Thursday, September 7, 2006

Plan B EC: Others Question its Effectiveness [Serge]

Here is a very recent letter to the editor in the Journal Pediatrics that poses some of the same questions that I have regarding the efficacy of emergency contraception (Pediatrics 117:4 April 2006, p1448).

To the Editor.-

The American Academy of Pediatrics Committee on Adolescence policy statement on emergency contraception1 reports the effectiveness of the Yuzpe regimen (ethinyl estradiol and levonorgestrel) in terms of a pregnancy reduction of 70% to 80% and of levonorgestrel-only emergency contraception of 85%. These estimates are outdated. Using current methods for estimating effectiveness, the effectiveness rates seem to be in the range of 50% to 66% and 72% to 80%, respectively.2-5 Because there are no randomized trials with a placebo arm, considerable uncertainty remains about the effectiveness of emergency contraception.3,5

The policy statement also proposes that "[e]mergency contraception has tremendous potential to reduce unintended pregnancy rates in teens and adults." This statement remains, as yet, a hypothesis that is unsupported by empirical evidence. Several studies have failed to document a decrease in rates of unintended pregnancy or abortion in populations that are provided with advance access to emergency contraception.6-8 This suggests that the studies that have demonstrated no changes in sexual behavior with advance access (other than increased use of emergency contraception) have used inadequate surrogate end points or have failed to detect small changes in sexual behavior that were nevertheless sufficient to negate any decrease in unintended pregnancy.

Joseph B. Stanford, MD, MSPH

Department of Family and Preventive Medicine

University of Utah

Salt Lake City, UT 84108

Rafael T. Mikolajczyk, MD

Department of Public Health Medicine

School of Public Health

University of Bielefeld

D-33501 Bielefeld, Germany

Wednesday, September 6, 2006

Plan B: Is the FDA Using Outdated, Inaccurate Information? [Serge]

An e-mailer recently asked about the fact that the FDA does list prevention of implantation as a potential mechanism of action of Plan B. You can see that in the FDA Q&A here as well as the package insert here. Does the FDA know something that we don't?

The FDA relies on information provided by the manufacturer for the mechanism of action of any medication (they do not do their own research). I responded to the information provided by the manufacturer in this post here. In short, the manufacturer has a responsibility to list any possible mechanisms of action for any medications. Since there is an open question in the literature regarding the mechanism of Plan B, and since post-fertilization events are listed as one possible mechanism, it is not surprising (nor particularly helpful) that interruption of implantation is included as a possible mechanism of action.

In other words, the fact that the manufacturer mentions this as a possible mechanism is evidence that the question is an open one that we have no definitive answers to. Therefore, the presence of this information by the FDA does not trump the most recent literature on the topic. In fact, the opposite is true.

I can illustrate this in another way that does not directly address the mechanism of action of Plan B. The manufacturer makes this claim in its literature, and its repeated on the packaging of Plan B that the FDA agreed to:

A double-blind, controlled clinical trial in 1,955 evaluable women compared the efficacy and safety of Plan B (one 0.75 mg tablet of levonorgestrel taken within 72 hours of intercourse, and one tablet taken 12 hours later) to the Yuzpe regimen (two tablets of 0.25 mg levonorgestrel and 0.05 mg ethinyl estradiol, taken within 72 hours of intercourse, and two tablets taken 12 hours later). Plan B was at least as effective as the Yuzpe regimen in preventing pregnancy. After a single act of intercourse, the expected pregnancy rate of 8% (with no contraception) was reduced to approximately 1% with Plan B. Thus, Plan B reduced the expected number of pregnancies by 89%.

The exact citation isn't listed, but clearly they were citing this study from 1998 (both studies had 1955 women enrolled), Lancet 1998 Aug 8;352(9126):428-33. This is the same study that I posted about here. They used a crude method of determining ovulation: they added 14 days to the last period. The primary author for this paper was H Von Hertzen.

In other words, the FDA is allowing data 8 years old that used a very inaccurate way of determining ovulation, which is essential in determining effectiveness in stopping pregnancy. In fact, the author of that study has more recently contributed to an article which acknowledges the inaccuracy of their data in estimating the expected rate of pregnancy(Contraception 2003 Apr;67(4):259-65.)

This article, in which Von Hertzen is an author, states in the abstract:

The expected pregnancy rate among typical users was 6.2% in the Population Council trial and 7.4% in the WHO trial based on conception probabilities by cycle day relative to the day of ovulation. Based on conception probabilities by cycle day relative to the first day of bleeding, the expected pregnancy rates dropped to 5.4% and 5.2%, respectively. The two trials yield conflicting evidence regarding whether effectiveness declines with treatment delay. CONCLUSIONS: Our results suggest that the absolute levels of effectiveness for the Yuzpe regimen of emergency contraception and the cost-effectiveness of this regimen have probably been overstated when based on conception probabilities by cycle day relative to day of ovulation.

Although the authors only mention the Yuzpe regimen the same pregnancy estimation was also used to determine the efficacy of Plan B. If the effectiveness of the Yuzpe regimen had been overstated, then the same can be inferred with Plan B. It should also be noted that even with the "more accurate" method of determining ovulation, there is a significant chance for error in determining the actual date of ovulation.

I hope I haven't lost anyone. Here's the bottom line: the FDA is allowing the manufacturer of Plan B to claim that it can be almost 90% effective based on a study from 1998. This study has been shown to be inaccurate due to its crude way of estimating ovulation. This fact was pointed out by none other than the author of the original study. Yet there it is on the packaging being readied for OTC sale.

Still confident in the FDA information now? There is significant reason why we should not be. In any event, it should be clear that the information given by the FTC does not refute more recent scientific studies.

Tuesday, September 5, 2006

Plan B EC: What is its Real Effectiveness? [Serge]

Sixth in a series.

I wish to challenge the most compelling line of evidence that Plan B works at least some if the time via a post-fertilization mechanism. In this post, I believe those who are very pro-emergency contraception will be quite disappointed.

The most common evidence used to support a post-fertilization effect of Plan B is its proposed effectiveness. Quoting from this post:

1. The reported effectiveness of EC cannot be fully explained by a suppression of ovulation. In other words, if EC worked through non-fertilization events, we would not expect it to be as effective as it appears to be. Therefore there must be some post-fertilization event that is responsible for at least part of its effectiveness.

The effectiveness of Plan B is reported to be somewhere between 90 and 75% in stopping an unintended pregnancy. If this is true, it seems impossible that it could work via a purely anti-ovulatory action. As Steve states here, the most important question to ask would be when did a woman ovulate. If Plan B is taken after a woman ovulates, and it contributes to the 75% effectiveness, then it must work at least part of the time via a post-fertilization event.

If, on the other hand, Plan B works through predominantly anti-ovulatory actions, its effectiveness would be expected to be less than 75%. What does the data support? If one looks at some of the more recent studies, it is reasonable to conclude that the effectiveness of EC is significantly less than 75%.

First, it is a known fact that studying the effectiveness of EC is quite challenging. The main reason is that in order to have a comparison group, an accurate determination of the date of ovulation is essential. An ideal study would use a placebo control group - but that would entail giving a woman who is seeking to prevent a pregnancy a placebo, which is considered unethical. For that reason, estimates of ovulation are used. It has been shown that these estimations are often very inaccurate, as shown by this article: (Contraception 2003 Apr;67(4):259-65)

Calculations of the efficacy of EC depend on knowing the timing of intercourse in relation to the estimated day of ovulation. The results of this study suggest that these calculations are likely to be inaccurate for a significant minority of women.

Is there evidence that EC may not be effective as advertised? Absolutely. I will cite two very recent studies. In this article about EC in JAMA (JAMA 2005;293:54-62), the authors specifically choose a number of women that would have direct access to EC vs pharmacy access in order to show a difference in pregnancy rate between the two groups (they choose about 890 women in each group). They say so in the article, and this was not a small study. As it was, the group who had to go to the pharmacy to get EC used it 197 times, while the group who had direct access used it 309 times. The result on pregnancy: absolutely nothing! The pregnancy rate for the first group was identical despite the fact that they used EC one third more often. This caused the authors of the study to state:

While we set out to demonstrate a large reduction in pregnancy rates, even a10% or 20% reduction in unintended pregnancy rates would be a significant and desirable public health achievement.

What ever happened to 75%? They set out to demonstrate a large reduction in pregnancies, and got zero despite the fact that so many more women took EC. Now they would be happy to see a 10-20% reduction. This is solid evidence that in the "real world", EC doesn't work nearly as often as stated.

Here's one more (Contraception 69 (2004) 361-366). These researchers showed that having EC at home did not reduce pregnancy or abortion rates in that population. Lest anyone think that my reasoning is novel here, the authors seem to agree with me:

Finally, it is possible that EC may be less effective than we belief. Estimates of efficacy are unsubstantiated by randomized trials. Efficacy is based on rather unreliable data and a great many assumptions [28] and have been questioned both in the past [29] and more recently [30].

In conclusion, I believe there is an increasing amount of evidence that the proposed efficacy of EC is not nearly what was originally thought. There is no doubt in my mind that those who support increased access of EC as a public policy issue are not in any hurry to publicize this data. On the other hand, the decreased efficacy of EC is also key evidence that Plan B works predominately prior to ovulation.

Friday, September 1, 2006

Plan B EC: No Morphological Changes Found in Endometrium [Serge]

Fifth in a series.

In this post, I spoke of three evidences that have been presented to support a post-fertilization mechanism of action from Plan B EC. I promised to challenge each one, and this was #2:

2. Since EC has the same types of hormones found in regular oral contraceptives, and there is evidence that regular OCs can have a post-fertilization event, then it stands to reason that EC would also have a post-fertilization mechanism of action.

I believe this point is the easiest one to refute, and my research in this area has turned up some surprises.

First, this point implies that there is a known post-fertilization effect from regular OCs. There is no consensus on that issue, and there is no direct evidence that OCs cause a "hostile endometrium." However, even if you believe that regular OCs do cause abortions, that does not indicate that Plan B EC does work via a post-fertilization event. This was a surprising aspect of this research: if Plan B acts after fertilization, the evidence states argues that it must do so by a mechanism that is different than regular OCs. I will show why.

Most who believe that regular OCs can act as an abortifacient use what I call the "hostile endometrium" theory". The theory is that continued use of OCs create a thinner, less vascular endometrium that would be less likely to accept an embryo attempting to implant. Randy Alcorn, who has written extensively on this topic, explains it this way:

When the Pill thins the endometrium, it seems self-evident a zygote attempting to implant has a smaller likelihood of survival. A woman taking the Pill puts any conceived child at greater risk of being aborted than if the Pill were not being taken...

First, after a woman stops taking the Pill, it usually takes several cycles for her menstrual flow to increase to the volume of women who are not on the Pill. This suggests to most objective researchers that the endometrium is slow to recover from its Pill-induced thinning

Now if the effect of regular OCs take months to for a woman's body to "undo", then how does Plan B EC create a hostile environment in a matter of hours? It seems that if EC works via a post-fertilization event, it must use some different mechanism than regular OCs, which appears to be based on a chronic thinning of the endometrium.

However, I did not have to depend on the argument of the last paragraph. There is actually experimental evidence that shows that Plan B taken after ovulation does not have any significant change in the morphology of the endometrium. Take a look at the abstract here and the full article here that presents this evidence. (Contraception. 2001 Oct;64(4):227-34.) They performed endometrial biopsies on women who took Plan B EC and control groups and found no difference in the morphology between the two. The paper states:

No significant changes were observed between treated and control specimens in any of the studied parameters. No significant differences among groups were observed. Of particular importance was the finding that the predecidual changes as evaluated by the presence of prominent spiral arteries, which are considered crucial for implantation [24], were not altered by LNG.

Remember, the proposed mechanism of regular OCs is to create a significantly thinner endometrium. This does not occur when a woman takes Plan B.

Although the medications are the same, if Plan B acts to cause abortions, it seems to have to do so via a different mechanism than does regular OCs. Instead of being evidence for a post-fertilization mechanism of action, this actually gives support to the theory that Plan B does not act after ovulation.