Friday, January 20, 2017

the 21st Century Cures Act: Key Provisions

Last week and this week, Hyman, Phelps &McNamara, P.C. gave two excellent webinars to explain the key provisions from the 21st Century Cures Act

The first webinar is about 'Pharmaceutical & Biologics Provisions'. The webinar can be replayed here. The webinar discussed top 13 pharmaceutical & biological issues listed below: 
  • Patient Experience Data (Section 3001)
  • Patient-Focused Drug Development (Sections 3002-3004)
  • Qualification of Drug Development Tools (Section 3011)
  • Priority Review Vouchers (Sections 3013, 3014, & 3086)
  • Human Research Protections (Sections 3023 & 3024)
  • Expanded Access Policies (Section 3032)
  • Limited Population Pathway (Section 3042)
  • Health Care Economic Information (Section 3037)
  • Real World Evidence (Section 3022)
  • Regenerative Advanced Therapies (Sections 3033-3036)
  • Hiring Authority (Section 3072)
  • Targeted Drugs for Rare Diseases (Section 3012)
  • Novel Clinical Trial Designs (Section 3021)

The second webinar is about ‘Combination Products andMedical Device Provisions’. The webinar can be replayed here. The following 11 provision topics were discussed.
  • Combination products (Sec. 3038)
  • Breakthrough devices (Sec. 3051)
  • Humanitarian device exempt. (Sec. 3052)
  • Recognition of standards (Sec. 3053)
  • 510(k) exemptions for Class I/II devices (Sec. 3054)
  • Classification panels (Sec. 3055)
  • Institutional review board (IRB) flexibility (Sec. 3056)
  • CLIA waiver improvements (Sec. 3057)
  • Least burdensome device review (Sec. 3058)
  • Cleaning instructions and validation (Sec. 3059)
  • Clarifying medical software regulation  (Sec. 3060)

Thursday, January 12, 2017

FDA Has Just Released Its Draft Guidance for Industry "Multiple Endpoints in Clinical Trials"

For those who are interested in the design and analysis of clinical trials, FDA has just released its long-anticipated draft guidance for industry: Multiple Endpoints in Clinical Trials. The release has been delayed for about 4 years. I have heard several years ago this guidance has been completed and ready to be released. For example, in a presentation by Dr Huque in 2013, it was mentioned "The Draft Guidance, Multiple Endpoints in Clinical Trials, is near completion.  It is expected to be released soon for public comments."

In contrast, EMA issued its guidance “Points to Consider on Multiplicity Issues in Clinical Trials” more than a decade ago. I believe that EMA is considering to update its guidance and its guidance released in 2002 is obsolete now. This can be reflected in its "Workshop on multiplicity issues in clinical trials" organized in 2012. Perhaps this will be delayed due to Brexit.

Similarly to other statistical heavy FDA guidance (such as the guidance on adaptive design and non-inferiority clinical trials), the guidance "Multiple Endpoints in Clinical Trials" provided a lot of details, not only about the situations the adjustment for multiplicity is needed, but also the various procedures for handling the multiplicity issues.

The next FDA guidance in statistical area should be in missing data and Bayesian clinical trial. For missing data, EMA published its "Guidance on Missing Data in Confirmatory Clinical Trials". FDA sort of relies on the report "the Prevention and Treatment of Missing Data in Clinical Trials" as its general guidance. For Bayesian clinical trials, FDA CDRH division is ahead of CDER/CBER and has published its "Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials". This makes sense since Bayesian approach is more often used in medical device trials and CDRH is more amenable to accepting the Bayesian designs.

       RAPS (2016) Multiple Endpoints in Clinical Trials: FDA Issues Draft Guidance

Saturday, January 07, 2017

Exclusion of pregnant women from clinical trial and pregnancy test for women of childbearing potential (WOCBP)

Even though it is encouraged for clinical trials to include the women subjects, the clinical trial protocols commonly (almost always) contain the exclusionary criterion "pregnant and lactating women and women of childbearing potential". The term ‘women of childbearing potential’ may be abbreviated as WOCBP and means ‘pregnable women’. The protocols usually have languages in inclusion or exclusion criteria to exclude the pregnant and lactating women. For women of childbearing potential, they have to have acceptable birth control approaches in order to be included in clinical trials.

Here are some example languages for inclusion / exclusion criteria regarding the WOCBP:
Inclusion criteria:

The subject, if female, is physiologically incapable of childbearing or practicing an acceptable method of birth control (i.e., surgical sterilization, approved hormonal contraceptives, barrier methods [such as a condom or diaphragm] used with a spermicide, or an intrauterine device). For women of childbearing potential, a negative serum pregnancy test will be required at Screening.
If a subject is a female of childbearing potential, she must have a negative result on an approved urine pregnancy test at the time of screening, and must agree to practice contraception by a method of proven reliability (includes abstinence) for the duration of the study.
Exclusion criteria:

Females of childbearing age who have not used or do not plan to use acceptable birth control measures, for the duration of the study. Oral, injected or implanted hormonal contraceptive, barrier methods (condom or diaphragm with spermicide), intrauterine device, surgical sterilization, transdermal delivery, congenital sterility or sexual abstinence are considered acceptable forms of birth control. If sexually active the subject must have been using one of the accepted birth control methods at least one months prior to study entry;

The language regarding the exclusion of pregnancy women from clinical trials apparently derived from the Food and Drug Administration's Guidelines for researchers. While the Guidelines are not legally binding, research conducted in accordance with the Guidelines qualifies for FDA consideration in a New Drug Application, and most investigators take the Guidelines seriously.

FDA guidance (1977) General Considerations for the Clinical Evaluation of Drugs has a specific chapter about the “Women of Childbearing Potential”
A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable, or mechanical contraception; women who are single; women whose husbands have been vasectomized or whose husbands have received or are utilizing mechanical contraceptive devices. Women in certain institutions, e.g., prisions, although of childbearing potential, could be considered as not in the appropriate environment to become pregnant during administration of an investigational drug. However, women in mental institutions could become pregnant.

In general, women of childbearing potential should be excluded from the earliest dose ranging studies. If adequate information on efficacy and relative safety has been amassed during Phase II, women of childbearing potential may be included in further studies provided Segment II and the female part of Segment I of the FDA Animal Reproduction Guidelines have been completed. All three Segments should be completed before large-scale clinical trials are initiated in women of childbearing potential.
In some cases, women of childbearing potential may receive investigational drugs in the absence of adequate reproduction studies in animals. These include, for example, the use of the drug as a life-saving or life-prolonging measure; use of a drug belonging to a class of compounds (e.g., anti-metabolites) where a teratogenic potential has already been established in animals; use of women who have been institutionalized for a time period adequate to establish a non-pregnant state.
When an investigational drug is used in a woman of childbearing potential for treatment of a serious disease and animal reproduction studies have not been performed, the lack of reproduction studies should be pointed out and fully informed consent should be obtained.

Pregnancy tests should be performed prior to introduction of the investigational drugs and the patient should be advised about suitable contraceptive measures.

For drugs that are absorbed systemically, transplacental passage and secretion in milk of the drug should be assumed until proven otherwise. Fetal follow-up should be carried out in women who become pregnant while on the drug. Excretion of the drug or its metabolites in the milk of lactating women should be determined, when feasible, prior to use of the drug in nursing mothers.
National Academy Press (1999) Women and Health Research: Ethical and Legal Issues of Including Women in Clinical Studies. Chapter :11 Impact of Current Federal Regulations on the Inclusion of Female Subjects in Clinical Studies had extensive discussion about the exclusion of pregnant women. It also mentioned the following:
The head of the FDA's Office on Drug Evaluation, Dr. Robert Temple, maintains that the Guidelines should not be interpreted by researchers to require the exclusion of women from protocols. This observation is a welcome one, but apparently it has not been widely disseminated and is not widely shared by researchers.
Excluding the pregnant women from clinical trials may also be driven by the fears of the liability issues. The clinical trial sponsors usually don’t want to deal with the potential effect on the pregnancy by the investigational drug. The risk of liability issue is much greater than benefit of including the pregnant women in the clinical trials.

We expect that it will remain as the norm for clinical trials to exclude the pregnant women (and the lactating women).

The pregnancy test at the screening can identify the female subjects who are pregnant. The pregnancy tests are usually performed periodically throughout the study to make sure that any pregnancy during the study can be caught as early as possible. Once study subjects are found to be pregnant, they will be immediately discontinued for the study drug. The subsequent study assessments will also usually not be performed (for efficacy analysis purpose, the missing data will be created). The new pregnancy will be reported using the pregnancy registration form. I have a blog article about this topic a while ago. “Report pregnancies in clinical trials

I remembered the discussions with my colleagues about some of the issues related to the pregnancy test:

Is there an age cut point for childbearing potential? 
For a study including pediatric subjects, we were debating what would be the appropriate age cut point so that the pregnancy test would not be needed for girls below the age cut point because they would not be considered as ‘childbearing potential”. We could not decide on an age cut point. There is also no age limit in the childbearing potential definition in FDA’s guidance. Essentially, for all female subjects (regardless of the age), the pregnancy were tested.
Should the information about pregnancies of female partners of male subjects in clinical trial be collected?
In another time, we were debating whether or not the information about pregnancies of female partners of male subjects should be collected. While this topic has been raised and discussed, the norm at this point is still not to collect. First Clinical Research website has a discussion about this topic.