New biological products should only be tested on healthy volunteers if the risk is “minimal”, say new guidelines on Phase I clinical trials issued by the Association of the British Pharmaceutical Industry (ABPI).

Where the risk of giving a biological investigational medicinal product (IMP) to healthy subjects is more than minimal, patients with the target disease should be studied instead, the guidelines state. This includes repeated doses of a biological IMP or any dose of a higher-risk IMP.

Even in these cases, the guidelines add, if there is no prospect of therapeutic benefit to the patient, the risk of harm “must still be very low. The mass of tissue being targeted by the IMP may be much increased in patients compared with healthy subjects”.

Inevitably the revised guidelines are coloured by the events at London’s Northwick Park Hospital last year, when a first-in-human (FIH) trial of TeGenero’s monoclonal antibody TGN1412 left six healthy volunteers in intensive care. Accordingly, the new ABPI guidelines incorporate key recommendations from the report on Phase I trials published last November by an Expert Scientific Group under Sir Gordon Duff.

At the same time, the ABPI guidelines delve into areas not covered by the Duff report, such as arrangements for volunteer recruitment, insurance provisions and more detailed advice on facilities, equipment and staffing at Phase I units.

Comprehensive overhaul

The first edition of the ABPI Guidelines for Phase I Clinical Trials was published in 1970, with subsequent revisions in 1977 and 1988. The latest version is a comprehensive overhaul of the guidelines, based on consultation with industry, clinical experts and other stakeholders. All of the existing sections have been updated and various new sections added to reflect changes in the regulations and the way Phase I trials are conducted.

Some elements of previous guidelines are now legal requirements, the ABPI notes. For example, following the transposition of the European Union’s Clinical Trials Directive (2001/20/EC) into UK law, trials of IMPs are now regulated (they were previously excluded from the Medicines Act 1968, as healthy volunteers gained no therapeutic benefit from an IMP) and sponsors must secure pre-approval from the Medicines and Healthcare products Regulatory Agency (MHRA).

In addition, previous versions of the guidelines were written when many ABPI member companies had their own facilities and used their own staff as a source of healthy volunteers, the association points out. These days, contract research organisations (CROs) conduct most of the Phase I studies in the UK and many trial sponsors are from countries outside the UK.

Despite its caveats on testing biological IMPs in healthy volunteers, the ABPI says the risk involved in moving from preclinical studies to FIH trials “may be no higher than it is during other transition trials, such as from single to multiple doses, from young to elderly subjects, and from administration of the IMP alone to giving it with established medicines during interaction trials”.

Nonetheless, the guidelines point to the relative paucity of safety data on biological IMPs and give a number of reasons why these – and monoclonal antibodies in particular – should be treated differently from new chemical entities (e.g., effects may be amplified downstream from the IMP target, risk of anaphylactic or infusion reactions).

In the case of TGN1412, the guidelines note, the FDA [US Food and Drug Administration] Guidance method was used to calculate the starting dose, whereas the Minimal Anticipated Biological Effect Level (MABEL) approach favoured by the ABPI and the UK’s BioIndustry Association “gives a much lower starting dose”.

Recruitment methods

One question raised in the wake of the TGN1412 trial was whether recruitment methods for Phase I trials were encouraging healthy volunteers to overlook any potential risks involved.

At the time it was clear some advertising by CROs was going far beyond the boundaries of the ABPI’s Guidelines for medical experiments in non-patient human volunteers. These recommended, for example, that public notices soliciting volunteers should mention neither “payment nor the level thereof”. Moreover, “widespread or public advertising, especially if it is aimed at the poor, needy or socially disadvantaged” was considered unacceptable.

The revised guidelines on Phase I trials say potential trial subjects may be recruited from existing databases, through word of mouth or a doctor referral, as well as “by advertisements in a newspaper or magazine, or on a notice board in places such as a university or hospital, or on the radio or television, or on a website”.

All advertisements must be approved by a research ethics committee (REC), the guidelines point out. And while there is no general recommendation against mentioning payment, adverts must “never over-stress payment, use REC or MHRA approval as an inducement, name and promote the product, or claim that it is safe”, they say.

The level of payment for a Phase I trial should be related to “the duration of residence on the unit, the number and length of visits, lifestyle restrictions, and the type and extent of the discomfort involved”, the guidelines state. As a guide, they suggest, payments “should be based on the minimum hourly wage and should be increased for procedures requiring extra care on the part of the subject or involving more discomfort. Payment must never be related to risk”.

ABPI spokesman Matt Worrall stressed the changes were not a “dilution” of the ABPI’s original stance on recruitment but reflected a shift in approval responsibility to other bodies such as RECs. The Clinical Trials Directive also spoke to this issue, as did the ABPI’s own Guideline on advertising for subjects for clinical trials.

This latter document, published in November 2002, cites an appendix on advertising for trial subjects added by the European Commission to its detailed guidance on applications for ethics committee opinions on clinical trials. The ABPI cautions against “undue emphasis on reimbursement” in advertising for trial subjects while adding that “mention of reimbursement is permitted”.

As Worrall pointed out, the incorporation of recent best practice on the use of healthy volunteers is one of three main distinctions between the revised Phase I guidelines and previous editions. This includes new recruitment techniques and databases that allow companies to monitor the volunteer population and prevent over-exposure to Phase I trials.

The other most significant departures are that the whole structure of the guidelines has changed in the light of the Duff recommendations, which have been taken up in full; and the new version incorporates the EU’s Clinical Trials Directive. It also takes into account the final guideline on FIH trials recently adopted by the European Medicines Agency’s Committee for Medicinal Products for Human Use, Worrall said.

Bedding in

In the meantime, the MHRA’s new arrangements for FIH trials of higher-risk compounds, which have caused some consternation among biotechnology companies in particular, are “bedding in”, Worrall commented, adding that the system “does need time”.

The ABPI is currently working with the MHRA to ensure that the new procedures are as streamlined as possible. “We wouldn’t like to see it become too bureaucratic,” Worrall commented.