Top 10 Unproven Infertility Tests and Treatments

 In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”^[1] alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”^[2] The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.

From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.

1. Blood testing: Prolactin and FSH

In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!

Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.

2. Endometrial scratch

The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.^[3]

3. Diagnostic laparoscopy

In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”

In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”^[1] alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”^[2] The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.

From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.

1. Blood testing: Prolactin and FSH

In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!

Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.

2. Endometrial scratch

The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.^[3]

3. Diagnostic laparoscopy

In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”

10. Immunologic tests/treatments

Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.^[12]

Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.^[13] Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.^[13]

Conclusion

To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.

Mark P. Trolice, MD

Director, IVF Center; Professor of Obstetrics and Gynecology, University of Central Florida, Orlando

Disclosure: Mark P. Trolice, MD, has disclosed no relevant financial relationships.

https://www.medscape.com/viewarticle/984553

Pfizer, BioNTech re-up iHeartRadio holiday sponsorship

 It’s that time of year again for pop music fans with the return of the iHeartRadio Jingle Ball tour — and Pfizer and BioNTech’s sponsorship. For the second year, the Covid-19 vaccine collaborators are the pharma national sponsors among consumer brand partners, including ESPN, Dunkin, M&Ms, Mercedes and Pepsi.

Pfizer and BioNTech are also sponsoring the official Jingle Ball Radio streaming station on iHeart’s network, programmed with music from past and present concert performers. This year they include Lizzo, Dua Lipa, Dove Cameron and Charlie Puth. Pfizer-sponsored radio ads and online video and digital banner ads encourage listeners to get updated Covid-19 booster shots.

https://endpts.com/marketingrx-roundup-pfizer-biontech-re-up-iheartradio-holiday-sponsorship-who-renames-monkeypox-to-mpox/

Instagram, TikTok social media influencers lead healthcare and pharma sponsorships

 When it comes to social media healthcare influencers, Instagram and TikTok are the go-to platforms for paid brand collaborations. That’s according to influencer and brand marketplace Collabstr, which also found that 44% of healthcare influencers surveyed have inked brand deals.

The average payout? $287 per collaboration.

https://endpts.com/instagram-tiktok-social-media-influencers-lead-healthcare-and-pharma-sponsorships-survey/

Bristol Myers, AbbVie drugs shake up first-line prescribing among gastroenterologists

 Bristol Myers Squibb and AbbVie are changing up the inflammatory bowel disease (IBD) market with gastroenterologists, thanks to newer-to-market drugs Zeposia and Skyrizi, respectively. The two drugs have made big gains since 2021 in first-line prescriptions, according to Spherix Global Insights’ latest real world tracking report.

Bristol Myers’ first-in-class S1P Zeposia has landed particularly strong, picking up “a sizeable portion of first line patients” in ulcerative colitis (UC), Spherix’s analysis

https://endpts.com/bristol-myers-abbvie-drugs-shake-up-first-line-prescribing-among-gastroenterologists-report/

Twitter pharma advertisers extend pauses and look around for options, but keep tweeting

 Pharma advertisers on Twitter are done — at least for now. Ad spending among the previous top spenders flattened even further last week, according to the latest data from ad tracker Pathmatics, amid ongoing turmoil after billionaire boss Elon Musk’s takeover now one month ago.

https://endpts.com/twitter-disarray-continues-as-pharma-advertisers-extend-pauses-and-look-around-for-options-but-keep-tweeting/

FDA remains silent on orphan drug exclusivity after last year's court loss

 Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

“These sponsors cannot even be certain that their orphan-designated products will be protected by orphan exclusivity, because FDA’s OOPD has effectively stopped making exclusivity determinations since late 2021. The agency appears to be seeking to avoid having to recognize an orphan exclusivity broader than a product’s approved use, as the Catalyst decision would seem to require of FDA,” O’Brien wrote yesterday.

The FDA said in an emailed statement that FDA “is not currently finalizing ODE [orphan drug exclusivity] determinations” because of the “far-reaching implications” of the court’s decision. The agency added:

The decision has caused uncertainty for rare disease drug development. Under the court’s interpretation of the scope of ODE, ODE would block approval of another company’s application for the same drug for the entire disease or condition for which the drug is granted orphan-drug designation, regardless of whether the drug was approved only for a narrower use or indication.  Under that interpretation, a sponsor could seek approval and exclusivity for a drug by focusing on the smallest, easiest-to-study populations and such exclusivity would block the drug for the entire disease, even though the sponsor did not invest in studying and developing the drug for all individuals with the disease. This could adversely affect children—particularly the youngest pediatric populations—and other populations that are typically studied later in drug development.

What’s unique about this situation, O’Brien told Endpoints News in a phone interview, is that any congressional fix would have to be retroactive. And if there isn’t a congressional fix in the near term, “this is really going to snowball and force FDA’s hand” as any second-in-line competitors for a novel product could seek approval for a different subset of the same disease, essentially dividing up the disease and winning exclusivity for all subsets if Catalyst remains the law.

“It’s pretty unusual for FDA to try to un-ring the bell, and go back to recodify an interpretation,” O’Brien added.

The agency made clear last May that the court’s decision would have a profound impact on rare disease drug development and in the way it assesses exclusivity as it “blocks approval of another company’s application for the same drug for the entire disease or condition for which the drug is granted orphan-drug designation, regardless of whether the drug was approved only for a narrower use or indication.”

The agency even went so far as to lobby Congress on the issue, seeking a permanent resolution, but to no avail yet.

Orphan exclusivity is granted to drugs designated and approved to treat diseases or conditions affecting fewer than 200,000 people in the US (or more than 200,000 and no hope of recovering costs).

O’Brien said his pharma clients are confident that if an approval is a first-ever approval, the exclusivity will be there down the road, but there are “still some frustrations” particularly as the Inflation Reduction Act exempts drugs from Medicare negotiations if they have only one orphan indication, so some sponsors may also be worried about losing that exemption.

He also said he thought FDA could grant the exclusivity and put the dates down in its database because Catalyst “is about scope of exclusivity, not eligibility for earning it.”

The Catalyst case in question from last October saw a US appeals court overturn a prior FDA court win, saying that the agency never should’ve approved a rare disease drug because a previously approved but more expensive drug with the same active ingredient has orphan drug exclusivity barring such an approval.

After asking the Supreme Court to review the case, the two companies announced a settlement in July, whereby Jacobus agreed to withdraw its petition to SCOTUS and Catalyst dismissed its patent infringement claims and acquired rights to distribute Jacobus’ Ruzurgi in the US as a treatment for the rare Lambert-Eaton myasthenic syndrome in pediatric patients.

“As a result, the outcome that FDA appears to have sought to avoid — a single approved amifampridine product on the market — remains the status quo, at least until the expiration of the seven-year orphan exclusivity period for Catalyst’s Firdapse in November 2025,” O’Brien wrote.

In the coming months, Congress will either need to pass a long-term fix for all orphan indications, or the FDA will need to finally consider how the court’s flip affects drugs with active terms of orphan drug exclusivity as well as currently marketed drugs, including generics.

The FDA previously said it expects that some drugs that are in late-stage development, or that have already been submitted for marketing application review, would be blocked from approval under the Catalyst decision’s interpretation of the Orphan Drug Act.

“The agency could also consider opening a public docket to solicit stakeholder feedback on proposed resolutions, should a legislative fix not arrive soon,” O’Brien wrote, adding:

In the meantime, we recommend that sponsors carefully assess whether a competitor is likely to seek approval for the indication or use whose orphan exclusivity has not yet been recognized by FDA. In that situation, consideration should be given to a more assertive approach, including petitioning FDA to award the orphan exclusivity or preparing for potential litigation prior to a competitor approval.

Synlogic president and CEO Aoife Brennan received an orphan drug designation today for its potential treatment of homocystinuria, a rare metabolic disease, telling Endpoints via email:

The Orphan Drug Designation makes a real and critical difference for life sciences companies – especially development stage companies – attempting to tackle serious medical needs that affect smaller populations. With Orphan Drug Designation the opportunities for more open dialogue with the FDA during the development and registration process, tax benefits and fee waivers are material and can affect investment decisions in areas of significant medical need. We support any actions that will continue to bring access to Orphan Drug designation for eligible companies to help them advance programs.

https://endpts.com/fda-remains-silent-on-orphan-drug-exclusivity-after-last-years-court-loss/

'New Tool to Report Medical Trainee Mistreatment Reveals Thorny Issues'

 With the introduction of an online tool at an academic medical center, trainees there were able to report incidents of mistreatment and show that a small number of faculty were responsible for the bulk of unprofessional behavior, according to a cohort study.

From a pool of 4,200 medical students, residents, clinical fellows, graduate students, and postdoctoral fellows at Mount Sinai Health System in New York City, there were 196 reports submitted to the institution's novel reporting system from its launch in October of 2019 to December 2021.

Nearly 90% of the reports described unprofessional interactions, and over 60% described behavior from faculty. Under 1% of the 2,900 faculty members who interact with trainees accounted for half of the reports describing unprofessional behavior, reported I. Michael Leitman, MD, a surgeon and graduate medical education dean at Icahn School of Medicine at Mount Sinai, and colleagues in JAMA Network Open.

The most common reported behaviors were related to:

• Public embarrassment or humiliation (54.9%)
• Offensive remarks related to gender, sexual orientation, national origin, race, color, or religion (32.9%)
• Denial of opportunities like training or rewards on the basis of membership in a protected group (9.2%)

The vast majority of the reports (94%) were handled by a discussion with the subject. Ten reports were escalated to a written warning or change in duties, and 14 reported faculty were referred for a physician wellness evaluation.

"We continue to be challenged by a perception, particularly among some students, arguably more so among graduate students as well as postdoctoral trainees, that the system is inaccessible, that nothing will be done, and that it is not safe to report these behaviors. Concerns about retaliation and psychological safety might discourage reporting," Leitman's group wrote.

"We managed to overcome initial substantial resistance to explicitly acknowledging and addressing mistreatment and unprofessional behaviors directed at trainees," the authors added, noting that buy-in from stakeholders in developing and implementing the online reporting tool "has allowed us to begin shifting the mental models that are at the heart of historical inertia related to mistreatment."

Research has found that mistreatment of medical trainees is both prevalent and has negative consequences for mental health and performance.

Mount Sinai's reporting tool was based on the Association of American Medical Colleges (AAMC) definition of mistreatment. People using the tool could report anonymously, or delay action on the report to reduce fears of retaliation.

Residents and fellows were the most frequent reporters, at 55.5% of all reports. Complaints were directed at faculty in 61.3% of cases and residents and fellows in 13.9%. The majority of negative feedback was centered around just 20 faculty members.

To have so few members of faculty responsible for so much of the negative feedback is notable -- but perhaps not surprising, according to Bryan Carmody, MD, a pediatric nephrologist at Children's Hospital of The King's Daughters in Norfolk, Virginia, and an advocate for medical students, who was not involved in the study.

"My feeling is that, at most institutions, who the problem faculty are is no secret," he told MedPage Today. "The issue is that they're powerful -- and anyone in a position to do something about their behavior knows that they can't go off half-cocked."

Mount Sinai was initially motivated to create a professional accountability system after an analysis of data collected for accreditation showed "greater than national average mistreatment incidents directed at trainees, lower than national average reporting and awareness of policies, and fear of retaliation," according to Leitman and colleagues.

Leading up to the implementation of the new tool, a group of stakeholder representatives met for 12 months and designed the feedback form and protocol for triaging reports, providing feedback, disclosing aggregate data publicly, and addressing problems via remediation, formal investigation, or disciplinary action.

Participants could also submit positive experience reports, and did so in 14 reports.

Carmody pointed out that around 20 to 30 reports were submitted in most quarters of 2021, amounting to a report every 3 to 4 days at Mount Sinai.

"Even this represents some fraction of the reportable incidents that occurred," he said. "Some institutions may think they don't have a problem with trainee mistreatment -- but this goes to show that if you make it easier to hear about bad behavior, you'll hear about it."

For the present study, the authors counted 2,900 faculty that interact with trainees, 600 medical students, 2,600 residents and clinical fellows, and over 1,000 graduate students and postdoctoral fellows across Mount Sinai Health System's medical school, eight teaching hospitals, and over 400 ambulatory practices.

In reporting negative feedback, more reporters remained anonymous (60.1%) than self-identified (39.9%). The reverse was true for positive feedback (60.9% identified vs 39.1% anonymous).

Overall, medical students were aware of policies and procedures for reporting, but fewer actually reported them.

Although an estimated 35.7% of Mount Sinai medical students indicating experience with mistreatment subsequently reported it -- higher than the national average at 27.3% -- only 33.3% of medical students were satisfied or very satisfied with outcomes of reporting. This is better than in past years, but worse than the national average of 46.3%.

However, student satisfaction scores were hard to evaluate because the authors extrapolated from the AAMC Graduate Questionnaire but did not survey trainees before and after implementing the reporting tool.

Other limitations of the present analysis include not having a method to track patterns of behavior across departments or within different categories of trainees. The study was also conducted in a single, urban institution, and may have limited generalizability.

Disclosures

The authors reported no conflicts of interest.

Primary Source

JAMA Network Open

Source Reference: Leitman IM, et al "Implementation of an online reporting system to identify unprofessional behaviors and mistreatment directed at trainees at an academic medical center" JAMA Netw Open 2022; DOI: 10.1001/jamanetworkopen.2022.44661.

https://www.medpagetoday.com/publichealthpolicy/medicaleducation/102044