Medical writing: vigilance for ethics

As of the beginning of this year, the American Medical Writers Association (AMWA) has added its code of ethics to membership application and renewal materials. New and renewing members are asked to indicate that they have read and accepted the principles of the code. The goal is to increase awareness of ethical principles and, it is hoped, to contribute to maintenance of high ethical standards among medical writers.

AMWA, despite its name, is an organisation of medical writers from not only the United States but also around the world. Its members come from a variety of disciplines, including academic, pharmaceutical, marketing and regulatory.

The code of ethics itself is not new. It was first developed in 1973 and revised in 1989, 1994, and 2008. The 1994 revision came in response to a Food and Drug Administration (FDA) guideline that proposed severe restrictions on industry-sponsored medical writers. AMWA worked with the regulators to educate them on what medical communicators actually do and also strengthened the code of ethics by adding wording about “scientific rigour” and “fair balance.”

The code, intentionally brief, consists of a preamble that explains the role of AMWA in promoting excellence in medical communication, followed by eight principles to be applied in developing materials in the various media in which medical writers work. Among the principles are recognition and observance of applicable statutes and regulations; application of objectivity, scientific accuracy and rigour; maintenance of the highest professional standards, whether or not the materials they develop fall under the purview of any regulatory agency; and insistence on conditions that allow them to properly apply their own judgment and skills, with refusal to participate in assignments that require unethical or questionable practices. Additional principles include professional development, respect for the confidentiality of materials provided by clients, and expectation and acceptance of fair remuneration of and acknowledgment for their services.

AMWA will not enforce adherence to the code of ethics, and the organisation does not encourage individuals to become “ethics police.” Its goal is rather to increase awareness of ethical issues and principles.

Ethical issues are also addressed by AMWA’s sister organisation, the European Medical Writers Association (EMWA, www.emwa.org). EMWA includes on its website its own guidelines on the role of medical writers in developing peer-reviewed publications. The guidelines include the importance of respecting and acknowledging the role of medical writers in the development of scientific publications.

Direct-to-Consumer Advertising – in Europe?

Since 1996, DTCA has existed only in the USA and New Zealand , but recent declarations from the European Commission (EC) suggest that the rules governing pharma communication with patients may be loosened.

In October, both the Wall Street Journal (WSJ) and the Financial Times (FT) reported intriguing recommendations from the “High Level Pharmaceutical Forum”, a 3-year programme run by the European Union to address specific public health considerations regarding pharmaceuticals and to promote industry competitiveness while sustaining national healthcare systems. The Forum was the brainchild of Günther Verheugen, the Vice President of the European Commission and Commissioner for Enterprise and Industry. The FT also reports that Mr Verheugen is drafting legislation to formally ease marketing rules for pharma.

Concerns about DTCA in Europe emerge from one of the Forum’s three mandates: that patients and citizens need access to better information on disease states and available drugs. But who should provide that information? Both the WSJ and FT report that proposed new rules would weaken the existing strict limits on pharma-provided information to patients. Under the new proposed rules, “objective and unbiased” print and on-line information about drugs would be permissible, but direct advertising would not.

But who determines what is objective and permissible? Where is the line drawn between information and advertising? What role would the European Medicines Evaluation Agency (EMEA, a European equivalent of the US Food and Drug Administration) play?

Efforts to have Mr Verheugen answer those questions were unsuccessful. Queries to his press officer were unanswered and his spokesman stated that “our experts are still working on this and will not be available for the coming weeks.”

The published final conclusions and recommendations from the Forum clearly state that “the ban on advertising of prescription medicines to the general public should continue”, but it also names the industry as one of the relevant players in healthcare that should ensure high quality information for patients.

Thus, it is not clear exactly what the EC is proposing and, if agreed to, when the changes would be implemented. But this discussion does suggest a possible change in attitude toward the role of pharma in providing healthcare information in Europe.

Development Safety Update Reports (DSURs): simplifying periodic safety reporting

The US Food and Drug Administration (FDA) in August proposed a new guideline asking the sponsors of clinical trials to submit annual development safety update reports (DSURs). The guideline, titled “E2F Development Safety Update Report,” is in draft form and describes the format, content, and timing of a DSUR. It specifies that a DSUR update the status of the clinical trial, summarise the sponsor’s understanding and management of identified and potential risks, describe new safety concerns that could affect the protection of trial subjects, and examine whether the information collected in the previous year accords with current knowledge of the product’s safety.

DSURs would be required for investigational drugs, including biologicals, with or without marketing approval, and whether or not the clinical trials are being conducted by commercial or non-commercial sponsors. A DSUR would have to be submitted within 60 days of the DSUR data lock-point, determined by the date of the sponsor’s first authorisation to conduct a clinical trial in any country (the “Development International Birth Date”).

The guideline instructs sponsors to focus on data from interventional trials. However, it also advises the inclusion of other findings that may have a bearing on the safety of trial subjects. Such information could include findings of non-clinical trials, as well as clinical trials conducted by the sponsor’s development partners and non-interventional or compassionate-use studies.

The FDA draft guideline matches one developed by the International Conference on Harmonisation (ICH).

Will DSURs create more work for the sponsors of clinical trials? Apparently not, at least in the long run. First, the guideline follows a standard format that has been developed for submission in the three ICH regulatory regions (the United States , the European Union, and Japan ). A report produced in accordance with the guideline could be submitted simultaneously in all three regions. Second, the DSUR would replace some reports that are currently required, such as the IND Annual Report. For already marketed products, some of the information required for the DSUR may be provided in the periodic safety update report (PSUR), on which the DSUR is patterned.

The draft guideline may be obtained online at www.regulations.gov or www.fda.gov/cber/guidelines.htm. The FDA has solicited comment on the draft. To be useful, comments should be submitted by 3 November 2008.

Preventing medication errors

“Since 2000, the US Food and Drug Administration (FDA) has received more than 95,000 reports of medication errors. These reports are voluntary, so the number of actual medication errors is believed to be higher,” says Carol Holquist, director of the division of medication error prevention in the FDA’s Center for Drug Evaluation and Research.

The FDA works with many partners to track medication errors, one of which is the Institute for Safe Medication Practices (ISMP), based in a Philadelphia suburb. They review drug names, rejecting some 25% of the 400 submitted each year; and they examine drug labelling and packaging.

Occupying the same building as the ISMP, and a wholly-owned subsidiary of the Institute, is a company called Med-E.R.R.S – the letters standing for Error Recognition and Revision Strategies. The company’s CEO, pharmacist Susan Proulx (pictured left), says that while they don’t invent drug names – that’s a whole other speciality – they do work with names, to test for possible confusion, and therefore error. She cites as examples the similar-sounding cholesterol drug Omacor and the anti-bleeding drug Amicar. They also had similar dosages. Eventually, in concert with the FDA, Omacor became Lovaza.

Similarly, Med-E.R.R.S works with graphics people to ensure that labelling and packaging are designed for maximum information and minimal likelihood of confusion. As Proulx puts it: “We put great emphasis on the design of the package label; it must be unambiguous… and the first priority is the name of the drug and the dosage.”

The company has worked with over a hundred pharma companies in its ten-year history, and relies on a group of doctors, nurses, pharmacists, and other professionals to review and assess names and labels. They work mainly online and receive a small honorarium for their involvement. One test is to produce a handwritten version of a new drug name and show it to pharmacists who assess its potential to be confused with another product.

Med-E.R.R.S uses a sophisticated analytical tool called FMEA. It’s commonly used in the aviation and automotive industries, as well as by NASA, and stands for Failure, Mode, Effect, Analysis. Says Proulx: “If a car’s steering wheel failed, you’d look at that; then see how it happened; then see the result (such as loss of control) and then find out why.”

Check www.fmeainfocentre.com for more details of how this works.

Medication errors can be approached along the same lines. Most occur for a variety of reasons, such as miscommunication of drug orders through poor handwriting, confusion between drugs with similar names, poor packaging design, and confusion of metric or other dosing units. The FDA’s Holquist says that they “usually occur because of multiple complex factors. All parts of the healthcare system – including health professionals and patients – have a role to play in preventing medication errors.”

And a major part of that role is played by organisations like ISMP and Med-ERRS.

W(h)ither the FDA?

There has been much written lately about the perceived failings of the FDA. The Wall Street Journal claims that “the place is a mess,” and a physician who served in the FDA from 1979 to 1994 commented in a letter to the New York Times: “the agency’s most significant problems are mismanagement and a culture that is excessively risk-averse.”

That same physician went beyond this diagnosis to offer a potential cure. What the FDA needs, he suggested, is competent management, discipline in the ranks, more effective risk-benefit balancing, a commitment to permitting patients to assume more responsibility for the risk of medicines, and the banishment of politics from regulatory decisions and policy.

One of the FDA’s advisory panels, the Science Board, notes that the Agency is in a precarious position because it’s chronically under funded. And the US Government accountability office asserts that at the FDA’s current pace of operations, it would take 13 years to inspect every foreign drug plant exporting to the US.

The under funding issue comes into sharp focus when one realises that the Agency’s mandate has increased exponentially over the past decade or so. In fact, the Science Board states that “while the world of drug discovery and development has undergone revolutionary change, the FDA’s evaluation methods have remained largely unchanged over the last half-century.” The Board proposes that the FDA modernise current regulatory pathways, especially the narrowness with which it balances risk and benefit for the most promising new therapies before they are allowed to reach the public.

The FDA was founded in 1906 with the laudable objective of protecting the populace against ingesting harmful or dangerous substances. It has grown into a bureaucratic monster, employing some 10,000 workers, and with a budget of more than $1.5 billion.

And the role of Commissioner has not been an entirely happy one. Since Dr. David Kessler, the so-called ‘scourge of the tobacco industry,’ stepped down after a record six year tenure, his three successors have lasted an average of two years. The present incumbent, Dr. Andrew C. von Eschenbach, has filled the role since last December. In an interview I conducted with Kessler for the British Medical Journal shortly after he resigned, he said that he had achieved his three major aims: developing and mandating the nutritional labels that now appear on all foodstuffs sold in the US; shortening the time for approving new drugs; and bringing about the legal definition of nicotine as an addictive drug and therefore subject to FDA regulation.

Often accused of zealotry and of politicising the Agency, Kessler also became the object of a congressional investigation of his allegedly padded expense accounts. But if you want to be liked, don’t be a regulator, he told me, noting that “it’s no secret that if you take on difficult issues in this town you’ll be attacked. You learn to live with criticism; you don’t confront it.”

Is there a case for privatising the Agency? Despite the 1992 scandal of some FDA scientists accepting bribes… and some dubious drug approvals, it might be that this is one area where public enterprise might be a preferable guardian of the public interest. Under the Prescription Drug User Fee Act (PDUFA) some privatisation is already occurring, with drug companies paying user fees to the FDA in order to reduce approval times. Another suggestion, put forward by Henry Miller, MD, a former head of the FDA’s Office of Biotechnology, is to appoint a powerful, independent Agency ombudsman with the authority to impose sanctions on FDA employees responsible for flawed decisions or policies.

In Europe, several countries use ‘notifying bodies’ to approve drugs and devices. A two-pronged system under which drug companies could hire private labs to certify the results of testing for safety and efficacy … with the FDA regulating the labs and retaining authority to accept or reject their findings, might be a sensible middle of the road option.

Drug approval agencies

Health Outcomes Communicator is starting a regular series describing the major drug approval agencies and healthcare systems in countries across the world. In this first article, we’ll start with two of the largest drug approval agencies – the Food and Drug Administration in the United States (US FDA) and the European Medicines Evaluation Agency (EMEA).

US FDA

The main role of the US FDA is ensuring the safety and efficacy of human and veterinary drugs and medical devices, although it also regulates the safety and accurate representation to the public of foods, cosmetics, and electronic products that emit radiation.

The FDA’s role in biological products includes product and manufacturing establishment licensing, safety of the nation’s blood supply, and research to establish product standards and develop improved testing methods. With regard to drugs, its oversight includes product approvals, over-the-counter and prescription drug labelling, and drug manufacturing standards, through the Center for Drug Evaluation and Research (CDER).

It is also involved in post-drug approval processes, such as post-marketing surveillance, prescription drug advertising and promotional labelling, pharmaceutical industry surveillance, medication errors, drug shortages, and therapeutic inequivalence reporting. It does not have oversight over drugs of abuse with no approved medical use.

According to the FDA’s website, “The agency grew from a single chemist in the US Department of Agriculture in 1862 to a staff of approximately 9100 employees and a budget of $1.294 billion in 2001”. The formal agency emerged from the passage of the Federal Food and Drugs Act of 1906.

EMEA

A newer body, the EMEA was developed in 1995. Like the FDA, its main role is “the protection and promotion of public and animal health by regulating medicines for human and veterinary research”. The EMEA is a decentralised body in the European Union (EU), with headquarters in London. As such, the EMEA uses scientific resources from the 25 EU member states.

However, because it is a single agency, companies wishing to apply for a new drug approval file a single marketing authorisation application to the EMEA. Upon review and approval by the Committee for Medicinal Products for Human Use (CHMP), a positive opinion is sent to the Commission, ultimately resulting in a single market authorisation valid for the entire EU.

The CHMP also arbitrates disagreements among member states concerning the marketing authorisation of a particular medicinal product, and can issue an “urgent safety restriction” to inform healthcare professionals about changes in the way a medication can be used (similar to the “black box warning” by the FDA). Moreover, the EMEA is involved in post-authorisation evaluation of drugs for human consumption including pharmacovigilance. The EMEA also reviews applications regarding orphan drugs (ie, drugs for rare diseases) and provides scientific opinion on traditional herbal medicines via the Committee on Herbal Medicine (HMPC), established in 2004.