Breaking into clinical research.

Practicing physicians possess numerous marketable skills. Those looking for a change of pace from clinical practice might consider the full array of opportunities available in drug and medical device development.

You can enter the field without leaving patient care by incorporating clinical research into your existing practice. In fact, by doing so you can enjoy the intellectual stimulation and satisfaction of advancing the field of medicine, while offering your patients access to new treatments.

That's how I got started. I enjoyed the field so much that I left clinical practice to pursue a career in pharmaceutical medicine full-time.

There currently is a major shortage of clinical investigators. Pharmaceutical and medical device companies are constantly looking for more clinical investigators--clinicians who can help them complete clinical trials of new molecules and devices. One of the greatest impediments to conducting successful clinical trials worldwide at the beginning of the 21st century is the shortage of good clinical investigators who can meet enrollment goals and produce reliable data for submission to regulatory agencies.

A common misconception is that one must be faculty on tenure track at a medical school or teaching hospital to qualify as a clinical investigator. Nothing could be further from the truth. The majority of clinical investigators are in private practice in the U.S. or elsewhere in the world.

Getting started

So you've decided you'd like to become a clinical investigator and incorporate clinical trials into your practice. Where do you start?

First you need some basic knowledge. There are many excellent books covering this subject, but before drug and device companies and contract research organizations (companies drug and device firms hire to perform clinical trials for them) will call on you to perform clinical trials, they need to know that you have a basic understanding of good clinical practice (GCP).

GCP doesn't refer to accepted standards of patient care. In the world of drug and device development, it has a special meaning. GCP refers to the principles and processes investigators worldwide are expected to follow to ensure patient safety, protection and privacy, and to assure collection of reliable, valid data for submission to regulatory agencies like the U.S. Food and Drug Administration's (FDA) three divisions dealing with drugs (CDER), biologics (CBER), and devices (CDRH).

Where do you acquire this knowledge? A number of organizations offer instructor-led and even Web-based courses, as well as clinical investigator certification examinations. At present certification is not necessary to conduct clinical research, although it may become mandatory in the future.

For those who wish to become certified clinical investigators, the good news is that it is currently less onerous than achieving medical or surgical board certification. The American Academy of Pharmaceutical Physicians, AAPP (www.aapp.org), and the Drug Information Association, DIA (www.diahome.org), are two reputable sources for GCP training. Both also offer investigator certification.

You will need to put some infrastructure into place in your practice. You probably already have most of the necessary resources, but you will have to reallocate some of them. The first thing you will need is a clinical research coordinator (CRC), someone capable of handling the management and documentation overhead for each trial.

Investigator sites with experienced CRCs are known to have fewer problems with compliance with FDA's rules. While certified CRCs are available for hire, when you are just getting started, your trusted, lead back-office person would be a logical choice to take on this function. He or she must, however, be at least as conversant with GCP as you. In making the decision to add clinical research to your practice, you should budget for sending this person for GCP training when you go.

Also, you are giving this person significant additional responsibility, so you will need to offload some of your CRC designate's current duties onto other office staff members while making it clear to them that clinical research is to become an integral part of your practice. Offering your CRC a raise along with other staff members forced to assume additional duties wouldn't hurt either, as you want everyone to be motivated to achieve the new goals you have set.

Nothing will torpedo a new office-based clinical research program faster than staff members who view their added duties simply as an imposition.

Some of the GCP courses include practical training, even interactive exercises, on how to incorporate clinical research into your practice, in addition to formal GCP instruction.

You and your proposed CRC will certainly need a thorough understanding of the principles of conducting clinical trials in accordance with all ethical and regulatory requirements, and of maintaining the necessary documentation. But that is only part of what you both need to know.

You will also have to become familiar with the practical aspects of conducting clinical trials, such as how to decide which trials best fit your site's resources and patient population, and how to evaluate an experimental protocol for hidden pitfalls.

Routine but important issues such as how to store investigational agents, how to set budgets, and how to negotiate contracts with sponsors, all factor into your success in incorporating clinical research into your practice.

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Landing trials

Let's assume you have taken a GCP course and are ready to get your feet wet. What's the next step? First you need to find clinical trials for which your site would be well suited. There are a number of places you can look. Certainly www.clinical-trials.gov/ is a good place to start.

I personally recommend CenterWatch Monthly, www.centerwatch.com/, a publication of Thomson, the same people who bring you the Physicians Desk Reference (PDR), and publish Medical Economics every month.

Once you have identified a clinical trial that appears to fit your site's capabilities, and contacted the sponsor or its agent, what's next?

Sponsors interested in using your site for their trials will send you a site information form (SIF) to complete. This simple form asks for a rough estimate of what you believe to be the prevalence of the condition to be studied in your own patient population. It also briefly asks about your facilities, for example, whether you have refrigeration for special drug storage (not just your lunch refrigerator). Most will also ask for an estimate of the number of patients per month you believe would meet the enrollment (inclusion/exclusion) criteria and could be enrolled.

If, based on your answers, the sponsor believes there is a potential fit, then you will receive a confidentiality agreement (CDA) to sign, after which you will receive at least two things: a copy of the experimental protocol, a complete description of the trial design and requirements, and a copy of the investigator drug brochure (IDB), describing what is known about the drug (or device) to date, both good and bad, both preclinical (animal studies) and clinical (human studies).

The sponsor may also send you a contract, a clinical trial agreement (consider it a sample). This is where the part of your training in evaluating a protocol and in negotiating a contract will come in handy.

Let's assume you feel the experimental protocol is ethical (some may not be, e.g. a pediatric asthma trial with a placebo control), is one for which your practice is capable of finding appropriate patients, and one for which you have the necessary resources. What happens next?

Responsibility

Generally, a representative of the sponsor, usually called a "clinical research associate" (CRA), will come out to inspect your site. It is extremely important that you plan to make yourself and your CRC available to meet with the CRA. The CRA will need to meet you personally. This personal meeting with you seldom takes more than about an hour to an hour and a half.

Your attendance is required because the CRA needs evidence that you have read both the protocol and the IDB and that you have a firm grasp of their content. The CRA must be convinced that you are absolutely committed to over-seeing the trial personally in accordance with FDA regulations.

The CRA's visit to your site may last all day, but most of that time will be spent either with your CRC or inspecting your facilities to assure that you have:

* Adequate locked storage for investigational agents

* Temperature controlled storage (if necessary for the protocol)

* Safe storage for study documentation

* Adequate patient population to ensure meeting enrollment goals

* Commitment of everyone involved in the trial to ensure success

I cannot overemphasize the importance of the last item. That is why it is imperative that you, as the principal investigator (PI), set aside time to meet with the CRA, for, if you are too busy to spend just an hour or so with him/her, it will cast serious doubt on your commitment to the entire project.

You will be asked to send the sponsor a copy of your own curriculum vitae as well as one for every other physician, physician assistant, or certified nurse practitioner in your practice who will be participating in the trial. You and your participating licensed colleagues (subinvestigators, or "SubIs"), which can include physician assistants and nurse practitioners, will be required to execute a copy of the FDA form 1572 that represents a contract between you and the FDA.

I call it the "Harry Truman" form, because, in essence, it says that. "The buck stops with you!" To it you attach your CV as well as those of any subinvestigators, and a copy of the clinical protocol. In signing FDA Form 1572, you are guaranteeing that you will:

* Conduct the trial strictly according to protocol

* Personally oversee and be responsible for conduct of the trial

* Obtain informed consent from every patient who participates in the trial

* Promptly report any adverse events occurring during conduct of the protocol to the sponsor

* Read the IDB personally so that you understand all potential risks and side effects of the experimental agent

* Ensure that all your associates, colleagues, and employees assisting with the trial understand their obligations in meeting these commitments

* Be responsible for working with your staff to maintain adequate and accurate records of all aspects of the trial's conduct

* Obtain approval from your institutional review board (IRB, sometimes called an "ethics committee"), for all aspects of the clinical trial and that you will keep the IRB informed of any changes in the protocol and of any unanticipated problems involving risks to human subjects

* Not deviate from the experimental plan, which the IRB has approved except where necessary to protect your human subjects from immediate hazard

* Comply with all other obligations of clinical investigators in human trials laid out in 21 CFR (section 21 of the Code of Federal Regulations) part 312, (N.B. Any good GCP course will insure you are intimately familiar with all portions of 21 CFR).

Assuming everything goes well at your site's initial inspection visit, you will be sent a contract specifying your duties as PI and spelling out your compensation and how it will be paid. In most cases you will be compensated for each subject who completes the trial, but, in long trials there may be mile-stone payments.

In those requiring screening of many patients for each actual subject enrolled, there may also be payments for screening patients. In trials where enrollment may require reaching outside your practice, there will be an advertising budget.

Most sponsors will provide you with a sample informed consent form (ICF) customizable for your practice, and, if deemed necessary, proposed advertising content. These, too, must be submitted to your IRB for approval.

Liability

Most sponsors will provide you with indemnification against causes of action stemming directly from conduct of the trial in strict adherence to the experimental protocol.

Nevertheless, in the current tort climate, this is definitely a detail of the contract you should study carefully.

In turn, most reputable sponsors will need proof that you carry malpractice insurance. The bottom line is that incorporating clinical research into your practice usually will not impact your malpractice premium. Implicit in this statement, though, is the assumption that you hew to the experimental protocols.

Before the trial begins, the sponsor's CRA will visit your site once more for a site initiation visit (SIV), for which you must again be present. This is to assure that everything is in place for you to begin enrolling human subjects.

The visit may be shorter than the initial visit, but no less important. Prior to this visit, you and your CRC should meet to discuss the protocol, any concerns you may have that require answers (e.g. what to do if X happens or would preexisting conditions Y or Z still permit your patient to participate in the trial?).

After the SIV, you and your CRC will be invited to attend an investigators' meeting (IM) paid for by the sponsor. You, as the PI, along with your CRC, must plan to attend this meeting. The sponsor covers your airfare, hotel and meals. Recognizing how busy you are, most sponsors schedule such meetings on Saturdays.

You usually fly in Friday afternoon to the meeting destination. A welcome banquet is held Friday evening. On Saturday morning, you and your CRC will begin receiving intense instruction about what is known about the investigational agent or device to date, rationale for the protocol's design, how to conduct the protocol, how to report results and how to report any adverse events.

In addition there will often be breakout sessions on Saturday afternoon detailing specifics unique to the particular trial and how to conduct it. On Saturday night, the sponsor will often host a special event in appreciation of you and your CRC's participation.

Sometimes there may be additional sessions on Sunday mornings, but generally sponsors recognize your time constraints and will be sure you are on your way back home by about noon on Sunday.

Enrolling your first patient

All your preparation and hard work are about to come to fruition. You are about to enroll your first patient. Speaking to you as a former PI, I can only tell you that this feeling is indescribable.

Remember your GCP training, and you will do just fine. Never forget that you are responsible not only for your own patient's wellbeing, but also for the safety and human rights of your clinical trial subject. The two are not equivalent. If you truly understand this, you are well on your way to making a success of your endeavor.

During the course of your clinical trial, CRAs as well as a separate (or even FDA) monitor, will visit your site to assure that you are conducting the trial in accordance with protocol, that

* You are reporting all adverse events (drug-related or not)

* All patients have executed proper informed consent documents

* The IRB has been informed of any changes to the protocol and/or important adverse events

* All investigational agent and trial records are being properly maintained

* All involved staff is still committed to the successful completion of the trial.

If you are successful navigating through your first trial, the likelihood of participating in additional trials will increase greatly.

Ross Tonkens, MD, is director of medical and scientific services and global scientific head of the cardiovascular therapeutics division of Quintiles, an international contract research organization. He can be reached at 919-998-2396 or [e-mail]

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Acknowledgement: The author wishes to express his thanks to regulatory expert Dr. Raymond Huml, legal expert Judith Beach, and communications advisor Jay Johnson, for their valuable assistance in preparing this manuscript.

Web Lecture on Clinical Trials www.acpe.org/toolkit

By Ross M. Tonkens, MD, FACP

RELATED ARTICLE: Acronyms Commonly Used in Clinical Trials

1572    FDA Form 1572
AAPP    American Academy of Pharmaceutical Physicians
CBER    (FDA) Center for Biologics Evaluation and Research
CDA     Confidentiality Agreement
CDER    (FDA) Center for Drug Evaluation and Research
CDRH    (FDA) Center for Devices and Radiologic Health
CFR     Code of Federal Regulations
CRA     Clinical Research Associate
CRO     Clinical Research Organization
CRC     Clinical Research Coordinator
DIA     Drug Information Association
EC      Ethics Committee
FDA     United States Food and Drug Administration
GCP     Good Clinical Practice
ICF     Informed Consent Form
ICH     International Conference on Harmonization
IDB     Investigator Drug Brochure
I/E     Inclusion/Exclusion (Criteria)
IM      Investigator Meeting
IRB     Institutional Review Board
PI      Principal Investigator
SIF     Site Information Form
SIV     Site Initiation Visit
SubI    Subinvestigator

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