8th Annual Retrovirus Conference
Late Breakers
Chicago, Feb 4-8 2001


Women and Clinical Trials

›››› Written for NATAP by Debra Johnson, N.P., P.A.-C and Kathleen E. Squires, M.D.

Clinical trials can be confusing and frightening to understand, let alone participate in.› Prior to 1993, women were for the most part excluded from participating in clinical trials.›› Treatment interventions, toxicity and safety data were studied in men and then applied or assumed to be the same in women.› In 1993, as a result of pressure from activists, the Food and Drug Administration (FDA) finally mandated the inclusion of women into clinical trials. Unfortunately, women still only comprise approximately 12 to 23 percent of the total participants in clinical trials.

What is a clinical trial?
Randomized controlled clinical trials are considered to be the gold standard of determining whether a treatment or device is effective, safe and tolerable.

A clinical study or investigation means any experiment that involves a testing a medication in one or more human subjects in preparation for submitting an application to the FDA [1] for approval to distribute and market the agent.› In the treatment of HIV infection, a clinical trial can offer access to a novel drug , vaccine or combination regimen for treatment of the underlying HIV disease or an opportunistic infection.›The clinical trial is the current standard for assessing drugs and therapeutic procedures.› Clinical trials are generally double blind, which means neither the patient or the investigator knows the patientís treatment assignment although all patients receive active drugs in all arms of the study.› Randomized (assignment to a treatment arm occurs randomly ñlike tossing a coin) clinical trials provide evidence that a new therapy or other intervention is efficacious.›› When the new therapy is used in a well-controlled setting of clinical practice, it may or may not have the efficacy expected in the clinical trial (this is sometimes called assessing the drug in the ìreal worldî).›› Reasons for these differences are numerous, including compliance, tolerance, drug interactions, differences in patient population and other factors.› The interest is in determining whether the new treatment provides the benefit expected in clinical practice.› A new drug or device is tested in stages, called phases (Table I). The earliest phase of clinical trials for is conducted to determine safety, followed by trials which test the effectiveness of the intervention/s while still collecting information on the safety profile.› Clinical trial phases are organized into 4 phases that usually follow each other although some studies can combine the objectives of more than one phase (i.e. phase I/II).››› Federal RegulationsRegulatory processes have changed in the last several years due to public pressure.› For years, the FDAís cautious approach to the licensure of new drugs was based on the experience of prescribing thalidomide to pregnant women and the subsequent abnormalities in their children [2] .

The urgency of the AIDS epidemic has changed the position of regulators from extreme caution to active participation and record speed in drug approvals.› Zidovudine (ZDV) was approved after only one controlled trial in 282 patients.› In addition, by allowing implementation of expanded access programs for unlicensed drugs, the FDA has taken a more active role in the early planning and conduct of clinical trials.Many individuals in the AIDS activist community held heated debates with FDA officials arguing that patients with terminal diseases and no effective treatment had the right to waive their rights as human subjects to become involved in an investigational drug trial [3] .

In response to continued pressure, the FDA in 1987 softened their position and issued regulations that allowed widespread distribution of investigational drugs for therapeutic purposes provided the disease is serious or life threatening.› Also, in 1988 the FDA allowed terminal patients to import small quantities of an unapproved drug for their personal use.› These drugs cannot be sold commercially and the patient must supply the name of the physician who will be responsible for monitoring these drugs.

Clinical trials are based on a set of rules called a protocol. The protocol describes:

1) the types of patients who may participate in the study,
2) the schedule of tests and procedures to be conducted during the study,
3) the drugs and dosages to be used,
4) the procedures to be used to monitor safety and toxicity and
5) the length of the study. [4]

Each patient participating in a clinical trial must agree to be treated by the rules of the protocol.› In most trials, the protocol teams look for patients who have similar medical conditions.› Patients who participate can gain access to treatments and drugs that are not available commercially.› They are usually followed up more frequently and receive intensive clinical monitoring than would be the case in standard medical care to ensure that safety and toxicity is systematically determined. One benefit of participating in a clinical trial is the chance for the patient to contribute to medical research and mankind by allowing his/her experience to be recorded and analyzed.All clinical trials are conducted in accordance with the concept of ìGood Clinical Practicesî or GCPs.› These guidelines were designed with input from researchers, statisticians, clinical personnel, regulatory and legal specialists, and the pharmaceutical industry.› They provide a framework for conducting a well-designed and well-controlled clinical study. [5] › The document outlining the GCPís is available upon request from the FDA.

Conduct of Clinical Trials
Clinical trials can be sponsored by a number of organizations such as: 1) the National Institutes of Health, 2) non-profit foundations, 3) academic institutions and 4) the pharmaceutical industry.› The studies are implemented and monitored through contractual agreements with specialized providers of clinical services.› The FDA requires that an Institutional Review Board (IRB) review and have authority to approve, require modifications in, or disapprove all research activities covered by the IRB regulations.› An IRB is required to ensure that appropriate safeguards exist to protect the rights and welfare of research subjects.› In fulfilling these responsibilities, an IRB is expected to review all the research documents and activities that bear directly on the rights and welfare of the subjects of proposed research.›› Case report forms (CRFs) that record information about the patientís experience are filled out by the investigator who conducts the study.› These forms may be reviewed by the sponsor of the clinical trial and the FDA.› However, the patient is not identified by name in these forms and all records are kept under lock and key at the study site. [6]

Expanded Access
The most recent changes in drug trial regulation have occurred with expanded access or parallel track program.› This allows patients with HIV infection to obtain certain drugs that have not yet been approved by the FDA.› The basic concept is to provide access to treatment for persons with no other treatment options and who do not meet protocol criteria to enroll in studies of the drug.› Expanded Access programs are usually implemented by the pharmaceutical companies when the results of clinical trials indicated that the medication has activity› but has not yet been approved by the FDA.› This mechanism allows patients to obtain medication that may be desperately needed and maintains the integrity of controlled trials by reducing the incentive to enroll inappropriate subjects as a way of obtaining treatment.›› This represents a response to the› HIV-affected community who have demanded access to medications before full FDA approval in light of a consistently fatal disease.›› For example, a new drug called PMPA has just been made available through Expanded Access by the manufacturer Gilead Sciences. This program is to provide access to patients with low CD4s & few treatment options. PMPA is expected to help many people who have resistance to NRTIs such as AZT, d4T and 3TC. It will not help everyone but should help a number of people. You can ask your doctor or NATAP about PMPA. You can speak to your doctor about the Expanded Access Program, and they can contact Gilead for more information. The manufacturer will be applying to the FDA for approval of the drug this Summer (2001).

Informed Consent
Ethical issues can arise in the relationship between the clinician and the woman who is interested or participating in a particular clinical trial.› These include problems of confidentiality, informed consent, and respect for the womenís autonomy.› Although some evidence suggests that regulations for human experimentation based on informed consent was recognized as early as the nineteenth century [7] -9, the Nuremberg code of 1947 is generally regarded as the first document to set out ethical regulations in human experimentation based on informed consent.› The issue of ethics with respect to medical experimentation in Germany during the 1930's and 1940's was a crucial part of the Nuremberg trials and related trials of doctors and public health officials.› Those involved in the horrible crimes against humankind attempted to excuse themselves by arguing that there were no explicit rules governing medical research on human beings in Germany during the period and that research practices in Germany were not different from those in allied countries.From the Nuremberg trials 10 principles to guide physician, physician assistants and nurse practitioners that are investigators in experiments conducted in human subjects were established.› These principles include a ìvoluntary consent formî that is written in an educational level that can be understood by the average individual.› The treatment consent protects the patientís right to privacy and confidentiality and helps to determine liability and responsibility to prevent abuse of people in various experiments.

Consent to treat has become an important part of clinical trials, private practice, public practices and hospitalization along with the ìpatientís bill of rightsî (see table 2).› So, what does this all mean to the primary care provider of a patient involved in a clinical trial?Clinical PracticeGuidelines for clinical practice have also been developed based on not only clinical trials, but on other types of studies, synthesis of data, and expert opinion.› The publications of the federal Agency for Health Care Policy and Research (AHCPR) can be useful.› AHCPR was established to promote effective medical research, develop databases for research, develop clinical guidelines, and disseminate research findings and clinical guidelines.› It has published reviews of studies on clinical problems with summaries of treatment effectiveness.› AHCPR has also published research-based clinical practice guidelines on multiple topics. The free publication of the AHCPR, clinical practice guidelines, research activities and the publication catalog can be obtained by contacting AHCPR Publications Clearinghouse, P.O. Box 8547, Silver Spring, MD 20907 [(800) 358-9295].The primary care records of each patient should be structured in a manner that facilitates the recording and accessibility of important information from the primary care provider as well as from consultants and/or the research team.› It is the obligation of the patientís primary care provider to obtain specific information about the clinical trial that his/her patient is participating in such as: the duration of the study, metabolism and side effects of the drugs being studied, the other drugs that the patient may be taking and potential interactions between these drugs.› Your physician should have the names and phone numbers of the research protocol team and contact the team for any questions he/she may have.

Why should I participate in a clinical trial?

Data on the natural history of HIV disease in women are still limited.› In addition to getting many of the opportunistic infections seen in men, women have sex-specific symptoms that are often either hormone related or gynecological in nature.› Recently, information in several different studies suggest that women have lower viral loads than men, although HIV disease appears to progress at the same rate in both sexes.› Women probably differ from men in absorbing, metabolizing and experiencing the clinical effects of certain medications.› Drug dosing, absorption, efficacy and toxicity are likely to be affected by differences in hormones, weight and body-composition between men and women.

Until more women become involved in clinical trials, they will continue to be treated based on information that is gleaned from men.› Become involved, look for a trial that interests you and join a clinical trial!Before enrolling in any clinical trial the doctor, nurse or other staff person must review the informed consent document with you. As part of this process they must discuss with whether or not this trial you are considering fits your needs or not. You should discuss with your personal physician whether or not this trial is appropriate for you & your situation. Often, trials randomize you to one treatment regimen or another. You want to make sure you are helping yourself regardless of which treatment regimen you receive. Please be sure to discuss this whether the study staff and your doctor.

Table 1-› The Four Phases of Clinical Trials to Approve Drugs

Phase I Clinical Trial

Objective: to determine safety & side effect profile› of the highest dose tolerated

Small number of patients
Study duration days to weeks

Phase II Clinical Trial

Objective: to determine Treatment is effective and ne) Small number of patients

Phase III Clinical Trial

Objective: to determine the effectiveness of the treatment in the affected population

Large number of subjects Study duration months to yrs

Phase IV Clinical Trial

Objective: to determine the activity and safety profile over the long term

Post FDA approval

Table 2 - The Patient's Bill of Rights

  1. The nature and purpose of the study.
  2. The procedures in the study and any drug or device to be used.
  3. Discomforts and risks to be expected from the study.
  4. Benefits to be expected from the study.
  5. Alternative procedures, drugs or devices that might be helpful and their risks and benefits.
  6. Availability of medical treatment should complications occur.
  7. The opportunity to ask questions about the study or the procedure.
  8. The opportunity to withdraw at any time without affecting your future care at this institution.
  9. A copy of the written consent form for the study.
  10. The opportunity to consent freely to the study without the use of coercion.
  11. Statement regarding liability for physical injury, if applicable

[1] .››Code of Federal Regulations.› New Printing of Revised 1994 Code of Federal Regulations. Good Clinical Practices Parts 50, 56, 312, 314.› Barnett International Learning Group.›

[2] .››Broder S, Merigan T, Bolgnesi D.› The Textbook of AIDS.› Williams & Wilkins.› Baltimore, Maryland. 1994.

[3] .›Rothman DJ, Edgar H. AIDS, activism and ethics.› Hosp Pract 1991;26:87-94.

[4] .›AIDS Clinical Trials Information Service. #FBC25487.

[5] .›Food and Drug Administration
            Associate Director for Science and Medical Affairs
            Center for Drug Evaluation Research
            5600 Fishers Lane
            Rockville, MD 20857
            Phone: 301 443-2894››› FAX 301 443-2763

[6].››››National Institutes of Health.› Guidelines on subjects in clinical research.› Federal Register 1994;59:11146-11151.

[7].›Vollmann J. Winau R.› Informed consent in human experimentation before the Nuremberg code.› BMG. 1996 Dec 7, vol.› 313 (7979):1445-9.1.
           Baron J.› History of Informed Medical Consent.› Lancet, 1996 Feb 10, vol. 347 (8998):410.2.
           Mendelson D.› Historical Evaluation and Modern Implications of Concepts of Consent to, and Refusal of, Medical Treatment in the Law of Trespass.› Journal of Legal Medicine.› 1996 Mar vol. 17 (1): 1-71.

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