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Preamble

In the landscape of pharmaceutical
marketing ethics, the UCPMP (Uniform Code of Pharmaceutical Marketing
Practices) has been a cornerstone, albeit with limited efficacy.

The inception of UCPMP-2014 as a
voluntary framework aimed to instil Good Marketing Practices within the Indian
pharmaceutical industry, yet its lack of enforcement mechanisms rendered it
toothless against transgressions.

Fast forward to March 2024, the
emergence of UCPMP-2024 introduces notable revisions, including mandatory
disclosure of expenses for medical promotion and grants to healthcare
professionals.

While these changes signify
progress, the efficacy of such voluntary measures remained debatable.

History of UCPMP

This editorial delves into the
evolution of UCPMP and explores the necessity for more robust legal frameworks
to truly deter unethical practices within the pharmaceutical sector.

On December 12, 2014,
the central government introduced the Uniform Code of Pharmaceutical Marketing
Practices (UCPMP-2014), intended for voluntary adoption and adherence by
pharmaceutical enterprises concerning marketing activities.

It was explicitly
stated that failure to effectively implement the code by pharmaceutical
associations/companies could prompt the government to enact it as a statutory
provision.

Despite the initial
stipulation of a six-month duration for the UCPMP-2014, subsequent extensions
by the Department of Pharmaceuticals (DoP), totaling five instances, culminated
in the extension of the UCPMP Code, 2014, until further directives were issued
on August 30, 2016. This series of extensions suggested a lack of enthusiasm on
the part of the DoP towards the implementation of the UCPMP-2014.

The implications for the
pharmaceutical industry were unequivocal, as evident from the prevailing
circumstances.

In the year 2021, the
Federation of Medical and Sales Representatives Association of India,
functioning as a non-governmental organization (NGO), lodged a petition with
the Supreme Court of India. Their plea sought the formulation of comprehensive
directives aimed at curbing unethical marketing strategies employed by
pharmaceutical entities.

This petition was made with the intent to fill the
regulatory void until the enactment of specific legislative measures by the
Parliament. Presently, the case remains under consideration by the Court,
awaiting its final adjudication.

The UCPMP-2014 aimed to create a level playing field for
pharmaceutical companies, encouraging innovation and patient-centered marketing
practices. However, practical challenges must be addressed for effective
enforcement.

Stricter regulations covering indirect influences, and robust
oversight mechanisms are essential to achieving UCPMP’s objectives and
promoting ethical practices in pharmaceutical and medical devices marketing.

The UCPMP-2014 had the intent of fostering equitable
conditions among pharmaceutical companies, fostering innovation, and advocating
for patient-centric marketing methodologies. Nevertheless, the realization of
its objective’s hinges upon the resolution of pragmatic hurdles.

Enforcing its
provisions effectively necessitates the implementation of more stringent
regulations encompassing indirect influences, alongside the establishment of
robust oversight mechanisms.

These measures are imperative for ensuring the
attainment of UCPMP-2014 goals and fostering a culture of ethical conduct
within the realms of pharmaceutical and medical devices marketing.

The Department of Pharmaceuticals (DoP) issued a
new policy on March 12, 2024. This policy, known as the Uniform Code for
Pharmaceutical Marketing Practices (UCPMP-2024), establishes guidelines for the
ethical promotion of pharmaceuticals.

The DoP directed all pharmaceutical
associations (like IPA, OPP; IDMA) to disseminate the UCPMP-2024 to their
members and ensure its strict compliance.

The UCPMP-2024 outlines acceptable practices for
activities such as interactions with healthcare professionals, distribution of
informational materials, and providing samples. It also establishes a framework
for addressing unethical marketing practices. This policy aims to promote
ethical conduct within the pharmaceutical industry.

Hopes with UCMP-2024

UCPMP-2024) establishes ethical guidelines for drug
promotion. It defines acceptable activities for medical representatives, brand
materials, samples, and interactions with healthcare professionals.
Additionally, it provides a framework for addressing unethical marketing
practices.

Here are some of the key and the new features of UCPMP-2024.

However, exceptions are made for
educational items such as books, calendars, and clinical guidelines, provided
their value does not exceed Rs. 1000 and they serve professional purposes
without independent commercial value.

Additionally, this means medical professionals can receive travel and
hospitality support for participating as speakers in Continuing
Medical Education (CME) or Continuing Professional Development (CPD) programs.

These measures aim to maintain the integrity of healthcare decision-making
processes and ensure that medical professionals prioritize patient welfare over
personal gain.

These programs must be held within the country and can be
organized by pharmaceutical companies independently or collaboratively.

Companies sponsoring such programs are required to
disclose their expenditures on a dedicated website. Additionally, organizers
must also publicly display a statement outlining funding sources and the
selection process for participants and speakers.

It’s important to note that all parties involved,
including the company, organizers, speakers, and participants, must comply with
the Income Tax Act (Section 194R) to ensure financial transparency and accountability.

These interactions must
prioritize patients’ well-being and the patient interest is not compromised.

It upholds HCP integrity,
adhering to relevant National Medical Commission (NMC) regulations and
guidelines. Research must be approved by a competent authority and conducted at
a designated location, if applicable.

Expenditure on
research by pharmaceutical companies is an allowable expenditure subject to the
provisions of the Income Tax Act 1961 as amended from time to time.

UCPMP-2024 further restricts pharmaceutical companies or
their agents including stockists and distributors from offering travel or
hospitality to HCPs or their families, except for approved speakers at
Continuing Medical Education (CME) or Continuing Professional Development (CPD)
events. This ensures unbiased interactions and discourages undue influence.

The UCPMP-2024 prohibits cash or monetary grants to
healthcare professionals or their families.

When it lacks clarity on
interactions with HCPs, adhere to the Indian Medical Council Regulations
(Professional Conduct, Etiquette, and Ethics) of 2002.

The Ethics Committee for Pharmaceutical Marketing Practices (ECPMP)
within each association holds authority to take necessary actions its members,
such as suspension or expulsion, upon confirming a breach of the UCPMP-2014.
When governmental intervention is required, recommendations are forwarded
through the DoP.

The UCPMP-2024 establishes a new appeals process. If parties
disagree with a decision by the ECPMP, they can appeal to the Apex Committee
for Pharma Marketing Practices (ACPMP). The ACPMP has the authority to impose
penalties or refer matters to relevant government agencies. Their decision is
final and binding on all parties involved.

Under UCPMP-2024 CEOs of pharmaceutical companies are held
accountable for following it meticulously. They must submit a yearly
self-declaration within two months of their fiscal year-end. This declaration
can be uploaded to their industry association’s website or directly to the
government’s UCPMP-2014 portal if they are not part of an association.

Conclusion

In
the realm of pharmaceutical marketing, a crucial aspect often overlooked is the
integration of a patient-centered approach.

UCPMP-2024,
while comprehensive, fails to acknowledge the pivotal role of
patient-centricity in promoting healthcare solutions. A patient-centered
marketing approach prioritizes the needs, preferences, and well-being of
patients above all else.

By
fostering open communication, understanding individual experiences, and
tailoring solutions accordingly, this approach enhances trust and engagement
within the healthcare ecosystem. Empowering patients with information and
involving them in decision-making processes not only improves treatment
adherence but also fosters a sense of ownership over their health journey.

Incorporating
patient narratives, feedback mechanisms, and support networks into marketing
strategies can bridge the gap between pharmaceutical companies and the
individuals they serve.

Embracing
a patient-centered mindset isn’t merely a moral imperative but a strategic
imperative for driving sustainable healthcare outcomes and fostering long-term
partnerships built on empathy and mutual respect.

Nevertheless,
UCPMP-2024 represents a significant advancement in ensuring ethical conduct
within the pharmaceutical industry. This code establishes clear guidelines for
marketing practices, fostering a more transparent and responsible environment.

We
must seriously consider the argument put forth by Sudhansh Pant, a former Joint
Secretary at the Department of Pharmaceuticals (DoP). His experience positions
him well to assess the potential of public exposure in deterring unethical
marketing practices.

The UCPMP-2024 can be significantly strengthened through
robust enforcement mechanisms that include the public disclosure of violations.
The threat of reputational damage can serve as a powerful motivator for both
pharmaceutical companies and medical professionals to adhere to the code’s
principles.

The Physician
Payments Sunshine Act – USA

The Physician
Payments Sunshine Act USA serves as a potential model for nations seeking to
promote ethical conduct among medical professionals and responsible marketing
practices within the pharmaceutical industry.

The Physician Payments Sunshine
Act (Sunshine Act), though enacted in 2010, continues to influence marketing
practices in 2024. We shall now assess the ramifications of this Sunshine Act
on both medical professionals and the pharmaceutical industry of USA.

For
Medical Professionals:

Excessive industry payments
might raise eyebrows about a doctor’s objectivity.

For the Pharmaceutical Industry:

This discourages lavish
gifts or sponsorships that might influence prescribing habits.

Pharma companies might shift
their focus towards educational programs, research collaborations, or offering
tools that genuinely improve patient care.

The Act’s public disclosure of financial ties
between these entities fosters transparency and accountability, ultimately
aiming to ensure patient well-being remains the primary focus. It creates a system where financial relationships are exposed, fostering
a shift towards interactions based on genuine value exchange and ultimately
promoting better practices in the healthcare industry.

In light of the Sunshine
Act’s effectiveness, the author proposes the DoP to leverage its strengths when
crafting a new legislative framework to supersede the UCPMP-2024. The author
contends unequivocally that the UCPMP-2024 should transition from a voluntary
initiative to statutory law. This small incremental step paves the way for
potentially stronger regulations in the future.

Food and Drug Administration (FDA) has granted emergency use authorization (EUA) for monoclonal antibody pemivibart to prevent COVID-19 in immunocompromised patients.

Invivyd, Inc. (Nasdaq: IVVD), a biopharmaceutical company today announced that PEMGARDA™ (pemivibart), formerly VYD222, a half-life extended monoclonal antibody (mAb), has received emergency use authorization (EUA) from the U.S. Food and Drug Administration (FDA) for the pre-exposure prophylaxis (prevention) of COVID-19 in adults and adolescents (12 years of age and older weighing at least 40 kg) who have moderate-to-severe immune compromise due to certain medical conditions or receipt of certain immunosuppressive medications or treatments and are unlikely to mount an adequate immune response to COVID-19 vaccination. Recipients should not be currently infected with or have had a known recent exposure to an individual infected with SARS-CoV-2.

“The PEMGARDA EUA marks a transformational moment for Invivyd and for the many moderately to severely immunocompromised people who are vulnerable to COVID-19 disease in the U.S. This EUA milestone represents strategic proof-of-concept for our company and platform, affirming the unique strategy we embarked on over a year ago: to use rapid innovation and surrogate markers to bring new antibodies to market repeatedly,” said Dave Hering, Chief Executive Officer of Invivyd. “PEMGARDA is the first authorized monoclonal antibody from our proprietary platform approach. We are committed to ongoing process improvement while working with global regulatory agencies with the aim to increase the speed and efficiency of new mAb candidate development even further. Additionally, we are planning to explore the protective clinical benefits of mAb prophylaxis for symptomatic COVID-19 disease in future studies.”

Mr. Hering added, “We are proud that roughly one year after initiating the Phase 1 trial of our mAb now known as PEMGARDA, we are expecting to have product available for order imminently, with initial supply already packaged and awaiting final release at our U.S.-based third-party logistics provider. I’m deeply grateful to our dedicated team members who made this achievement possible and everyone else who has supported our work, especially our clinical trial participants and investigators. Finally, we also appreciate the continuous engagement from the FDA as they have worked with urgency to make this medicine available to populations in serious need.”

“People who are immunocompromised continue to be disproportionally impacted by COVID-19 even after receiving multiple vaccine doses,” said Cameron R. Wolfe, M.B.B.S., M.P.H., Professor of Medicine, Transplant Infectious Disease at Duke University School of Medicine. “I’m excited to have PEMGARDA as an additional COVID-19 preventive option for moderately to severely immunocompromised adult and adolescent patients, such as solid organ transplant recipients and those with hematological malignancies. These types of patients, among others, continue to have both an impaired response to vaccines and a higher risk for severe COVID-19 outcomes.”

“COVID-19 continues to pose a significant threat and major concern to those who are moderately to severely immunocompromised,” said Jorey Berry, President and CEO of the Immune Deficiency Foundation and a steering committee member of the Immunocompromised Collaborative. “As such, we are delighted that a new monoclonal antibody for pre-exposure prophylaxis of COVID-19 will be available soon for certain vulnerable populations.”

Multiple medical conditions or treatments may result in moderate-to-severe immune compromise and an impaired immune response to COVID-19 vaccination including, for example, hematologic malignancies (blood cancers) or treatment with immunosuppressive therapy after a solid organ or stem cell transplant.1 Observational studies have demonstrated that people with immune dysfunction have a higher risk of COVID-19-related hospitalization and death, despite vaccination, than the general population.2-3

The EUA of PEMGARDA is based on the totality of scientific evidence available, such as data showing that immunobridging was established in the CANOPY clinical trial and that the calculated serum neutralizing antibody titers against JN.1 were consistent with the titer levels associated with efficacy in prior clinical trials of adintrevimab (ADG20), the parent mAb for VYD222, and other monoclonal antibody products. JN.1 is currently the dominant variant circulating in the U.S. according to estimates from the Centers for Disease Control and Prevention (CDC).4 PEMGARDA (pemivibart) (4500 mg) is administered as an intravenous (IV) infusion.

PEMGARDA is Invivyd’s first authorized mAb and the first mAb to receive EUA based on a rapid immunobridging trial design that is expected to be repeatable to help address the need to mitigate ongoing viral evolution. It was developed using INVYMAB™, the company’s platform approach which combines state-of-the-art viral surveillance and predictive modeling with advanced antibody engineering. INVYMAB is designed to enable the rapid, serial generation of durable mAbs targeting conserved epitopes that could be deployed to keep pace with SARS-CoV-2 viral evolution or other viral threats. With a commitment to serial innovation, Invivyd aims to ensure that vulnerable populations, such as immunocompromised people, have continuous access to innovative antibody therapies.

The Company estimates it had approximately $200.6 million of cash and cash equivalents as of December 31, 2023. The estimated amounts are preliminary, have not been audited and are subject to change upon completion of the Company’s audited financial statements for the year ended December 31, 2023. In February 2024, the Company sold shares of common stock totaling $40.5 million in gross proceeds under its At-the-Market facility further strengthening the Company’s balance sheet ahead of PEMGARDA launch. Based on current operating plans and excluding anticipated cash collections from PEMGARDA sales, Invivyd expects its existing total cash and cash equivalents will enable the company to fund its operating expenses and capital expenditure requirements into the fourth quarter of 2024.

Interim CANOPY Clinical Data Update

CANOPY is an ongoing Phase 3 clinical trial of VYD222 (PEMGARDA) for the pre-exposure prophylaxis of COVID-19 which enrolled adults ≥18 years of age in two cohorts. Cohort A is a single-arm, open-label trial in adults who have moderate-to-severe immune compromise (n=306); Cohort B is a 2:1 randomized, placebo-controlled trial in which adults who do not have moderate-to-severe immune compromise received VYD222 (n=317) or placebo (n=162). The interim data presented below are subject to further analysis.

There seems no clarity on whether the protracted duration of SGLT2 inhibitor DKA is a result of inadequate insulin dosing or the ongoing effect of SGLt2i. The findings of the study were published online in JAMA Network Open.

“Median intravenous (IV) or subcutaneous insulin dose during the initial 24 hours of treatment was 44 units for patients with SGLT2 inhibitor-associated DKA versus 87 units for those with type 1 diabetes DKA,” the researchers reported.

Previous studies have shown a difference in the pathophysiology of sodium-glucose cotransporter 2 inhibitors (SGLT2i)–associated DKA and that of T1D DKA. T1D DKA is driven by absolute insulin deficiency, leading to hyperglycemia and ketosis. In contrast, SGLT2i DKA occurs due to a reduction in plasma glucose (PG) from urinary glucose losses, which lowers insulin secretion and stimulates glucagon secretion, leading to ketosis. PG levels in GLT2i DKA are often normal or mildly elevated. The implication is that ketosis and glycemia and ketosis are less closely linked than in T1D DKA.

Despite these differences, the American College of Endocrinology and the American Association of Clinical Endocrinologists recommend treatment with the same protocols as T1D. This may result in hypoglycemia when patients receive fixed-dose insulin infusion or inadequate insulin dosing and reduced ketone clearance when patients receive dynamic insulin infusions.

Against the above background, Mahesh M. Umapathysivam, Flinders Medical Centre, Adelaide, South Australia, Australia, and colleagues performed a retrospective cohort study to examine the natural history of SGLT2i DKA and its response to treatment.

To assess the suitability of T1D DKA protocols use, particularly the dynamic insulin infusion protocol, in SGLT2i DKA, the research team compared bicarbonate and ketone level change after 24 hours of treatment in individuals presenting with SGLT2i DKA and T1D DKA.

The study was conducted across two tertiary centers with a research interest in SGLT2 inhibitor-associated DKA, with input from the endocrine team in all cases.

The following were the key findings of the study:

• The researchers identified thirty-seven episodes of SGLT2i DKA (n = 27) and SGLT2i-associated ketosis (n = 10), and 19 episodes of T1D DKA were identified in the specified age range.
• The groups were well matched for age and sex, but the SGLT2i group had significantly higher body weight, lower HbA1c levels, and a significantly lower admission PG levels.
• Patients with SGLT2i DKA had milder DKA versus T1D-DKA (median ketone peak: 5.3 versus 6.5 mmol/L).
• The SGLT2i group had delayed resolution (median time: 36 versus 18 hours) compared with the T1D group.
• Despite having a greater median weight (81.8 versus 67.7 kg), patients with SGLT2i DKA received a significantly lower insulin dose (intravenous and subcutaneous) in the first 24 hours of treatment compared with patients with T1D DKA (median dose: 44.0 versus 87.0 units).
• The regression model was statistically significant. Change in ketone concentration over the first 24 hours was significantly associated with baseline insulin therapy (β = 6.67), lower bicarbonate nadir (β = −0.56), and higher admission PG level (β = 0.30) in SGLT2i DKA.

“Based on the evidence presented and the safety profile of IV dextrose, it would be reasonable to increase dextrose infusion rates and concentration to allow increased insulin administration and suppression of ketosis,” the researchers wrote.

The study’s limitations are its retrospective nature and size. Prospective randomized clinical trial evidence is lacking.

Reference:

Umapathysivam MM, Morgan B, Inglis JM, et al. SGLT2 Inhibitor–Associated Ketoacidosis vs Type 1 Diabetes–Associated Ketoacidosis. JAMA Netw Open. 2024;7(3):e242744. doi:10.1001/jamanetworkopen.2024.2744

Supplemental oxygen is ubiquitously used in patients with COVID-19 and severe hypoxemia, but a lower dose may be beneficial. A study was done to assess the effects of targeting a Pao2 of 60 mm Hg vs 90 mm Hg in patients with COVID-19 and severe hypoxemia in the intensive care unit (ICU). Multicenter randomized clinical trial included 726 adults with COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 11 European ICUs from August 2020 to March 2023. The trial was prematurely stopped prior to outcome assessment due to slow enrollment. End of 90-day follow-up was June 1, 2023. Patients were randomized 1:1 to a Pao2 of 60 mm Hg (lower oxygenation group; n = 365) or 90 mm Hg (higher oxygenation group; n = 361) for up to 90 days in the ICU. The primary outcome was the number of days alive without life support (mechanical ventilation, circulatory support, or kidney replacement therapy) at 90 days. Secondary outcomes included mortality, proportion of patients with serious adverse events, and number of days alive and out of hospital, all at 90 days. Results Of 726 randomized patients, primary outcome data were available for 697 (351 in the lower oxygenation group and 346 in the higher oxygenation group). Median age was 66 years, and 495 patients (68%) were male. At 90 days, the median number of days alive without life support was 80.0 days (IQR, 9.0-89.0 days) in the lower oxygenation group and 72.0 days (IQR, 2.0-88.0 days) in the higher oxygenation group (P = .009 by van Elteren test; supplemental bootstrapped adjusted mean difference, 5.8 days [95% CI, 0.2-11.5 days]; P = .04). Mortality at 90 days was 30.2% in the lower oxygenation group and 34.7% in the higher oxygenation group (risk ratio, 0.86 [98.6% CI, 0.66-1.13]; P = .18). There were no statistically significant differences in proportion of patients with serious adverse events or in number of days alive and out of hospital. In adult ICU patients with COVID-19 and severe hypoxemia, targeting a Pao2 of 60 mm Hg resulted in more days alive without life support in 90 days than targeting a Pao2 of 90 mm Hg.

Reference:

Nielsen FM, Klitgaard TL, Siegemund M, et al. Lower vs Higher Oxygenation Target and Days Alive Without Life Support in COVID-19: The HOT-COVID Randomized Clinical Trial. JAMA. Published online March 19, 2024. doi:10.1001/jama.2024.2934

Keywords:

Higher, supplemental oxygenation levels, COVID-19 patients, experiencing hypoxia, JAMA, Nielsen FM, Klitgaard TL, Siegemund M