In the Clinical Trials Zone

A new product takes a long and winding road from a laboratory to the patients it is designed to help. Many factors and organizations affect just how many months and dollars it will take to shepherd a new product from preclinical studies to market. Carefully documented, regulatory-compliant clinical trials are key to marketing approval.

Clinical trials involve a choreographed network of regulatory agencies, sponsor companies, and clinical investigators. Myriad specialists in that network include those who produce and deliver an investigational product, medical directors, project managers, statisticians, clinical research monitors, institutional and independent review boards (IRBs, also known as ethics committees), recruitment specialists, data managers, contract managers, medical writers, clinical investigators, clinical research coordinators, auditors, regulatory agency inspectors — and the list goes on.

Many of those clinical research professionals are employed by sponsor companies. Increasingly, however, contract research organizations (CROs) carry out many of a sponsor’s functions. A small company may have one or two products in its pipeline and a small group of managers, each with duties in two or three areas. By contrast, in a large company each of those areas has its own department and a manager supervising a staff of specialists. For smaller companies, working with a CRO and its experienced personnel (with expertise in many facets of clinical research) can offer significant advantages.

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Most important to the entire clinical trials enterprise are those subjects who consent to participate. Their importance to medical research is honored by House Resolution 248 now being considered in the US House of Representatives. Representative Rick Boucher (D-VA) introduced the resolution in 2007, “honoring the contributions of patient participants in clinical trials.” It has eight cosponsors and has been referred to the Subcommittee on Health. It “encourages everyone to learn about the importance of clinical trials and the important role of trial participants.”Recruiting and Enrolling Subjects

Often cited as a major roadblock delaying submission of a biologic license or new drug application (BLA or NDA) is the time required for clinical trials. The process of recruiting, screening, and enrolling study subjects often slows a study’s progress. This section focuses on recruitment and enrollment of subjects for phase 2 and phase 3 studies. Some issues in phase 1 (first-in-human) studies are discussed later.

The length of time it takes to enroll the required number of subjects who meet the inclusion criteria for a trial is influenced by a variety of factors. These include the complexity of the protocol, interactions with the institutional or independent review board (IRB) or ethics committee, the recruitment budget, and the available pool of treatment-naïve patients who have a prevalent disease or condition.

A complex protocol can not only hinder timely subject enrollment, but also build waste into a study’s budget. Unduly restrictive inclusion/exclusion criteria can slow enrollment, as can a greater than necessary number of visits and tests.

Jan Drayer, a California consultant in drug development strategies, offers some protocol-writing suggestions for risk-averse trial designers, who sometimes define as many as 20 or 30 exclusion criteria, making it extremely difficult to enroll subjects. When describing enrollment criteria, Drayer points out the importance of considering “what kind of disease and what kind of drug” you are working with. “Anything you add can be a burden,” Drayer says, “and cost time and money.” When deciding on the number of visits and tests to require, ask, “Do I really need it? Is it worth doing that if it places too much burden on the subject for little benefit?” In short, Drayer prescribes respect for both investigators and subjects by burdening them no more than necessary to get the valuable data needed.

A description of the 2008 BIO International Convention session on “Patient Recruitment Strategies for Global Mega-Studies” reinforces that advice:

It must be easy and convenient for people to participate in clinical studies. Clinic staff must be attentive and treat subjects courteously and professionally during each clinic visit. Centers must have proven, localized recruitment strategies to f—ulfill subject population targets.

It is equally important to retain subjects, as it is to initially recruit them into a study. Visit reminders, social gatherings, and nominal gifts for holidays and birthdays are effective means of ensuring study participants remain connected to the site for the duration of the study.

Kenneth Faulkner, vice president of business development and scientific services for Synarc (www.synarc.com), points out that, according to a recent study from Cutting Edge Information (www.cuttingedgeinfo.com), “screening and enrolling subjects can consume as much as 30% of the clinical timeline.” Faulkner’s session will present detailed recruitment strategies and discuss the advantages of a multinational clinical research center model. Such centers, he says, “offer centralized management that provides sponsors with a single point of contact for study management.”Conducting Trials Abroad

For conditions with a relatively small pool of treatment-naïve Americans, sponsors may choose to conduct trials in countries with larger pools of untreated patients. Other reasons for going abroad to study a new product are sometimes obvious. For example, a high incidence of skin cancer in Australia makes it a logical place to study products designed for that indication. Nothing much could be learned by testing a treatment or vaccine for a tropical disease, such as malaria, in an industrialized nation in the Temperate Zone.

Setting up clinical trials in other countries as a way to cut costs is a less clear-cut choice. Some barriers to be considered include regulatory agencies and their timelines, cultural differences, and infrastructure. “Certainly it is not easy to do studies abroad,” says Drayer. Some companies have had disappointing results in other countries. China, for example, has a vast pool of potential study subjects, but he says that although “huge companies may have the resources to takes the risks in China, it is often too risky for small companies” to place studies there.

Enrollment can be rapid at sites in India, China, Thailand, Philippines, Singapore, Taiwan, and Vietnam. Also, the fees of physician-investigators are lower there than in the United States. But Dina José, president of Research Strategies Inc. (www.researchstrategiesinc.com), wonders whether it is really more cost-effective for companies to place studies in those places or whether sponsors are simply “carried away by the lower rates charged by investigators there.” Even with her ambivalence about the situation, José says, “Now is the time to gather information, acquire training, build relationships, and bridge cultural differences — little things that can make a big difference in defining success.”

It is possible to create an atmosphere that takes advantage of cost and time savings, and get to market more quickly. Presentations at the session on “Clinical Trials Challenges and Solutions in Asia-Pacific,” organized by Australia’s Queensland Clinical Trials Network (QCTN), will focus on cost-effective ways for biotech companies to accelerate their clinical development programs in that region.

QCTN’s CEO, Mario Pennisi, calls Australia a “stepping stone to Asia,” and mentions that, geographically, Australia is part of Asia. “Japan, China, South Korea, and Taiwan have been restructuring their regulatory agencies, regulatory rules, IRB composition and functioning, skills programs, and hospital-based clinical research capabilities” he says, so those countries will be more attractive locales for conducting clinical trials. Pennisi also says, “Excellent medical facilities and know-how in Australia and Taiwan make them ideal places to the gather early-phase data acceptable to the EMEA and FDA.”Safety

Safety concerns have risen near the top of the list of issues affecting the clinical research community — along with subject enrollment. Adverse reaction reports have prompted the FDA to require more black box warnings. Recent drug recalls are altering some physicians’ prescribing habits and have made consumers wary.

THE CLINICAL TRIALS PRODUCT-FOCUS ZONE

Exhibitors in the Clinical Trials Zone at the 2008 BIO International Convention will highlight products, services, and literature to help you navigate the myriad components of taking your product to the clinic.

Agorithme Pharma Inc. (Booth #2114): www.algopharm.com

Clinsys Clinical Research, Inc. (Booth #2111): www.clinsyscro.com

CRC Press, Taylor & Francis (Booth #2123): www.crcpress.com

Datapharm Australia Pty Ltd. (Booth #2224): www.datapharm.com.au

Decision Resources, Inc. (Booth #2222): www.decisionresources.com

Diosynth Biotechnology (Booth #2003): www.diosynthbiotechnology.com

Envirotainer (Booth #2017): www.envirotainer.com

Esoterix Clinical Trials Services (Booth #2108): www.esoterix.com

Fulcrum Pharma Developments, Inc. (Booth #2001): www.fulcrumpharma.com

HollisterStier (Booth #2105): www.hollisterstier.com

Kentucky BioProcessing (Booth #2015): www.kbpllc.com

Patient Based Research (Booth #2116): www.patientbasedresearch.com

PharmaNet (Booth #2025): www.pharmanet.com

pnas (Booth #2009): www.pnas.org

Queensland Clinical Trials Network, Inc. (Booth #2125): www.qctn.com.au

ResearchPoint (Booth #2023): www.researchpoint.com

Triligent International (Booth #2101): www.triligent.com

Wolters Kluwer Health — Adis (Booth #2200): pharma.wkhealth.com

World Courier, Inc. (Booth #2019): www.worldcourier.com

As if some genuine news reports about recalls aren’t making consumers uncomfortable enough, misleading “safety alerts” are circulated by people who probably mean well, but who don’t bother to determine whether they are accurate. One widely forwarded email prompted the FDA to post the following on its Phenylpropanolamine (PPA) Information Page: “FDA is aware of emails circulating widely that list many products allegedly containing PPA. These emails, however, generally contain dated and inaccurate information and should be ignored” (1).

Any person with email generally also has access to a website that debunks such urban myths. Two well-known sites are Hoax-Slayer (www.hoax-slayer.com) and Snopes.com (http://snopes.com). It seems sensible for people involved in recruiting and enrolling study subjects to be aware of negative, but inaccurate, information floating around and be prepared to reassure potential subjects. First-in-Human Studies

Just one week before the tragic outcome of the high-profile TGN1412 trial in the UK (2), an expert group from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) had agreed upon a draft “Guideline on Requirements for First-In-Man Clinical Trials for Potential High-Risk Medicinal Products.”

Among comments submitted during the consultation period was a detailed document from the Biotechnology Industry Organization (BIO) that included these suggestions:

[M]any of the most important requirements will be equally applicable to both ‘high-risk’ and non-high-risk products.… The emphasis of the guideline should be more focused on risk mitigation strategies through the integrated analysis of all pre-clinical data and the appropriate design of clinical trials. This would remove the need for a definition of ‘high risk,’ while still addressing appropriate risk management strategies.”

CLINICAL TRIALS PRESENTATIONS

Here are just a few of the sessions at the 2008 BIO International Convention relevant to conducting clinical trials.

Adaptive Clinical Trials — An Evolutionary Concept

A New Improved Directive 2001/20/EC Boosting Clinical Research in Europe?

Developing Efficient Operations to Enable Collaborative Clinical Development

Driving Adoption of Tomorrow’s Cancer Diagnostics in Today’s Clinical Practice

Large Scale Genotyping Projects in Developing Countries: Future Opportunities

Taking It Into Their Own Hands: Working with Patient Advocacy Groups to Fund Research

The final “Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products” incorporated many of BIO’s suggestions and took effect on 1 September 2007 (3) Contract Research Organizations

Twenty-some years ago, contract research organizations (CROs) were new players in clinical research. In the mid-1980s, most pharmaceutical companies had their own research departments that worked directly with physician-investigators who conducted clinical studies of their new products. During the 1980s, increasing numbers of sponsor companies recognized the expense of staffing clinical research departments that often experienced down time when nothing in the pipeline was moving out of toxicology studies toward first-in-human trials. A logical solution was to begin layoffs. Perhaps impatient with waiting to be rehired, experienced, but unemployed, professionals began to solicit contract work from sponsor companies.

In the early days, many CROs began as niche providers. One might focus on data collection and analysis — EDC was still a few years away — another on monitoring or medical writing. It wasn’t long before full-service companies emerged. By the mid-1990s, CROs of all kinds were a major presence on the exhibition floors at large industry meetings, such as the Drug Information Association (DIA) and the Association of Clinical Research Professionals (ACRP). Now it is possible to contract with one CRO for everything from protocol writing to preparing submission documents. Whole conferences are devoted to industry-CRO relationships. Perhaps the largest and best known is “Partnerships with CROs and other Outsourcing Providers” (www.iirusa.com/cropartners/eventhome.xml).

More than one industry journal has published an entire issue focused on finding the right CRO for a particular company or product. A recent example is the ACRP’s The Monitor (February 2008), with a cover featuring pieces of a jigsaw puzzle behind the announcement of its theme: “Outsourcing and Partnerships: Finding the Right Fit.” Many articles discuss how to make industry–CRO relationships work, and some of the most recent are listed in the “Recommended Reading” list.

Each biopharmaceutical company has its own culture and needs. So it is not only necessary to find a CRO with experience in the indication your new product is intended to treat, but also important to find a good match in work habits, philosophy, and culture. That
can take considerable research and several meetings — but it’s worth the trouble. Working on a sponsor’s behalf, a CRO represents the sponsor in the clinical research community. Because the sponsor is ultimately responsible to regulators for the conduct of a study as well as regulatory submissions, it is a relationship that a biopharmaceutical company needs to enter into with the best information it can gather. From the Laboratory to Patients

No single article can create a complete roadmap of the journey from a scientist’s insights and creativity to a pharmacist’s formulary. Nevertheless, the FDA does a creditable job of explaining it in lay terms in a series of articles under the heading From Test Tube To Patient: Protecting America’s Health Through Human Drugs. That can be useful when you are speaking with friends and family members unconnected with the pharmaceutical industry.

For professionals to be as effective as possible in their own part of the journey, government agencies offer documents to guide sponsors toward regulatory compliance; and associations offer practical help through conferences, workshops, and publications. The BIO International Conference for 2008 is a great place to start.

SELECTED RESOURCES

Cellular and Gene Therapies: www.fda.gov/cber/genetherapy/gtpubs.htm

Guidance for Industry: Gene Therapy Clinical Trials — Observing Subjects for Delayed Adverse Events; www.fda.gov/cber/gdlns/gtclin.htm

Guidances, Information Sheets, and Important Notices on Good Clinical Practice in FDA-Regulated Clinical Trials: www.fda.gov/oc/gcp/guidance.html

Office for Human Research Protections (OHRP): www.hhs.gov/ohrp

Understanding Clinical Trials: www.clinicaltrials.gov/ct2/info/understand

Code of Federal Regulations

Title 21 of the Code of Federal Regulation (CFR): Updates are posted at www.access.gpo.gov in May and June.

Clinical trials regulations: See especially 21 CFR 50, 54, 56, 312, and 314; www.access.gpo.gov/cgi-bin/cfrassemble.cgi?title=200721; also 45 CFR 46 Protection of Human Subjects; www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

Compliance Oversight: www.hhs.gov/ohrp/compliance

eTrials

21 CFR 11 Electronic Records; Electronic Signatures: www.access.gpo.gov/nara/cfr/waisidx_07/21cfr11_07.html

Clinical Data Interchange Standards Consortium: http://cdisc.org

Guidance for Industry: Providing Regulatory Submissions in Electronic Format — Receipt Date (Draft Guidance). www.fda.gov/cber/gdlns/esubreceipt.htm

International Conference on Harmonisation: www.ich.org; ICH guidelines in four topic categories: www.ich.org/cache/compo/276-254-1.html Efficacy topics: www.ich.org/cache/compo/276-254-1.html

Associations, Conferences, Publications

Applied Clinical Trials: Actmagazine.com

Association of Clinical Research Professionals: www.acrpnet.org

Contemporary Clinical Trials): www.elsevier.com/wps/find/journaldescription.cws_home/704636/description#description

Drug Information Association: www.diahome.org/DIAHome

Free weekly email newsletter, GXPNews.com:http://gxpnews.com

Good Clinical Practice Journal: www.jbpubs.com/gcpj/index.html

International Clinical Trials: www.amedanltd.com/magazine/13

The Federal Register:www.gpoaccess.gov/fr/index.html

“Partnerships with CROs and other Outsourcing Providers” (conference): www.iirusa.com/cropartners07/2000.xml

REFERENCES

1.) Phenylpropanolamine (PPA) Information Page.

2.) 2006. Will Volunteers Still Want to Take Part in Research after the TGN1412 Trial?. The Pharmaceutical Journal www.pjonline.com/Editorial/20060930/news/news_tgn1412.html.3.) Guideline on Strategies to Identify and Mitigate Risks for First-In-Human Clinical Trials with Investigational Medicinal Products.4.) Anderson, C, C Tashiro, and L. Taddonio. 2007.Vendor Quality Assurance Audits: A Formula for Success, Applied Clinical Trials.5.) Attig, RB, and A. Clabaugh. 2008.Clinical Trials and Statistical Tribulations, Applied Clinical Trials:42-48.6.) Calaprice, D, and P. Leuachten. 2008.The State of Clinical Outsourcing, The Monitor:19-26.7.) Carita, A. 2008.When Will Outsourcing Mature?, The Monitor:57-60.8.) Charlon, V. 2003.A Clinical Development Solution Tailored for Biopharmaceutical Companies, Applied Clinical Trials.9.) Christensen, JR. 2006. More Than Close Cousins: Clinical Development and Quality Assurance. BioExecutive International 14–15:S29.10.) DePalma, DA, I Kassatkina, and M. Stober. 2007.Being Smart About Global Versus Local During Clinical Research Trials, The Monitor:47-50.11.) Drayer, JI, and T. Twaddell. 2006.How to Manage the Jump to the Clinic in Drug Development, BioTrials (supplement to BioExecutive International):10-13.12.) Farinacci, JV. 2006. Long Distance Relationships: Finding the Right Partner. International Clinical Trials (ICT) www.researchpoint.com/RightPartner.pdf.13.) Fernandes, SL. 2007.SOPs: The Importance of Training Yourself to Train Others, The Monitor:59-62.14.) Furman, Elise 2007. Automated Site Technical Assessment: Unlocking the Secret to a Successful Electronic Data Capture Clinical Trial. The Monitor:29-32.15.) Getz, KA. 2007.CRO Shifts in the Outsourcing Market, Applied Clinical Trials.16.) Getz, KA. 2007.Industry Trials Poised to Win Back Academia, Applied Clinical Trials.17.) Harper, B. 2006.Critical Success Factors When Planning Site Selection and Patient Recruitment, BioTrials (supplement to BioExecutive International):16-28.18.) Hegde, SS. 2008.Clinical Research Education in India, The Monitor:43-46.19.) Higgins, J. 2007.The Art and Science of Community-Based Clinical Trial Recruitment, The Monitor:21-22.20.) Kibby, M. 2007.Multinational Clinical Trial Recruitment: Understanding Site Initiation Delays and Planning for Their Impact, The Monitor:15-19.21.) Kush, R. 2006.Electronic Data Capture — Pros and Cons, BioTrials (supplement to BioExecutive International):48-52.22.) Mackintosh, DR, and VJ. Molloy. 2006.The Art and Science of Auditing Clinical Trials, BioTrials (supplement to BioExecutive International):40-46.23.) O’Neill, B. 2007.Laying with the Lions: Big Pharma Collaborates on Routine Audits and Quality Management of Third-Party Service Providers Applied Clinical Trials.24.) Richard, G. 2007.Preferred Providers Face Outsourcing Challenges: Performance and Noncompliance Clauses Change the Partnership Between Sponsor and Vendor, Applied Clinical Trials.25.) Saligan, D. 2008.Special Requirements When Partnering with Technology Providers, The Monitor:31-34.26.) Vice, H. 2007.Enhancing Public Awareness About Clinical Research, The Monitor:67-70.27.) Vogel, JR, and KA. Getz. 2005.Successful Outsourcing: Tracking the Evolving Use of Full-Service and Niche-Service CROs, Applied Clinical Trials.28.) Vogel, J, and KA. Getz. 2006.Successful Outsourcing of Clinical Drug Developments, BioExecutive International:S30-S38.29.) Widener, N. 2008.Creating and Maintaining Sponsor-CRO Relationships, The Monitor:29-30.