Health Care Law and Regulations 8
Chapter 19
Clinical Trials
Clinical Trials
“The history of the last 20 years is one of crises with drugs and medical devices, many approved despite the objections of the FDA’s own scientists.”
— Sidney M. Wolfe
Lecture Overview
Research and Development Investments Fund a Complex Multistage Pathway
Clinical Trials of Generic Drugs
Health Risk Assessments
Expanded Access Protocols
Termination of Clinical Trials
Observational Studies
International Clinical Trials
Informed Consent in General
Transparency and Full Disclosure in Clinical Testing
Financial Conflicts of Interest
Commitment to the Life Sciences
Source: Hammaker, D. K., & Knadig, T. M. with Tomlinson, S.J. (2017). Clinical trials. In Health care management and the law: Principles and applications (pp. 389-412). (2nd Ed.) Burlington, MA: Jones & Bartlett Learning.
Research and Development Investments Fund a Complex Multistage Pathway
Some major expenses are research materials, advanced computers, and other highly sophisticated machines that support research activities, and salaries of scientists. Stage specific activities include:
Drug discovery
Preclinical testing
Clinical trials
Approval by the FDA
Post marketing surveillance
Research and Development Investments Fund a Complex Multistage Pathway
Drug Discovery:
While most compounds will never be approved for use, each one is evaluated to determine its potential value compared to existing therapies, complexity of large scale manufacturing, and other factors.
Preclinical Testing:
Candidate drugs from the discovery stage receive 1 to 3 years of extensive testing to assess safety and show biological activity against a disease.
Chemical tests establish the purity, stability, and shelf life of a compound.
Manufacturing tests determine mass production of the drug.
Pharmaceutical development studies explore dosing, packaging, and formulation of the drug.
Research and Development Investments Fund a Complex Multistage Pathway: Clinical Trials
For drugs in development, there are low odds of reaching the market.
While Phase I, II, and III of studies are taking place, research investigators are also conducting toxicity tests and other long-term safety evaluations, evaluating dosage forms, planning for mass production, designing packaging, and preparing the extensive application required for FDA approval.
One out of five drugs that enter clinical testing is never approved by the FDA:
20% of the drugs that enter Phase I are approved to enter Phase II
30% of the drugs that enter Phase II are approved to enter Phase III
60% of the drugs that enter Phase III are approved for a new drug application
80% of the new drug applications are approved by the FDA for market entry
Research and Development Investments Fund a Complex Multistage Pathway
Approval by the U.S. Food and Drug Administration
According to the FDA, the documentation required in a new drug application is supposed to tell the whole story of a drug, including what happened during the clinical trial tests, what the ingredients of the drug are, results of the preclinical animal studies, how the drug behaves in the human body, and how the drug is manufactured, processed, and packaged.
Post Marketing Surveillance
Firms are meant to continue to monitor all approved drugs for long-term safety and regularly report results to the FDA.
It is important to note that clinical trials cannot always detect risks that are:
Relatively rare
Have long latency periods
Affect vulnerable populations
Clinical Trials of Generic Drugs
Distinction Between Bioequivalent and Biotherapeutic
Generic versions of branded drugs need not demonstrate their scientific merits by controlled human clinical trials or other testing the brand name pharmaceutical firms conducted.
By definition, generics may be up to 45% less or 25% more efficacious than branded drugs, yet still meet the legal definition of being bioequivalent.
Generics are not required to provide independent proof of their safety or efficacy to be labeled bioequivalent.
Distinction Between Branded Generics and Generics
The pharmaceutical industry also markets authorized branded generics, which are branded drugs that have lost their patent status but are labeled and marketed as generics.
Both empirical and theoretical studies evince that generic entry is inversely related to price: More generics = lower prices.
Health Risk Assessments
Information on Post Phase I Clinical Trials
Congress expanded the requirements for all sponsors and research investigators to share information about post Phase I clinical trials, including selected aspects of trial results, on the U.S. government website, ClinicalTrials.gov.
Balancing Risks and Benefits
Proper health risk assessment is critical for new drug product treatments. Patients, physicians, and the FDA often weigh the pros and cons of one treatment versus another.
An ongoing issue is whether the FDA should do more to ensure the safety of new drug products and expose potential side effects before a drug product comes into widespread use.
Expanded Access Protocols (1 of 2)
An investigational new drug application, or treatment protocol, is a relatively unrestricted study intended to authorize shipment of an unapproved drug product into interstate commerce.
Right to Life Saving Experimental Drugs: Abigail Alliance v. Von Eschenbach
Issue: Does a fundamental right exist under the Fifth Amendment (which contains the Due Process Clause) provide terminally ill patients access to potentially lifesaving experimental drugs?
Holding: No, terminally ill patients do not have a fundamental right to access experimental drugs
Expanded Access Protocols (2 of 2)
Abigail Alliance: Two Tier Approval Proposal
Grants terminally ill patients who have exhausted all FDA approved therapies the autonomy of selecting post Phase I experimental medical products with their physicians.
Lifts the current prohibition of charging any price higher than the cost for experimental products.
Balancing Patient Rights: Access versus Personal Autonomy
The right to personal autonomy affects individual interests in obtaining investigational medical treatments and medical products, while the right to access pertains to the public’s interests in filtering safe and efficacious products through clinical trials.
Termination of Clinical Trials (1 of 3)
Clinical trials usually get halted for one of two reasons:
New drug shows overwhelming promise and it would not be fair to delay its release
Results suggest great risks
The medical products industry will likely avoid fiduciary status and binding agreements with respect to clinical trial participants by:
Designing sponsor protocols to comply with FDA regulations
Outsourcing clinical trial design and administration
Forgoing control over clinical studies
Termination of Clinical Trials (2 of 3)
Monitoring Board Decisions
While each clinical trial is different, for many trials, monitoring boards set numerical thresholds for bad outcomes before the trial begins. When the thresholds are crossed, the trials are stopped.
Relative Risks
Patients taking Lipitor plus in a Pfizer clinical trial were 60% more likely to die. This statistic suggests why Pfizer might have wanted to stop the trial. As in most clinical trials, the difference between stopping and proceeding comes down to just a few deaths.
Termination of Clinical Trials (2 of 3)
Statistical Boundaries
When an imbalance in deaths crosses the statistical boundary set before the trial begins, clinical trials are automatically halted. This statistical boundary is not some arbitrary figure, but rather a single number, the p value, that is calculated as part of the trial protocol.
Statistical Significance
Thresholds are usually set at 0.05 for statistical significance.
Thresholds are set higher when there are frequent measurements of p, to make sure that too much weight is not given to any single reading.
Christine Freaney (CF) -
Observational Studies
Researchers found breakfast cereals eaten before conception were the most significant food linked with baby boys.
Nature of Nontrivial Chance
Behind the cereal debate is the divide between statisticians and epidemiologists about the nature of nontrivial chance in observational studies where research investigators track clinical trial participants’ habits and look for associations with their health, but do not intervene
Validation
Some want a tougher standard of proof required for investigators looking at large data sets
Bonferroni adjustment method: Requires multiplying the usual mathematical formula by the number of variables; if 100 foods are studied, the link must be 100 times as strong as usual to be considered significant
International Clinical Trials (1 of 2)
Fifty Percent Cost Savings
Late stage clinical trials in lower income countries cost less than half as much as they do in the United States and Europe because of lower salaries for physicians and clinical research personnel.
Patient recruitment is faster in countries such as India, China, and in Eastern Europe, where:
Patients are more willing to enroll in studies because of lack of alternative treatment options
Competition for patients is less intense
Clinical trial participants are far less likely to be taking other medicines
Patient populations are larger
Good Clinical Practices
The FDA has adopted standards used by many countries and organizations known as good clinical practices that encourage postmarket drug access to be discussed during protocol design, mandate that studies be reviewed by international ethics committees, permit placebo controlled trials only under certain circumstances, and require informed consent from all clinical trial participants.
Inconsistent Oversight and Informed Consent
Research suggests oversight and adequate informed consent for clinical trial participants in clinical trials is inconsistent in resource limited countries.
While the medical products industry generally uses the same protocol regardless of where its clinical trials occur, international sites are not routinely monitored and not all research investigators have experience conducting clinical trials.
International Clinical Trials (2 of 2)
Informed Consent in General (1 of 7)
Informed consent:
Protects individual autonomy and the participant’s status as a human being
Helps avoid charges of fraud or duress against clinical trial sites
Encourages research investigators to carefully consider their clinical decisions
Fosters rational decision making by the clinical trial participants
Involves the public generally in medicine
Informed Consent in General (2 of 7)
Informed consent continued
Medical custom dictates that a reasonable physician should disclose what would be reasonable under the circumstances, including:
Diagnosis
Nature and purpose of the proposed treatment
Risks of the treatment
Legitimate treatment alternatives, including doing nothing
Federal regulations govern clinical research protocols and define what information is required to obtain informed consent.
Informed Consent in General (3 of 7)
Placebos
Placebos may be used in order to test the rate of success.
Institutional review boards must continually review the research and determine that: confidentiality is maintained, data collected is monitored, informed consent was obtained, risks are minimized and reasonable, selection of volunteer subjects is equitable.
Declaration of Helsinki
The Declaration of Helsinki sets forth the international ethical principles for medical research involving human subjects.
Research on human subjects who cannot give consent is only permissible if the condition that prevents consent from being given is what is being tested or researched
Informed Consent in General (4 of 7)
Battery Claims
If there was no consent given, clinical trial participants may have a battery claim, which simply requires a showing that there was unconsented contact.
Informed Consent Claims
If there was insufficient consent, clinical trial participants may have an informed consent claim, which is pursued under a theory of negligence.
Informed consent forms are not generally an important part in the decisionmaking process because they are treated as a formality.
Informed Consent in General (5 of 7)
Newborn Screening Programs
The Bearder v. State of Minnesota decision highlights the issues of informed consent in the debates surrounding the genetic privacy of newborn blood samples
Issue: Should states enhance protections for the genetic privacy of newborn blood samples?
Holding: Yes, the genetic information contained in DNA brings newborn blood samples falls within the protection of the genetic privacy law
Informed Consent in General (6 of 7)
Emergency Research Rule
There has been a substantial increase in the use of the Emergency Research Rule, with most of this increase related to studies supported by the National Institutes of Health (NIH)
Currently, NIH is funding emergency research studies, which consider consent waived after institutional review boards sign off on each clinical trial, if:
A physician and an institutional review board agree that the life of a patient is in danger
Proven treatments will not work
Clinical research is necessary to determine what intervention is best
Research could not be done otherwise
Informed Consent in General (7 of 7)
Informed Consent and Participation of Children in Human Subject Research
Children in general are considered vulnerable research subjects
Minors cannot provide informed consent because they are considered incapacitated under the law, meaning that they lack the ability to acquire the knowledge necessary to make a truly informed, voluntary decision
Institutional review boards can approve pediatric research only in three risk-benefit categories:
Greater than minimal risk but with a prospect of direct benefit
Minimal risk
Minor increase over minimal risk without a prospect of direct benefit
Transparency and Full Disclosure in Clinical Testing
Major shortcoming of the full disclosure requirement (also referred to as the § 801 requirement) is that:
The results of older clinical trials of drugs that were approved before the disclosure requirement became law in 2007 do not need to be made public
Such drugs constitute the vast majority of the drugs currently used by patients
Financial Conflicts of Interest
The increase in financial conflicts of interest is likely a result of the change in federal policy that was designed to expedite the progress of research results from the laboratory to patients.
Concern mainly centers on financial conflicts of interest, particularly regarding the relationship between academic and industry interests.
Commitment to the Life Sciences
First and foremost, the health care industry and the government must renew their commitment to science:
The ability to reach this goal depends heavily upon strict adherence to scientifically motivated decision making
Scientists should be insulated from financial and political pressures when making decisions about which medical treatments and products warrant approval to enter the marketplace and about which measures are appropriate when addressing unforeseen risks to patients.