10 steps to Clinical Study Startup

An Overview for Sponsors and Sites A summary of the key steps in starting a study! 1

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 startingclinical studies is way too cumbersome.Our “10 Steps” blog series has gotten the attention of readers worldwide and has helpedgrow goBalto’s online readership to over 13,000 visits per month. Due to the unexpectedpopularity of this series and in response to numerous requests, we have combined the 10Steps series into this PDF ﬁle which will take you, step-wise through study start up. Thoughour 10 steps are fairly comprehensive and typical of the start up process as it is conducted inthe US, it is not necessarily all-inclusive. Also, the order of the steps may vary fromcompany to company and/or study to study.We sincerely appreciate and welcome the comments from our readers - these keep us going!- The goBalto Team! 2

IntroductionWe all know that managing studies are challenging. However, how much thought do yougive to improving the startup phase, where much of the critical groundwork is being laid? Ifyou’re like most folks we’ve spoken to, you’ve accepted that study startup is done throughnumerous tools including, phone, fax, email and Excel spreadsheets.The study startup phase, which includes investigator initiation and submission of newinvestigator packages, is a time-consuming component of the clinical study process. It isburdened by a manual, heavy paper-based process that involves a legacy IT infrastructure,which is ripe for optimization.The Clinical Study Startup SeriesThis series will focus on this key area of the clinical trial process – study startup – and showways on how to optimize each of the steps to gain a significant competitive advantage innew drug product development. We’ve spent the past 9 months, interviewing sponsors,contract research organizations (“CROs”) and investigative sites (“sites”) to determinewhat 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 stillbeing finalized as study start up kicks o . Our 10 Steps assumes a completed protocol andstarts with Site Identification.! 3

One of the most cumbersome and time consuming activities for anyone starting up aclinical trial is identifying high performing investigative sites.Recruiting high performing investigators and e ective research sites is critical for researchoutcomes for a sponsor because this activity directly correlates to quick subject enrollment,attainment of overall enrollment goals, high-quality data, fewer queries, and subjectretention for any clinical study.The start-up phase of clinical trials has been targeted by the clinical research industry aslabor 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 sitesand 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 sitesthat they’ve worked with in the past. The advantages of utilizing an internal database arethat it is readily accessible and is pre-populated with sites with which the sponsor hasexperience. An internal database helps sponsors and CROs maintain relationships withsites 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 withsites 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 morelabor intensive as the database becomes larger. By virtue of it being a static database, itsimply cannot be comprehensive enough to accommodate any research study. Therefore,sponsors and CROs find themselves looking outside their own databases when startingnew trials. Regardless of the type of trial, sponsors and CROs are in constant search of newsites that will work well for them.CRO/SMOIt is commonplace for drug and device sponsors to utilize a CRO’s service in the siteidentification and initiation processes. Even when the sponsor provides its own initial listof sites, the CRO augments the list utilizing their own site database; and still, the CRO willlook to outside resources for further site identification assistance. Sponsors and CROs gobeyond their own site databases for a variety of reasons. In part, they realize that theirown lists have limitations. Oftentimes they are in search of new sites and/or investigatorsin a specific geographic area or within a specific therapeutic area of research. The reasonsvary from trial to trial and no matter the size of the CRO – the CRO manager will search! 4

outside their own database and sponsor recommendations for new investigators and sitesusing a hodge-podge of resources available. Resources available to the clinical trialmanager include SMOs, investigator or site networks, directories, databases, internetsearches, word-of-mouth, and referrals. Some of theseresources cost the CRO and/or Sponsor a significant investmentof time and money. The common variable among the toolsavailable to the CRO manager is that they must be managedindividually through the identification and start-up phases, andpossibly throughout the entire trial.Referrals (KOLs + other investigative sites)Another e ective means of finding sites is identifying a keyopinion leader (“KOL”) in a particular indication. Generally, KOLsare 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 be have interest and ability in a particular trial. Directories Sponsors utilize both online and o ine directories to identify sites tocast a wide net for site feasibility. Some online directories allow sponsors to search forsites free of charge, while others require a fee. Directories can be large and help sponsorsbroaden their list of sites, however the drawback is that it’s still di cult to judge thequality of the sites in the directory1 .Plus, website administrators maintain static directories, therefore the information onindividual sites or investigators is only updated yearly if at all. While online and o inedirectories can help quickly generate a short list of potential research sites, clinical trialmanagers will need to contact and track each site individually throughout the identificationand start up processes, spending a significant amount of time and money in the process.ConclusionThe methods for finding sites are many and we have covered but a few here. When usingany 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 alsofluctuate. Some of the best sources of intel on research sites are the CRAs that monitoryour trials. They deal with the sites first-hand and often have valuable information thatcan be used during the identification process. No matter the tool or method you use infinding potential sites, a focused approach that ties directly to your protocol will yield thebest results.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.! 5

Extra time spent in site ID to speak with the PIs and really gauge their interest and abilitywill pay dividends throughout the rest of the trial. Once you have a list of possible sites,you must contact them.IntroductionOnce sponsors have finished generating a short list of investigative sites, the next keyactivity is to contact the sites to assess whether the site has the required facilities andknowledgeable sta to successfully enroll patients and produce high-quality data for theclinical trial. Communication is typically initiated via email, telephone, or fax and aretracked using spreadsheets. Sounds simple right?How requests are sent and tracked todayImagine if a sponsor needs to engage 50 investigative sites to enrollpatients for a Phase III trial. The sponsor would need to find the site’scontact information, send an email, fax or call, and then document/record each response received. As it turns out, most sponsors usespreadsheets and email folders to track all replies from the sites. Though some sponsors have developed in-house systems to tackle thisactivity in study startup, most companies don’t have the resources tobuild and implement an internal solution to facilitate this process. Themajor drawback of using spreadsheets to manage and track responsesfrom sites is the amount of manual work needed to keep them updated. A clinical researchassistant/associate or clinical project manager needs to manually update the spreadsheetwhen responses from sites are received. This is tedious and also leaves room for humanerror 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 customizationand are not the ideal solution for such an important activity of managing and documentingresponses from multiple investigative sites. This is a time-consuming activity and everyday saved represents a significant amount of money and helps pharmaceutical companiesultimately deliver medicines to those in need faster. Sponsors need to activate sites asquickly 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 sponsorneeds to perform the same steps, which adds even more complexity to the trackingprocedures.! 6

Caveat: These tasks and activities are performed in a variety of ways depending on the sizeof the Sponsor, phase, and CRO involvement. However we covered the activities sponsorsperform that are general enough to cut across most organizations regardless of thespeciﬁcs 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 inthe study, the next step is execute a conﬁdentiality agreement with each of the sites...! 7

IntroductionSponsors and CROs must collect and fully execute Confidentiality Disclosure Agreements(“CDAs”) with all sites and investigators intended for inclusion in their particular clinicaltrial. As is the case with any aspect of a clinical trial, the e ciency by which this step isaccomplished can have a significant impact on the timelines and milestones set for thestudy.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 forunnecessary delays. Add to that the cumbersome nature of managing the dissemination,completion, and collection of CDAs for all sites/Investigators, this simple and crucialdocument 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 adelay could be that the site wants to negotiate terms of the CDA, which involves the legaldepartment of the sponsor &/or CRO, and several days, if not weeks, can go by before anagreement is reached. Other possible delays could be due to shipping mishaps or multipleparties 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 beginfalling behind schedule, thus delaying site initiations, first patient enrolled, and databaselock. 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:! 8

To ensure e ciency with the CDA process, the sponsor/CRO should communicate theirneeds 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 CDA. Communication by the site shouldalso 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 signatureASAP?The timeline in this process for a site should not exceed 48 hours.ConclusionThis is an expected and standard process within all clinical trials. Open and clearcommunication by all parties as well as sound, professional processes in place will assurethe e cient completion of this step, usually within 48 hours. Next, you’ll need to conductfeasibility through a site questionnaire.! 9

IntroductionIt 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 towork on their trial. This document will be circulated with far more sites than are requiredby the protocol. Note: this document may go by many names, and multiple questionnairesmay 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 initialcontact with potential sites for new clinical trials. Its content length varies from a halfpage to more than 10 pages. It is common for this questionnaire to be sent in conjunctionwith a brief study synopsis. If a CDA has not been executed at this point, the synopsis andquestionnaire must be brief and vague. This will take its toll in the form of time-hungryfollow up required later on when the Study Manager is sorting through responses andcontacting various potential sites regarding the next step in their selection process.The next step, as you may have surmised, is often anotherquestionnaire. An intermediary step may exist where the CDA isdistributed, signed, and collected. This will achieve the privacyrequirements necessary for the sponsor to share more of, or acomplete protocol. The next questionnaire will be detailed andspecific with regard to the protocol. Following the mayhem ofthe 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 criteriafor the individual protocol in question, one of the first challenges the study team will faceis 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 upA couple common reasons why the SFQ is late include: • Immediate lack of proper personnel to answer SFQ! 10

• 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 theinitiators of the SFQ; oftentimes they simply do not have enough information toadequately address the questions. A common ramification is that questions on the SFQmay go unanswered, which of course requires additional follow up. Also, it is common forthe SFQ to ask for estimations in which case the site is plagued with the question – do Iestimate high or low?Summary & TipsAlmost 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 companiesare utilizing online tools - such as SurveyMonkey - or their own internal distribution andtracking 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 thestudy team in the qualification process.5) This system would also help manage the responses to sites, helping to close the loopon this process.Most often though, these high-e ciency, automated tools are not in place. The personresponsible for this task will need to be adept at shifting between hard copies, electroniccopies, their e-mail software, and some lengthy and cumbersome spreadsheet(s) to trackthe 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 andtechnological advancements can help bring much-needed e ciencies in the process ofmanaging the SFQ.At this point, you may need to complete the last step of feasibility, which may include apre-study visit...! 11

IntroductionThere has been a lot of discussion about the topic of the pre-study visit (“PSV”) over theyears. Much of this discussion has come about due to a possible disconnect betweensponsor 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 sitesthey need for a given protocol, they must engage in discussions with sites with which theyhave no previous experience. And it remains the case that there is no other way to collectinformation about potential sites than to initially rely on the site’s own, self-reportedmetrics 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 visitmay 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 protocolThe PSV is oftentimes viewed as a necessary evil by the site. This is mostly due to theinconvenience in hosting a study monitor for what is often a full day (can be longer). Thisinconvenience translates to the site, a real expense in terms of resources required toadequately 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 opportunityfor a site to make a good impression and get o on the right foot with their sponsor andCRO customer.! 12

Tips for a successful PSV:Be prepared! This goes for the site as well as the sponsor/CRO. It is not uncommon forsites to receive multiple calls rescheduling the PSV. Common complaints from sites includehosting ill-prepared monitors. Likewise, common complaints from sponsors/CROs, includelack of adequate preparation by site sta , including PIs.Be professional! This may seem elementary, but unfortunately, it is common for thisconcept to be lost on individuals when conducting PSVs. All parties from both sides shouldnot have a mindset of this being an adversarial event; rather an approach that both partiesare 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 theresponsibilities of any good host: make the environment comfortable and welcoming,accommodate, prepare, and maintain a pleasant and professional demeanor. Likewise, thecompany and person making the visit should do everything in their power to take inconsideration the inconvenience to the site and the resources they must expend to make ita 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 withwhom the site will work if they are chosen to participate in the trial. Keep in mind that thevast majority of sites hosting a PSV will be selected and activated on the study. Sponsorsand CROs do not take the decision to spend their resources on PSVs lightly. From abusiness development angle, this meeting is an opportunity to make an excellent firstimpression; which will pay dividends in future business with the sponsor and CRO. This is asite and PI’s opportunity to show ability, expertise, and most of all, interest in theparticular protocol. Conduct at a PSV will often set the stage for relationship managementthroughout the completion of the protocol in question. If it starts well, often that is theoverall impression throughout the trial; likewise, if it begins with conflict – conflict can bepredicted throughout.A final and very biased opinion of the authors on PSVs: strong consideration should bemade by the collective participants in this industry (sites, sponsors, and CROs) to provide amonetary reimbursement to sites for PSVs. Something reasonable and more than nominalshould be provided to the site/PI for this activity. It is common for study budgets toinclude line items such as non-refundable start-up fees, but it is also common for thesefees not to be itemized and thus they fall short of providing comprehensive coverage forsite start-up costs. I feel safe in voicing this opinion because there are far more PIs andsites in the world than sponsors and CROs, so I believe I am arguing for the “majority” andmost readers will agree.Assuming that the site passed the pre-study visit, now it’s time complete the Clinical TrialAgreement (CTA)...! 13

The Clinical Trial Agreement (CTA):This document which goes by many names, is mandatory and often proves to beresponsible 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; whereasthe sponsor typically provides the study drug or device, financial support, and proprietaryinformation. The institution provides data and results, publication or input intopublication, and potential further intellectual property. The CTA clarifies critical termsbetween 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 CTAThe CTA will almost always include the sponsor and institution/site, and may also include aCRO as a third party; in which case the document will outline the same parameters for CROinvolvement. Since ultimate responsibility at the institution rests on the principalinvestigator, it is almost always the case that the PI must sign the CTA.! 14

Sponsors have template CTAs that they use with every site, though they may havedi erent templates for di erent kinds of institutions with which they may work(independent research site, academic institution, site network, etc). The contractingprocess begins when the site receives the template contract from the sponsor. Followinginstitutional review of the CTA template, one of two things may happen. They may eithersign and return it to the sponsor for full execution, or they may redline their requestedchanges and return the edited version to the sponsor for approval.HurdlesAs one can guess by looking at the contents of a CTA, there are many potential points ofcontention outlined within this document; indemnification, insurance, intellectual property,and budget being some of the hot spots. Again, each topic within the CTA merits its ownstudy and the purpose of this blog will be to look at the bigger picture of road blocks andremedies in the CTA execution process.Both parties (or all three if a CRO is also included) may present limiting factors in e cientlyexecuting the CTA.Beginning from when the CTA is first generated, most sites will want to see the budget andCTA prior to completing the regulatory package for the IRB. It is reasonable for theinstitution/site to want to confirm that the study will be equitable for them. Typically,sites are not compensated throughout the start-up process, so completion of regulatorywork 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 orCRO SOPs, the budget, CTA and regulatory pack are all delivered simultaneously. It is notuncommon 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 thedelivery method can also impede e cient CTA processing. The sponsor that sends theregulatory pack with 3 hard copies of executable CTAs when first delivering the CTA ismaking a big presumption – that is that the site will approve the language within the CTAas is, sign, and return all three copies. While it is still common place for sites to accept theinitial language in the CTA as well as the budget o ered, it’s ba ing why so manyvariables 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 mostsponsors and CROs will be able to negotiate the language of their templates. Therefore, itwould behoove all parties to exchange the CTA in an editable, electronic format in the firstplace. This allows both sides to make and track change requests easily. Ideally, this wouldbe done immediately after the site has been approved for initiation. Truthfully, it does nothurt to send them even earlier in the start-up process. It is not uncommon for sites toforgo initiation due to an inability to come to mutually acceptable terms in the budget orCTA. If delivery is done prior to the pre-study visit, and the site does not agree to theterms, at least the early identification of this will minimize the loss of dollars and timespent by the sponsor &/or CRO in the start-up process. Furthermore; recognizing the site’s! 15

need to negotiate these documents and facilitating that process for them will assure thatsponsor 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 thisdocument...! 16

IntroductionIt is rare these days, for a site to accept an original CTA template, verbatim. This, in and ofitself, is not a bad thing – quite the contrary: negotiation is a good thing, and when doneproperly the process should serve to meet the needs of all parties.There are numerous complex and distinctly issues that arise when negotiating CTAs (e.g.indemnification, insurance, IP and publication rights, payment terms, etc.) and each ofthese topics merit their own discussion. Because of this, the scope of this article will coverthe 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 problemSpeaking from Experience…Dan Manak2 has negotiated over 1,000 CTAs and can count on one hand the number ofinstances in which mutually agreeable terms eluded him. In no instance did any of theseagreements undergo legal challenge or law suits. In most cases, when it appears there isno middle ground it is because one or more parties either do not know their limitations orthey do not accurately convey them up front. If you reach an apparent dead-end, do notgive up hope before escalating as much as you need to with the parties with whom you arenegotiating.Often times, the sponsor or CRO person with whom a site is initially negotiating can onlydo so much in terms of altering their standard agreement. This does not mean thatalternative terms are unavailable, but it may require more leg work to get to the rightpeople that can help find that middle ground. Whether or not escalation is called for, neverlose your poise or professionalism, or let the negotiation turn into an argument. Keep inmind that you would not be in negotiations in the first place if all parties did not want thesame thing – a fully executed agreement outlining mutual involvement in the trial.Define and rank priority interests. The key here is to understand that these negotiations are based on di erent interests ofthe di erent parties and the likely result will be concessions regarding these interests. 2 Dan Manak is a Director of Business Development at goBalto with over 20 years experience in clinical operations.! 17

Make certain that you are trading items or issues of less importance in order to gainsubstance of greater importance.Access the priorities of the other parties. The better you understand the other perspectives, the greater likelihood of successfuloutcomes through negotiation. This may involve some guess work on your part; hopefullythey are educated guesses. This exercise alone will foster thought and ideas regardingconflict resolution. As we don the shoes of the people across the negotiating table, ourminds will begin to creatively think of possible solutions, while considering the otherparty’s respective positions.If you are a site and have had to pass on “We cannot negotiate with those whomultiple contracts due to a single internal say, “What’s mine is mine and what’spolicy, it may be a good idea to have a full yours is negotiable.””… “Let us neverreview of that policy. For example, Dan has negotiate out of fear. But, let us neverworked with sites that had such stringent fear to negotiate.” -JFKinsurance requirements they wereprecluded from most trials. The solutionmay be to find an alternate provider. Whenit comes to payment terms and monetaryreimbursement – if suitable terms are not met; the best choice may be to walk away, ratherthan accept a contract which would be financially unreasonable for your site to perform. Awin-win scenario is what everyone is shooting for and there is no ‘win’ if your site will losemoney 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...! 18

Are Investigator Meetings an essential component to bringing new drug therapies tomarket?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 asthe “initiation visit,” meaning when the site sta return home, they are ready to screentheir first subject.A PI’s commitment to and understanding of the protocol is of utmost importance tothemselves 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 theprocesses and paperwork involved, and strive to ensure that site sta from all sites have afull and complete understanding of the protocol and their individual responsibilities. StudyManagers and Medical Directors from the sponsor and CRO, corporate meeting managers,independent planners, communications companies, and academic CME departments are allstakeholders 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 thesponsor company. Therefore, it is argued that from an ethical standpoint, it is perfectlyreasonable for the sponsor company to pay their expenses and honoraria. It is commonknowledge that to entice the PIs to this major commitment of their time, the venue mustbe 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 inresearch, oftentimes driven by their own patient populations. These physicians are alwayslooking at current and future trends that may have a positive impact on their patientoutcomes. They will read, attend meetings, participate as PIs and whatever else they feelthey can do to contribute towards the advancement of medicine, as they know it. They are! 19

not all standing in the bu et line counting their research dollars and soaking in the rays onthe beach with their families at IMs.The contribution made by the PIs at IMs is crucial and those physicians with true researchinterests and abilities bring a wealth of material to an IM. The open forum at an IM fostersexcellent dialogue, paramount to the success of the trial. Aside from disseminatingmaterials, ensuring buy-in to andunderstanding of the protocol, this is a keycomponent 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 lostBut this is not the 80’s and all of us as several times. The final destination was a high-class resortindividuals are watching our expenses more with it’s own private beach.! Each of the three nights ofclosely than we did back then. So is it the the meeting, when I entered my room, I found a new giftresponsibility of the individuals in the from our hosts.! Nice gifts, but not lavish or expensive. Iclinical research community to do will never forget standing in line at the buffet for our firsteverything 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 wasincrease e ciency, and ultimately improve excited to be there. He went on about the treatment weoutcomes of pharmaceutical research. were receiving, the venue, and his $4k/subject study budget.! (Nevermind that he probably found out 2 yearsThe 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 those days were jam-packed with Sponsor / CROIn today’s technologically rich environment, established agendas leaving half the day “free” to relax.!is it really necessary for us to spend billions Over the course of the next two days, I met three other PIs that conveyed elation about their all-expense paidof dollars on bringing physicians across the “family vacation.” My attendance at IM’s has been from acountry for IMs? Perhaps, perhaps not. I unique perspective, representing a Site Managementreally do not know the answer. I know many Organization (SMO), rather than a sponsor, CRO, orwill argue that having the physicians in specific site.! And my purpose here is not to bash theperson provides a platform for outcomes concept of IMs or those companies who host them; Iotherwise unattainable over the internet don’t even plan a negative slant for this post.! Rather, my perspective comes from the same place it always doesand phone. when I consider individual aspects of clinical research – efficiency, resource allocation, and cost, perhaps in thatI am in business development – I more than order.understand the benefits of bringing peopleface to face. But, even in this relationship-intense profession, vendors and clients across all industries are “meeting” face to face withfar 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 allaware of the staggering number of sites that do not perform on their protocols…somethinglike one third of all sites. WHAT IF all of the PIs on the protocol were physicians with a truepassion for research. Would we really need to bring them all together at a resort, with 900count cotton sheets, Steak Diane, and Bananas Foster?! 20

There is no doubt strong value in a “meeting of the minds” when kicking o a newprotocol. If we, as an industry, decided to do this online and reallocate only a portion ofthose dollars spent on IMs to the sites and PIs performing the trials; I suspect that mostphysicians would not be disappointed or dissuaded from participating in clinical research.In closingDare 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 ﬁndthe right PIs, with genuine interest in and ability to conduct clinical research. Follow thatstep with adequate time spent training and educating the research sta , while also gettingtheir feedback, either at their site initiation visit and/or via web conferences. Thesephysicians are eager to do what they can for their patients and contribute to medicine atlarge, and most would probably just appreciate adequate compensation for theircontribution in research. In trade, I am betting that they will happily wiggle their toes inthe sand and sip drinks from coconuts on their own time and expense.Next, are the regulatory documents...! 21

Allan Valmonte 3 shares his experiences and perspectives on Reg Docs.The “Essential” DocumentsMany times during the start up process of a clinical trial, not enough attention is given tothe collection of regulatory documents (aka “essential” documents). Many of thee ciencies during the study start up process can be gained in proper management andtracking of all the essential documents that can be broken down in to three maincategories: 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’skey here is that these essential documents indicate the approval and compliance of theSponsor/CRO, Investigator, and IRB/EC as it relates to current regulations and Good ClinicalPractice (GCP). Furthermore, the essential documents are typically the first things that arereviewed during an audit by the Sponsor/CRO/Monitor, IRB and regulatory agencies.Federal/National Regulatory SubmissionWhen it comes to documents related to submission to federal/national regulatoryagencies, 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 1572plays quite an important role, in that this is a federal form and is the statement by theinvestigator that he/she will abide by the federal guidelines set forth in the Code of FederalRegulations as it relates to the use of drugs in an investigational setting (i.e. clinical trial).3Allan Valmonte has served as a clinical research consultant for KAI Pharmaceuticals and StemCells, Inc., and heldpositions 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).! 22

What many don’t pay much attention to is the actual completion of the form for accuracyand completeness in conjunction with the review of the other essential documents forsubmission such as the CV and license of the PI. Many times, mistakes are found in thenames of Sub-Investigators, addresses, and even the name of the protocol. This canimpact 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 SubmissionIRB/EC submissions contain many of the same documents for regulatory agencysubmissions 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 toensure a complete regulatory package is provided. In many countries in the EuropeanUnion (EU) for example Germany, not only do you have to contend with the requirements oftheir national regulatory agency BfArM (Bundesinstitut für Arzneimittel undMedizinprodukte or Federal Institute for Drugs and Medical Devices), but there may be aCentral 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 keywhen 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 essentialdocuments 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 shipmentof investigational product (IP) to a site. In no way does this indicate that they can startenrolling in the clinical trial. There are other activities required such as conducting o cialtraining of the site sta in the protocol and protocol-required procedures, typically donethrough an Investigator’s Meeting (IM) and/or Site Initiation Visit (SIV).! 23

Helpful tipsAs you can see, the preparation and collection of regulatory documents can seemoverwhelming especially with the vast amount of documents needed for regulatory, IRB/ECsubmissions as well as those required for internal SOPs. What’s important to always keepin 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 licensesand FDFs must match those listed on the 1572. Approvals themselves should reference theactual protocol as well as the ICF along with any other materials you’ve submitted forreview.ConclusionLastly, have a system that tracks this preparation, submission, and review of not only eachof the essential documents but the overall process. This will enable you as the studymanager to determine whether study start up is moving along as expected. This will furtherallow you to: 1) determine if there will be any delays and 2) proactively address thembefore they become unruly. Ultimately, your ability to be able to communicate both up anddown your organization in a transparent manner will keep all key individuals aligned withrespect to study start up.Almost done...! 24

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 anadequate number of subjects in an acceptable amount of time. Happy Day! If this hashappened for you with any significant amount of recruitment time left, you should patyourself on the back. With the staggering statistic that only 30% of research sites meettheir enrollment goals, there is a large balance that needs to be accounted for (andultimately, these sites probably need to be closed and replaced). It should come as nosurprise then, when you ask a study manager “How long does study start up last?” theiranswer often is – “it never ends, sometimes it goes on as long as the trial itself.”Case StudySeveral 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 wasawarded the contract, they knew they had to find another 100 sites for this trial. The studymanager was able to get a jump on recruiting sites as the sponsor was putting the finishingtouches on the protocol. [WARNING] Selecting sites prior to a completed protocol isusually not a good idea.About 10 weeks later, the study team had found another 120 sites. The contract andbudget have been successfully negotiated with 90 sites, and many had IRB approval andwere enrolling by week 6-8. The protocol was finalized 3 weeks into the process and onlyminor 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 fewweeks. Fourteen weeks into the process we had 150 sites initiated and over 70% of themhave been screening subjects for about 6 weeks. By week 16, it was recognized that thestudy would not meet the enrollment deadline with the current rate of enrollment. Bring inthe 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 tothe 5th month of the enrollment period. At week 16 the surplus 20 sites originally found bythe 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 weekafter enrollment closed. (It took over 3 months to initiate the last 20 sites.)! 25

Study Startup Sometimes NEVER Ends…Taking apart this study and examining all of the pitfalls of SSU (like beginning siteselection without a complete protocol) goes way beyond the scope of this post…perhapsgood subject matter for a future white paper. The moral of the story is: all too often, studystart up does not end. The upshot of this fact is: increased costs and prolonged studyduration. Another industry statistic that should knock you sideways is: >96% of all clinicaltrials 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 delvedharder into our product development and engaged more and more experts from theindustry, it has been a pleasure to meet so many passionate people about SSU who sharethe 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 foundingPhESi. He was the head of productivity for development operations for Pﬁzer GlobalResearch and Development, and Director of Business Analytics for Pharmacia and BristolMeyers Squibb.Gen has tremendous experience in and fascination with SSU. He has written severalpublications on and around the topic of SSU. Of particular interest and relevance to thesubject matter of this post is his article titled Site Activation: The Key to More E cientClinical Trials. (Recommended reading for anyone interested in SSU.)In his most recent publication, titled “Planning the Right Number of Investigative Sites fora Clinical trial, found in the August 2010 issue of The Monitor, you will see a continuation ofhis unique thoughts on the importance of study start up.This article states,“…it is possible to forecast enrollment more accurately.” “Calculating the appropriatenumber of sites is a vital piece of the puzzle in successful planning and execution of aclinical trial.”Gen recognizes that his perspective looks at some of the factors impacting accurateplanning 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 theplanning and execution of clinical trials.”! 26

In conclusionTo Gen and others out there interested in reinventing the process of study start up – GoodNews! 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 andcorrespondence in study start up, while at the same time intuitively tracking the process inreal time. This will not only provide you with study start up metrics and reports butultimately lead to a new era in industry transparency not yet enjoyed! The dawn of a newage in SSU is near. Even a one percent improvement in the process will potentially save theindustry billions of dollars!! 27

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 smallclinical research service organization as the President and Director of BusinessDevelopment. 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 thousandinvestigative research sites. In his spare time, Dan is a volunteer EMT and martial artist/Instructor. Erik Sam is a Director of Customer Development at goBalto and 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.! 28

About goBaltogoBalto (www.gobalto.com) is an award-winning "ca eine addicted" team that createssimple, focused and a ordable web based software for the global clinical trial industry.Based out of San Francisco, we build products which o er drug trial sponsors the easiestpossible way to start their clinical studies on the web and make them smile.Simpler. Easier. Faster. Making you feel better. Thats goBalto.To learn more about how goBalto can help you start your study, visit www.gobalto.com/studystartup or contact us at:goBalto, Inc.230 California Street, Suite 601San Francisco, CA 94111Tel: 1-877-230-4168dmanak@gobalto.comesam@gobalto.com

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10 steps to Clinical Study Startup

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10 steps to Clinical Study Startup — Document Transcript