sponsor or CRO objectives and expectations when compared to those of the research site.

It remains the case that in order for a sponsor or CRO to find the number of research sites
they need for a given protocol, they must engage in discussions with sites with which they
have no previous experience.  And it remains the case that there is no other way to collect
information about potential sites than to initially rely on the site’s own, self-reported
metrics and information.

This necessitates that the sponsor or CRO will inevitably perform what is called the pre-
study visit (PSV).  If there is some previous experience with the site in question this visit
may be replaced with a pre-study phone call.

Some objectives (sponsor/CRO) of the PSV are:

  •    Validate site claims made on SFQ and in previous discussions during site ID
  •    Evaluate condition of site
  •    Review essential study documents
         ◦    Protocol
         ◦    Source Docs
         ◦    ICF
  •    Review patient recruitment strategies
  •    Review advertising campaigns
  •    Provide training
  •    Special set-up
  •    Meet PI to gain comfort regarding his/her ability and interest for the protocol


The PSV is oftentimes viewed as a necessary evil by the site.  This is mostly due to the
inconvenience in hosting a study monitor for what is often a full day (can be longer).  This
inconvenience translates to the site, a real expense in terms of resources required to
adequately prepare for and conduct the PSV; resources which typically are not reimbursed. 
It is considered a cost of doing business.  However, the PSV also is an excellent opportunity
for a site to make a good impression and get o on the right foot with their sponsor and
CRO customer.
Tips for a successful PSV:

Be prepared! This goes for the site as well as the sponsor/CRO.  It is not uncommon for
sites to receive multiple calls rescheduling the PSV.  Common complaints from sites
include hosting ill-prepared monitors.  Likewise, common complaints from sponsors/CROs,
include lack of adequate preparation by site sta , including PIs.

Be professional! This may seem elementary, but unfortunately, it is common for this
concept to be lost on individuals when conducting PSVs.  All parties from both sides should
not have a mindset of this being an adversarial event; rather an approach that both parties
are entering into a professional relationship of mutual benefit and interest.

Be a Gracious Host! The site should be prepared to host this meeting, keeping in mind the
responsibilities of any good host: make the environment comfortable and welcoming,
accommodate, prepare, and maintain a pleasant and professional demeanor.  Likewise, the
company and person making the visit should do everything in their power to take into
consideration the inconvenience to the site and the resources they must expend to make it
a successful meeting.

Take advantage of face-to-face time to build a stronger business relationship.
Often, this is the first meeting between a company as well as probably the individual with
whom the site will work if they are chosen to participate in the trial.  Keep in mind that the
vast majority of sites hosting a PSV will be selected and activated on the study.  Sponsors
and CROs do not take the decision to spend their resources on PSVs lightly.  From a
business development angle, this meeting is an opportunity to make an excellent first
impression; which will pay dividends in future business with the sponsor and CRO.  This is a
site and PI’s opportunity to show ability, expertise, and most of all, interest in the
particular protocol.  Conduct at a PSV will often set the stage for relationship management
throughout the completion of the protocol in question.  If it starts well, often that is the
overall impression throughout the trial; likewise, if it begins with conflict – conflict can be
predicted throughout.

A final and very biased opinion of the authors on PSVs: strong consideration should be
made by the collective participants in this industry (sites, sponsors, and CROs) to provide a
monetary reimbursement to sites for PSVs.  Something reasonable and more than nominal
should be provided to the site/PI for this activity.  It is common for study budgets to
include line items such as non-refundable start-up fees, but it is also common for these
fees not to be itemized and thus they fall short of providing comprehensive coverage for
site start-up costs.  I feel safe in voicing this opinion because there are far more PIs and
sites in the world than sponsors and CROs, so I believe I am arguing for the “majority” and
most readers will agree.

Assuming that the site passed the pre-study visit, now it’s time complete the Clinical Trial
Agreement (CTA)...
The Clinical Trial Agreement (CTA):

This document which goes by many names, is mandatory and often proves to be
responsible for substantial delays in site activation measured in days, weeks, or months.

The CTA is a legally binding agreement between the sponsor and the institution; whereas
the sponsor typically provides the study drug or device, financial support, and proprietary
information. The institution provides data and results, publication or input into
publication, and potential further intellectual property.  The CTA clarifies critical terms
between the sponsor and site including: the allocation of risk, responsibilities, obligations,
and financial commitments.  It also serves to protect both parties with regard to academic,
legal, and intellectual property rights.

Typical sections of the CTA are:

  •    Preamble
  •    Acknowledgements & Responsibilities
  •    Term & Termination
  •    Payment/Reimbursement of Costs
  •    HIPAA, Patient Privacy
  •    Publication
  •    Intellectual Property
  •    Confidentiality/
  •    Proprietary Information
  •    Indemnification
  •    Insurance
  •    Subject Injury
  •    Waiver of Consequential Damages
  •    Miscellaneous
         ◦     Export Controls
         ◦     Governing Law
         ◦     Dispute Resolution/ Arbitration/Mediation
  •    Exhibits (e.g. budget & payment terms)




Executing the CTA

The CTA will almost always include the sponsor and institution/site, and may also include
a CRO as a third party; in which case the document will outline the same parameters for
CRO involvement.  Since ultimate responsibility at the institution rests on the principal
investigator, it is almost always the case that the PI must sign the CTA.

Sponsors have template CTAs that they use with every site, though they may have
di erent templates for di erent kinds of institutions with which they may work
(independent research site, academic institution, site network, etc).  The contracting
process begins when the site receives the template contract from the sponsor.  Following
institutional review of the CTA template, one of two things may happen.  They may either
sign and return it to the sponsor for full execution, or they may redline their requested
changes and return the edited version to the sponsor for approval.

Hurdles

As one can guess by looking at the contents of a CTA, there are many potential points of
contention outlined within this document; indemnification, insurance, intellectual property,
and budget being some of the hot spots. Again, each topic within the CTA merits its own
study and the purpose of this blog will be to look at the bigger picture of road blocks and
remedies in the CTA execution process.

Both parties (or all three if a CRO is also included) may present limiting factors in e ciently
executing the CTA.

Beginning from when the CTA is first generated, most sites will want to see the budget and
CTA prior to completing the regulatory package for the IRB.  It is reasonable for the
institution/site to want to confirm that the study will be equitable for them.  Typically,
sites are not compensated throughout the startup process, so completion of regulatory
work before they are certain they will be working on the study (i.e. they can a ord to),
would be a marked misuse of resources.  Oftentimes; however, due to internal sponsor or
CRO SOPs, the budget, CTA and regulatory pack are all delivered simultaneously.  It is not
uncommon for the CTA and budget to follow the regulatory pack weeks later.

Poor delivery of the CTA can include ill-thought out timing as discussed above, but the
delivery method can also impede e cient CTA processing.  The sponsor that sends the
regulatory pack with 3 hard copies of executable CTAs when first delivering the CTA is
making a big presumption – that is that the site will approve the language within the CTA
as is, sign, and return all three copies.  While it is still common place for sites to accept the
initial language in the CTA as well as the budget o ered, it’s ba ing why so many
variables within these documents are negotiable and site or state or country specific.

Expect sites to negotiate some portion of the contract. Also, you may expect that most
sponsors and CROs will be able to negotiate the language of their templates. Therefore, it
would behoove all parties to exchange the CTA in an editable, electronic format in the first
place. This allows both sides to make and track change requests easily.  Ideally, this would
be done immediately after the site has been approved for initiation.  Truthfully, it does not
hurt to send them even earlier in the start-up process.  It is not uncommon for sites to
forgo initiation due to an inability to come to mutually acceptable terms in the budget or
CTA.  If delivery is done prior to the pre-study visit, and the site does not agree to the
terms, at least the early identification of this will minimize the loss of dollars and time
spent by the sponsor &/or CRO in the start-up process.  Furthermore, recognizing the site’s
need to negotiate these documents and facilitating that process for them will assure that
sponsor and CRO teams have done what they can to minimize delays due to contracting.

Tips:

•       Sites should spend adequate time and resources in developing their own internal
        CTA/budget SOPs and trainings to not be at a disadvantage
•       Knowing well what the guidelines and restrictions are for your state and site will
        service sites well when red-lining the sponsor’s template
•       Practice basic negotiation skills are essential for the sites to facilitate an e cient
        completion of the CTA (subject of the next blog posting)
•       A phone call, in tandem to the email with the edited CTA is a nice touch and helps
        pave the way for successful negotiations
•       Basic preparation such as having an up-to-date insurance policy to share should the
        sponsor require verification
•       48-72 hours is a reasonable expectation in turnaround time for the first red-line draft
        to be delivered.

You’re not done with the CTA just yet. Now comes the negotiation piece of this
document...
Introduction

It is rare these days, for a site to accept an original CTA template, verbatim.  This, in and of
itself, is not a bad thing – quite the contrary.  Negotiation is a good thing, and when done
properly the process should serve to meet the needs of all parties.

There are numerous complex and distinct issues that arise when negotiating CTAs (e.g.
indemnification, insurance, IP and publication rights, payment terms, etc.) and each of
these topics merit their own discussion.  Because of this, the scope of this article will cover
the general concept of negotiation and not any specific clause or section of the CTA.

Preliminary actions to consider when approaching CTA negotiation include:

     •      Need identification
     •      Objective identification
     •      Scope of the problem


Speaking from Experience…

Dan Manak2 has negotiated over 1,000 CTAs and can count on one hand the number of
instances in which mutually agreeable terms had eluded him.  In no instance did any of
these agreements undergo legal challenge or law suits.  In most cases, when it appears
there is no middle ground it is because one or more parties either do not know their
limitations or they do not accurately convey them up front.  If you reach an apparent dead-
end, do not give up hope before escalating as much as you need to with the parties with
whom you are negotiating.

Often times, the sponsor or CRO person with whom a site is initially negotiating can only
do so much in terms of altering their standard agreement.  This does not mean that
alternative terms are unavailable, but it may require more leg work to get to the right
people that can help find that middle ground.  Whether or not escalation is called for, never
lose your poise or professionalism, or let the negotiation turn into an argument.  Keep in
mind that you would not be in negotiations in the first place if all parties did not want the
same thing – a fully executed agreement outlining mutual involvement in the trial.

Define and rank priority interests. 



2   Dan Manak is a Director of Business Development at goBalto with over 20 years experience in clinical operations.
The key here is to understand that these negotiations are based on di erent interests of
the di erent parties and the likely result will be concessions regarding these interests. 
Make certain that you are trading items or issues of less importance in order to gain
substance of greater importance.

Access the priorities of the other parties. 

The better you understand the other perspectives, the greater likelihood of successful
outcomes through negotiation.  This may involve some guess work on your part; hopefully
they are educated guesses.  This exercise alone will foster thought and ideas regarding
conflict resolution.  As we don the shoes of the people across the negotiating table, our
minds will begin to creatively think of possible solutions, while considering the other
party’s respective positions.

If you are a site and have had to pass on        “We cannot negotiate with those who
multiple contracts due to a single internal      say, “What’s mine is mine and what’s
policy, it may be a good idea to have a full     yours is negotiable.””…  “Let us never
review of that policy.  For example, Dan has     negotiate out of fear.  But, let us never
worked with sites that had such stringent        fear to negotiate.”  -JFK
insurance requirements they were
precluded from most trials.  The solution
may be to find an alternate provider.  When
it comes to payment terms and monetary
reimbursement – if suitable terms are not met; the best choice may be to walk away, rather
than accept a contract which would be financially unreasonable for your site to perform.  A
win-win scenario is what everyone is shooting for and there is no ‘win’ if your site will lose
money to perform a trial.  Always make sure you are well-educated on the subject matter,
persistent in your follow up, and courteous and professional in every respect.

Now that the CTA is finalized, the investigator meeting is next...
Are Investigator Meetings an essential component to bringing new drug therapies to
market?

The purpose of an IM is to train physicians and their sta on all aspects of the protocol. 
Typically, the PI and coordinator are required to attend.  Sometimes the IM also counts as
the “initiation visit,” meaning when the site sta return home, they are ready to screen
their first subject.

A PI’s commitment to and understanding of the protocol is of utmost importance to
themselves and their patients, the sponsor and the study’s possible success.

Presenters delve into reams of data, go through the study binder, which contains all of the
processes and paperwork involved, and strive to ensure that site sta from all sites have a
full and complete understanding of the protocol and their individual responsibilities.  Study
Managers and Medical Directors from the sponsor and CRO, corporate meeting managers,
independent planners, communications companies, and academic CME departments are all
stakeholders at the IM.

“Today, I read the 8th step. I               Depending upon the specific nature of the
remembered my first and enjoyed those         study, anywhere between 100 to several
moments once again. This is a                thousand participants may be invited.  As I
wonderful series and I learned and           have described in my opening, these meetings
enjoyed it a lot.”                           usually involve a certain amount of “red
                                             carpet” treatment.  The meeting is typically
- Dr. Rajendra Mehta, Sep 29th               held over the weekend to minimize the impact
                                             on PI time away from their patients (and
                                             income).

The physicians are “guests” of the meeting and e ectively become consultants to the
sponsor company.  Therefore, it is argued that from an ethical standpoint, it is perfectly
reasonable for the sponsor company to pay their expenses and honoraria.  It is common
knowledge that to entice the PIs to this major commitment of their time, the venue must
be held in a place of interest.

In my 20+ years working in the pharmaceutical industry I have met all kinds of people,
including PIs and physicians.  Many medical professionals have true and sincere interests in
research, oftentimes driven by their own patient populations.  These physicians are always
looking at current and future trends that may have a positive impact on their patient
outcomes.  They will read, attend meetings, participate as PIs and whatever else they feel
they can do to contribute towards the advancement of medicine, as they know it.  They are
not all standing in the bu et line counting their research dollars and soaking in the rays on
the beach with their families at IMs.

The contribution made by the PIs at IMs is crucial and those physicians with true research
interests and abilities bring a wealth of material to an IM.  The open forum at an IM fosters
excellent dialogue, paramount to the success of the trial.  Aside from disseminating
materials, ensuring buy-in to and
understanding of the protocol, this is a key
component of an IM from the sponsor                Dan shares his experiences and opinions.
company’s perspective.                             I recall the first Investigator Meeting (IM) that I attended. 
                                                          It was held in a remote place on a tropical island.  The
                                                          ride from the airport was close to 2 hours and we got lost
But this is not the 80’s and all of us as
                                                          several times. The final destination was a high-class resort
individuals are watching our expenses more                with it’s own private beach.  Each of the three nights of
closely than we did back then.  So it is the              the meeting, when I entered my room, I found a new gift
responsibility of the individuals in the                  from our hosts.  Nice gifts, but not lavish or expensive. I
clinical research community to do                         will never forget standing in line at the buffet for our first
everything in our power to reduce costs,                  dinner.  Next to me was a first time principal investigator
                                                          (PI).  I would not be exaggerating to say that he was
increase e ciency, and ultimately improve
                                                          excited to be there. He went on about the treatment we
outcomes of pharmaceutical research.                      were receiving, the venue, and his $4k/subject study
                                                          budget.  (Nevermind that he probably found out 2 years
The impact of technology on the future of                 later that the study cost him $6k.).
IMs.
                                                          The meeting was three days long and two and a half of
In today’s technologically rich environment,              those days were jam-packed with Sponsor / CRO
is it really necessary for us to spend billions           established agendas leaving half the day “free” to relax. 
                                                          Over the course of the next two days, I met three other
of dollars on bringing physicians across the
                                                          PIs that conveyed elation about their all-expense paid
country for IMs?  Perhaps, perhaps not.  I                “family vacation.” My attendance at IM’s has been from a
really do not know the answer.  I know                    unique perspective, representing a Site Management
many will argue that having the physicians                Organization (SMO), rather than a sponsor, CRO, or
in person provides a platform for outcomes                specific site.  And my purpose here is not to bash the
otherwise unattainable over the internet                  concept of IMs or those companies who host them; I
                                                          don’t even plan a negative slant for this post.  Rather, my
and phone.
                                                          perspective comes from the same place it always does
                                                          when I consider individual aspects of clinical research –
I am in business development – I more than                efficiency, resource allocation, and cost, perhaps in that
understand the benefits of bringing people
face to face.  But, even in this relationship-
intense profession, vendors and clients across all industries are “meeting” face to face with
far less frequency than even 3 years ago.  No matter who you are, or what you do, Time =
Money.  And the e ciencies provided by internet and phone are not lost on most.

Sadly, the guy at the bu et line is in the majority of all PIs – those that only sign one 1572,
and are referred to a ectionately by this author as “tourists” in our industry.  We are all
aware of the staggering number of sites that do not perform on their protocols…something
like one third of all sites. WHAT IF all of the PIs on the protocol were physicians with a true
passion for research.  Would we really need to bring them all together at a resort, with 900
count cotton sheets, Steak Diane, and Bananas Foster?
There is no doubt strong value in a “meeting of the minds” when kicking o a new
protocol.  If we, as an industry, decided to do this online and reallocate only a portion of
those dollars spent on IMs to the sites and PIs performing the trials; I suspect that most
physicians would not be disappointed or dissuaded from participating in clinical research.

In closing

Dare I say, that the existence of extravagant meetings in enticing locations may, in fact,
draw physicians to become “tourists.”  Let’s put it on the Site Identification sta to find
the right PIs, with genuine interest in and ability to conduct clinical research.  Follow that
step with adequate time spent training and educating the research sta , while also getting
their feedback, either at their site initiation visit and/or via web conferences.  These
physicians are eager to do what they can for their patients and contribute to medicine at
large, and most would probably just appreciate adequate compensation for their
contribution in research.  In trade, I am betting that they will happily wiggle their toes in
the sand and sip drinks from coconuts on their own time and expense.

Next, are the regulatory documents...
Allan Valmonte 3 shares his experiences and perspectives on Reg Docs.

The “Essential” Documents

Many times during the start up process of a clinical trial, not enough attention is given to
the collection of regulatory documents (aka “essential” documents).  Many of the
e ciencies during the study start up process can be gained in proper management and
tracking of all the essential documents that can be broken down in to three main
categories:

    1.   Federal/National Regulatory Agency (i.e. FDA-USA, BfArM-Germany),
    2.   Institutional Review Board (IRB)/Ethics Committee (EC) submissions,
    3.   Standard Operating Procedure (SOP) requirements.


A minimum list of essential documents can be referenced in the ICH E6 Guidelines.  What’s
key here is that these essential documents indicate the approval and compliance of the
Sponsor/CRO, Investigator, and IRB/EC as it relates to current regulations and Good
Clinical Practice (GCP).  Furthermore, the essential documents are typically the first things
that are reviewed during an audit by the Sponsor/CRO/Monitor, IRB and regulatory
agencies.

Federal/National Regulatory Submission

When it comes to documents related to submission to federal/national regulatory
agencies, of vital importance are:

    •    Protocol,
    •    Investigators Brochure (IB),
    •    FDA Form 1572
    •    Principal Investigator (PI) signed CV (within last 2 years) and current Medical
         License,
    •    PI signed Financial Disclosure Form (FDF); depending on regulatory agency.


The protocol and IB are provided by the Sponsor and are final, approved versions.  The 1572
plays quite an important role, in that this is a federal form and is the statement by the

3Allan Valmonte has served as a clinical research consultant for KAI Pharmaceuticals and StemCells, Inc., and held
positions in clinical research and development at OXiGENE, Cerexa, and Telik. He has also worked on early, late, and post-
approval programs for Integrilin® (Millennium), Vectibix® (Amgen), Lipitor® (Pfizer), and Xolair® (Genentech).
investigator that he/she will abide by the federal guidelines set forth in the Code of Federal
Regulations as it relates to the use of drugs in an investigational setting (i.e. clinical trial).

What many don’t pay much attention to is the actual completion of the form for accuracy
and completeness in conjunction with the review of the other essential documents for
submission such as the CV and license of the PI.  Many times, mistakes are found in the
names of Sub-Investigators, addresses, and even the name of the protocol.  This can
impact your start up timelines, as the PI may not be available to sign o on a revised 1572. 
Remember, a thorough review will prevent delays.

IRB/EC Submission

IRB/EC submissions contain many of the same documents for regulatory agency
submissions with the addition of the:

  •    Informed Consent Form (ICF),
  •    Health Insurance Portability and Accountability Act (HIPAA) or Electronic Medical
       Records (EMR) Consent Form,
  •    Executed Clinical Trial Agreement (CTA) and Budget,
  •    CVs, Medical Licenses and FDFs of Sub-Investigators as listed on the 1572.


Keeping in mind the requirements of each of the di erent IRB/EC is essential in order to
ensure a complete regulatory package is provided.  In many countries in the European
Union (EU) for example Germany, not only do you have to contend with the requirements of
their national regulatory agency BfArM (Bundesinstitut für Arzneimittel und
Medizinprodukte or Federal Institute for Drugs and Medical Devices), but there may be a
Central Ethics Committee (CEC) as well as the PI’s Local Ethics Committee (LEC)
requirements.  Being able to track and manage the di erent requirements for each is key
when it comes to ensuring timely start up of your clinical trial.

As Sponsor/CRO SOPs vary, what is standard for all in the collection of essential
documents include:

  •    Signed protocol signature page,
  •    Regulatory agency approval of Protocol,
  •    IRB/CEC/LEC approval of Protocol and ICF with accompanying roster or assurance
       number,
  •    Central and/or Local Laboratory reference ranges and Certifications (i.e. CAP, CLIA)
  •    Clinical Trial Insurance.


All of these documents ultimately result in the completion of a form authorizing shipment
of investigational product (IP) to a site.  In no way does this indicate that they can start
enrolling in the clinical trial.  There are other activities required such as conducting o cial
training of the site sta in the protocol and protocol-required procedures, typically done
through an Investigator’s Meeting (IM) and/or Site Initiation Visit (SIV).
Helpful tips

As you can see, the preparation and collection of regulatory documents can seem
overwhelming especially with the vast amount of documents needed for regulatory, IRB/EC
submissions as well as those required for internal SOPs.  What’s important to always keep
in mind is ensuring accuracy and consistency between all the documents, as they are inter-
related.  For example names and addresses of PI and Sub-I’s on their CVs, medical licenses
and FDFs must match those listed on the 1572.  Approvals themselves should reference the
actual protocol as well as the ICF along with any other materials you’ve submitted for
review.

Conclusion

Lastly, have a system that tracks this preparation, submission, and review of not only each
of the essential documents but the overall process.  This will enable you as the study
manager to determine whether study start up is moving along as expected. This will further
allow you to:  1) determine if there will be any delays and 2) proactively address them
before they become unruly.  Ultimately, your ability  to be able to communicate both up
and down your organization in a transparent manner  will keep all key individuals aligned
with respect to study start up.

Almost done...
Dan Manak shares his thoughts and past experiences in the conclusion of this blog series.

Study Start Up is Finished…Or Is it?

You know you are completely finished finding and initiating sites when you enroll an
adequate number of subjects in an acceptable amount of time.  Happy Day!  If this has
happened for you with any significant amount of recruitment time left, you should pat
yourself on the back.  With the staggering statistic that only 30% of research sites meet
their enrollment goals, there is a large balance that needs to be accounted for (and
ultimately, these sites probably need to be closed and replaced).  It should come as no
surprise then, when you ask a study manager “How long does study start up last?” their
answer often is – “it never ends, sometimes it goes on as long as the trial itself.”

Case Study

Several years ago, I was part of a Phase III Hypertension study that required 150 U.S. sites. 
The sponsor had selected 50 prior to even contracting a CRO.  By the time the CRO was
awarded the contract, they knew they had to find another 100 sites for this trial.  The study
manager was able to get a jump on recruiting sites as the sponsor was putting the finishing
touches on the protocol.  [WARNING]  Selecting sites prior to a completed protocol is
usually not a good idea.

About 10 weeks later, the study team had found another 120 sites.  The contract and
budget have been successfully negotiated with 90 sites, and many had IRB approval and
were enrolling by week 6-8.  The protocol was finalized 3 weeks into the process and only
minor adjustments were needed in our site selection criteria.

Whew, only 10 sites to go, and most of them seem likely to be ready to go within a few
weeks.  Fourteen weeks into the process we had 150 sites initiated and over 70% of them
have been screening subjects for about 6 weeks.  By week 16, it was recognized that the
study would not meet the enrollment deadline with the current rate of enrollment.  Bring in
the back-up sites!  Cut the dead weight, and close the non-performing sites.

The total enrollment period for this study was supposed to be 6 months.  Fast forward to
the 5th month of the enrollment period.  At week 16 the surplus 20 sites originally found by
the CRO were contacted and engaged in discussion about being initiated as ‘back up sites’. 
The last 7 of these sites ultimately received fully executed contracts and “site initiation”
the same week enrollment closed, giving them approximately 1-3 days to enroll subjects. 
Sadly, 2 sites actually received their fully executed agreements from the sponsor the week
after enrollment closed.  (It took over 3 months to initiate the last 20 sites.)
Study Startup Sometimes NEVER Ends…

Taking apart this study and examining all of the pitfalls of SSU (like beginning site
selection without a complete protocol) goes way beyond the scope of this post…perhaps
good subject matter for a future white paper.  The moral of the story is: all too often, study
start up does not end.  The upshot of this fact is: increased costs and prolonged study
duration.  Another industry statistic that should knock you sideways is: >96% of all clinical
trials run overtime and over budget.

Study Start Up needs to be reinvented!

When you start talking to people from all corners of the industry about the topic of SSU –
you almost immediately see the eyes roll back and the cringing begins.  As we have delved
harder into our product development and engaged more and more experts from the
industry, it has been a pleasure to meet so many passionate people about SSU who share
the belief that SSU needs to be reinvented!

One such individual is Gen Li, founder of Pharmaceutical Pipeline Enhancement Strategies,
LLC (PhESi).  Gen has a PhD in Chemistry and Masters in Finance and prior to founding
PhESi. He was the head of productivity for development operations for Pfizer Global
Research and Development, and Director of Business Analytics for Pharmacia and Bristol
Meyers Squibb.

Gen has tremendous experience in and fascination with SSU.  He has written several
publications on and around the topic of SSU.  Of particular interest and relevance to the
subject matter of this post is his article titled Site Activation: The Key to More E cient
Clinical Trials.  (Recommended reading for anyone interested in SSU.)

In his most recent publication, titled “Planning the Right Number of Investigative Sites for
a Clinical trial, found in the August 2010 issue of The Monitor, you will see a continuation
of his unique thoughts on the importance of study start up.

This article states,

“…it is possible to forecast enrollment more accurately.”  “Calculating the appropriate
number of sites is a vital piece of the puzzle in successful planning and execution of a
clinical trial.”

Gen recognizes that his perspective looks at some of the factors impacting accurate
planning for the right number of investigative sites and hopes that

“…we will soon be able to examine (these factors) in a structured way to better guide the
planning and execution of clinical trials.”
In conclusion

To Gen and others out there interested in reinventing the process of study start up – Good
News!  We, at goBalto are on the verge of launching a product that will bring simplicity,
elegance, and ease to this monumental job of organizing the documents and
correspondence in study start up, while at the same time intuitively tracking the process in
real time.  This will not only provide you with study startup metrics and reports but
ultimately lead to a new era in industry transparency not yet enjoyed!  The dawn of a new
age in SSU is near.  Even a one percent improvement in the process will potentially save the
industry billions of dollars!
About the authors:
                    Dan Manak is a Director of Business Development at goBalto and a
                    graduate of the University of Wisconsin – Madison. After earning his
                    bachelor of science degree in Molecular Biology he began his career in
                    pharmaceuticals with Ho man-La Roche, holding positions in sales,
                    sales management, and training. He has worked in pharmaceuticals,
                    health care, and clinical research for over 20 years with Fortune 100
                    companies as well as start-ups. For the past seven years he led a small
clinical research service organization as the President and Director of Business
Development. His expertise and passion exist specifically in the area of clinical study start-
up, having worked on several hundred protocols and initiating close to a thousand
investigative research sites. In his spare time, Dan is a volunteer EMT and martial artist/
Instructor.
                     Erik Sam is a former Director of Customer Development at goBalto. He
                     began his career as an engineer in the Process Research and
                     Development department at Genentech, Inc. There he developed and
                     optimized manufacturing processes in Late Stage Purification for
                     numerous products entering clinical trials. He also ran successful GMP
                     campaigns and collaborations with outside vendors to develop new
                     technologies for the entire biotech industry. Erik holds a B.S. in
                     chemical engineering, with a focus in biotechnology, from the
                     University of California, Berkeley.
                     Allan Valmonte is a consultant with over 12 years of biopharmaceutical
                     drug development experience. He served as a clinical research
                     consultant for KAI Pharmaceuticals and StemCells, Inc., and held
                     positions in clinical research and development at OXiGENE, Cerexa, and
                     Telik. He has also worked on early, late, and post-approval programs for
                     Integrilin® (Millennium), Vectibix® (Amgen), Lipitor® (Pfizer), and
                     Xolair® (Genentech). Allan holds a B.A. in psychology from California
                     State University, Hayward.

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10 steps to Clinical Study Startup

  • 1. An Overview for Sponsors and Sites A summary of the key steps in starting a study 1
  • 4. Dear Reader: In early 2010, goBalto started its highly acclaimed “10 Steps to Clinical Study Start Up” series on our blog - the Chromosome. We believe that the existing approach to starting clinical studies is way too cumbersome. Our “10 Steps” blog series has gotten the attention of readers worldwide and has helped grow goBalto’s online readership to over 13,000 visits per month. Due to the unexpected popularity of this series and in response to numerous requests, we have combined the 10 Steps series into this PDF file which will take you, step-wise through study start up. Though our 10 steps are fairly comprehensive and typical of the start up process as it is conducted in the US, it is not necessarily all-inclusive. Also, the order of the steps may vary from company to company and/or study to study. We sincerely appreciate and welcome the comments from our readers - these keep us going! - The goBalto Team
  • 5. Introduction We all know that managing studies are challenging. However, how much thought do you give to improving the startup phase, where much of the critical groundwork is being laid? If you’re like most folks we’ve spoken to, you’ve accepted that study startup is done through numerous tools including, phone, fax, email and Excel spreadsheets. The study startup phase, which includes investigator initiation and submission of new investigator packages, is a time-consuming component of the clinical study process.  It is burdened by a manual, heavy paper-based process that involves a legacy IT infrastructure, which is ripe for optimization. The Clinical Study Startup Series This series will focus on this key area of the clinical trial process – study startup – and show ways on how to optimize each of the steps to gain a significant competitive advantage in new drug product development. We’ve spent the past 9 months, interviewing sponsors, contract research organizations (“CROs”) and investigative sites (“sites”) to determine what goes on in the study startup phase and ways the process can be improved. Here, we’ve summarized the 10 key steps that sponsors take to select sites and activate them for a clinical study.   We will break down each of these steps and provide you with our key learnings. The goal is to initiate a dialogue with the broader clinical research community on how to improve how things are done. In a perfect world the protocol for a given clinical trial is complete before site identification begins and study start up gets underway. The reality is that oftentimes the protocol is still being finalized as study start up kicks o . Our 10 Steps assumes a completed protocol and starts with Site Identification.
  • 6. One of the most cumbersome and time consuming activities for anyone starting up a clinical trial is identifying high performing investigative sites. Recruiting high performing investigators and e ective research sites is critical for research outcomes for a sponsor because this activity directly correlates to quick subject enrollment, attainment of overall enrollment goals, high-quality data, fewer queries, and subject retention for any clinical study. The start-up phase of clinical trials has been targeted by the clinical research industry as labor intensive, costly in terms of lost time and dollars, and rich in room for improvement. Here, we have outlined some common methods that are used to identify research sites and commented upon their e ectiveness along with some of their drawbacks. Internal Databases of Investigators: It comes as no surprise that sponsors and CROs already have internal databases of sites that they’ve worked with in the past. The advantages of utilizing an internal database are that it is readily accessible and is pre-populated with sites with which the sponsor has experience. An internal database helps sponsors and CROs maintain relationships with sites that have performed well in the past. Since quality sites are di cult to find, maintaining an internal database helps sponsors cultivate long-term relationships with sites they would like to use for future studies. One major drawback is that the sponsor or CRO needs to actively maintain the database. Data must continually be updated, manually entered and tracked, which gets even more labor intensive as the database becomes larger. By virtue of it being a static database, it simply cannot be comprehensive enough to accommodate any research study. Therefore, sponsors and CROs find themselves looking outside their own databases when starting new trials. Regardless of the type of trial, sponsors and CROs are in constant search of new sites that will work well for them. CRO/SMO It is commonplace for drug and device sponsors to utilize a CRO’s service in the site identification and initiation processes. Even when the sponsor provides its own initial list of sites, the CRO augments the list utilizing their own site database; and still, the CRO will look to outside resources for further site identification assistance. Sponsors and CROs go beyond their own site databases for a variety of reasons. In part, they realize that their own lists have limitations. Oftentimes they are in search of new sites and/or investigators in a specific geographic area or within a specific therapeutic area of research. The reasons vary from trial to trial and no matter the size of the CRO – the CRO manager will search outside their own database and sponsor recommendations for new investigators and sites using a hodge-podge of resources available. Resources available to the clinical trial
  • 7. manager include SMOs, investigator or site networks, directories, databases, internet searches, word-of-mouth, and referrals. Some of these resources cost the CRO and/or Sponsor a significant investment of time and money. The common variable among the tools available to the CRO manager is that they must be managed individually through the identification and start-up phases, and possibly throughout the entire trial. Referrals (KOLs + other investigative sites) Another e ective means of finding sites is identifying a key opinion leader (“KOL”) in a particular indication. Generally, KOLs are professionals with firsthand knowledge and experience working in a particular indication. They may be found by scouring scientific publications. While these KOLs themselves may not conduct research, they and other research sites may provide relevant referrals to yet other sites that may have interest and ability in a particular trial. Directories Sponsors utilize both online and o ine directories to identify sites to cast a wide net for site feasibility. Some online directories allow sponsors to search for sites free of charge, while others require a fee. Directories can be large and help sponsors broaden their list of sites, however the drawback is that it’s still di cult to judge the quality of the sites in the directory1 . Plus, website administrators maintain static directories, therefore the information on individual sites or investigators is only updated yearly if at all. While online and o ine directories can help quickly generate a short list of potential research sites, clinical trial managers will need to contact and track each site individually throughout the identification and start up processes, spending a significant amount of time and money in the process. Conclusion The methods for finding sites are many and we have covered but a few here. When using any lists or databases of sites it is important to know how often the content is updated. PIs and sites can come and go, and their respective areas of research expertise may also fluctuate. Some of the best sources of intel on research sites are the CRAs that monitor your trials. They deal with the sites first-hand and often have valuable information that can be used during the identification process. No matter the tool or method you use in finding potential sites, a focused approach that ties directly to your protocol will yield the best results. Extra time spent in site ID to speak with the PIs and really gauge their interest and ability will pay dividends throughout the rest of the trial. Once you have a list of possible sites, you must contact them. 1If you’d like to learn more, check out one of our past blog postings on the Chromosome: We Review 5 Clinical Search Tools on the Web - April 2nd, 2010.
  • 8. Introduction Once sponsors have finished generating a short list of investigative sites, the next key activity is to contact the sites to assess whether the site has the required facilities and knowledgeable sta to successfully enroll patients and produce high-quality data for the clinical trial. Communication is typically initiated via email, telephone, or fax and are tracked using spreadsheets.  Sounds simple right? How requests are sent and tracked today Imagine if a sponsor needs to engage 50 investigative sites to enroll patients for a Phase III trial.  The sponsor would need to find the site’s contact information, send an email, fax or call, and then document/record each response received. As it turns out, most sponsors use spreadsheets and email folders to track all replies from the sites.  Though some sponsors have developed in-house systems to tackle this activity in study startup, most companies don’t have the resources to build and implement an internal solution to facilitate this process. The major drawback of using spreadsheets to manage and track responses from sites is the amount of manual work needed to keep them updated.  A clinical research assistant/associate or clinical project manager needs to manually update the spreadsheet when responses from sites are received. This is tedious and also leaves room for human error and mistakes. The follow-up procedure when dealing with sites can be cumbersome and lengthy. Spreadsheets might get the job done, however they require a great deal of customization and are not the ideal solution for such an important activity of managing and documenting responses from multiple investigative sites. This is a time-consuming activity and every day saved represents a significant amount of money and helps pharmaceutical companies ultimately deliver medicines to those in need faster. Sponsors need to activate sites as quickly as possible so that they can reach the first-patient-in milestone much more quickly. Sending requests to investigative sites can happen throughout the entire clinical trial.   Should enrollment fall behind and the sponsor needs to recruit sites quickly, the sponsor needs to perform the same steps, which adds even more complexity to the tracking procedures. Caveat: These tasks and activities are performed in a variety of ways depending on the size of the Sponsor, phase, and CRO involvement. However we covered the activities sponsors perform that are general enough to cut across most organizations regardless of the
  • 9. specifics and details. These activities are not necessarily performed in a step-wise fashion, but can happen in parallel with other tasks and at multiple points during study startup. Assuming that you’ve heard back from all of your sites with an interest in participating in the study, the next step is to execute a confidentiality agreement with each of the sites...
  • 10. Introduction Sponsors and CROs must collect and fully execute Confidentiality Disclosure Agreements (“CDAs”) with all sites and investigators intended for inclusion in their particular clinical trial.  As is the case with any aspect of a clinical trial, the e ciency by which this step is accomplished can have a significant impact on the timelines and milestones set for the study. The process varies dependent upon sponsor and CRO standard operating procedures (“SOPs”).  By virtue of the inconsistencies around CDAs, the trial is already at risk for unnecessary delays.  Add to that the cumbersome nature of managing the dissemination, completion, and collection of CDAs for all sites/Investigators, that this simple and crucial document can be held accountable for noteworthy study startup delays. There are a wide variety of reasons that could lead to delays in this step.  One reason for a delay could be that the site wants to negotiate terms of the CDA, which involves the legal department of the sponsor &/or CRO, and several days, if not weeks, can go by before an agreement is reached. Other possible delays could be due to shipping mishaps or multiple parties requiring multiple CDAs (Sub-I’s, site, and PI). How CDAs are currently sent and tracked Currently, the Sponsor/CRO needs to send the CDA to each site through email, fax, or mail.  After circulating the document back and forth with the sites and obtaining the appropriate signatures, moving to the next step may involve the sponsor/ CRO “batching” the signed CDAs.  This means that the partially executed CDAs will be taken for full execution at a set time (e.g. every Friday).  This is followed by the next step (e.g. sending the protocol) in a similar ‘batch’ fashion.  Alternatively, the CDAs may be handled in a piece-meal fashion, where each site moves on to the next step as soon as their returned CDA is received. This all has to be done on a set time-line, otherwise investigator recruitment can begin falling behind schedule, thus delaying site initiations, first patient enrolled, and database lock.  In many companies, this is an extremely manual and labor intensive process, requiring much followup on the part of the sponsor/CRO to assure timeliness and accuracy. Some key tips for the sponsor/CRO as well as the site are:
  • 11. To ensure e ciency with the CDA process, the sponsor/CRO should communicate their needs early and clearly with the sites. 1. Does the CDA need to be executed prior to the receipt of the study questionnaire synopsis? 2. Does the execution of the CDA only precede the sharing of the protocol, following the first wave of feasibility questionnaires? 3. How will the site/PI specific information be incorporated into the CDA? 4. Who are the party(s) with whom CDAs will be required?  (Some require the site to sign, others the PI, and still others will require both, including any sub-Is.) 5. Will the sponsor or CRO send an editable version in Word, or do they want just the pertinent information from the site, so that they may customize the document? 6. Will the sponsor/CRO accept a scanned version of the signed CDA to expedite the process of moving on to the next step? A system should be in place for the sponsor/CRO to: 1. Create and disseminate CDAs en masse to sites and investigators 2. Track receipt of signed CDAs 3. Generate internal and external alerts when time lines are not met 4. Internally manage site requests for custom CDA’s with e ciency 5. Incorporate in the SOPs the acceptance of an electronic version to move on to the next step in the process, reducing the impact of this process by several days to a week. Sites should have processes in place for the management of CDAs, including the receipt, review, execution, return, and internal filing of the document. Communication by the site should also be transparent.  For example, if the PI is required to sign and is currently on a vacation, is it acceptable to wait, or will it be required to track the PI down and obtain a signature ASAP? The timeline in this process for a site should not exceed 48 hours. Conclusion This is an expected and standard process within all clinical trials.  Open and clear communication by all parties as well as sound, professional processes in place will assure the e cient completion of this step, usually within 48 hours. Next, you’ll need to conduct feasibility through a site questionnaire.
  • 12. Introduction It is standard practice for the sponsor or CRO to utilize the Site Feasibility Questionnaire (“SFQ”) to gain an initial assessment of the investigative site’s interest in and ability to work on their trial.  This document will be circulated with far more sites than are required by the protocol.  Note: this document may go by many names, and multiple questionnaires may be used. Commentary herein is pertinent to all site evaluation questionnaires. The only constant in this document is that it is almost always used to make an initial contact with potential sites for new clinical trials.  Its content length varies from a half page to more than 10 pages.  It is common for this questionnaire to be sent in conjunction with a brief study synopsis.  If a CDA has not been executed at this point, the synopsis and questionnaire must be brief and vague.  This will take its toll in the form of time-hungry follow up required later on when the Study Manager is sorting through responses and contacting various potential sites regarding the next step in their selection process. The next step, as you may have surmised, is often another questionnaire.  An intermediary step may exist where the CDA is distributed, signed, and collected.  This will achieve the privacy requirements necessary for the sponsor to share more of, or a complete protocol.  The next questionnaire will be detailed and specific with regard to the protocol.  Following the mayhem of the questionnaire flurry, usually a pre-study visit, or pre- selection visit (or phone call) is scheduled. Common Roadblocks: Assuming the initial short list of investigative sites targeted enough sites to fill the criteria for the individual protocol in question, one of the first challenges the study team will face is in the above-mentioned tracking process. To add to the time-line and aggravation in this process it is common that study teams: • Receive incomplete questionnaires, requiring additional follow up • Receive no response by the deadline (It is common for sites to be asked to respond within 48 hours of receipt of the SFQ), requiring additional follow up A couple common reasons why the SFQ is late include: • Immediate lack of proper personnel to answer SFQ
  • 13. Backlog of SFQs at sites.  Often, because of poor early identification techniques, sites receive an inordinate number of SFQs, many of which pertain to studies inappropriate for their site. • Receive inaccurate data* *This problem merits further explanation.  Sites are not intentionally trying to deceive the initiators of the SFQ; oftentimes they simply do not have enough information to adequately address the questions.  A common ramification is that questions on the SFQ may go unanswered, which of course requires additional follow up.  Also, it is common for the SFQ to ask for estimations in which case the site is plagued with the question – do I estimate high or low? Summary & Tips Almost 3 years ago, it was common for the SFQ to be distributed through fax blasts.  Now, of course, e-mailing Word documents or PDFs are popular options.  Still other companies are utilizing online tools - such as SurveyMonkey - or their own internal distribution and tracking tools.  Factors to keep in mind for this process are: 1)    Establish e ective tactics to pre-identify sites for receipt of the SFQ. 2)    Employ e cient methods for the SFQ distribution. 3)    Utilize simple, easy-to-use, tracking tools to help monitor SFQ activity. 4)    Ideally, data from SFQs received would also be organized and sort-able, to help the study team in the qualification process. 5)    This system would also help manage the responses to sites, helping to close the loop on this process. Most often though, these high-e ciency, automated tools are not in place.  The person responsible for this task will need to be adept at shifting between hard copies, electronic copies, their e-mail software, and some lengthy and cumbersome spreadsheet(s) to track the receipt of SFQs and manually input data obtained from SFQs received. As is the case with many steps in the clinical trial process – greater transparency and technological advancements can help bring much-needed e ciencies in the process of managing the SFQ. At this point, you may need to complete the last step of feasibility, which may include a pre-study visit...
  • 14. Introduction There has been a lot of discussion around the topic of the pre-study visit (“PSV”) over the years.  Much of this discussion has come about due to a possible disconnect between sponsor or CRO objectives and expectations when compared to those of the research site. It remains the case that in order for a sponsor or CRO to find the number of research sites they need for a given protocol, they must engage in discussions with sites with which they have no previous experience.  And it remains the case that there is no other way to collect information about potential sites than to initially rely on the site’s own, self-reported metrics and information. This necessitates that the sponsor or CRO will inevitably perform what is called the pre- study visit (PSV).  If there is some previous experience with the site in question this visit may be replaced with a pre-study phone call. Some objectives (sponsor/CRO) of the PSV are: • Validate site claims made on SFQ and in previous discussions during site ID • Evaluate condition of site • Review essential study documents ◦ Protocol ◦ Source Docs ◦ ICF • Review patient recruitment strategies • Review advertising campaigns • Provide training • Special set-up • Meet PI to gain comfort regarding his/her ability and interest for the protocol The PSV is oftentimes viewed as a necessary evil by the site.  This is mostly due to the inconvenience in hosting a study monitor for what is often a full day (can be longer).  This inconvenience translates to the site, a real expense in terms of resources required to adequately prepare for and conduct the PSV; resources which typically are not reimbursed.  It is considered a cost of doing business.  However, the PSV also is an excellent opportunity for a site to make a good impression and get o on the right foot with their sponsor and CRO customer.
  • 15. Tips for a successful PSV: Be prepared! This goes for the site as well as the sponsor/CRO.  It is not uncommon for sites to receive multiple calls rescheduling the PSV.  Common complaints from sites include hosting ill-prepared monitors.  Likewise, common complaints from sponsors/CROs, include lack of adequate preparation by site sta , including PIs. Be professional! This may seem elementary, but unfortunately, it is common for this concept to be lost on individuals when conducting PSVs.  All parties from both sides should not have a mindset of this being an adversarial event; rather an approach that both parties are entering into a professional relationship of mutual benefit and interest. Be a Gracious Host! The site should be prepared to host this meeting, keeping in mind the responsibilities of any good host: make the environment comfortable and welcoming, accommodate, prepare, and maintain a pleasant and professional demeanor.  Likewise, the company and person making the visit should do everything in their power to take into consideration the inconvenience to the site and the resources they must expend to make it a successful meeting. Take advantage of face-to-face time to build a stronger business relationship. Often, this is the first meeting between a company as well as probably the individual with whom the site will work if they are chosen to participate in the trial.  Keep in mind that the vast majority of sites hosting a PSV will be selected and activated on the study.  Sponsors and CROs do not take the decision to spend their resources on PSVs lightly.  From a business development angle, this meeting is an opportunity to make an excellent first impression; which will pay dividends in future business with the sponsor and CRO.  This is a site and PI’s opportunity to show ability, expertise, and most of all, interest in the particular protocol.  Conduct at a PSV will often set the stage for relationship management throughout the completion of the protocol in question.  If it starts well, often that is the overall impression throughout the trial; likewise, if it begins with conflict – conflict can be predicted throughout. A final and very biased opinion of the authors on PSVs: strong consideration should be made by the collective participants in this industry (sites, sponsors, and CROs) to provide a monetary reimbursement to sites for PSVs.  Something reasonable and more than nominal should be provided to the site/PI for this activity.  It is common for study budgets to include line items such as non-refundable start-up fees, but it is also common for these fees not to be itemized and thus they fall short of providing comprehensive coverage for site start-up costs.  I feel safe in voicing this opinion because there are far more PIs and sites in the world than sponsors and CROs, so I believe I am arguing for the “majority” and most readers will agree. Assuming that the site passed the pre-study visit, now it’s time complete the Clinical Trial Agreement (CTA)...
  • 16. The Clinical Trial Agreement (CTA): This document which goes by many names, is mandatory and often proves to be responsible for substantial delays in site activation measured in days, weeks, or months. The CTA is a legally binding agreement between the sponsor and the institution; whereas the sponsor typically provides the study drug or device, financial support, and proprietary information. The institution provides data and results, publication or input into publication, and potential further intellectual property.  The CTA clarifies critical terms between the sponsor and site including: the allocation of risk, responsibilities, obligations, and financial commitments.  It also serves to protect both parties with regard to academic, legal, and intellectual property rights. Typical sections of the CTA are: • Preamble • Acknowledgements & Responsibilities • Term & Termination • Payment/Reimbursement of Costs • HIPAA, Patient Privacy • Publication • Intellectual Property • Confidentiality/ • Proprietary Information • Indemnification • Insurance • Subject Injury • Waiver of Consequential Damages • Miscellaneous ◦ Export Controls ◦ Governing Law ◦ Dispute Resolution/ Arbitration/Mediation • Exhibits (e.g. budget & payment terms) Executing the CTA The CTA will almost always include the sponsor and institution/site, and may also include a CRO as a third party; in which case the document will outline the same parameters for
  • 17. CRO involvement.  Since ultimate responsibility at the institution rests on the principal investigator, it is almost always the case that the PI must sign the CTA. Sponsors have template CTAs that they use with every site, though they may have di erent templates for di erent kinds of institutions with which they may work (independent research site, academic institution, site network, etc).  The contracting process begins when the site receives the template contract from the sponsor.  Following institutional review of the CTA template, one of two things may happen.  They may either sign and return it to the sponsor for full execution, or they may redline their requested changes and return the edited version to the sponsor for approval. Hurdles As one can guess by looking at the contents of a CTA, there are many potential points of contention outlined within this document; indemnification, insurance, intellectual property, and budget being some of the hot spots. Again, each topic within the CTA merits its own study and the purpose of this blog will be to look at the bigger picture of road blocks and remedies in the CTA execution process. Both parties (or all three if a CRO is also included) may present limiting factors in e ciently executing the CTA. Beginning from when the CTA is first generated, most sites will want to see the budget and CTA prior to completing the regulatory package for the IRB.  It is reasonable for the institution/site to want to confirm that the study will be equitable for them.  Typically, sites are not compensated throughout the startup process, so completion of regulatory work before they are certain they will be working on the study (i.e. they can a ord to), would be a marked misuse of resources.  Oftentimes; however, due to internal sponsor or CRO SOPs, the budget, CTA and regulatory pack are all delivered simultaneously.  It is not uncommon for the CTA and budget to follow the regulatory pack weeks later. Poor delivery of the CTA can include ill-thought out timing as discussed above, but the delivery method can also impede e cient CTA processing.  The sponsor that sends the regulatory pack with 3 hard copies of executable CTAs when first delivering the CTA is making a big presumption – that is that the site will approve the language within the CTA as is, sign, and return all three copies.  While it is still common place for sites to accept the initial language in the CTA as well as the budget o ered, it’s ba ing why so many variables within these documents are negotiable and site or state or country specific. Expect sites to negotiate some portion of the contract. Also, you may expect that most sponsors and CROs will be able to negotiate the language of their templates. Therefore, it would behoove all parties to exchange the CTA in an editable, electronic format in the first place. This allows both sides to make and track change requests easily.  Ideally, this would be done immediately after the site has been approved for initiation.  Truthfully, it does not hurt to send them even earlier in the start-up process.  It is not uncommon for sites to forgo initiation due to an inability to come to mutually acceptable terms in the budget or CTA.  If delivery is done prior to the pre-study visit, and the site does not agree to the
  • 18. terms, at least the early identification of this will minimize the loss of dollars and time spent by the sponsor &/or CRO in the start-up process.  Furthermore, recognizing the site’s need to negotiate these documents and facilitating that process for them will assure that sponsor and CRO teams have done what they can to minimize delays due to contracting. Tips: • Sites should spend adequate time and resources in developing their own internal CTA/budget SOPs and trainings to not be at a disadvantage • Knowing well what the guidelines and restrictions are for your state and site will service sites well when red-lining the sponsor’s template • Practice basic negotiation skills are essential for the sites to facilitate an e cient completion of the CTA (subject of the next blog posting) • A phone call, in tandem to the email with the edited CTA is a nice touch and helps pave the way for successful negotiations • Basic preparation such as having an up-to-date insurance policy to share should the sponsor require verification • 48-72 hours is a reasonable expectation in turnaround time for the first red-line draft to be delivered. You’re not done with the CTA just yet. Now comes the negotiation piece of this document...
  • 19. Introduction It is rare these days, for a site to accept an original CTA template, verbatim.  This, in and of itself, is not a bad thing – quite the contrary.  Negotiation is a good thing, and when done properly the process should serve to meet the needs of all parties. There are numerous complex and distinct issues that arise when negotiating CTAs (e.g. indemnification, insurance, IP and publication rights, payment terms, etc.) and each of these topics merit their own discussion.  Because of this, the scope of this article will cover the general concept of negotiation and not any specific clause or section of the CTA. Preliminary actions to consider when approaching CTA negotiation include: • Need identification • Objective identification • Scope of the problem Speaking from Experience… Dan Manak2 has negotiated over 1,000 CTAs and can count on one hand the number of instances in which mutually agreeable terms had eluded him.  In no instance did any of these agreements undergo legal challenge or law suits.  In most cases, when it appears there is no middle ground it is because one or more parties either do not know their limitations or they do not accurately convey them up front.  If you reach an apparent dead- end, do not give up hope before escalating as much as you need to with the parties with whom you are negotiating. Often times, the sponsor or CRO person with whom a site is initially negotiating can only do so much in terms of altering their standard agreement.  This does not mean that alternative terms are unavailable, but it may require more leg work to get to the right people that can help find that middle ground.  Whether or not escalation is called for, never lose your poise or professionalism, or let the negotiation turn into an argument.  Keep in mind that you would not be in negotiations in the first place if all parties did not want the same thing – a fully executed agreement outlining mutual involvement in the trial. Define and rank priority interests.  2 Dan Manak is a Director of Business Development at goBalto with over 20 years experience in clinical operations.
  • 20. The key here is to understand that these negotiations are based on di erent interests of the di erent parties and the likely result will be concessions regarding these interests.  Make certain that you are trading items or issues of less importance in order to gain substance of greater importance. Access the priorities of the other parties.  The better you understand the other perspectives, the greater likelihood of successful outcomes through negotiation.  This may involve some guess work on your part; hopefully they are educated guesses.  This exercise alone will foster thought and ideas regarding conflict resolution.  As we don the shoes of the people across the negotiating table, our minds will begin to creatively think of possible solutions, while considering the other party’s respective positions. If you are a site and have had to pass on “We cannot negotiate with those who multiple contracts due to a single internal say, “What’s mine is mine and what’s policy, it may be a good idea to have a full yours is negotiable.””…  “Let us never review of that policy.  For example, Dan has negotiate out of fear.  But, let us never worked with sites that had such stringent fear to negotiate.”  -JFK insurance requirements they were precluded from most trials.  The solution may be to find an alternate provider.  When it comes to payment terms and monetary reimbursement – if suitable terms are not met; the best choice may be to walk away, rather than accept a contract which would be financially unreasonable for your site to perform.  A win-win scenario is what everyone is shooting for and there is no ‘win’ if your site will lose money to perform a trial.  Always make sure you are well-educated on the subject matter, persistent in your follow up, and courteous and professional in every respect. Now that the CTA is finalized, the investigator meeting is next...
  • 21. Are Investigator Meetings an essential component to bringing new drug therapies to market? The purpose of an IM is to train physicians and their sta on all aspects of the protocol.  Typically, the PI and coordinator are required to attend.  Sometimes the IM also counts as the “initiation visit,” meaning when the site sta return home, they are ready to screen their first subject. A PI’s commitment to and understanding of the protocol is of utmost importance to themselves and their patients, the sponsor and the study’s possible success. Presenters delve into reams of data, go through the study binder, which contains all of the processes and paperwork involved, and strive to ensure that site sta from all sites have a full and complete understanding of the protocol and their individual responsibilities.  Study Managers and Medical Directors from the sponsor and CRO, corporate meeting managers, independent planners, communications companies, and academic CME departments are all stakeholders at the IM. “Today, I read the 8th step. I Depending upon the specific nature of the remembered my first and enjoyed those study, anywhere between 100 to several moments once again. This is a thousand participants may be invited.  As I wonderful series and I learned and have described in my opening, these meetings enjoyed it a lot.” usually involve a certain amount of “red carpet” treatment.  The meeting is typically - Dr. Rajendra Mehta, Sep 29th held over the weekend to minimize the impact on PI time away from their patients (and income). The physicians are “guests” of the meeting and e ectively become consultants to the sponsor company.  Therefore, it is argued that from an ethical standpoint, it is perfectly reasonable for the sponsor company to pay their expenses and honoraria.  It is common knowledge that to entice the PIs to this major commitment of their time, the venue must be held in a place of interest. In my 20+ years working in the pharmaceutical industry I have met all kinds of people, including PIs and physicians.  Many medical professionals have true and sincere interests in research, oftentimes driven by their own patient populations.  These physicians are always looking at current and future trends that may have a positive impact on their patient outcomes.  They will read, attend meetings, participate as PIs and whatever else they feel they can do to contribute towards the advancement of medicine, as they know it.  They are
  • 22. not all standing in the bu et line counting their research dollars and soaking in the rays on the beach with their families at IMs. The contribution made by the PIs at IMs is crucial and those physicians with true research interests and abilities bring a wealth of material to an IM.  The open forum at an IM fosters excellent dialogue, paramount to the success of the trial.  Aside from disseminating materials, ensuring buy-in to and understanding of the protocol, this is a key component of an IM from the sponsor Dan shares his experiences and opinions. company’s perspective. I recall the first Investigator Meeting (IM) that I attended.  It was held in a remote place on a tropical island.  The ride from the airport was close to 2 hours and we got lost But this is not the 80’s and all of us as several times. The final destination was a high-class resort individuals are watching our expenses more with it’s own private beach.  Each of the three nights of closely than we did back then.  So it is the the meeting, when I entered my room, I found a new gift responsibility of the individuals in the from our hosts.  Nice gifts, but not lavish or expensive. I clinical research community to do will never forget standing in line at the buffet for our first everything in our power to reduce costs, dinner.  Next to me was a first time principal investigator (PI).  I would not be exaggerating to say that he was increase e ciency, and ultimately improve excited to be there. He went on about the treatment we outcomes of pharmaceutical research. were receiving, the venue, and his $4k/subject study budget.  (Nevermind that he probably found out 2 years The impact of technology on the future of later that the study cost him $6k.). IMs. The meeting was three days long and two and a half of In today’s technologically rich environment, those days were jam-packed with Sponsor / CRO is it really necessary for us to spend billions established agendas leaving half the day “free” to relax.  Over the course of the next two days, I met three other of dollars on bringing physicians across the PIs that conveyed elation about their all-expense paid country for IMs?  Perhaps, perhaps not.  I “family vacation.” My attendance at IM’s has been from a really do not know the answer.  I know unique perspective, representing a Site Management many will argue that having the physicians Organization (SMO), rather than a sponsor, CRO, or in person provides a platform for outcomes specific site.  And my purpose here is not to bash the otherwise unattainable over the internet concept of IMs or those companies who host them; I don’t even plan a negative slant for this post.  Rather, my and phone. perspective comes from the same place it always does when I consider individual aspects of clinical research – I am in business development – I more than efficiency, resource allocation, and cost, perhaps in that understand the benefits of bringing people face to face.  But, even in this relationship- intense profession, vendors and clients across all industries are “meeting” face to face with far less frequency than even 3 years ago.  No matter who you are, or what you do, Time = Money.  And the e ciencies provided by internet and phone are not lost on most. Sadly, the guy at the bu et line is in the majority of all PIs – those that only sign one 1572, and are referred to a ectionately by this author as “tourists” in our industry.  We are all aware of the staggering number of sites that do not perform on their protocols…something like one third of all sites. WHAT IF all of the PIs on the protocol were physicians with a true passion for research.  Would we really need to bring them all together at a resort, with 900 count cotton sheets, Steak Diane, and Bananas Foster?
  • 23. There is no doubt strong value in a “meeting of the minds” when kicking o a new protocol.  If we, as an industry, decided to do this online and reallocate only a portion of those dollars spent on IMs to the sites and PIs performing the trials; I suspect that most physicians would not be disappointed or dissuaded from participating in clinical research. In closing Dare I say, that the existence of extravagant meetings in enticing locations may, in fact, draw physicians to become “tourists.”  Let’s put it on the Site Identification sta to find the right PIs, with genuine interest in and ability to conduct clinical research.  Follow that step with adequate time spent training and educating the research sta , while also getting their feedback, either at their site initiation visit and/or via web conferences.  These physicians are eager to do what they can for their patients and contribute to medicine at large, and most would probably just appreciate adequate compensation for their contribution in research.  In trade, I am betting that they will happily wiggle their toes in the sand and sip drinks from coconuts on their own time and expense. Next, are the regulatory documents...
  • 24. Allan Valmonte 3 shares his experiences and perspectives on Reg Docs. The “Essential” Documents Many times during the start up process of a clinical trial, not enough attention is given to the collection of regulatory documents (aka “essential” documents).  Many of the e ciencies during the study start up process can be gained in proper management and tracking of all the essential documents that can be broken down in to three main categories: 1. Federal/National Regulatory Agency (i.e. FDA-USA, BfArM-Germany), 2. Institutional Review Board (IRB)/Ethics Committee (EC) submissions, 3. Standard Operating Procedure (SOP) requirements. A minimum list of essential documents can be referenced in the ICH E6 Guidelines.  What’s key here is that these essential documents indicate the approval and compliance of the Sponsor/CRO, Investigator, and IRB/EC as it relates to current regulations and Good Clinical Practice (GCP).  Furthermore, the essential documents are typically the first things that are reviewed during an audit by the Sponsor/CRO/Monitor, IRB and regulatory agencies. Federal/National Regulatory Submission When it comes to documents related to submission to federal/national regulatory agencies, of vital importance are: • Protocol, • Investigators Brochure (IB), • FDA Form 1572 • Principal Investigator (PI) signed CV (within last 2 years) and current Medical License, • PI signed Financial Disclosure Form (FDF); depending on regulatory agency. The protocol and IB are provided by the Sponsor and are final, approved versions.  The 1572 plays quite an important role, in that this is a federal form and is the statement by the 3Allan Valmonte has served as a clinical research consultant for KAI Pharmaceuticals and StemCells, Inc., and held positions in clinical research and development at OXiGENE, Cerexa, and Telik. He has also worked on early, late, and post- approval programs for Integrilin® (Millennium), Vectibix® (Amgen), Lipitor® (Pfizer), and Xolair® (Genentech).
  • 25. investigator that he/she will abide by the federal guidelines set forth in the Code of Federal Regulations as it relates to the use of drugs in an investigational setting (i.e. clinical trial). What many don’t pay much attention to is the actual completion of the form for accuracy and completeness in conjunction with the review of the other essential documents for submission such as the CV and license of the PI.  Many times, mistakes are found in the names of Sub-Investigators, addresses, and even the name of the protocol.  This can impact your start up timelines, as the PI may not be available to sign o on a revised 1572.  Remember, a thorough review will prevent delays. IRB/EC Submission IRB/EC submissions contain many of the same documents for regulatory agency submissions with the addition of the: • Informed Consent Form (ICF), • Health Insurance Portability and Accountability Act (HIPAA) or Electronic Medical Records (EMR) Consent Form, • Executed Clinical Trial Agreement (CTA) and Budget, • CVs, Medical Licenses and FDFs of Sub-Investigators as listed on the 1572. Keeping in mind the requirements of each of the di erent IRB/EC is essential in order to ensure a complete regulatory package is provided.  In many countries in the European Union (EU) for example Germany, not only do you have to contend with the requirements of their national regulatory agency BfArM (Bundesinstitut für Arzneimittel und Medizinprodukte or Federal Institute for Drugs and Medical Devices), but there may be a Central Ethics Committee (CEC) as well as the PI’s Local Ethics Committee (LEC) requirements.  Being able to track and manage the di erent requirements for each is key when it comes to ensuring timely start up of your clinical trial. As Sponsor/CRO SOPs vary, what is standard for all in the collection of essential documents include: • Signed protocol signature page, • Regulatory agency approval of Protocol, • IRB/CEC/LEC approval of Protocol and ICF with accompanying roster or assurance number, • Central and/or Local Laboratory reference ranges and Certifications (i.e. CAP, CLIA) • Clinical Trial Insurance. All of these documents ultimately result in the completion of a form authorizing shipment of investigational product (IP) to a site.  In no way does this indicate that they can start enrolling in the clinical trial.  There are other activities required such as conducting o cial training of the site sta in the protocol and protocol-required procedures, typically done through an Investigator’s Meeting (IM) and/or Site Initiation Visit (SIV).
  • 26. Helpful tips As you can see, the preparation and collection of regulatory documents can seem overwhelming especially with the vast amount of documents needed for regulatory, IRB/EC submissions as well as those required for internal SOPs.  What’s important to always keep in mind is ensuring accuracy and consistency between all the documents, as they are inter- related.  For example names and addresses of PI and Sub-I’s on their CVs, medical licenses and FDFs must match those listed on the 1572.  Approvals themselves should reference the actual protocol as well as the ICF along with any other materials you’ve submitted for review. Conclusion Lastly, have a system that tracks this preparation, submission, and review of not only each of the essential documents but the overall process.  This will enable you as the study manager to determine whether study start up is moving along as expected. This will further allow you to:  1) determine if there will be any delays and 2) proactively address them before they become unruly.  Ultimately, your ability  to be able to communicate both up and down your organization in a transparent manner  will keep all key individuals aligned with respect to study start up. Almost done...
  • 27. Dan Manak shares his thoughts and past experiences in the conclusion of this blog series. Study Start Up is Finished…Or Is it? You know you are completely finished finding and initiating sites when you enroll an adequate number of subjects in an acceptable amount of time.  Happy Day!  If this has happened for you with any significant amount of recruitment time left, you should pat yourself on the back.  With the staggering statistic that only 30% of research sites meet their enrollment goals, there is a large balance that needs to be accounted for (and ultimately, these sites probably need to be closed and replaced).  It should come as no surprise then, when you ask a study manager “How long does study start up last?” their answer often is – “it never ends, sometimes it goes on as long as the trial itself.” Case Study Several years ago, I was part of a Phase III Hypertension study that required 150 U.S. sites.  The sponsor had selected 50 prior to even contracting a CRO.  By the time the CRO was awarded the contract, they knew they had to find another 100 sites for this trial.  The study manager was able to get a jump on recruiting sites as the sponsor was putting the finishing touches on the protocol.  [WARNING]  Selecting sites prior to a completed protocol is usually not a good idea. About 10 weeks later, the study team had found another 120 sites.  The contract and budget have been successfully negotiated with 90 sites, and many had IRB approval and were enrolling by week 6-8.  The protocol was finalized 3 weeks into the process and only minor adjustments were needed in our site selection criteria. Whew, only 10 sites to go, and most of them seem likely to be ready to go within a few weeks.  Fourteen weeks into the process we had 150 sites initiated and over 70% of them have been screening subjects for about 6 weeks.  By week 16, it was recognized that the study would not meet the enrollment deadline with the current rate of enrollment.  Bring in the back-up sites!  Cut the dead weight, and close the non-performing sites. The total enrollment period for this study was supposed to be 6 months.  Fast forward to the 5th month of the enrollment period.  At week 16 the surplus 20 sites originally found by the CRO were contacted and engaged in discussion about being initiated as ‘back up sites’.  The last 7 of these sites ultimately received fully executed contracts and “site initiation” the same week enrollment closed, giving them approximately 1-3 days to enroll subjects.  Sadly, 2 sites actually received their fully executed agreements from the sponsor the week after enrollment closed.  (It took over 3 months to initiate the last 20 sites.)
  • 28. Study Startup Sometimes NEVER Ends… Taking apart this study and examining all of the pitfalls of SSU (like beginning site selection without a complete protocol) goes way beyond the scope of this post…perhaps good subject matter for a future white paper.  The moral of the story is: all too often, study start up does not end.  The upshot of this fact is: increased costs and prolonged study duration.  Another industry statistic that should knock you sideways is: >96% of all clinical trials run overtime and over budget. Study Start Up needs to be reinvented! When you start talking to people from all corners of the industry about the topic of SSU – you almost immediately see the eyes roll back and the cringing begins.  As we have delved harder into our product development and engaged more and more experts from the industry, it has been a pleasure to meet so many passionate people about SSU who share the belief that SSU needs to be reinvented! One such individual is Gen Li, founder of Pharmaceutical Pipeline Enhancement Strategies, LLC (PhESi).  Gen has a PhD in Chemistry and Masters in Finance and prior to founding PhESi. He was the head of productivity for development operations for Pfizer Global Research and Development, and Director of Business Analytics for Pharmacia and Bristol Meyers Squibb. Gen has tremendous experience in and fascination with SSU.  He has written several publications on and around the topic of SSU.  Of particular interest and relevance to the subject matter of this post is his article titled Site Activation: The Key to More E cient Clinical Trials.  (Recommended reading for anyone interested in SSU.) In his most recent publication, titled “Planning the Right Number of Investigative Sites for a Clinical trial, found in the August 2010 issue of The Monitor, you will see a continuation of his unique thoughts on the importance of study start up. This article states, “…it is possible to forecast enrollment more accurately.”  “Calculating the appropriate number of sites is a vital piece of the puzzle in successful planning and execution of a clinical trial.” Gen recognizes that his perspective looks at some of the factors impacting accurate planning for the right number of investigative sites and hopes that “…we will soon be able to examine (these factors) in a structured way to better guide the planning and execution of clinical trials.”
  • 29. In conclusion To Gen and others out there interested in reinventing the process of study start up – Good News!  We, at goBalto are on the verge of launching a product that will bring simplicity, elegance, and ease to this monumental job of organizing the documents and correspondence in study start up, while at the same time intuitively tracking the process in real time.  This will not only provide you with study startup metrics and reports but ultimately lead to a new era in industry transparency not yet enjoyed!  The dawn of a new age in SSU is near.  Even a one percent improvement in the process will potentially save the industry billions of dollars!
  • 30. About the authors: Dan Manak is a Director of Business Development at goBalto and a graduate of the University of Wisconsin – Madison. After earning his bachelor of science degree in Molecular Biology he began his career in pharmaceuticals with Ho man-La Roche, holding positions in sales, sales management, and training. He has worked in pharmaceuticals, health care, and clinical research for over 20 years with Fortune 100 companies as well as start-ups. For the past seven years he led a small clinical research service organization as the President and Director of Business Development. His expertise and passion exist specifically in the area of clinical study start- up, having worked on several hundred protocols and initiating close to a thousand investigative research sites. In his spare time, Dan is a volunteer EMT and martial artist/ Instructor. Erik Sam is a former Director of Customer Development at goBalto. He began his career as an engineer in the Process Research and Development department at Genentech, Inc. There he developed and optimized manufacturing processes in Late Stage Purification for numerous products entering clinical trials. He also ran successful GMP campaigns and collaborations with outside vendors to develop new technologies for the entire biotech industry. Erik holds a B.S. in chemical engineering, with a focus in biotechnology, from the University of California, Berkeley. Allan Valmonte is a consultant with over 12 years of biopharmaceutical drug development experience. He served as a clinical research consultant for KAI Pharmaceuticals and StemCells, Inc., and held positions in clinical research and development at OXiGENE, Cerexa, and Telik. He has also worked on early, late, and post-approval programs for Integrilin® (Millennium), Vectibix® (Amgen), Lipitor® (Pfizer), and Xolair® (Genentech). Allan holds a B.A. in psychology from California State University, Hayward.